Anti-Aging: State of the Art

[JackH]

Aging is a problem that ought to be solved, and most Less Wrongers recognize this. However, few members of the community seem to be aware of the current state of the anti-aging field, and how close we are to developing effective anti-aging therapies. As a result, there is a much greater (and in my opinion, irrational) overemphasis on the Plan B of cryonics for life extension, rather than Plan A of solving aging. Both are important, but the latter is under-emphasised despite being a potentially more feasible strategy for life extension given the potentially high probability that cryonics will not work.

Today, there are over 130 longevity biotechnology companies and over 50 anti-aging drugs in clinical trials in humans. The evidence is promising that in the next 5-10 years, we will start seeing robust evidence that aging can be therapeutically slowed or reversed in humans. Whether we live to see anti-aging therapies to keep us alive indefinitely (i.e. whether we make it to longevity escape velocity) depends on how much traction and funding the field gets in coming decades.

In this post, I summarise the state of the art of the anti-aging field (also known as longevity biotechnology, rejuvenation biotechnology, translational biogerontology or geroscience). If you feel you already possess the necessary background on aging, feel free to skip to Part V.

Part I: Why is Aging a problem?

Aging is the biggest killer worldwide, and also the largest source of morbidity. Aging kills 100,000 people per day; more than twice the sum of all other causes of death. This equates to 37 million people—a population the size of Canada—dying per year of aging. In developed countries, 9 out of 10 deaths are due to aging.

Aging also accounts for more than 30% of all disability-adjusted life years lost (DALYs); more than any other single cause. Deaths due to aging are not usually quick and painless, but preceded by 10-15 years of chronic illnesses such as cancer, type 2 diabetes and Alzheimer’s disease. Quality of life typically deteriorates in older age, and the highest rates of depression worldwide are among the elderly.

To give a relevant example of the effects of aging, consider that aging is primarily responsible for almost all COVID-19 deaths. This is observable in the strong association of COVID-19 mortality with age (below, middle panel):

The death rate from COVID-19 increases exponentially with age (above, middle). This is not a coincidence—it is because biological aging weakens the immune system and results in a much higher chance of death from COVID-19. On a side note, waning immunity with age also increases cancer risk, as another example of how aging is associated with chronic illness.

The mortality rate doubling time for COVID-19 is close to the all-cause mortality rate doubling time, suggesting that people who die of COVID-19 are really dying of aging. Without aging, COVID-19 would not be a global pandemic, since the death rate in individuals below 30 years old is extremely low.

Part II: What does a world without aging look like?

For those who have broken free of the pro-aging trance and recognise aging as a problem, there is the further challenge of imagining a world without aging. The prominent ‘black mirror’ portrayals of immortality as a curse or hubristic may distort our model of what a world with anti-aging actually looks like.

The ‘white mirror’ of aging is a world in which biological age is halted at 20-30 years, and people maintain optimal health for a much longer or indefinite period of time. Although people will still age chronologically (exist over time) they will not undergo physical and cognitive decline associated with biological aging. At chronological ages of 70s, 80s, even 200s, they would maintain the physical appearance and much lower disease risk of a 20-30-year-old.

This may sound like science fiction but is a phenomenon exhibited by other species such as hydras, naked mole rats, tortoises, whales, and sharks—the latter of which can live up to 400 years old. While these species do eventually die, their risk of disease does not change over time—a phenomenon known as ‘negligible senescence’ - and these species do not age. In contrast, as humans, we experience an exponentially increasing risk of death over time due to aging, a phenomenon known as Gompertz law. Yet this law is not an ingrained law of biology or the result of entropy, as it does not apply to other species, and the goal of anti-aging is to attain negligible senescence in humans.

There would be many benefits to an ageless population such as:

• Very low rates of cancer, heart disease, Alzheimer’s disease etc.

• Increased healthy lifespans

• Increased cognitive function in older age

• Lower death rates globally

• Trillions of dollars saved on healthcare systems globally

Transitioning to an ageless population would come with several social implications that will need to be considered such as overpopulation, climate impact, immortal dictators and distributional justice. I’ll save a deeper discussion of these for a future post, but you can read responses to these objections here and by Aubrey de Grey, David Wood and others.

Part III: What is aging?

Aging is essentially damage that accumulates over time, which exponentially increases the risk of the diseases that kill most people (shown below):

This ‘damage’ associated with aging comes in essentially 9 forms, known as the hallmarks of aging:

• Genomic instability

• Telomere attrition

• Epigenetic alterations

• Loss of proteostasis

• Deregulated nutrient-sensing

• Mitochondrial dysfunction

• Cellular senescence

• Stem cell exhaustion

• Altered intercellular communication

The hallmarks of aging are shown in the context of the cellular and extracellular microenvironment are depicted below:

These forms of cellular damage drive the increased risk of disease, frailty, cognitive decline as well as observable signs of aging such as grey hair, frailty and wrinkles. I’m going to save a deeper discussion of the hallmarks and their link to chronic diseases for a future post, but for excellent reviews on this topic I recommend this, this and this.

Where does this ‘damage’ come from?

The ‘damage’ (hallmarks of aging) occurs as a by-product of normal metabolism—the biochemical reactions that keep us alive. More and more damage accumulates and eventually leads to pathology, i.e. disease. When we talk about anti-aging we are talking about fixing the damage using an engineering approach before it accumulates to a dangerous level at which diseases emerge.

The ‘engineering’ approach of geroscience aims to combat aging by ameliorating the damage associated with aging before it causes pathology. The engineering approach differs from gerontology which aims to intervene by altering metabolism, but fails since metabolism is essentially too complicated for us to intervene in. It also differs from geriatrics, which aims to intervene once the damage has already accumulated and the disease is emerging but fails since it intervenes too late. Source: here.

This basic model of aging can be understood as similar to the damage accumulated by a car. In its normal use, a car accrues damage that increases the likelihood that it will break down. Anti-aging is equivalent to maintaining a car, to prevent it from breaking down in the first place.

Anti-aging vs current medicine

Anti-aging is more feasible for extending healthy lifespan rather than solving the individual diseases of aging due to Taueber’s paradox and the highly comorbid nature of age-related diseases. Even if a person survives one age-related disease such as cancer, another (e.g. diabetes, cardiovascular disease) will kill them if aging is not solved. This accounts for the much smaller increase in healthy lifespan associated with curing the diseases of aging, such as cancer (2-3 years), versus slowing aging itself (30+ years):

Slowing aging is more effective than curing disease. Displayed are the calculated impacts on life expectancy for a typical 50-year-old woman from curing cancer, heart disease, or both, relative to the impact of slowing aging. The figure was generated from data presented in Lombard et al. (2016). The coloring illustrates the hypothetical impact on health expectancy in each case, where green represents the absence of a comorbidity and red represents a severe comorbidity. Source here.

The difference between anti-aging and current medicine is the former prevents illness by targeting the hallmarks of aging, whereas the latter intervenes once a disease has emerged. If we compare current medical interventions associated with geriatrics with anti-aging—the former extends unhealthy lifespan, whereas only the latter extends healthy lifespan.

Therefore, there is strong reason to think that anti-aging will be more successful in extending healthy lifespan than the ‘sick-care’ approach of current medicine.

Part IV: Can aging actually be slowed?

In the lab, we have demonstrated that various anti-aging approaches can extend healthy lifespan in many model organisms including yeast, worms, fish, flies, mice and rats. Life extension of model organisms using anti-aging approaches ranges from 30% to 1000%:

The methuselahs in lab: The increase in maximum lifespan in the laboratory is shown in 5 animal species, both without any interventions, and by dietary, chemical, or genetic interventions. For each organism, the impact of the increase in maximum lifespan through intervention is indicated in the graph using fold change. Source here.

These results demonstrate that aging is plastic, and not a fixed process. In mice, some of the most effective approaches to life extension are summarised below:

Source: here

The plasticity of aging in model organisms that share similar metabolic physiology to us provides us good proof-of-principle that aging can be slowed in humans. It remains to be seen how much life extension is possible, and improved biomarkers of aging will be needed to accurately measure the effectiveness of new therapies in a reasonable time-frame.

Part V: Most promising anti-aging strategies

The past 5 years of research have demonstrated several anti-aging strategies as particularly promising. The diagram below, taken from a 2019 review by researchers at Stanford University summarises four of the most promising approaches to slow or reverse aging in humans, based on studies in mice:

A comparison of the four emerging rejuvenation strategies: blood factors, metabolic manipulation, ablation of senescent cells and cellular reprogramming. The figure depicts the features that improve when treatment in mice is initiated at midlife or later. The top panel shows organs or tissues that exhibit a rejuvenated phenotype in wild-type (WT) mice. For rapamycin, features that have been shown to improve also in young mice following treatment are indicated with an asterisk (*). The effect on lifespan, proposed primary mode (or modes) of action and possible trade-offs of these strategies are also presented. Finally, the translational potential in humans is indicated by the increasing number of plus signs (+) based on present evidence in human ageing and current feasibility. NT, not tested. Question marks indicate possible modes of action and trade-offs. Original source here.

The above diagram may be quite technical for non-biomedical scientists, so I’ll briefly describe the approaches individually in simpler terms. Note that each of these strategies helps to reverse one or more of the hallmarks of aging.

1. Parabiosis (blood exchange)

Parabiosis (heterochronic parabiosis) is putting young blood into old mice, to make the old mice biologically younger. This is achieved in the lab by connecting the circulatory systems of young mice and old mice. Certain factors in the blood help to rejuvenate muscle, heart brain and liver tissues in old mice and restore their biological function.

Equivalent procedures that modify the compounds within blood in humans such as apheresis (blood filtering) could be used to slow aging in humans and thereby prevent or slow the progression of many types of age-related diseases including Alzheimer’s disease.

Recently, a group of Russian biohackers recently took part in the first plasma dilution experiments in humans. In a research context, the safety and effectiveness of apheresis is being tested in a clinical trial in humans by the company Alkahest.

Hallmarks reversed: parabiosis reverses age-related decline by targeting several hallmarks of aging including stem cell exhaustion, cellular senescence and altered intercellular communication (inflammation).

2. Metabolic manipulation (mTOR inhibitors)

Dietary restriction has been shown to extend healthy lifespan across several species. Drugs that mimic the metabolic effects of dietary restriction also have beneficial effects on lifespan. Nutrient-sensing biochemical pathways (such as IGF-1, mTOR and AMPK) play a key role in these effects. Metformin is a drug that is FDA-approved for diabetes that extends healthy lifespan in mice by inhibiting mTOR and activating autophagy. Metformin is currently being tested in a large clinical trial in humans to test its anti-aging properties.

Source: here

Hallmarks of aging targeted: The widespread mechanisms of action of metformin help to improve all of the 9 hallmarks of aging, shown below. I’ll save the details for those interested, who can read a more thorough review here.

Source: here.

Another promising drug that manipulates metabolism is rapamycin (also known as siromilus), an FDA-approved immunosuppressant that extends healthy lifespan in mice and similarly acts to inhibit mTOR. Rapamycin is currently in a clinical trial in humans to test its anti-aging properties.

3. Senolytics—drugs that kill senescent cells

Senescent cells are a kind of ‘zombie’-like cell that accumulate with age. They are death-resistant cells that secrete proinflammatory factors associated with a range of age-related diseases (below, right):

Cellular senescence is associated with multiple human disorders. The development of galactose‐conjugated and fluorescent probes to detect and highlight senescent cells offers an important opportunity for longitudinal monitoring of senescence in clinical trials. Pharmacologically active small compounds known as senolytics inhibit pro‐survival pathways in senescent cells leading to apoptosis, a therapeutic strategy that may additionally be enhanced by the use of immune modulators promoting natural clearance of senescent cells. Finally, nanoparticles encapsulating cytotoxic drugs, tracers and/​or small molecules can be used as theranostic tools, both for therapeutic and diagnostic purposes. Source: here

There are various strategies being explored to kill or reprogram senescent cells (above, left), including senolytics. Senolytics are drugs that kill senescent cells to improve physical function and healthy lifespan. When administered to older mice, senolytics have been shown to reverse many aspects of aging such as cataracts, and arthritis (below):

Killing senescent cells with senolytics extends the median healthy lifespan by up to 27% in mice (below). Several senolytics, such as the combination of dasatinib and quercetin, and fisetin are in clinical trials in humans today.

Study design for clearance of senescent cells mouse cohort. Median survival (in days, d) and percentage increase in median survival are indicated. Source: here

Hallmarks of aging reversed: senolytics decelerate cellular senescence, improve epigenetic markers and restore intercellular communication (by reducing inflammation associated with senescent cells) to extend healthy lifespan.

4. Cellular reprogramming

Cellular reprogramming is the conversion of terminally differentiated cells (old cells) into induced pluripotent stem cells (IPSCs) (‘young’ cells). Cells can be re-programmed to a youthful state using a cocktail of 4 factors known as Yamanaka factors, a finding for which a Nobel prize was awarded in 2012.

Induced pluripotent stem cells (IPSCs) have essentially unlimited regenerative capacity and carry the promise for tissue replacement to counter age-related decline. Partial reprogramming in mice has shown promising results in alleviating age-related symptoms without increasing the risk of cancer.

(A) The diagram depicts cellular programming to pluripotency, in other words, the conversion of terminally differentiated somatic cells into induced pluripotent stem cells (iPSCs) by cellular reprogramming through forced expression of Yamanaka factors (Oct4, Sox2, Klf4, and c-Myc). (B) The diagram depicts the rejuvenation of aged cells by cellular reprogramming. The process results in the amelioration of hallmarks of aging such as mitochondrial dysfunction, shortening of telomere length, changes in epigenetic marks, increased DNA damage, and senescence. Source: here.

An impressive example of cellular reprogramming was the restoration of vision in blind mice with a severed optic nerve using 3 of the 4 Yamanaka factors. The researchers from Harvard Medical School were able to regrow a fully functioning optic nerve in mice using cellular reprogramming. This approach could be used in future to regenerate other tissues as a new anti-aging strategy.

Using the eye as a model tissue, expression of Oct4, Sox2 and Klf4 genes (OSK) in mice resets youthful gene expression patterns and the DNA methylation age of retinal ganglion cells, promotes axon regeneration after optic nerve crush injury, and restores vision in a mouse model of glaucoma and in normal old mice. Source: here.

Hallmarks of aging targeted: Cellular reprogramming has been shown to reverse many of the hallmarks of aging, such as mitochondrial dysfunction, shortening of telomere length, changes in epigenetic marks, genomic instability, and cellular senescence.

5. Additional anti-aging approaches

Although not covered here, there are many other promising strategies for rejuvenation including thymic rejuvenation which has been shown to reverse biological age in humans, sirtuin enzyme activation with drugs such as resveratrol, and boosting mitochondrial function with NAD+ precursor molecules. All of these show the potential to increase healthy lifespan by targeting the hallmarks of aging.

Part VI: Conclusion

Aging is essentially damage accumulation that occurs as a by-product of metabolism and causes the diseases that kill most people today. This damage comes in 9 forms, which are the hallmarks of aging. Many therapeutic strategies show great promise in extending healthy human lifespan by reversing the damage accumulated with aging. Four of the most promising strategies to extend lifespan in humans include parabiosis, metabolic manipulation, senolytics, and cellular reprogramming.

Part VII: Call to Action

For those wanting to help aging be solved in our lifetime so we can avoid being the last generation to die, consider taking the following actions:

• Sharing this post with others

• Joining the Longevity subreddit or the Lifespan Discord server to plug into longevity channels

• Learning more about the field (suggested reading materials below)

• Donating to the SENS research foundation. They fund the most neglected and high-impact research in this field as explained in this LessWrong post.

• Becoming involved in the longevity field as a researcher in one of the hundreds of laboratories around the world, or working for a longevity biotech company. You can find available jobs at LongevityList.com

Part VIII: Learn more

Books:

Ending Aging (2007) - Aubrey de Grey, PhD

Lifespan (2019) - Prof. David Sinclair, PhD

Age Later (2020) - Dr Nir Barzilai, PhD

Ageless (2020) - Andrew Steele, PhD

The Abolition of Aging (2016) - David Wood

YouTube:

Any talks by Prof David Sinclair, Dr Aubrey de Grey, Prof Brian Kennedy, or Dr Nir Barzilai for anti-aging science. For personal longevity strategies, I recommend talks by Dr Rhonda Patrick, Dave Asprey and Dr Peter Attia.

You can also follow the Oxford Society of Ageing and Longevity channel here.

Websites and blogs:

https://​​www.reddit.com/​​r/​​longevity

https://​​www.lifespan.io/​​

https://​​www.fightaging.org/​​

https://​​www.longevity.technology/​​

Good review articles:

The hallmarks of aging (2013)

Geroscience: linking aging to chronic disease (2014)

The business of anti-aging science (2017)

Turning back time with emerging rejuvenation strategies (2019)

From discoveries in aging research to therapeutics for healthy aging (2019)

If you wish to contact me outside this forum, please email me at [e-mail]


Edit:
Based on recommendations in the comments, I’ve added a short bio, below.

About me:
I’m not a geroscience researcher, but I am conducting neuroscience research at Oxford University after finishing my studies here and have a reasonable grasp of the geroscience field. I am vice president of the Oxford Society of Ageing and Longevity and in this role have had the privilege of interviewing influential figures in the field such as Aubrey de Grey, and researchers in the field such as Joao Pedro de Magalhaes. I’ve also had meetings with many other key figures in the field including David Sinclair. I have attended most of the major conferences in the field (ARDD2020, EARD2020, CSL Mechanisms of Aging 2020 etc.) last year, and read over 1000 academic papers in this field. I have also been been invited to give guest lectures on this topic at Oxford University and Monash University, Australia. I’ve been a content writer at Mindset Health for 2 years so I have some background in science communication.

[niplav]

I read this post at the same time as reading Ascani 2019 and Ricón 2021 in an attempt to get clear about anti-aging research. Comparing these three texts against each other, I would classify Ascani 2019 as trying to figure out whether focusing on anti-aging research is a good idea, Ricón 2021 trying to give a gearsy overview of the field (objective unlocked: get Nintil posts cross-posted to LessWrong), and this text as showing what has already been accomplished.

In that regard it succeeds perfectly well: The structure of Part V is so clean I suspect that it sweeps a bunch of complexity and alternative approaches under the rug, and the results described seriously impressed me and some of the people I was reading this text with at the time (We can reverse arthritis and cataracts in mice‽ We can double their maximum lifespan‽). It is excellent science propaganda: Inspiring awe at what has been accomplished, desire to accomplish more, and hope that this is possible.

While the post shines in parts III, IV and V, I have some quibbles and complaints about the introduction, part I and part II. First, I disliked the jab against cryonics in the first paragraph without considering the costs and benefits, which rightly received some pushback in the comments (the strongest counter-observation being that barring some practical suggestions for slowing down aging right now, cryonics and anti-aging research occupy very different parts of the strategy for life-extension, and can be pursued in parallel). Part II disappointed me because it was pro-longevity advocacy under the veneer of a factual question: Has anybody actually tried to think through how a world without aging might actually look like, instead of re-treading the same pro-aging trance and anti-aging science arguments? That seems like a question that is both interesting and pretty relevant, even when you believe that ending aging is important enough that it should definitely be done, if just to prepare for weird second- and third-order effects.

(Part I felt like I was a choir being preached to, which isn’t that bad, but still…)

I really liked learning a bunch of new facts about aging (as for example the list of species that don’t age, that aging is responsible for 30% of lost DALYs, and distinction between gerontology, engineering and geriatrics). Factposts are underrated.

The comments on this post were often very good, and had some nice discussion about whether the advice in section VII was to be focused on.

I’ve been overly negative in this review, but overall I still like this post, and have voted a 4 on it (which I might change to a 1). The parts III-V are excellent, and I have only minor problems with the preceding parts. This is the kind of post I would give a science-interested skeptic of anti-aging research. I’d like to have this post in the review, because it represents something some part of the core to the LessWrong transhumanist aesthetic that often gets overlooked.

[Matthew Barnett]

As an effective altruist, I like to analyze how altruistic cause areas fare on three different axes: importance, tractability and neglectedness. The arguments you gave for the importance of aging are compelling to me (at least from a short-term, human-focused perspective). I’m less convinced that anti-aging efforts are worth it according to the other axes, and I’ll explain some of my reasons here.

The evidence is promising that in the next 5-10 years, we will start seeing robust evidence that aging can be therapeutically slowed or reversed in humans.
[...]
In the lab, we have demonstrated that various anti-aging approaches can extend healthy lifespan in many model organisms including yeast, worms, fish, flies, mice and rats. Life extension of model organisms using anti-aging approaches ranges from 30% to 1000%:

When looking at the graph you present, a clear trend emerges: the more complex and larger the organism, the less progress we have made on slowing aging for that organism. Given that humans are much more complex and larger than the model organisms you presented, I’d caution against extrapolating lab results to them.

I once heard from a cancer researcher that we had, for all practical purposes, cured cancer in mice, but the results have not yet translated into humans. Whether or not this claim is true, it’s clear that progress has been slower than the starry-eyed optimists had expected back in 1971.

That’s not to say that there hasn’t been progress in cancer research, or biological research more broadly. It’s just that progress tends to happen gradually. I don’t doubt that we can achieve modest success; I think it’s plausible (>30% credence) that we will have FDA approved anti-aging treatments by 2030. But I’m very skeptical that these modest results will trigger an anti-aging revolution that substantially affects lifespan and quality of life in the way that you have described.

Most generally, scientific fields tend to have diminishing marginal returns, since all the low-hanging fruit tends to get plucked early on. In the field of anti-aging, even the lowest hanging fruit (ie. the treatments you described) don’t seem very promising. At best, they might deliver an impact roughly equivalent to adding a decade or two of healthy life. At that level, human life would be meaningfully affected, but the millennia-old cycle of birth-to-death would remain almost unchanged.

Today, there are over 130 longevity biotechnology companies

From the perspective of altruistic neglectedness, this fact counts against anti-aging as a promising field to go into. The fact that there are 130 companies working on the problem with only minor laboratory success in the last decade indicates that the marginal returns to new inputs is low. One more researcher, or one more research grant will add little to the rate of progress.

In my opinion, if robust anti-aging technologies do exist in say, 50 years, the most likely reason would be that overall technological progress sped up dramatically (for example, due to transformative AI), and progress in anti-aging was merely a side effect of this wave of progress.

It’s also possible that anti-aging science is a different kind of science than most fields, and we have reason to expect a discontinuity in progress some time soon (for one potential argument, see the last several paragraphs of my post here). The problem is that this argument is vunerable to the standard reply usually given against arguments for technological discontinuities: they’re rare.

(However I do recommend reading some material investigating the frequency of technological discontinuities here. Maybe you can find some similarities with past technological discontinuities? :) )

[JackH]

I am also an effective altruist and have been involved in the movement since 2012. I and others think that anti-aging and donating to SENS is probably a more important cause area than most EA cause areas (especially short-term ones) besides X-risk for the reasons below.

As a side note, from the longer (200+ comment) discussion about anti-aging from an EA perspective on the EA Facebook group here, the main objection that held weight seemed to be ‘bang for buck’, and is also addressed below.

In this piece: Why SENS Makes Sense and this piece: A general framework for evaluating aging research. Part 1: reasoning with Longevity Escape Velocity Emanuale Ascani evaluates the cost effectiveness of anti-aging, and donations to SENS Research Foundation using the EA criteria of scale, neglectedness and tractability. His estimation of cost-effectiveness of a SENS donation is $2.50 per 1000 quality-adjusted years life years saved, which dwarfs most other short-term cause areas in EA.

In terms of tractability and neglectedness, I’ll add a few more thoughts:

(1) Tractability

I understand that considering the models of aging (mice, flies, yeast etc.) alone might give the impression that these therapies may not translate to humans. However:

Human trials for aging specifically for three of the four approaches I mentioned are currently underway, but the lack of human data for these approaches ought not to undermine the scientific feasibility of, given results of other trials in humans. Data from human trials suggest many of these approaches have already been shown to reduce the rate of cognitive impairment, cancer, and many other features of aging in humans. Given these changes are highly correlated with biological aging, the evidence strongly suggests the capacity for the approaches mentioned to slow biological in humans.

In addition, in the past 2 years, human biological aging has already been reversed using calorie restriction, and with thymic rejuvenation, as measured by epigenetic (DNAm) aging. DNAm aging is fairly accurate in predicting time-to-death due to age-related conditions, so this is a promising finding for the field. Once more clinical trial data comes in, it will be easier to evaluate, but the preliminary evidence has demonstrated biological aging can be slowed in humans in the near future.

Regarding tractability, it’s also worth noting that the above has been made despite the research field receiving such comparatively little funding (explained in (2)).

Of course, part of the research in anti-aging is to develop more accurate biomarkers of aging (e.g. multi-omics biomarkers of aging), since it’s inherently a difficult process to measure. Funding in the field is required to develop better biomarkers of aging so that we can indeed provide more robust evidence that aging can be slowed in humans. Neverless the limited tools we have to measure aging (e.g. DNAm/​Horvath’s clock, Levine’s clock) there has been sufficient proof-of-principle that aging in humans can be slowed to suggest that time-scales for anti-aging are fairly short, or could be with increased funding.


(2) Neglectedness

I understand that the number of longevity biotech companies may (wrongly) suggest that the field is well-funded. But this number is not an accurate proxy for the relative funding received by basic geroscience to develop cures for aging, from which these companies are spun-out of.

The crucial point is that although there is a lot of money in ‘aging’ in general (e.g. NIA’s budget of $3 billion), and a lot of private money to finance longevity biotech companies spun out of basic aging research laboratories, there is a pitifully small amount of money financing basic geroscience research to find therapies to treat aging. This is especially true when compared to any other biomedical field, such as cancer, or neurodegeneration, which receive 1-2 orders of magnitude greater funding (e.g. NCI has an annual budget of $6.5 billion, compared to $100 million for geroscience research). I think many EA’s assume academia is an efficient market that will self-correct to prioritise research with the greatest potential impact; but unfortunately, that’s not how things work due to the incentives in academia. For example, cancer researchers have no incentive to start investigating aging, since it’s outside the scope of their grant funding. Until the public realizes aging is a problem, and lobby governments to increase expenditure towards geroscience, the rate of progress remains comparatively slow, given what it could be.

To give some numbers: Less than 0.2% ($100 million) of the NIH’s $45 billion budget goes towards geroscience research to find cures for aging, even though the NIA has a budget of around $3 billion. Moreover, organisations such as SENS finance some of the best research in the field have even smaller budgets ($5-10 million) which is why private small donations can still have a significant impact.

Aubrey de Grey who has significant insight into the landscape of funding for anti-aging believes that $250-500 million over 10 years is required to kickstart the field sufficiently so that larger sources of funding will flow in. In most timelines, this will happen inevitably, but given 100,000 lives are lost per day until we reach longevity escape velocity, getting to these milestones as soon as possible is a key priority, and the numbers suggest doing so represents one of the most cost-effective cause areas.

Other comments:

(1) Timelines
Regarding timelines and predictions, I think regardless of whether the FDA approves senolytics by 2030 or not, which is primarily a question of bureaucracy and politics more than science, the more interesting question is do senolytics actually work to slow aging. I would put the probability at 90% that one or more type of senolytic or senotherapeutic compound extend healthy lifespan by 5 years or more on average in humans if taken from a young enough age, regardless of whether they sufficiently meet the endpoints for specific disease indications required for FDA approval.

(2) AI
I agree that AI, if it doesn’t kill us all will probably have a huge impact on solving aging. However, this doesn’t actually change my calculus as the importance of solving aging very much, given that most AI timelines imply millions or billions of people will most likely die of aging before aging is solved by AI, unless we have anti-aging drugs to keep as many people alive as possible in the meantime.

Developing anti-aging compounds ‘by hand’ without the help of AI may seem slow and inefficient, but remember that we don’t need to achieve negligible senescence before AI—we only need drugs that are sufficiently effective to bring as many people as possible to the point in time at which AI solves aging. For example, a drug or cocktail of therapies that extend life of all humans on Earth by 10 years essentially allows 10-years’ worth of people who would otherwise have died of aging (~400 million people) to potentially reach the point at which AI solves aging and hence, longevity escape velocity. From an EA perspective, this seems like an incredible amount of good, and far better than most other cause areas out there, barring x-risks like AI safety.

(3) Starry-eyed optimism
Current evidecne suggests curing in cancer is probably much harder than slowing aging, because you have to reverse the damage associated with aging (which predisposes to tumorogenesis) as well as kill of the cancer to restore a person to a state of health, since aging alters the tumor microenvironment in a way that causes cancer. Therefore I’m not sure how apt the analogy is.

An analogy that is often thrown around in anti-aging circles is that of flight, which had a remarkably short timeline, or the Apollo missions. David Wood in his book, The Abolition of Aging makes a good case for how anti-aging could follow a similar timeline to flight.

[Matthew Barnett]

I appreciate the detailed and thoughtful reply. :)

I and others think that anti-aging and donating to SENS is probably a more important cause area than most EA cause areas (especially short-term ones) besides X-risk for the reasons below.

I agree that anti-aging is neglected in EA compared to other short-term, human focused cause areas. The reason is likely because the people who would be most receptive to anti-aging move to other fields. As Pablo Stafforini said,

Longevity research occupies an unstable position in the space of possible EA cause areas: it is very “hardcore” and “weird” on some dimensions, but not at all on others. The EAs in principle most receptive to the case for longevity research tend also to be those most willing to question the “common-sense” views that only humans, and present humans, matter morally. But, as you note, one needs to exclude animals and take a person-affecting view to derive the “obvious corollary that curing aging is our number one priority”. As a consequence, such potential supporters of longevity research end up deprioritizing this cause area relative to less human-centric or more long-termist alternatives.

I wrote a post about how anti-aging might be competitive with longtermist charities here.

Data from human trials suggest many of these approaches have already been shown to reduce the rate of cognitive impairment, cancer, and many other features of aging in humans. Given these changes are highly correlated with biological aging, the evidence strongly suggests the capacity for the approaches mentioned to slow biological in humans.

Again, this is nice, and I think it’s good evidence that we could achieve modest success in the coming decades. But in the post you painted a different picture. Specifically, you said,

The ‘white mirror’ of aging is a world in which biological age is halted at 20-30 years, and people maintain optimal health for a much longer or indefinite period of time. Although people will still age chronologically (exist over time) they will not undergo physical and cognitive decline associated with biological aging. At chronological ages of 70s, 80s, even 200s, they would maintain the physical appearance and much lower disease risk of a 20-30-year-old.

If humans make continuous progress, then eventually we’ll get here. I have no issue with that prediction. But my objection concerned the pace and tractability of research. And it seems like there’s going to be a ton of work going from modest treatments for aging to full cures.

One possible response is that the pace of research will soon speed up dramatically. Aubrey de Grey has argued along these lines on several occasions. In his opinion, there will be a point at which humanity wakes up from its pro-aging trance. From this perspective, the primary value of research in the present is to advance the timeline when humanity wakes up and gets started on anti-aging for real.

Unfortunately, I see no strong evidence for this theory. People’s minds tend to change gradually in response to gradual technological change. The researchers who said this year that “I’ll wait until you have robust mouse rejuvenation” will just say “I’ll wait until you have results in humans” when you have results in mice. Humans aren’t going to just suddenly realize that their whole ethical system is flawed; that rarely ever happens.

More likely, we will see gradual progress over several decades. I’m unsure whether the overall project (ie. longevity escape velocity) will succeed within my own lifetime, but I’m very skeptical that it will happen within eg. 20 years.

In addition, in the past 2 years, human biological aging has already been reversed using calorie restriction, and with thymic rejuvenation, as measured by epigenetic (DNAm) aging.

I don’t think either of these results are strong evidence of recent progress. Calorie restriction has been known about for at least 85 years. The thymic rejuvenation result was a tiny trial with ten participants, and the basic results have been known since at least 1992.

The recent progress in epigenetic clocks is promising, and I do think that’s been one of the biggest developments in the field. But it’s important to see the bigger picture. When I open up old Alcor Magazine archives, or old longevity books from the 1980s and 1990s, I find pretty much same arguments that I hear today for why a longevity revolution is near. People tend to focus on a few small laboratory successes without considering whether the rate of laboratory successes have gone up, or whether it’s common to quickly go from laboratory success to clinical success.

Given that 86 percent of clinical trails eventually fail, and the marginal returns to new drug R&D has gone down exponentially over time, I want to know what specifically should make us optimistic about anti-aging, that’s different from previous failed predictions.

I understand that the number of longevity biotech companies may (wrongly) suggest that the field is well-funded. But this number is not an accurate proxy for the relative funding received by basic geroscience to develop cures for aging, from which these companies are spun-out of.

If the number of companies working on rejuvenation biotechnology did not accurately represent the amount of total effort in the field, then what was the point of bringing it up in the introduction?

I think many EA’s assume academia is an efficient market that will self-correct to prioritise research with the greatest potential impact

Interestingly, I get the opposite impression. But maybe we talk to different EAs.

Aubrey de Grey who has significant insight into the landscape of funding for anti-aging believes that $250-500 million over 10 years is required to kickstart the field sufficiently so that larger sources of funding will flow in.

I don’t doubt Aubrey de Grey’s expertise or his intentions. But I’ve heard him say this line too, and I’ve never heard him give any strong arguments for it. Why isn’t the number $10 billion or $1 trillion? If you think about comparably large technological projects in the past, $500 million is a paltry sum; yet, I don’t see a good reason to believe that this field is different than all the others. Moreover, there is a well-known bias that people within a field are more optimistic about their work than people outside of it.

For example, a drug or cocktail of therapies that extend life of all humans on Earth by 10 years essentially allows 10-years’ worth of people who would otherwise have died of aging (~400 million people) to potentially reach the point at which AI solves aging and hence, longevity escape velocity.

This is only true so long as the drug can be distributed widely almost instantaneously. By comparison, it usually takes vaccines several decades to be widely distributed. I also find it very unlikely that any currently researched treatment will add 10 years of healthy life discontinuously. Again, progress tends to happen gradually.

[JackH]

I agree that anti-aging is neglected in EA compared to other short-term, human focused cause areas. The reason is likely because the people who would be most receptive to anti-aging move to other fields. As Pablo Stafforini said

I agree with Pablo’s reasoning as to why anti-aging has not taken off in the EA community.

If humans make continuous progress, then eventually we’ll get here. I have no issue with that prediction. But my objection concerned the pace and tractability of research. And it seems like there’s going to be a ton of work going from modest treatments for aging to full cures.

I agree that the ‘white mirror’ scenario might be some time off (even 100+ or 1000+ years away), but remember that we only need to reach longevity escape velocity for everyone on Earth to make it to the ‘white mirror’ scenario, not reach the ‘white mirror’ scenario right away. For example, within the next 50 years, we might have drugs that keep us alive for another 100 years, meaning even if it takes 80 years to develop drugs that keep us alive for 1000 years, and then it takes 800 years for us to develop drugs that would bring us to the ‘white mirror’ scenario, we would still reach it. This is the beauty of longevity escape velocity—we only need drugs that keep us alive until better drugs arrive, to stay alive indefinitely and reach the ‘white mirror’ scenario.

Unfortunately, I see no strong evidence for this theory. People’s minds tend to change gradually in response to gradual technological change. The researchers who said this year that “I’ll wait until you have robust mouse rejuvenation” will just say “I’ll wait until you have results in humans” when you have results in mice. Humans aren’t going to just suddenly realize that their whole ethical system is flawed; that rarely ever happens.

I, and many others in the field, would disagree with you here for a simple reason: once we start getting drugs that work, and good evidence that they work—for example, a drug that prevents cancer—people will take them. People generally care about their health enough to take medicines that improve/​protect their health—for example, vaccines, statins, cancer therapies and so on. Aubrey de Grey explains that a primary reason people remain in the pro-aging trance is because they are too scared to get their hopes up. However, this all changes as soon as you have drugs that work, even modestly.

If you look historically, there is a relevent parallel with infectious diseases such as tuberculosis 100 years ago, as David Wood explains in my interview with him. Back then, the population generally accepted the disease as ‘natural’, ‘normal’ and an ‘act of god’ (as they do with aging today) rather than fight it, primarily because they didn’t think there was a way to fight it. But as soon as Rober Koch created a vaccine for tuberculosis, people’s values shifted immediately and they began making use of these vaccines.

So, the goal isn’t necessarily to persuade the world to consider aging a problem. It’s to convince enough people with the capacity to speed up the research to become interested, so that the first generations of anti-aging therapies come into the world, and have strong evidence behind them, after which people will begin taking them.

Tractability:

I don’t think either of these results are strong evidence of recent progress. Calorie restriction has been known about for at least 85 years. The thymic rejuvenation result was a tiny trial with ten participants, and the basic results have been known since at least 1992.

Regarding calorie restriction, the key significance of this finding was that this is one of the first indications that a marker of biological aging (DNA methylation age) has been significantly modulated using an intervention. This is a big step up from lifespan studies using calorie restriction in mice, since as you noted, not all interventions in mice translate well to humans.

Given that 86 percent of clinical trails eventually fail, and the marginal returns to new drug R&D has gone down exponentially over time, I want to know what specifically should make us optimistic about anti-aging, that’s different from previous failed predictions.

This is a reasonable concern to have, and one that many outside of the field (i.e. not attending the conferences, not having kept up to date with the literature) do have. I too shared this view when I was studying neuroscience, before I started becoming more involved in the field.

What makes it different is that anti-aging is targeting the root cause of the problem, rather than the symptoms of the problem. So although 86% of clinical trials fail, this is because the approach to most of these trials (sick-care, essentially) that attempt to treat chronic diseases such as cancer, heart disease, awithout treating the root cause (aging) is ineffectual. Let’s take Alzheimer’s disease for example. This is a neurodegenerative illness that emerges as a result of decades of damage accumulation associated with the hallmarks of aging. Now, attempting to cure Alzheimer’s without treating any of the underlying damage that continues to perpetuate the disease (such as senescent cells, mitochondrial dysfunction and other hallmarks of aging) is clearly ineffectual. How are you going to reverse the huge amount of molecular damage that occurs in the brain due to Alzheimer’s, if you are not addressing the root causes of this damage, such as senescent cells, which are continuing to secrete pro-inflammatory factors that are driving neurodegeneration? Hence, it’s really no surprise that over 100 clinical trials for Alzheimer’s have failed and the $5.6 billion spent on trying to treat Alzheimer’s since the approach is misguided. It’s a similar story for cancer, too. There is a multi-decade long process of damage accumulation that alters the microenvironment that predisposes to tumorogenesis. So again, simply attempting to kill the tumor without attenuating the underlying damage that predisposes to tumorogenesis is clearly an ineffective approach. By contrast, anti-aging is targeting the common causes of all of these age-related diseases (senescent cells, etc.), and the preliminary evidence in mice and humans suggest that this is not just theory—it works in practice to extend healthy lifespan.

A few other comments about tractability:

There is a huge range of therapeutic approaches that have a reasonable chance of slowing or reversing aging in the future besides those mentioned in the article, including nanotechnology (companies like Alzeca Biosciences and Bikanta), gene therapy to treat the cause of multiple diseases at once, 3D-printed organs, and research is now being augmented by AI platforms for anti-aging drug discovery. Importantly, the same could not be said as recently as 5 years ago, when these approaches had not been developed.

If you are still skeptical, considering watching this summary of the state of the field in 2020 by Bill Falloon from RAADfest 2020 and all of these lectures from ARDD 2020 and see if you still think that meaningfully slowing aging is not likely in the near future.

If the number of companies working on rejuvenation biotechnology did not accurately represent the amount of total effort in the field, then what was the point of bringing it up in the introduction?

To demonstrate to readers that anti-aging is a real thing, and a legitimate field of biomedical research that they can support, rather than a whimsical sci-fi fantasy. That said, the field needs more support.

I don’t doubt Aubrey de Grey’s expertise or his intentions. But I’ve heard him say this line too, and I’ve never heard him give any strong arguments for it. Why isn’t the number $10 billion or $1 trillion? If you think about comparably large technological projects in the past, $500 million is a paltry sum; yet, I don’t see a good reason to believe that this field is different than all the others. Moreover, there is a well-known bias that people within a field are more optimistic about their work than people outside of it.

He is forecasting, so there’s going to be some uncertainty. I don’t know what evidence he could really draw on, since this figure is based on his impression on the current state of the entire field. But it’s probably something like, his estimation of the marginal increase in progress towards achieving negligible senescence associated with increased funding, based on the marginal increase in progress associated with SENS’ existing funding. The progress the SENS-funded projects have made is significant, and if you extrapolate that out to the best of one’s abilities, you probably get something like the $250-500 million figure. Remember that this is not the total amount needed to make meaningful progress on aging, which indeed is probably in the order of many billions or tens of billions. But, the field fortunately is well placed to take advantage of huge leverage opportunities, since big pharma are watching closely to see how the field develops (I can dig up some reviews about this) as are other stakeholders. Once sufficient de-risking has been done, which is what that initial $250-500 million is needed for, bigger players are likely to enter the game and the field will take off. The public will also start taking note, since the $250-500 million is very likely to be enough to fund research that yields legitimate first-generation anti-aging therapies, enough to pique the public’s interest. Ultimately, given the biggest bottleneck is funding, and every few million to make a new discovery or promising geroprotective compound results in tens of millions flowing in to finance the longevity biotech company spin-outs of these findings, that $250-500 million for SENS really looks more like $10 billion+ for the field as a whole. To clarify though, this is probably hard for those outside the field who are not familiar with longevity biotech financing to conceptualize, and I plan to write a separate post about this explaining it in more detail.

This is only true so long as the drug can be distributed widely almost instantaneously. By comparison, it usually takes vaccines several decades to be widely distributed. I also find it very unlikely that any currently researched treatment will add 10 years of healthy life discontinuously. Again, progress tends to happen gradually.

If you don’t think that some combination of multi-omics-aging-biomarker-optimised combination of senolytics, mTOR inhibitors, gene therapies, nanotech, parabiosis, epigenetic reprogramming, exercise protocols, diet, 3D-printed organs—all of which are technologies available today—could extend life by 10 years, I’d be curious to know why. Even David Sinclair in his book Lifespan and interview explains that metformin+exercise+not smoking+intermittent fasting alone adds 14 years of healthy life.

[DirectedEvolution]

I’d also highlight that we have fine-grained empirical data about clinical trial success rates, though not for geroscience-based therapies. The overall success rate for a therapeutic can range from 3.4% (cancer drugs) to 33.4% (vaccines), with an average including oncology of 13.8% and an average excluding oncology of 20.9%. Some of the most promising drug candidates, like rapamycin, have already passed clinical trials for other indications, so we know they’re safe. The work now is to show they can be safe enough at lower doses to justify giving them to healthy people.

[Victorel Petrovich]

I have to disagree on 2 points:

1. “When looking at the graph you present, a clear trend emerges: the more complex and larger the organism, the less progress we have made on slowing aging for that organism”—the trend is not clear. Rather, the worms are an outlier on that graph. Mice are much more complex than flies and killifish (and much closer to humans) and yet, the results achieved are on par.

2. “The fact that there are 130 companies working on the problem with only minor laboratory success in the last decade indicates that the marginal returns to new inputs is low. ”—Most of them have their individual approaches to “the problem” . There are orders of magnitude more variables that affect the health and lifespan, and those companies are trying just a few of them. So, they are just scratching the surface of what it needs to be tried and done. More researchers and companies is definitely what is needed.

[Matthew Barnett]

You’re right about (1). I seemed to have misread the chart, presumably because I was focused on worms.

Concerning (2), I don’t see how your argument implies that the marginal returns to new resources are high. Can you clarify?

[Victorel Petrovich]

It depends on what you mean by “new resources”. In your text, you wrote “One more researcher, or one more research grant will add little to the rate of progress. ”—and that’s what I argued against, above.

Simply put, more researchers & companies=> more longevity-influencing factors to be evaluated ⇒ higher chance to find ones that work, and work better.

[Chris Hibbert]

I once heard from a cancer researcher that we had, for all practical purposes, cured aging in mice, but the results have not yet translated into humans.

This seems untrue on its face. What we mean by “curing aging” is negligible senescence. The best that has been achieved in mice is doubling their life spans, AFAICT. Extended (human) lifespan would be nice, but it’s not the goal.

[Matthew Barnett]

This seems untrue on its face. What we mean by “curing aging” is negligible senescence.

And presumably what the cancer researcher meant by curing cancer was something like, “Can reliably remove tumors without them growing back”? Do you have evidence that we have not done this in mice?

[JackH]

I assumed that was a typo and that you meant curing cancer in mice. We have definitely have not yet ‘cured aging’ in mice, which is called robust mouse rejuvenation (RMR). RMR is usually discussed in the context of timelines for longevity escape velocity (LEV), as a relevant milestone on the way to LEV. Aubrey de Grey has put RMR timelines as occuring as soon as 2022, and LEV occurring by 2036.

[Matthew Barnett]

Oops, that was a typo. I meant curing cancer. And I overlooked the typo twice! Oops.

[Eli Tyre]

This was great.

Some things that made it great:

1. It was just in the sweet spot of length. Taking notes, this took me a half hour to read. (I think the ideal is in the 30 minutes to 60 minute range, so doubling the post would have been fine, but more than that would have been overwhelming).

2. It was written clearly.

3. It was full of links that I can use to follow up on the places that I am most interested /​ confused about.

I would love to read more posts like this one, on a whole variety of topics, and would be glad to help subsidize their production if there was a way to organize that.

[JackH]

Thanks for the compliment!

Although it only took two days to write, it was the product of several months of thinking about the topic, and putting the pieces together.

That said, if you’d like to sponsor me to complete this sequence and/​or create more content like this, I would be more than happy to. You can have a look at other content I’ve created for MindsetHealth.com.

Please feel free to drop me a line at [e-mail]

[DirectedEvolution]

I want to consider this post from a decision-making perspective. How can it inform my own future decisions?

First of all, this is the applied goal underlying my graduate-level research. As I continue to learn more about my field of tissue engineering, bioprinting, and regenerative medicine, I might be able to contribute to this growing anti-aging movement. So this post can inform my reading and writing decisions.

Without meaning to be rude, I’m not certain that these sources or this post is credible, simply because I’m only starting to read it and understand it myself. This question is due to my own lack of knowledge, not any issue with the OP. However, it might make a good starting point. It might be valuable to look at the sheer amount of reading it would entail, and the level of mastery I’d like to attain in this domain.

If I wanted to commit a total of 50 hours studying this body of literature, is this post the best place to start? If not, what is? I don’t have any better ideas. Perhaps the key question is really where to start within this post.

I think I’m having these credibility and “where to start” concerns because this is a blog post by an anonymous author on LessWrong, rather than a book, a public blog, or a piece of published scholarly literature. That doesn’t mean it’s wrong or bad at all, but it does suggest a class of online writings that would be generally valuable: a credible, community consensus “where to start?” website for some of the intellectual movements of our era that unite a particular scientific domain with a moral stance or applied project.

80,000 Hours is an example for the EA movement. What is the most substantial “where to start” guide for the anti-aging movement? In fact, wouldn’t it be wonderful if each of the cause areas on 80,000 Hours had their own field-specific equivalent to 80k? A user-friendly map to the field and how best to navigate it? Are there any textbooks, especially ones that deal fairly with the moral counterarguments and scientific issues?

On an even more meta level, if many such sites existed, it would be amazing to have a meta-site that was collectively curated somehow.

I’ve often benefitted in dramatic and surprising ways by expanding my network. Not only can I read these writings, but I can look up the online presence of many of these people and attempt to meet them. I can mine their brains for research ideas and bounce my own off of them. I could choose to devote some time to making personal connections with these authors and scientists.

[JackH]

I completely agree that it is absurd that the kind of content in the OP is not more widely publicized. This was my precise motivation for writing this post.

Unfortunately, there is no good ‘where to start’ guide for anti-aging. This is insane, given this is the field looking for solutions to the biggest killer on Earth today.

The closest approximations to a ‘where to start’ guide for anti-aging would be:

• Is Human Life Extension Possible? - LongevityAdvice.com

• Longevity FAQ—Laura Deming (who is a longevity biotech VC)

• Lifespan by David Sinclair

• Ending Aging by Aubrey de Grey

That said, none of the above communicated all of the ideas that I wished to communicate in the OP in a succinct way. Again, this is precisely why I wrote it.

It seems to be one of the better introductions out there, as those in touch with field on the longevity subreddit seem to have appreciated my introductory guide, as it’s one of the top-rated posts in the past week and has been given 5 awards. As an aside, I’m planning on turning this into a sequence, so if you have ideas for future topics please let me know.

I totally agree regarding funding for 80k equivalent sites. If someone wants to provide financing for an anti-aging outreach and careers platform, count me in. I suppose the closest site would be Lifespan.io, which is a non-for-profit that provides high-quality content about the field, and crowdfunds research.

I also recommend emailing 80k and asking them to provide information on anti-aging career paths. I think it would be valuable for EA in general. If they are open to it, I would be more than happy to write something.

About me:

I’m not a geroscience researcher, but I am conducting neuroscience research at Oxford University after finishing my studies here and have a reasonable grasp of the geroscience field. I am vice president of the Oxford Society of Ageing and Longevity and in this role have had the privilege of interviewing influential figures in the field such as Aubrey de Grey, and researchers in the field such as Joao Pedro de Magalhaes. I’ve also had meetings with many other key figures in the field including David Sinclair. I also attended most of the major conferences in the field (ARDD2020, EARD2020, CSL Mechanisms of Aging 2020 etc.) last year. I’ve read probably in the order of 2000 academic papers in this field, and have been invited to give lectures on this topic at Oxford University and Monash University, Australia. I’ve also been a content writer at Mindset Health for 2 years so I have some background in science communication. The above reasons are why I felt qualified to write the OP.

If you have a 50-hour time budget to learn about anti-aging I would recommend the following:

• Watch 5 hours-worth of interviews with David Sinclair on YouTube.

• Read Lifespan by David Sinclair and Ending Aging by Aubrey de Grey

• Read the Hallmarks of aging paper and this great 2019 review of the field, and this 2014 paper introducing Geroscience

• Become familiar with the major philosophical objections to anti-aging, and their responses, here.

• Spend the rest of the time watching as many talks from the 2020 ARDD conference, available free, here. Start with talks by Brian Kennedy, Nir Barzilai, Judith Campisi, Eric Verdin, David Sinclair, and Joao Pedro de Magalhaes as they are the biggest names in the field.

If you can get through all that, I can email you a huge list of over 50 papers to read that covers all aspects of the hallmarks of aging and the current state of the field.

In terms of contributing to the field, you might want to join the Longevity Subreddit and Lifespan discord server for advice about how best to leverage your specific skillsets, as there are many aging researchers in these communities. They can help advise you on career paths.

I like your idea about meta-sites and networking platforms. My advice would be—if you think it should be done, why not give it try and do it yourself? At the end of the day, someone has to do it, and it might as well be you! The worst that might happen is you might learn something. Or, pursue the idea a bit and realise that others have already attempted it and failed or abandoned the project for reasons X, Y or Z.

[Yoav Ravid]

I think mentioning your qualifications at the start (or at least the end) of the post would help. i wondered about it myself as i was reading it, and i would have been glad to read them if they were mentioned (instead of, say, feeling like it’s bragging).

[JackH]

Sure—I’ve just added that at the bottom. Thanks for the tip.

[David_Kristoffersson]

Unfortunately, there is no good ‘where to start’ guide for anti-aging. This is insane, given this is the field looking for solutions to the biggest killer on Earth today.

Low hanging fruit intervention: Create a public guide to that effect on a web site.

[JackH]

Completely agree—we have this planned on our Oxford Society of Ageing and Longevity website (ageingandlongevity.com). I also plan to write a sequence on LessWrong of perhaps 10-15 posts similar to this one.

Feel free to comment if you think there are specific angles you’d like me to focus on (e.g. explaining the science in more detail, discussing common philosophical objections, describing the financing of longevity biotech, etc.).

[Felix Karg]

Thank you for writing this, it was very helpful to me. I will read up on a number of links you provided in the post itself and other comments.

I’m starting to dabble in Biology since last Semester (Computer Science Bachelors, currently doing Master’s degree) as a minor, some of my current interests are:

• Epigenetics
  Especially related with newly available computational methods and experiments doable with CRISPR-modifications. What are the active areas of research?

• Simulation
  Particularly of biological pathways or other relevant parts. What is commonly simulated? To what degree?

• Measuring
  How easy it is to measure the ‘Hallmarks of Aging’, and how accurate are their relative predictions? What other measurements would be great to have (soon)?

For me, it is not ultimately clear that they are relevant for the field at all, so bear with my selfishness here. I would especially be interested in a (slightly more technical) introduction to the current state of the Art, active areas of research, how it is related to anti-aging research, and how to learn more about each of them.

Furthering anti-aging-research/​awareness is actually a secondary career goal of mine, the first/​current one is figuring out how to consistently raise the sanity waterline in organizations. It might even be possible to fulfill both at one organization, we’ll see.

[Victorel Petrovich]

I’ve been following the anti-aging field for almost 7 years: research news, overview articles, reviews etc.
I don’t know the author of OP, but I can say that the article he wrote here is as good as it gets (one of the best I’ve ever read), and, up to date. So are the recommendations he makes for further learning/​immersion. I happen to have read many of the articles he cites, and they are all of very good quality.

The names he cites (A. De Grey, Sinclair, Barzilai and others) are stars in this field, mentioned in most other anti-aging blogs as well.

IMO, the kind of background this author has (not exactly working in aging research, but still within biology and familiar with research in general) is great for writing an overview like this: because it is less biased in terms of a preferred theory and approach for anti-aging—unlike (to various extent) reviews written by a star researcher in the field. Even this author has a preference (SENS) (but perhaps for a good reason, you’ll have to judge yourself).

So, the pointers given here are all great (just reddit/​r/​longevity alone will give you as much immersion and leads as you want).

Personally, I read/​follow some of the sources he recommends, and also follow this blogger https://​​joshmitteldorf.scienceblog.com .

[JackH]

Thank-you for the kind words! Stay tuned for more articles like this one coming soon.

[DirectedEvolution]

I’m preparing for graduate school in tissue engineering via bioprinting. I was motivated by these considerations.

My sense is that ageing is both an evolutionary response to cancer and an entropic inevitability. No matter how much you supplement the body, eventually deleterious mutations will accumulate. The complexity of cellular systems makes them very difficult to improve on.

The strategy I envision is that we’ll learn how to manufacture healthy, fresh tissues and organs from the recipient’s own cells. While it’s very hard to improve on the cell’s natural mechanisms, we can harness it in this way to rejuvenate at the level of tissues and organs. People will receive periodic transplants of fresh organs built from their own cells.

[JackH]

(1) Aging is not entropy (second law of thermodynamics). In fact, both young and old individuals are in very high entropic states, and it is not entropy that kills people when they die of aging. Instead, it is the accumulation of biological ‘damage’ (i.e. hallmarks of aging) described in the original post. If aging was inevitable due to entropy it would be impossible according to the laws of physics for biological organisms such as the hydra and tortoise to display negligible senescence, and for sharks to achieve the 400+ lifespans that they do without any increase in mortality risk.

(2) Your description of ‘deleterious mutations’ is accurate—genomic instability which includes DNA damage (as well as chromosomal rearrangement) is one of the 9 hallmarks of aging. But like all of the hallmarks, it is something we can attenuate. There are currently clinical trials for several DNA repair therapies such as nicotinimide mononucleotide (NMN), an NAD+-precursor molecule in Sinclair’s lab at Harvard, and nicotinomide riboside (NR) which is being developed by the biotech company Chromadex.

For a good primer on genomic instability, I encourage you to read this article from Lifespan.io.

[DirectedEvolution]

Thanks for writing the OP and for your response, I now see you mentioned this in the original. I’m excited to check your links out.

Other commenters mentioned that an issue to anti-aging research in humans is the regulatory barriers.

Part of the reason I’m interested in tissue engineering is that it may circumvent that issue to some extent. You can do your research relatively freely on tissue until you’re able to replicate a certain organ, test it on people who need a transplant, and “patch together” an approach to life extension in this way.

[JackH]

Great to hear you are interested in contributing!

I wasn’t precisely sure about the anti-aging applications of tissue engineering, so I asked a colleague and this is what he said:

The first application of tissue engineering is preclinical drug testing. Drug development starts with preclinical animal testing, but the vast majority of drugs that work in animals do not work in people. Estimates vary, but about 97% of preclinical leads that enter clinical trials do not exit them. Human organoids are a potential alternative that could allow at least some of this preclinical data to be obtained from humans, not animals, and hopefully be more accurate.

The second application of tissue engineering is testing cell therapies. Many future rejuvenative aging therapies will probably involve permanently engrafting engineered cells into people. If you can, say, engineer dermis in the lab, you can assess whether therapeutic fibroblasts can engraft in that dermis and whether they evenutally become cancerous.

The third application of tissue engineering is clinically putting engineered tissue into people. For example, some aging researchers are interested in thymic regeneration, but a potentially easier alternative would be adding engineered thymus-like tissues to a person instead of regenerating the involuted thymus.

So, it definitely seems important!

[Victorel Petrovich]

I think the direction you’ve chosen, tissue engineering, will be very useful. One important organ for aging to be rejuvenated/​replaced is thymus, whose degeneration is a major cause of declining immunity with aging.

“No matter how much you supplement the body, eventually deleterious mutations will accumulate.” yes, however, in nature, deleterious mutations don’t accumulate in all species. Hydra is an example/​exception. It replaces its cells at such a fast rate, that this is an important reason why it doesn’t accumulate mutations (and other damage) and manages to be biologically immortal.
In fact, the direction you’ve chosen for research would do the same but at the level of tissues/​organs, not cells.

[Radford Neal]

It would be great if the mouse results turn out to apply to humans as well, but I have my doubts. These doubts are based on what I thought were pretty conventional biological assumptions, but that nevertheless don’t seem to be addressed in the anti-aging discussions I’ve seen.

The basic problem is that there’s a good reason mice don’t live long. Even if they didn’t age, the environment in which they live means they are very likely to die in a few years from starvation or predation. So genes that keep them from aging won’t be selected for because of either or both of two reasons: (1) The selective advantage of not aging, when you’re likely to die young anyway, isn’t enough to overcome random mutation that undoes the anti-aging genes. (2) The advantage of not aging comes at some (possibly rather small) cost in terms of increased likelihood of death from predation or starvation, or decreased fecundity early in life. (For instance, it might have an energy/​food cost, or might come with decreased physical performance, such as in running speed.)

Humans live in a different environment, in which slower aging is more advantageous. And indeed humans age much slower than mice, presumably because we have genes that enable various anti-aging strategies that mice lack.

So, when a drug is found to slow aging in mice, the first question in my mind would be, “is this drug enabling a mechanism that is already present in humans?”.

And the default answer to this question would seem to be “yes”. If there’s some simple biochemical way of slowing aging, why don’t humans already have this, given that slower aging in humans would give a significant selective advantage? (Even (especially?) in pre-civilizational societies, significant numbers of people die of old age rather than from violence or starvation.)

On this reasoning, one would expect that a successful anti-aging program would have to involve something complicated, not easily produced by evolution. Something like, for example, nanobots inspecting cells for damaged DNA (comparing against a consensus sequence derived from a large number of the person’s cells), and killing cells that are too damaged. Or at least, if there is some relatively simple intervention that helps, one would expect it to be sufficiently subtle that it doesn’t show up in mice (but only after decades of life, when selective pressure for it in humans is comparatively small).

[JackH]

You are correct that interventions in mice do not always translate well to humans. Fortunately, several human trials have already shown that aging can be reversed. Time will tell how many of the current anti-aging approaches that have worked in mice will translate to humans.

The basic problem is that there’s a good reason mice don’t live long. Even if they didn’t age, the environment in which they live means they are very likely to die in a few years from starvation or predation. So genes that keep them from aging won’t be selected for because of either or both of two reasons: (1) The selective advantage of not aging, when you’re likely to die young anyway, isn’t enough to overcome random mutation that undoes the anti-aging genes. (2) The advantage of not aging comes at some (possibly rather small) cost in terms of increased likelihood of death from predation or starvation, or decreased fecundity early in life. (For instance, it might have an energy/​food cost, or might come with decreased physical performance, such as in running speed.)

Humans live in a different environment, in which slower aging is more advantageous. And indeed humans age much slower than mice, presumably because we have genes that enable various anti-aging strategies that mice lack.

This comment doesn’t make a lot of sense to me since mice used in the lab for lifespan studies are not subject to evolution today—rather, specific strains used for different kinds of experiments are purchased from specialized laboratories, where they are selectively bred.

So, when a drug is found to slow aging in mice, the first question in my mind would be, “is this drug enabling a mechanism that is already present in humans?”.

And the default answer to this question would seem to be “yes”. If there’s some simple biochemical way of slowing aging, why don’t humans already have this, given that slower aging in humans would give a significant selective advantage? (Even (especially?) in pre-civilizational societies, significant numbers of people die of old age rather than from violence or starvation.)

I don’t agree with this. Senescent cells (one of the 9 hallmarks of aging) for example accumulate both in humans and mice with older age, and contribute to age-related tissue and organ dysfunction in both.

Senescent cells by definition are apoptosis-resistant, meaning they are resisting the mechanisms (found in both mice and humans) to remove them. Hence, senolytic drugs extend lifespan in mice and probably humans by removing these cells, since the machinery in the body is unable to.

On this reasoning, one would expect that a successful anti-aging program would have to involve something complicated, not easily produced by evolution. Something like, for example, nanobots inspecting cells for damaged DNA (comparing against a consensus sequence derived from a large number of the person’s cells), and killing cells that are too damaged. Or at least, if there is some relatively simple intervention that helps, one would expect it to be sufficiently subtle that it doesn’t show up in mice (but only after decades of life, when selective pressure for it in humans is comparatively small).

Following on from my previous comment, your comment here is not true. The most promising strategy to slowing aging is not overly complicated in principle, even though it is a technical challenge—it simply involves routinely repairing the damage associated with the hallmarks of aging as they emerge. This can be done even if the precise causes of that damage (from normal metabolism) are not known.

I suggest you learn more about the field by watching some talks on YouTube by David Sinclair, Brian Kennedy, Judith Campisi, Aubrey de Grey, Nir Barzilai, Joao Pedro de Magalhaes or any other of the speakers here to give you a better idea of the field of research.

[Eli Tyre]

Random question: Why is there such a large difference between the life extension results for mice vs. for rats. Naively, they seem like they’re pretty similar.

Are we trying different kinds of treatments on one than the other for some reason, or is it just much harder to intervene on rat life-spans?

[johnswentworth]

My understanding is that the usual lab mouse breeds are highly inbred, resulting in high levels of cancer. That makes is “easier”, in some sense, to extend their lifespans—especially by interventions which trade off cancer risk against other age-related deterioration. For instance, there are ways to make cells more sensitive to DNA damage, so they undergo senescence at lower damage levels. This can decrease cancer risk, at the cost of accelerating other age-related degeneration.

[Natália]

[F]ew members of [LessWrong] seem to be aware of the current state of the anti-aging field, and how close we are to developing effective anti-aging therapies. As a result, there is a much greater (and in my opinion, irrational) overemphasis on the Plan B of cryonics for life extension, rather than Plan A of solving aging. Both are important, but the latter is under-emphasised despite being a potentially more feasible strategy for life extension given the potentially high probability that cryonics will not work.

I think there is a good reason for there being more focus on cryonics than solving aging on LessWrong. Cryonics is a service anyone with the means can purchase right now, whereas there is barely anything anyone can do to slow their aging (modulo getting young blood transfusion and perhaps taking a few drugs, neither of which work that well).

If you are a billionaire, or very knowledgeable about biology, you might be able to contribute somewhat to anti-aging research — but only a very small fraction of the population is either of those things, whereas pretty much anyone that can get life insurance in the US can get cryopreserved.

[JackH]

I agree that the LessWrong community can have a positive impact on the cryonics field by signing up for cryonics and direct more capital in to this extremely under-funded field. Cryonics is especially relevant for people older than 40 today who are much less likely to make it to longevity escape velocity.

However, I disagree that (1) there is barely anything people can do now to slow their aging and (2) there is barely anything that the average person can do to support the research and development of anti-aging therapies. I plan to write a separate post covering these points, but I’ll provide a few thoughts here.

Regarding (1), there are a multitude of actions you can take now to slow your aging and risk of age-related diseases (disclaimer: NOT a substitute for medical advice):

Non-pharmacological:

• Exercise—attenuates many hallmarks of aging

• Intermittent fasting—improves metabolic switching and cellular stress resistance

• Maintain strong social ties—social relationships are a strong predictor of lifespan

• Overcome depression, which accelerates biological aging

• Optimize your circadian rhythm

• Take a biological age test such as myDNAage or InsideTracker and monitor your age over time.
  

Pharmacological:

On the safer end (for younger people or people with a lower risk tolerance):

• Metformin—calorie restriction mimetic that controls blood sugar

• Quercetin—anti-aging flavenoid that acts as a senolytic

• Resveratrol—sirtuin enzyme activator and calorie restriction mimetic

• Vitamin D—blood tested to optimize, ideally 2000IU per day

• Vitamin B12 - as many people are deficient

On the more extreme end (for older people or people with a higher risk tolerance):

• Rapamycin—an mTOR inhibitor that attenuates senescence

• NAD-boosters such as NMN and NR—enhancers of stem cell function

• Dasatinib—a senolytic usually used in combination with quercetin

In my cupboard at home, I have a bunch of these pills, as do other people involved in this field who are involved in this research. If you watch interviews from Harvard aging researcher David Sinclair, you will see he takes these supplements, as do many of his millions of followers. These are probably a good starting point given Sinclair is one of the most knowledgeable and researchers in the field.

Ultimately, much or all of the above strategies will be superseded by superior anti-aging technologies in the future (gene therapies, nanotechnologies etc.) but they are a good starting point for increasing longevity and bringing more awareness to the field.

A nice article about a 32-year old biohacker who spent $200k on biohacking his health based on the research is here.

Regarding (2), there are many ways to contribute to the field:

• Become a Lifespan.io hero (subscriber)

• Donate to SENS Research Foundation

• Learn more about the field and discuss it with others, to increase public awareness of the field to help increase:

  • Government expenditure in geroscience research, which is a crucial bottleneck

  • Larger private donations to organizations like SENS

  • Financing of longevity biotech startups
    

The above are important actions since funding into the basic geroscience research is a key rate-limiting step in progressing the field. There is a fair amount of money to finance the longevity biotech companies, but funding for geroscience is pitifully small—less than 0.2% ($100 million) of the NIH’s $45 billion budget, even though the NIA for example, has a budget of around $3 billion. Moreover, organisations such as SENS finance some of the best research in the field have even smaller budgets ($5-10 million) which is why private small donations can still have a significant impact.

[Matthew Barnett]

The personal strategies for slowing aging are interesting, but I was under the impression that your post’s primary thesis was that we should give money to, work for, and volunteer for anti-aging organizations. It’s difficult to see how doing any of that would personally make me live longer, unless we’re assuming unrealistic marginal returns to more effort.

In other words, it’s unclear why you’re comparing anti-aging and cryonics in the way you described. In the case of cryonics, people are looking for a selfish return. In the case of funding anti-aging, people are looking for an altruistic return. A more apt comparison would be about prioritizing cryonics vs. personal anti-aging strategies, but your main post didn’t discuss personal anti-aging strategies.

[JackH]

Both are important. Anti-aging is unique in the following way: since all of us are slowly dying of aging, it’s in our best interest to want the field progress for selfish reasons, but also our altruistic interest for society to solve aging as soon as possible, as this saves millions or billions of human life years.

On a personal level, maximising the probability of reaching longevity escape velocity is a min/​max problem with two important variables:
(1) maximising personal lifespan, by adopting personal longevity strategies
(2) minimising the time until society reaches longevity escape velocity by helping to progress the longevity field.

You can think of it as a ‘race against time’ - to live forever (or at least, a very long time) one has to live in the subset of worlds which represents the intersection of society achieving longevity escape velocity, and one living long enough to make the cut, to avoid being among the last generations to die.

Personal longevity strategies are important, since a few years of additional life from longevity strategies could be the difference as to whether one makes it to reach longevity escape velocity or not. I suspect that many baby boomers may, unfortunately, miss the cut, but many Millenials and Gen Z’s could make it, particularly if they are proactive with longevity strategies.
Progressing the field is also important, as living to 150 with personal longevity strategies doesn’t mean much if you fall 5 years short of reaching LEV because timelines were too long, for example.

Now, as to which is more important—personal longevity strategies or progressing the field—it’s unclear. Aubrey de Grey in his recent interview with me stated that the latter is much more important, since future therapies will vastly improve healthspan more than anything we can do today, and thus bringing these therapies into the world as soon as possible is the main priority for those who wish to make it to longevity escape velocity. This would suggest that money is perhaps better spent on SENS Research Foundation to support anti-aging research rather than purchasing resveratrol or a gym membership.

However, others I’ve spoken to in the field such as Sebastian Brunemeier who has co-founded two longevity biotech companies (Samsara Therapeutics and Cyclone Therapeutics) think that both progressing the field and adopting personal strategies are important. In his recent talk that our society, he alluded to his personal approach to longevity which involves taking anti-aging pills, meditating, exercising and more. I have a PDF of his full anti-aging protocol and it’s fairly sophisticated.

As an aside, approaches (1) and (2) are mutually supportive. The more people who adopt personal longevity strategies, the more attention (and in the long run, funding) the research side gets, since people are engaging with the research to guide their personal approach to longevity. And the more research that occurs, the better informed the population are to guide their personal longevity strategies.

On a population level, maximising the probability that most people alive today similarly requires optimising both (1) people’s personal longevity strategies and (2) the progression of the field. Overall, I’m inclined to think the latter is more important, although the former is important for those who wish to personally make it to longevity escape velocity in their lifetime.

Therefore, although the purpose of the original post was to highlight the need to increase research funding into anti-aging, adopting personal longevity strategies is also potentially important—both individually, and to bring more attention to the field.

[deskglass]

If Brunemeier’s PDF’s is something you can share, I’d like to read it.

[JackH]

Here’s some of the important stuff (not medical advice, obviously):

Daily multivitamin
Omega 3 fatty acids (EPA/​DHA)
Magnesium citrate
Turmeric (curcumin)
Resveratrol /​ pterostilbene
Metformin /​ berberine
Apigenin
Quercetin
NR (nicotinamide riboside)
EGCG (green or white tea)
Ocimum sanctum (Tulsi)
Bacopa monnieri (standardized 20% bacosides)
Gotu Kola (Centella asiatica)
Gingko biloba
B12 – many people are deficient
Vitamin D (get blood tested to optimize, ideally 30 min/​day full sun, 2000 IU)
Vitamin C (megadose, 5 g /​ day +, spread throughout the day)
Piracetam + Choline
Uridine
Acetylcarnitine + N-acetyl cysteine
Glycine
Supergreen/​superfruit blend*: “Blender Culture” .

[Synaptic]

I strongly support anti-aging research. I’m not clear on what your criticism is of cryonics. Perhaps I missed where you explained why you think that cryonics will not work? For example, where in the Drake equation does your probability differ from Steve Harris’s or Mike Perry’s?

Also, you point out the large number of organizations and companies involved in aging research. Surely the fact that there are way fewer in cryonics means that it is has merit from an underfunding perspective?

[JackH]

The estimates of Harris and Perry that cryonics doesn’t work range from 23% to 99.8% - which are potentially quite high (as I phrased it in the OP). Cryonics might work, but there’s a potentially very good chance that it doesn’t.

I agree that cryonics is underfunded even more than aging research. It seems likely that an increase in funding to cryonics could increase the probability that cryonics works, by improving the chance of success of the following variables:

• Favorable conditions for suspension

• Suspension preserves enough information

• Mishap-free storage

• Nanotechnology is perfected

• Cryonic revival is “cheap enough”

At the very least, it would help to reduce the uncertainty regarding some of the parameters, providing as a clearer picture of the feasibility of cryonics.

However, several of the parameters would be likely to be unaffected by increased funding:

• Materialism is correct

• Identity encoded in structure

• Sufficient social stability

• Cryonics is continuously legal

• Nanotechnology is physically possible

• Cryonic revival is permitted

Ideally, both cryonics and anti-aging would receive more funding.

The intention of my post was not to encourage reductions in funding into cryonics; rather, to increase awareness among LessWrongers readers about anti-aging.

[Synaptic]

However, several of the parameters would be likely to be unaffected by increased funding:

• Cryonics is continuously legal

• Cryonic revival is permitted

On the contrary, I very much expect that more funding would help with these factors. The success of cryonics is limited by sociopolitical factors, and the more people who have buy-in, the more likely people are to be protected when in long-term cryopreservation.

The intention of my post was not to encourage reductions in funding into cryonics; rather, to increase awareness among LessWrongers readers about anti-aging.

This is an admirable goal. =)

[JackH]

On the contrary, I very much expect that more funding would help with these factors. The success of cryonics is limited by sociopolitical factors, and the more people who have buy-in, the more likely people are to be protected when in long-term cryopreservation.

Yeah, that seems likely. Certainly ‘the social problem’ (which combines several of the parameters) in general will reduce in likelihood the more funding cryonics receives.

[Gerald Monroe]

Regarding cryonics not working: this depends on your definition of ‘working’. Let me describe the problem succinctly.

Assume at some future date you can build a ‘brain box’. This is a machine, using some combination of hardware and dedicated circuitry, that is capable of modeling any human brain that nature could build. It likely does this by simulating each synapse as a floating voltage, modulated by various coefficients (floating point weights) when an incoming pulse arrives.

Well, you can choose randomly the weights, and assuming you also attach a simulated or robotic human body (a body with sufficient fidelity), and train the robot or simualated body with an appropriate environment, the ‘being’ inside the box will eventually achieve sentience and develop skills humans are capable of developing.

But you don’t have to choose the weights at random. If you obtain just 1 bit of information from a frozen brain sample, you can use that bit to bias your random rolls, reducing the possibility space from “any brain possible within the laws of nature” to “a subset of that space”.

If you have an entire frozen brain, with whatever damage cryonics has done to it, and you first slice and scan it with electronic microscopes, you still get a lot more bits than just 1. You will be able to instantiate a brain that has at least some of the characteristics of the original. Will they have clear and coherent memories (as coherent as humans have...)? Depends on the quality of the sample, obviously.

But regardless of damage you can bring each cryonics patient ‘back’, limited by the remaining information. This is actually no different than caring for a patient with a neurodegenerative disease, except that the brain box will not have any flaws in it’s circuitry and once instantiated, the being occupying it will be able to redevelop any skills and abilities they are missing.

Now, yes, trying to ‘repair’ a once living brain to live again as a meat-system is probably unrealistic without technology we cannot really describe the boundaries of. (as in, we can posit that the laws of physics do let you do this if you could make nanoscale waldos and put all the pieces back together again, but we can’t really say with any confidence how feasible this is)

[JackH]

Hi Gerald,

In the original article, I linked to Alcor’s calculation of the probability that cryonics works. It ranges from 0.2-77% and this calculation is based on the 14 variables below:

1) Materialism is correct
2) Identity encoded in structure
3) Favorable conditions for suspension
4) Suspension preserves enough information
5) Mishap-free storage
6) Cryonics organization survives
7) Sufficient social stability
8) Cryonics is continuously legal
9) Nanotechnology is physically possible
10) Nanotechnology is perfected
11) Nanotechnology is non-catastrophic
12) Cryonic revival is “cheap enough”
13) Cryonic revival is permitted
14) The social problem

Depending on your probabilities for these variables, the estimation of the overall probability that cryonics will work overall will vary.

[magfrump]

Even 0.2% seems quite optimistic to me. Without going into detail, anything from 3-8 seems like it could be 10% or lower and 12-14 seem nearly impossible to estimate. I wouldn’t be surprised to find my personal estimate below one in a million.

[JackH]

Yeah. For your interest, here are the calculations from Alcor:

Steve Harris, MD:

1) Materialism is correct: 0.95-0.99
2) Identity encoded in structure: 0.95-0.99
3) Favorable conditions for suspension: 0.75-0.95
4) Suspension preserves enough information: 0.50-0.90
5) Mishap-free storage: 0.95-0.99
6) Cryonics organization survives: 0.20-0.60
7) Sufficient social stability: 0.70-0.90
8) Cryonics is continuously legal: 0.70-0.90
9) Nanotechnology is physically possible: 0.90-0.98
10) Nanotechnology is perfected: 0.95-0.98
11) Nanotechnology is non-catastrophic: 0.20-0.50
12) Cryonic revival is “cheap enough”: 0.85-0.95
13) Cryonic revival is permitted: 0.50-0.80
The social problem is non-catastrophic: 0.008-0.18
Technologically, will cryonics work? 0.29-0.81
Overall, will it work? 0.002-0.15

That is, a 0.2-15% probability that cyronics works overall.

Mike Perry, PhD:

Note: his calculation lumps 7 of the 13 parameters as ‘the social problem’ which he calls condition n.

1) Materialism is correct 1.00-1.00
2) Identity encoded in structure: 1.00-1.00
3) Favorable conditions for suspension: 0.75-0.95
4) Suspension preserves enough information: 0.50-0.90
5) Mishap-free storage: 0.90-0.99
6) Cryonics organization survives: n-n
7) Sufficient social stability n-n
8) Cryonics is continuously legal n-n
9) Nanotechnology is physically possible 1-1
10) Nanotechnology is perfected n-n
11) Nanotechnology is non-catastrophic n-n
12) Cryonic revival is “cheap enough” n-n
13) Cryonic revival is permitted n-n
The social problem is non-catastrophic: 0.39-0.86
Technologically, will it work? 0.34-0.89
Overall, will it work? 0.13-0.77

That is, a 13-77% probability that cyronics works overall.

[magfrump]

Yeah I think my main disagreements are 4 and 5.

Given stories I’ve heard about cryonics orgs, I’d put 10-50% on 5. Given my impression of neuroscience, I’d put 4 at 25-75%.

Given that I’m more pessimistic in general, I’d put an addition 2x penalty on my skepticism of their other guesses.

That puts me around 0.01%-20% spread, or one in ten thousand lower bound, which is better than I expected. If I was convinced that a cryo org was actually a responsible business that would be enough for me to try to make it happen.

[JackH]

Yes—it’s hard to perform the calculations and end up with a high probability that cryonics works.

I think cryonics overall is much less feasible than many Less Wrongers tend to assume. Overall, I think anti-aging has a much higher chance of working to keep us alive much longer than cryonics does.

[habryka]

Promoted to curated: I’ve been meaning to follow up on the state of anti-aging work for a while, and this was really a quite good overview. I also know of a number of other people who found it useful. Thank you for your work when compiling this overview!

[JackH]

Thank you very much, I appreciate it. This is only a short introduction to the field, and I plan to write several follow-up articles in the near future to create a larger sequence (covering: aging and COVID-19, the ethical arguments for/​against anti-aging, aging and cancer, and more anti-aging therapy approaches).

[ChristianKl]

For personal longevity strategies, I recommend talks by Dr Rhonda Patrick, Dave Asprey and Dr Peter Attia.

Dave Asprey is a person who claimed to increase their IQ by 40 points without engaging in any effort to measuring his IQ by taking the best results found in p-hacked trials for interventions and adding them up. I think that was even before he went into business as a supplement salesman.

More recently he argued that he believes in reincarnation because it helps him to lower his stress levels.

He references a lot of research, but I don’t see a good reason to trust him. Why do you believe he’s trustworthy? Why do you believe the other two are trustworthy?

[JackH]

Dave Asprey’s book, Superhuman is pretty good—it explains the hallmarks of aging in simple terms and provides generally good advice for limiting the damage associated with the hallmarks. He draws upon a lot of scientific literature, and has over 400 academic references.

Asprey does a good job synthesising the research into practical steps a person can take to lower their rate of biological aging—something that most of the researchers in the field don’t have the time to do. A few things are a bit wacky, but in general I’d say 95% of the advice he says is pretty good, and the other 5% won’t do any harm.

Dave Asprey is a pioneer of the longevity biohacking community, and runs a supplement company called bulletproof.

But, if you don’t like his advice, then you can look towards Rhonda and Attia.

Dr Rhonda Patrick has a PhD in cell biology and is extremely knowledgeable about aging and longevity—just watch her interviews with David Sinclair, Valter Longo or Steve Horvath—all big names in the field. She talks to them on the same level since she knows the literature very well.

Dr Peter Attia is an MD who is also very clued up on the aging field too, and on his podcast has also interviewed many big names such as David Sinclair and Nir Barzilai. I recommend this talk of his as an introduction to some important concepts in aging.

David Sinclair’s book Lifespanis also the gold standard for personal anti-aging strategies, which are summarised here.

[thomas9]

Hi, I was a talk at a conference, in 2019, that mentioned that many new breakthroughs in cancer research were down to improvements in the accessibility of data science, and large scale computing.

As a Software Engineer, is there any way I can contribute these type of skills towards longevity research? The only avenue I could find was to get a job at Calico, but realistically, I’m half a world away in Ireland.

[Victorel Petrovich]

Just of the top of my mind: an example lab that makes (relatively heavy) use of computational approaches is that of J.P. de Magalhaes (U.of Liverpool, so not too far from yourself).

More generally, I believe many labs nowadays could use the help of a software engineer. You could read more on aging research (this article has great links, AFAICT), choose a direction, a lab, and ask them if you can help them.

I might to the same, one day.

[JackH]

Hi Thomas,

Great to hear you are interested in contributing to the field!

You can have a look at LongevityList.com and see if there’s anything on there. It’s a new project so I’m not sure how regularly it’s updated.

Alternatively, you could join the Longevity Subreddit and the Lifespan Discord server and ask there, as there are many people involved in the field there willing to help. Often, people like yourself will ask about job opportunities and get connected with opportunities.

Hope that helps!

[AM]

Love this article.

After reading the The Fable of the Dragon-Tyrant a few years ago after my father died, I went into a deep dive on this and ended up making a calculator, comparing the impact of eliminating various causes of death on average /​ median lifespan. It’s very simplistic, but I found it interesting to use to illustrate how ageing contributes to death:

http://​​life.analogmantra.com/​​

[jmh]

Very interesting. Assuming we eliminated everything but accidental causes looks like we should live to about 120+ years. I think Sinclair had said that was the expected lifespan as well.

Taking the tool at face value, it seem that both personally and socially effort focused on circulatory diseases should give the biggest bang for the buck. Then again I didn’t run through different cases of combination so...

[CronoDAS]

If the actuarial statistics I’ve read are accurate, about 1 in 1000 18 year old men in the US die before their 19th birthday. If the chance of dying each year stayed perfectly flat, life expectancy would be about 1000 years...

[JackH]

Some have calculated lifespan would be 2800-8900 years on average without aging.
https://​​www.iii.org/​​fact-statistic/​​facts-statistics-mortality-riskhttps://​​math.stackexchange.com/​​questions/​​3044194/​​whats-the-average-life-expectancy-if-only-dying-from-accidents

[AM]

True, circulatory diseases would be a big win, but do you think the marginal buck there is likely to do as much as a marginal buck focused on aging giving the amount of funding allocated to each? If we add the R&D budgets focused on circulatory diseases to the treatment cost of circulatory diseases (potential profit pool for pharma companies), my intuition says that the number would be ~20-100x the total amount of funding to aging-stopping or -reversing technology. What do you think the ratio would be?

[JackH]

Really love the app, great work!

Just a bug I found (I think it’s a bug?) - if I untick all the boxes, the median age of death goes to 0.

[AM]

Definitely a bug! It was my first and only foray into D3.js so there are a lot of bad states you can get into fairly easily. Might rebuild it in something else one day.

[JackH]

I think it would be worth rebuilding if you have time. If you do, make sure to share it on Longevity Subreddit. You will get a lot of interest in it there.

[DirectedEvolution]

Here’s a Peter McCluskey review on “age later” from back in October.

[Alexey Lapitsky]

Thanks for an amazing post, Jack!

I think it’s worth mentioning that damage accumulation as the root cause is not the consensus view anymore.

To quote Josh Mitteldorf, there are three views:

1. (from the “programmed” school) Aging is programmed via epigenetics. The body downregulates repair mechanisms as we get older, while upregulating apoptosis and inflammation to such an extent that they are causes of significant damage.

2. (from the “damage” school) The body accumulates damage as we get older. The body tries to rescue itself from the damage by upregulating repair and renewal pathways in response to the damage.

3. (also from the “damage” school) Part of the damage the body suffers is dysregulation of methylation. Methylation changes with age are stochastic. Methylation becomes more random with age.

My belief is that (1), (2), and (3) are all occurring, but that (1) predominates over (2). The “damage” school of aging would contend that (1) is excluded, and there are only (2) and (3).

There has been a lot of progress with (1) in the last years which makes me more optimistic in short longevity timelines.

[JackH]

Hi Alexey,

So, having talked to a number of people in longevity biotech, I’m skeptical as to whether view (1) i.e. Sinclair’s ‘information theory of aging’ which posits epigenetic aging is the master regulator for the other hallmarks is accurate, and that cellular reprogramming alone is sufficient to slow aging. I think the information theory of aging is good PR for the field, but I don’t think it’s entirely correct.

Still, the next 5 years of research will provide more clarity as to the relationship between epigenetic alterations and the other hallmarks of aging. I hope (1) is true although from the data I’ve seen and people I’ve spoken to behind the scenes, I don’t think it’s likely that cellular reprogramming alone will be enough.

I think the hallmarks develop to some extent independently, even though there is some level of cross-talk between them, and will have to be individually addressed.

[Alexey Lapitsky]

Very curious to hear a bit more about why you are skeptical about epigenetics and information theory of aging as the primary cause. But I completely agree that it’s not the only cause!

“Being sufficient to slow aging” is a pretty low bar, I have virtually no doubt that reprogramming will slow aging (it already has been done experimentally with mice).

[JackH]

I don’t see a lot of evidence for the information aging theory in the literature, and most geroscientists don’t seem to think that epigenetics is the master regulator of the other hallmarks. This isn’t to say it’s not true, just that there’s insufficient evidence at this point.

Sinclair discusses all of the hallmarks, but focuses on epigenetics as the most important—which is incidentally the one he studies. Bear in mind as an academic this is something are incetivised to do—to tell a narrative that fits their research agenda, to attract funding.

Looking at the field as a whole, there is consensus about the hallmarks but not so much consensus about the information aging theory, and in fact I don’t know of any other major geroscience researchers who have endorsed the information theory of aging. It’s too early to say that he’s incorrect, but the theory seems unlikely from my reading.

[Alexey Lapitsky]

Interesting, thanks! My thinking is that:

1. Methylation increases with age and predicts biological age

2. Methylation affects protein synthesis in a semi-random way

Those points mean that epigenetics at least partially causes all hallmarks dependent on protein synthesis (loss of proteostasis, intercellular communication, etc). Meaning that epigenetics is at least partially upstream of at least a few hallmarks.

Not sure what being correct about information theory of aging would exactly mean or what other evidence to expect. Intuitively it feels that our efforts should focus upstream and that there are more low hanging fruits in epigenetics than in most of the other hallmarks.

[JackH]

That seems plausible! The only thing I’ll say is that from what I’ve heard, epigenetic reprogramming in vivo may be particularly challenging in many tissues in the body. Therefore, I suspect mTOR inhibitors and senolytics may be lower hanging fruit for anti-aging therapies approved first.

[avturchin]

There is a problem with most anti-aging interventions: long expected duration of human trials, as results and lack of side effects will be obvious only decades after the start oа such trials. Without trials, FDA will never approve such therapies.

However, there is a way to increase the speed of trials using biomarkers of aging—or testing of already known to be safe interventions, like vitamin D. But biomarkers need to be calibrated and safe interventions provide only small effects on aging. Thus, it looks like some way to accelerate trials is needed if we want radical solution to aging to 2030. What could it be?

[JackH]

Yes, we need improved biomarkers of aging. Once we have biomarkers that are accurate enough to detect changes in aging or anti-aging over the course of months, it will be much easier to obtain high-quality data for prospective anti-aging compounds.

Another solution that aging researchers have discussed is developing frameworks for decentralized clinical trials that could bypass institutional approval but still produce credible results.

There also needs to be a paradigm shift in society, biomedical research, and regulatory bodies like the FDA to recognise and classify aging as a disease.

Open science which aims to make all science accessible to everyone, whether amateur or professional, is would also help to accelerate the rate of research.

[pjeby]

already known to be safe interventions, like vitamin D

Any pointers on what to search to find more info on this from actual research? I wasn’t aware that vitamin D was considered to have anti-aging properties, or that there was much consensus on its safety.

[JackH]

For a good summary video on vitamin D and aging, I recommend this. For academic papers and other articles, I recommend this, this and this.

For information on personal longevity strategies, I recommend the following:

- Watching videos by Dr Rhonda Patrick, Dr Peter Attia and Dave Asprey
- Joining Facebook biohacking groups such as this, and this.
- Joining the Lifespan discord server and reading comments on the ‘personal longevity strategies’ channel.

[avturchin]

It is safe enough to be sold OTC, and there are some research which connects with life extension effects. The real problem is that we don’t have human tests of its effects on longevity, despite its widespread use. The first study like this will be TAME, which will explore life extension properties of metformin. There are several reasons why such studies are difficult to perform. Firstly, they are costly, but known safe things are non-patentable. Secondly, they need to be very long., and long human studies are especially costly.

[Yoav Ravid]

Another option is to advocate for emergency authorization for old people.

[avturchin]

Unfortunately, it seems that most intervention works before aging actually developed, so we need to give them to younger people, at least before 50.

[JackH]

This is not true. Aging doesn’t develop, rather, it is an ongoing process of damage accumulation (i.e. hallmarks of aging) that occurs as a by-product of metabolism, explained in the original post. Aging occurs in both young and old people, although the rate of aging accelerates as diseases of aging develop.

Reversing the damage associated with the hallmarks of aging at any chronological/​biological age is likely to improve their phenotype and expected longevity. The more advanced the anti-aging technologies become, the better equipped we will be to reverse large amounts of damage associated with advanced age. That said, there is no reason to think that there is a cliff after which aging cannot be reversed.

[avturchin]

That is true for therapies which work on damage (SENS). But if we see aging as a process which creates the damages, than it is reasonable to stop it on early age.

Also, I’ve seen a recent article “Longevity‐related molecular pathways are subject to midlife “switch” in humans” which implies that many interventions should happen early in life.

Thanks for great post!

[JackH]

Evidence in mice studies does indicate that earlier therapies (for example of senolytics) do facilitate greater life extension. However, with better anti-aging technologies the ‘switch’ (from the paper you refer to) could theoretically be reversed, as there’s no biological law that would prevent restoring a phenotypically older individual back to a more youthful state.

[Yoav Ravid]

I see. in that case perhaps we would need emergency authorization for anyone who needs it to stay within escape velocity timeline. though that definition is too complex for me to see a scenario where FDA approves it (at least not without massive pressure).

[JackH]

Yes, I hope regulators will give older individuals who are soon to die of aging the option to have access to more radical life-extension therapies.

[RobertM]

Minor correction: the metformin trial study (TAME) is not currently underway; they are still waiting for the FDA to designate aging as an “indication” to be treated (and also raising funding).

Good writeup, though, thanks!

[ChristianKl]

It got the necessary approval in 2015 and in 2019 a rich private individual seems to have given them the missing 40$ million to run the trial: https://​​www.longevity.technology/​​worlds-first-anti-aging-trial-gets-green-light/​​ and the plan was to start the trial at the end of 2019. It might very well be running currently. Maybe someone else has more info?

[RobertM]

Oh, interesting, thanks for the correction! I was just going by their website (linked in the OP), which may not have been updated since 2015(?!).

[Rune]

Besides donating money to SENS, is there any way for people with money to help speed up this research? Specifically, are there companies that one can invest in to help this research? Say if you’re in charge of a lot of investment money (maybe you’re a fund manager or ethical investment advisor or something) and want to make investments that make the world a better place. Anti-aging sounds like it would be a great place to invest some of the financial capital available. How would one do that?

[JackH]

Copied from the response to another, similar, comment:

There are a number of publicly-traded longevity biotechnology companies. You could invest in Unity Biotechnology (NASDAQ:UBX) or Proteostasis Therapeutics (NASDAQ:PTI), for example.

I also recommend the Longevity Market Cap newsletter.

Here are some links that may be useful:
https://​​investoraccess.masterinvestor.co.uk/​​events/​​investing-in-the-age-of-longevity/​​
https://​​transhumanplus.com/​​investments-on-antiaging/​​
https://​​investingnews.com/​​daily/​​life-science-investing/​​longevity-investing/​​longevity-research-companies/​​
https://​​www.nanalyze.com/​​2019/​​08/​​top-10-companies-longevity/​​

[Florin]

Aging Biotech Info
https://​​agingbiotech.info

LongevityList (companies search)
https://​​longevitylist.com/​​explore/​​?type=company&sort=latest

[danhite]

In part 1 is this error:

“This equates to 37 million people—a population the size of Canada—dying per day of aging.”

Fix: change “day” to “year”

[JackH]

Fixed, thanks!

[Shmi]

Do we understand why cats live longer than dogs?

[Mo Putera]

I’m curious, where were you going with this in the context of this post’s anti-aging SOTA approaches?

[Shmi]

I guess for me it’s a test of understanding the role of genetics in aging. If you cannot answer this question, you cannot hope to extend the duration of the non-senescent part of human life.

[ArtMi]

I may argue against the anti aging field (and probably now that i reflect about it, it seems more important than most non-essential productivity in society) that it is highly more probable that we reach an agi singularity during our lifetimes, before we die of aging. (depends on your age).
What do you think?

[gwern]

“Why not both?” If you have spent any time reading anti-aging & AGI literature, it’s clear that there is minimal funging: just not much overlap of funders, researchers, or hobbyists. Most of the people doing anti-aging research have little interest in AI and vice-versa, even if there are many people who are interested in both, they represent only a small fraction of the people interested in just one. Most of the money not spent on anti-aging won’t go to AGI safety but something else entirely, and vice-versa.

And if all the AI stuff ultimately whimpers out, as is still entirely possible, then you will be very glad that anti-aging research continued. Biology research tends to not be amenable to “throw lots of money at it at the last minute”.

[Vaniver]

just not much overlap of funders, researchers, or hobbyists

I feel like there is some? Like, I’m in the overlap, kind of, Nick Bostrom wrote The Fable of the Dragon Tyrant, cryonics /​ brain preservation is kind of like anti-aging, and so on.

[gwern]

There is some, but I think we greatly overestimate it in these circles. Go over to, like, Longecity or /​r/​longevity, or read comments to David Sinclair stuff. If you were to judge by LW comments, you might think that the funging factor is, like, >90%. “Obviously pretty much everyone concerned about AGI is also concerned about aging and vice-versa! Certainly everyone I know seems to be! How could you not be?!” Whereas I think it’s closer to, say, <10%. Either concern has a very low base-rate, so despite the enrichment, you still wind up with by far the absolute majority of people in AGI not being all that interested in anti-aging and vice-versa—such that if one area were zeroed out, it would barely improve funding or participation in the other. AGI people wouldn’t go work on anti-aging, they’d go work on, I dunno, cryptocurrency.

[Vaniver]

Oh, yeah, sorry; I don’t believe the “and vice-versa” bit and if that’s what you’re pointing out, I agree.

[Florin]

The probability of dying of aging is 100%.
The probability of dying of AGI is less than 100%.
The probability of the development of anti-aging tech via non-AGI means is close to 100% (e.g., senolytics).
The probability of the development of anti-aging tech via AGI is not close to 100%.
Therefore, some of us prefer to focus more on aging than AGI.

[Vaniver]

The probability of dying of aging is 100%.

Surely if I die of something other than aging, I don’t die of aging?

[Florin]

Sure, I could have added the caveat “if you don’t die of anything else first (and most people won’t),” but I wanted to keep the caveats to a minimum. Perhaps a general caveat would be that these statements should be understood to apply to most people alive today. About two thirds of deaths are caused by aging (100k out of 150k per day) and in the developed world, it’s 90%.

[Yoav Ravid]

I don’t have the skills nor the time to review this post properly, but I think it’s very good and it helped me understand the state of the art of anti-aging, so I think it should be part of the review.

[CronoDAS]

Science fiction author and physicist David Brin has pointed out a theoretical reason why we might expect anti-aging therapies that work in mice to fail in humans: the human lifespan is already a ridiculous outlier. Life spans vary with size, metabolism, and other factors, but one thing tends to hold constant: most mammals have a lifetime of about one billion heartbeats. Humans get a whopping 2.5 times that. An intervention would have to more than double a mouse’s lifespan just to catch up with whatever it is that evolution has already done to humans—if there are any simple mechanisms that can cause a mammal’s body to increase its lifespan, humans are probably already pushing them to their limits.

[JackH]

If you’re referring to median lifespan, we already know that many factors increase lifespan by up to 10-15 years in humans cumulatively: exercise, fasting, diet and so on. So it is highly likely that therapies (e.g. mTOR inhibitors) that potentially act through similar pathways will extend median lifespan.

In terms of maximal lifespan, I’m not sure of the strength of those theoretical reasons in light of mechanisms of aging such as cellular senescence, which is known to strongly contribute to the aging phenotype in mice and humans and which can be removed in humans now (2020 study).

Evolution is not optimizing for lifespan...only on gene transmission. So in general, I think arguments along the lines of ‘as humans we are hitting our natural limit of lifespan’ are poorly substantiated.

[Wedchidna]

Fellow humans, do forgive my newbieness, but I am surprised this following study has not been mentioned:
- https://​​www.aging-us.com/​​article/​​202188/​​text
I speak no chemics, so I might’ve lost something midway of the presentation. Yet, since I have celebrated the aforementioned article as my most cherished 2020 article, I’ve guessed the chance of it cherishing someone’s day upward was worthy of the hereby mentioning. I shall read replies probably: in case I take time to do so, one may consider oneself thanked for the reply, in advance.

[JackH]

I did not include the Tel Aviv/​HBOT study since it is not considered a promising approach to anti-aging by most researchers in the field. The conclusions of the study are potentially misleading, due to the highly improbable senolytic effect of oxygen therapy.

In my recent interview with Dr Aubrey de Grey, I asked him about this same study (timestamp: 40:30), and he said that it was enormously over-hyped.

I encourage you to read this article, which explains the media circus around the study, and critiques the science:
https://​​www.lifespan.io/​​news/​​media-circus-surrounds-hyperbaric-oxygen-study/​​

[Marek Veneny]

I purely enjoyed the read about the State of the Art. I had no clue there’s so much going on behind the scenes.

If I may, I would like to steer the discussion from technology towards ethical and practical matters.

The argument could go like this:

We’re living on the cusp of technological progress. We (most western countries) enjoy easy access to more resources than we could ever consume and enjoy. The accessibility of the internet means we can communicate globally. We have cars and fridges and smart homes and Nicolas Cage pillowcases. Yet are we living happier, more meaningful lives? Some data suggest we aren’t, as rising mental health disorders plague more and more people. With barest necessities taken care of, the western countries especially are, well, depressed. And with so much time to think about our existence, the question of meaninglessness crops up. As the famous quote from Fight Club goes:

“We’re the middle children of history, man. No purpose or place. We have no Great War. No Great Depression. Our Great War’s a spiritual war… our Great Depression is our lives. We’ve all been raised on television to believe that one day we’d all be millionaires, and movie gods, and rock stars. But we won’t. And we’re slowly learning that fact. And we’re very, very pissed off.”

My point is this: Age and suffering give meaning to our lives. Technology slowly but surely eliminates both. Without any struggle—and as close to paradise as ever—where will we find meaning? In continuous progress? In “higher” quality of life?*

Next, how are we to handle the non-aging population as a society? The initial question is purely pragmatic: more people on Earth living longer lives would mean more energy expenditure, more space needed to accommodate them. Even if this could be technologically solved with higher efficiencies (which themselves would not be offset by behavior adaptation), what will it do to the fabric of society? Will the “anti-aging cure” (considering aging as a disease still rings a bit weird to me) be available to all strata of society? Or will it only enlarge the cleft between haves and have nots?

While I’d definitely love to enjoy a longer life, in theory, I’m not convinced it would do me (and probably the society) any good. I wonder if, alongside developing the necessary technology to make anti-aging happen, people are considering such issues in parallel. Or if it’s another case of “go fast and break things.”

Anyway, thanks again for the post!

---

* a case can be made that we’ve enjoyed the peak happiness of our species back as hunter-gatherers. For an excellent and purely enjoyable read, I recommend Civilized to Death: What Was Lost on the Way to Modernity from Christopher Ryan.

[JackH]

Your comment alludes to 3 exceedingly common objections to anti-aging:

(1) ‘Death and aging bring meaning to life’

(2) Distributional justice (i.e. ‘only for the rich’)

(3) Overpopulation (resource overconsumption, environmental impact etc.)

All of these objections have been responded to at length by David Wood in his book The Abolition of Aging, Aubrey de Grey in his book, Ending Aging and David Sinclair in his book, Lifespan and on blogs such as FightAging.org and Lifespan.io.

Anyway, I plan to write a Part 2 post covering the main ethical arguments including the three you reference, but will provide a short summary here:

(1) ‘Death or aging brings meaning (or happiness) to life’

My point is this: Age and suffering give meaning to our lives. Technology slowly but surely eliminates both. Without any struggle—and as close to paradise as ever—where will we find meaning? In continuous progress? In “higher” quality of life?*

While chronological aging gives meaning to our lives, as existing over time allows to experience reality for longer (allowing for self-actualisation, building friendships and relationships, pursuing passions and so on) biological aging—that is, our slow and fatal physiological decline by the 9 hallmarks of aging that are slowly killing us, that currently accompanies chronological aging—doesn’t. If you think people get happier as they get more frail, weak, lose their sight, hearing, and have higher chances of cancer, heart disease, Alzheimer’s and type 2 diabetes just take a closer look at depression statistics—the highest rates of depression are among the elderly, who account for the most DALYs of any age demographic, from depression.

Honestly, ask yourself—do you think there is any meaning associated with neurodegeneration, and Alzheimer’s disease? Because as a neuroscientist I can tell you that it is impossible to age without neurodegeneration, which leads to extremely high rates of Alzheimer’s disease in the elderly. Neurodegeneration involves losing one’s memories, cognition and other mental faculties, which also predisposes to depression, so it’s unclear how this process would be valuable for improving wellbeing, as you suggest.

The attempt to ascribe ‘meaning’ to the suffering that accompanies biological age-related decline and the diseases it is associated with (cancer, heart disease, type 2 diabetes etc.) is just a manifestation of the naturalistic fallacy coupled with lazy conservatism inherent in human nature.

The reality is: biological aging f*cking sucks, and no person who is experiencing the decline associated with aging (frailty, heart problems, signs of cancer etc.) would give up the opportunity to take therapy to bring them to a more youthful state of being biologically 20-30 years old with complete physical and cognitive function, given the opportunity. If you have compelling evidence on the contrary, please provide it.

For more about deathism, the pro-aging trance and ‘death brings meaning to life’ arguments, read articles, here, here and here. Also consider reading Aubrey de Grey’s book, Ending Aging David Sinclair’s book, Lifespanand David Wood’s book, The Abolition of Aging.

(2) Distributional justice (i.e. ‘only for the rich’)

Will the “anti-aging cure” (considering aging as a disease still rings a bit weird to me) be available to all strata of society? Or will it only enlarge the cleft between haves and have nots?

I covered this in another comment in this thread, but will copy and paste the response for your convenience:

• Anti-aging therapies are in principle no different from existing medical treatments such as anti-viral or anti-cancer therapies. For example, there is little philosophically difference between a cancer therapy (e.g. molecules that kill cancer cells) to extend healthy lifespan and a senolytic drug (e.g. molecules that kill senescent cells) to extend healthy lifespan. In the same way that few would object to the development of better cancer therapies today (e.g. CAR T-cell therapies) that only the rich can afford (and are not, for example, currently available to people in Africa), few should object to anti-aging drugs that extend healthy lifespan, even if only the rich can initially afford them too. Basically, many lifesaving medical interventions are initially expensive, and therefore only available to the rich, but this isn’t a reason to inhibit research. An additional point: if you support current medical research—which functions essentially to extend healthy lifespan, you should also support anti-aging, which also aims to extend healthy lifespan, though through prevention rather than cures. The only difference between the two is the approach, and the likely effectiveness—anti-aging is likely to be more effective at accomplishing the goal. Hence, we should be more enthusiastic about this approach, if anything.

• Therapies are unlikely to stay expensive for long. When patents expire after 10-20 years, drugs usually become ridiculously cheap, and so any distributional inequality is unlikely to last long. Metformin, a life-saving diabetes drug (that is also being studied for its anti-aging properties) is a good example—it was initially expensive but the price has now plummeted to 31 cents per tablet in 2013. There are numerous economic forces that will drive low prices—governments are incentivised to subsidise these therapies, to populations healthy and stave off the diseases of old age that cost healthcare systems trillions of dollars worldwide annually (e.g. dementia alone costs over $1 trillion), which is otherwise set to grow due to an aging population. Insurance companies will similarly be incentivized to subside these therapies, to keep their clients healthier and able to avoid the chronic diseases of old age for longer. A good analogy is car sales—cars used to be too expensive for most people but are now ubiquitous and largely affordable. Since the market size for anti-aging therapies (i.e. all humans on Earth) is huge, as it is for cars, we would expect the huge demand to result in lower prices. Food technology is another, more recent example. In 2013 the first lab-grown burger was $325,000, and two years later the cost fell to $12.

• Not developing anti-aging technology doesn’t help the poor. Anti-aging technologies only available for the rich would not help the poor, but not having these technologies available to the rich—that is, allowing the rich to age and die like the rest of us—also wouldn’t help the poor. What matters is not only that the gap between rich and poor is closed, but also how it is closed. For example, those in Western countries could give up all their comforts and wealth to be economically equal to the lowest African countries. But this is not the goal—the goal is to bring the African countries up in wealth, not bring economically prosperous nations down. The same applies to anti-aging: the goal is to bring everyone’s healthspans up (even if it means there will exist some inequality, initially), not keep everyone’s healthspans down for the sake of equality.

(3) Overpopulation and resource constraints

The initial question is purely pragmatic: more people on Earth living longer lives would mean more energy expenditure, more space needed to accommodate them. Even if this could be technologically solved with higher efficiencies (which themselves would not be offset by behavior adaptation), what will it do to the fabric of society?

• Demographics The Earth’s population today is not expanding in an uncontrollable, exponential way and in fact in many parts of the world population is either now or soon will be declining (e.g. European countries, Japan, China etc.). The only regions of population growth are south-east Asia and Africa, both of are predicted to at around 11 billion in 2100 in line with the demographic transition model and then fall. In many parts of the world, underpopulation is likely to be a bigger problem than overpopulation in the near future due to dangerously low birth rates.

• Aging population A much bigger problem than overpopulation is the ‘aging population’ and carrying capacity (i.e. the proportion of individuals over 65+ and frail etc. due to age-related decline) which is increasing globally and will immensely burden the healthcare system, and the younger workforce, in the absence of anti-aging technologies. However, anti-aging technologies allow those in their 60s and beyond to remain in a healthy, functional state and able to work and remain free of chronic diseases for much longer.

• Neo-Malthusian collapse: The notion of overpopulation is common misconception that is completely unsubstantiated by empirical literature. Neo-Malthusian concerns have been touted since the 18th century but have not held up since as populations expand, so too does the technology to support larger populations. The whole notion of ‘carrying capacity’ assumed there was no possible way to (for instance) increase crop yields, fortify foods, significantly increase population density via taller buildings and so on.

• Won’t a larger population exacerbate climate change? Climate change is a huge problem and while population size is a multiplicative factor in environmental impact, developing technology to decrease carbon intensity and increase and recycling effectiveness, as described by MIT economist Andrew McAffee in his book, More from Less, is feasible and the rational solution. As David Wood says in my recent interview with him: ‘if we are serious about solving aging, we should not fetishize population size (as a factor), we should be working elsewhere’. Interestingly, many of the technologies that will make rejuvenation biotechnology possible can also assist with transforming agriculture to claim back land that is currently being used inefficiently, such as synthetic biology (lab grown meat) and nanotechnology (repair and recycling). Additionally, geoengineering solutions (green energy—solar/​wind), space tech, and policy changes may help to reduce emissions. So although the world is already transitioning to renewables, (for example, the UK recently passed the benchmark of 50% renewables) and the rate is not necessarily fast enough, restricting population size by allowing the widespread suffering and death from aging is not the most ethical nor effective way to manage climate impact. In the same way that allowing COVID-19 to kill millions of people is not an ethical solution to climate change (which, by the way, is primarily an age-related disease that would benefit greatly from anti-aging, as I will discuss in a future post).

• We won’t run out of space? In 2012, the team of the project “Per Square Mile” led by Tim de Chant produced an infographic to show how big a city would have to be to house the world’s 7 billion people. If populated as densely as New York, the entire world’s population could fit into an area the size of Texas. So there is more than enough space on Earth to accommodate a vastly greater population of many trillions.

• Won’t we run out of food? If we compare the food supply in 1965 and in 2013, we can clearly see that overeating is more of a global issue than undernourishment, as in most countries, the calorie intake has increased significantly. If we compare the food supply in 1965 and in 2007, we can clearly see that overeating is more of a global issue than undernourishment, as in most countries, the calorie intake has grown significantly. This means that a population explosion during this time of over 4 billion people
  has passed relatively unnoticed – all thanks to the “Green Revolution” (rapid development of new agriculture techniques, such as fertilizers, irrigation and selection). The concern that there will be a food shortage in the future neglects further technological advances such as aquaponics, hydroponics, aeroponics, vertical farming, 3D-printed housing, algae farms, and many other technologies that could provide enough food for all.

• Negligible senescence: Now, eventually if we completely abolish death (i.e. achieve ‘negligible senescence’), then yes population size will continue to grow, assuming populations continue to reproduce. But this population growth is 1) not as rapid as people imagine 2) not a concern that is unlikely to be solved by technological advances and 2) not a reason to deny those alive today access to life-saving anti-aging therapies.

For a more detailed response to this objection, I recommend this long-form article.

Final comment: Anti-aging is basically just today’s medicine, but better (and preventative)

It’s worth noting that all of the above objections also apply to current medicine too (which similarly aims to extend healthy lifespan) albeit to a lesser degree due to the ineffectiveness of this approach. The philosophical difference is that anti-aging is potentially more effective at accomplishing medicine’s goal—to extend healthy lifespan—by targeting the root cause of the problem (hallmarks of aging) rather than allowing the damage of aging to accumulate and then only targeting the ‘symptoms’ (i.e. diseases of aging—cancer, heart disease etc.). It seems strange to me that you would support (I assume) the less effective approach to healthspan extension of today’s medicine, but not support the more effective approach of anti-aging. Ultimately, the two approaches service the same goal, but one intervenes earlier, when the damage has accrued but before symptoms emerge rather than when damage has accrued to an even greater level that causes symptoms to emerge. ‘Prevention is better than a cure’ as they say, and this certainly looks to be the case with anti-aging.

Note: if you found some of these arguments more/​less compelling than others, please let me know as it will help to inform my second post :) thanks.

[Vanilla_cabs]

I am not under the impression that physical comfort is what was opposed in Fight Club. After all, hunter-gatherers also accessed more resources than they could ever consume, like top-quality fresh air and sunlight. I think it was consumerism. Under consumerism, consuming is not driven by personal motivation, but by the external general goal of supporting the economy. Instead of being an end, the consumer has to be turned into a means to that single end, a slave to consumption, through ads and social pressure.

[Yves Dorfsman]

Mike Lustgarten’s work should be added in the reference sections:

book: https://​​michaellustgarten.com/​​2016/​​11/​​18/​​microbial-burden-a-major-cause-of-aging-and-age-related-disease/​​
website: https://​​michaellustgarten.com/​​
twitter: https://​​twitter.com/​​mike_lustgarten

[ChristianKl]

When it comes to the idea of massively improving healthcare outcomes there seem to be two strategies. One is to focus on antiaging. The other is to focus on increasing our research capability by improving the tools we have available.

When Zuckerberg went out and interviewed heatlh care experts it seems they convinced him that tool building is more promising then object level research.

How strongly do you believe object level research on antiaging to be better then tool building? What’s your argument for it?

[JackH]

Developing platform technologies is important in pharma and biotech, and that’s happening. But the limiting factor seems to be testing anti-aging drugs, and developing better biomarkers. There is no shortage of potential anti-aging therapies—there are hundreds waiting to be tested. The limiting factors are funding and researchers. We need more laboratories working on testing new therapies for anti-aging.

[jmh]

I’m just wondering about the problems with funding and researchers. One would think that plenty of money is actual around but it’s more about both awareness and some belief that a tangible return to the investors would be likely. That seems like it might be more a problem of asymmetric information as it were—or perhaps a bit of “language” between the groups. What’s your sense there?

For research is there any structure that might work a bit like various gig-econcomy sites. Basically forums that work as an infrastructure to allow a wide audience of those capable of research/​analysis to form quick teams to tackle a problem. Or perhaps just do some of the initial leg work to see if some line of thinking is actually going somewhere? I have the suspicion that perhaps a lot of the effort here might be less about lab work and more about digging though the results (but that may well be completely wrong).

If both the above are kind of right and some type of open infrastructure that brings both together might be useful—though also suspect there must be a bunch of incubator type structures already in place.

[JackH]

I’m just wondering about the problems with funding and researchers. One would think that plenty of money is actual around but it’s more about both awareness and some belief that a tangible return to the investors would be likely. That seems like it might be more a problem of asymmetric information as it were—or perhaps a bit of “language” between the groups. What’s your sense there?

You’re 100% spot on here. ‘Curing aging’ and ‘longevity’ aren’t common ideas in biomedical research, but ‘curing cancer’, ‘curing Alzheimer’s’ and ‘curing heart disease’ are. This is unfortunate given aging is driving all of these conditions.

It can sometimes be frustrating being in the longevity field, because researchers in other fields are incentivised to remain in their silos in which the core premises (e.g. curing cancer is good and effective) are treated as dogma, rather than see the bigger picture and work on solving the problem in more efficient ways.

Once you suggest that slowing aging might be a more effective approach to extending healthy human lifespan, many researchers find it difficult to engage in the conversation. This is especially the case since education into the biology of aging is extremely poor in most biomedical and medical programs. Even in my case, I went through 5 years of tertiary education without learning the information in the OP. This information I gathered through speaking to experts in the field, reading books such as Lifespan, reading blogs like Lifespan.io and FightAging.org, reading thousands of papers on this topic and attending aging conferences. Still to this day, there are unfortunately very few channels educating people on the hallmarks of aging and the connection between these and the diseases of aging.

Most cancer researchers I spoke to know very little about the hallmarks of aging, for example, and the connection between the hallmarks and disease. This is because their work focuses on solving the problem of cancer once it arises, rather than solving it in advance by curing aging. All of their incentives (grant funding, publication opportunities) are towards trying to cure cancer, rather than trying to extend healthy human lifespan (and delay the onset of cancer, potentially for hundreds of years) by slowing or reversing aging. This is unfortunate since, as I outlined in my post, aging is by far the biggest driver of cancer (and all other age-related diseases) and rates of cancer in biologically young people are very low.

For the above reasons reason, most biomedical researchers don’t speak the language of the ‘hallmarks of aging’, and aren’t familiar with terms like ‘senolytics’, for example.

For research is there any structure that might work a bit like various gig-econcomy sites. Basically forums that work as an infrastructure to allow a wide audience of those capable of research/​analysis to form quick teams to tackle a problem. Or perhaps just do some of the initial leg work to see if some line of thinking is actually going somewhere? I have the suspicion that perhaps a lot of the effort here might be less about lab work and more about digging though the results (but that may well be completely wrong).

This is a great idea, and similar to what groups such as Deep Science Ventures are doing. They are essentially headhunting top biomedical researchers and funding them to work on important problems such as aging. There definitely needs to be more innovation like this to provide ways of funding anti-aging research so the field isn’t entirely dependent upon the small pennies it receives from government research councils.

Charities such as SENS research foundation fulfil a similar role too, though as a charity rather than a for-profit. They collaborate with research groups and fund what they deem the most high-impact research, and get the best research teams they can get to do it.

[Florin]

rates of cancer in biologically young people are very low.

And in the OP:

Anti-aging is more feasible for extending healthy lifespan rather than solving the individual diseases of aging

Sometimes, focusing on one disease is necessary, like in the case of cancer. To reach LEV, the risk of dying from cancer would need to be zero. The only way to get there in any reasonable amount of time is to developed a way (like WILT) of dealing specifically with cancer.

[ChristianKl]

Developing platform technologies is important in pharma and biotech, and that’s happening.

While it’s happening it’s worth pointing out that the article you linked says “Given that pharma companies depend on innovation, science, and research and development, it may seem counterintuitive that they lag behind the digital curve. In McKinsey’s ongoing survey to measure companies’ “Digital Quotient,” the pharmaceutical industry ranks in the bottom third of industries measured.”

It doesn’t happen as fast as it would be desirable.

But the limiting factor seems to be testing anti-aging drugs, and developing better biomarkers.

It’s my impression that SENS focuses on doing basic research and not testing anti-aging drug candidates.

If that’s how you see the current bottleneck why recommend SENS and Lifespan.io over Lifespan Research Institute which actually focuses on testing anti-aging drugs?

It could be that the problem of biomarkers is about doing a lot of measurement with our existing tools and looking for correlations. It could also be that we need tools that measure certain biometrics more accurately and cheaper then we currently can to progress. The position that we already have all the necessary measurement tools seems to me optimistic. If you hold it, why do you hold it?

[JackH]

I encourage you to read the full article, not just the first paragraph. Specifically:

A new breed of biotechnology firms, unencumbered by the accumulated practices and systems of large traditional ones, are pioneering impressive new digital capabilities. In the process, they are nudging the industry as a whole in this direction. This could significantly boost R&D productivity, benefiting both pharmaceutical companies and the patients they serve.

In recent years, a number of biotechnology companies have applied genetic-information-driven technologies to form “biomolecular platforms” (exhibit). These platforms intervene at different points in the information chain (often referred to as “the central dogma of biology”) to modify biomolecular processes at the source of various diseases. In that respect, they have a software-like nature, that allows for the ready design of multiple new therapies by a single platform, that provides the instructions to modify the hardware of molecular biology, that in turn addresses disease.

It’s my impression that SENS focuses on doing basic research and not testing anti-aging drug candidates.

SENS fund basic research that leads to new approaches to anti-aging drug development. Here is a good example of this. They sponsor both intramural and extramural research.

Several longevity biotech companies such as Underdog Pharmaceuticals has been spun out of research funded by SENS. The longevity biotech companies then take the technology through clinical trials.

I encourage you to have a browse of the research they have funded, here.

LRI and SENS fulfil essentially the same role—to fund important research in this field, to increase the probability that effective anti-aging therapies will be discovered. I think LRI is also a good place to donate, though I am less familiar with their work.

[ChristianKl]

There are two ways you can react to DeepMind making progress on protein folding. The one is to say: “Great there’s progress”. The other is to look at the inability of the existing companies to innovate.

When Illumina started having their monopol on sequencing technology, the cost effectiveness of the technology suddenly stopped going down like is was before.

After Theranos went bust we don’t have new companies that go after cheaper blood tests even through that would be important to reduce the costs of understanding what happens.

SENS fund basic research that leads to new approaches to anti-aging drug development.

If we live in a world where we have a bunch of promising approaching for anti-aging drug development and our problem is that not enough capital goes towards persuing them, research that provides additional perspectives doesn’t seem to be most important.

If the model is that if SENS provides more approaches Greeves or Deming can fund more startups, the bottleneck isn’t about moving exisiting approaches to trials.

[PeterMcCluskey]

Baze has technology for cheaper and more convenient blood tests. So far they’re only using it to sell vitamins. I presume regulatory obstacles are delaying more valuable uses.

[JackH]

Just looked it up—looks promising. Thanks for sharing.

[JackH]

There are two ways you can react to DeepMind making progress on protein folding. The one is to say: “Great there’s progress”. The other is to look at the inability of the existing companies to innovate.

When Illumina started having their monopol on sequencing technology, the cost effectiveness of the technology suddenly stopped going down like is was before.

After Theranos went bust we don’t have new companies that go after cheaper blood tests even through that would be important to reduce the costs of understanding what happens.

Sorry, I don’t quite follow—what’s the point here? That funding SENS alone is unwise? If so, I don’t think that’s the major concern, as SENS has a tiny budget (~$5 million) and have a good track record funding some of the best work in the field.

If we live in a world where we have a bunch of promising approaching for anti-aging drug development and our problem is that not enough capital goes towards persuing them, research that provides additional perspectives doesn’t seem to be most important.

By ‘approaches’ I meant, ‘therapeutic approaches’, not ‘perspectives on aging’.

What I tried to emphasize in the OP is we have a good-enough model (or, ‘perspective’) on aging which is the hallmarks of aging, and that the limiting factor now is funding to (1) develop new approaches to therapeutically addressing these hallmarks and (2) translate these findings into humans through the financing of longevity biotech startups, though (1) is the more important than (2).

[ChristianKl]

I have two motivations here:

(1) Having that argument between tool-spending and more application focused spending. Arguing that clash in detail is good for giving people an overview over it.

The OpenPhil report on Mechanism for Aging asks here “How likely is it that general-application tools and basic research areas that might not be thought of as part of “aging research” (analogous to epigenetics, stem cells, neuroscience, and drug delivery) will be bottlenecks to accomplishing the core objectives described above? ”

(2) On average I think that tool research is not emphasied enough in biomedicine. It frequently happens that better tools make important new research possible.

Thomas Kuhn argued that focusing to much on application usually leads to an academic field being very unproductive.

When doing academic research you never know beforehand what you will find. Sometimes reserarch can evolve into a tool direction instead of an application direction. If a person is too much committed to an application direction (towards anti-aging) they might not persue valuable research directions.

Similar things go when seeking jobs. I would expect that average person who works at DeepMind on protein folding to have a larger impact on ending aging then the average person at a biotech companies which has fighting aging as it’s mission statement.

In the large scale of funding, SENS budget is at the moment a rounding error, so I don’t think that the extend towards which it’s currently funded is a problem. I think it would be reasonable for SENS to have 10X the money it has but I’m doubtful 100X would currently be justified.

[JackH]

I gave a more thorough analysis of why OpenPhil missed the mark somewhat in their ‘medium-depth’ inquiry of anti-aging research in response to your comment lower in this thread, which is relevant to this point.

I’ll add a couple of points:

I completely agree with you that technology from other areas (AI, platform technologies etc.) will benefit aging research. But that’s not the point − 100,000 people per day are dying of aging and we have the tools to test a bunch of drugs, and a huge laundry list of possible drugs to test (AKG, Gemfibrozil, rapamycin, spermidine, etc.) but we don’t have the funding to do it. So, donating to SENS is important to pick the lowest hanging fruit i.e. testing drugs we are already pretty sure do slow aging. To give an analogy—you could say that given advances in materials engineering would help us get to Mars, but you also need Elon Musk (or equivalent) to put the pieces together and do the thing. Anti-aging is the same—although today’s platform technologies are not perfect (just like today’s material science is not perfect) there are so many experiments we can perform now that would save potentially millions of lives, and should be prioritized. Remember that anti-aging almost certainly will happen eventually if society doesn’t collapse, and what the field is fighting for is for this to happen sooner rather than later, so that many more people alive today will benefit.

The above is actually an additional criticism I had of the OpenPhil. It’s not that Aubrey de Grey and and others in the field don’t think advances in other areas will help (AI, etc.), it’s that there are so many feasible projects that should be funded that could potentially have a huge impact on populations today, that are not being funded. The neglectedness of the field is the primary reason SENS needs more funding, - think of SENS as funding a locus of research that has among the highest probability of progressing the field in the near future, given this research is working directly on the problem.

So yes, I agree that increasing SENS’ budget by 10-20X would probably be sufficient and that once this point has been reached, the marginal ROI would fall. However, it’s also worth considering that the type of research funded by SENS could also drastically change as the field grows, which may still make SENS donations above the 20X point remain cost-effective. Either way, SENS needs more money today.

[ChristianKl]

I gave a more thorough analysis of why OpenPhil missed the mark somewhat in their ‘medium-depth’ inquiry of anti-aging research in response to your comment lower in this thread, which is relevant to this point.

I think it’s worth putting such a critique into it’s own top-level post sooner or later. It more likely engage OpenPhil.

we have the tools to test a bunch of drugs, and a huge laundry list of possible drugs to test [...] testing drugs we are already pretty sure do slow aging

And we have a very profit oriented industry that makes money with making good calls on judging which possible drugs as worth testing.

It’s relatively easy to make an argument that certain basic research that’s valuable but not directly profitable are underfunded.

The term valley of death is about drugs where we are not pretty sure that they have a clinically useful effect.

To give an analogy—you could say that given advances in materials engineering would help us get to Mars, but you also need Elon Musk (or equivalent) to put the pieces together and do the thing. Anti-aging is the same—although today’s platform technologies are not perfect (just like today’s material science is not perfect) there are so many experiments we can perform now that would save potentially millions of lives, and should be prioritized.

There’s no reason to believe that material science progresses in a way that makes building starship 10X cheaper within a decade unless people are working on the technology.

On the hand there are plenty of experiments that are run in antiaging that plausibly could get 10X cheaper through tooling improvements.

[JackH]

I think it’s worth putting such a critique into it’s own top-level post sooner or later. It more likely engage OpenPhil.

Will do.

It’s relatively easy to make an argument that certain basic research that’s valuable but not directly profitable are underfunded.

If it works (slows aging) then it will be profitable.

On the hand there are plenty of experiments that are run in antiaging that plausibly could get 10X cheaper through tooling improvements.

If by ‘tooling improvements’ you mean, biomarkers of aging then I completely agree with you. This is also research within the aging field that requires more funding. Besides that, I’m not sure what kind of tools you think we need. The bottom line is that we have a bunch of drugs, and we need a measuring stick (accurate biological age test) to tell us whether the drugs slow aging or not. What other platform technologies would be needed to expedite this process?

[freyley]

I’m in support of anti-aging research, and think we should fund it more highly, specifically because the long-term benefits are so high once we get it right. Does anyone have any comments on whether SENS is the best place to put money if you’re interested in donating to anti-aging?

As a side note, my experience working with complex codebases has led me to disbelieve your optimism for how quickly we can find reliable ways to get more than a decade of increased healthspan. The human body is vastly, vastly, vastly more complex than nearly any codebase humans have developed, and less well factored by far. And working to make notable improvements to complex codebases that are well-factored still takes years of dedicated effort, with much better tooling than we have for modifying the body.

[Victorel Petrovich]

Yes, organisms (even worms) are way more complex than any codebase so far, and researchers don’t fully understand them and yet—as you can see from this and other reviews—very significant lifespan (and healthspan) increases have been achieved. Even in mice and rats, which, aside from an inferior brain, are about as complex as humans.

To me, this indicates that the aging process is quite malleable, with many ways to tweak it, which researchers are finding through theories, educated guesses and trial and error.

[JackH]

(1) Charity recommendations

I would recommend donating to SENS Research Foundation or Lifespan.io.

SENS has funded a lot of really great research in the field, which you can view here.

Lifespan is involved in advocacy, and have been successful in hosting conferences and providing a platform for information sharing in the field. They have also crowdfunded some research.

Both the research and advocacy components are crucial for helping to expand the longevity field.

(2) Complexity of aging

Yes, the causes of aging are complicated—that is, how the damage accumulates—is complicated. But treating aging doesn’t actually require understanding how the damage accrues, using the SENS (strategies for engineering negligible senescence) approach. It only requires how to ameliorate the various types of damage (hallmarks of aging).

Bear in mind that overwhelming evidence in the past 20 years has suggested that all aging-related processes are, looking upstream, a result of the hallmarks of aging and that there is no other cellular phenomenon besides these 7-10 processes (depending on how they are classified) responsible for the aging process that cannot be reduced to them. In the past 20 years, no new hallmarks have been discovered and researchers are fairly confident that these are the only hallmarks there are to discover.

Here’s Aubrey de Grey’s explanation of the SENS approach:

“The basic point we’re making there is to contrast the regenerative approach with the more traditional idea of trying to make metabolism create molecular and cellular damage more slowly. In order to do the latter, we would need to understand our biology massively better than we do at present, so as to avoid creating unforeseen side-effects. By contrast, with the regenerative approach we don’t need to know much about how damage comes about: it’s enough just to characterize the damage itself, so as to figure out ways to repair it. We’re effectively sidestepping our ignorance of metabolism. Rejuvenation biotechnologies are simply regenerative therapies that pre-empt the diseases and disabilities of old age. They consist of molecular, cellular or whole-organ interventions that restore the structure of the target to something like how it was in early adulthood.”

[ChristianKl]

Bear in mind that overwhelming evidence in the past 20 years has suggested that all aging-related processes are, looking upstream, a result of the hallmarks of aging and that there is no other cellular phenomenon besides these 7-10 processes (depending on how they are classified) responsible for the aging process that cannot be reduced to them.

Is there any polling about how many of the anti-aging researchers believe this thesis?

[JackH]

To the best of my knowledge, there has not been polling of this question to anti-aging researchers (geroscientists) specifically.

However, if you watch lectures by anti-aging researchers, and the major conferences such as ARDD, EARD, CSHL Mechanisms of Aging and so on, most of them seem to use this paradigm when discussing aging and many even have a slide on the hallmarks of aging. All of the big names such as David Sinclair, Brian Kennedy, Lynne Cox, Judith Campisi, Alex Zhavarankov, and many others all mention the hallmarks of aging.

If you want further evidence, consider that the original paper, The Hallmarks of Aging (2013) published in the journal Cell is the most highly cited academic paper in the entire field—with over 6800+ citations. Although it was Aubrey de Grey who first conceived of the Hallmarks (which he called the ‘7 deadly SENS’ and categorised them slightly differently in his 2007 book, Ending Aging) it has now become the framework used by researchers in the field, and even included in academic courses—such as the lectures I was invited to give to clinical neuroscience students here at Oxford University about aging and neurodegeneration.

So it’s fair to say that it is now the consensus that the hallmarks of aging is the predominant view of the field, even though this was not the case 10-15 years ago when other theories of aging such as the free radical theory of aging held more weight.

[ChristianKl]

such as the lectures I was invited to give to clinical neuroscience students here at Oxford University about aging and neurodegeneration.

If you are in a position to be invited to such talks, it might be worthwhile to put information about your identity into your post. Maybe as part of a epistemic status tag on the top.

The thing that’s very unclear to me is why SENS has so little funding if that’s framework is now consensus.

It seems like while the metformin trial study seems like good value for money in contrast to typical NIH funding, funding it with a decade worth of SENS funds wouldn’t be good value for money if SENS works. Why doesn’t SENS succeed at having a 8 or 9 figure budget? Which arguments are keeping the billionaire money from funding it stronger while the metformin trial study did get it’s money?

[Victorel Petrovich]

Which arguments are keeping the billionaire money from funding it stronger while the metformin trial study did get it’s money?

I guess one reason is that billionaires don’t have time to do their research in detail, to see for themselves whether de Grey and Sens are worthy, but rely on reputation and opinions of popular names in the field. And the reputation of SENS seems to have suffered a bit initially, when many scientists found their proposals for rejuvenation too bold or futuristic https://​​en.wikipedia.org/​​wiki/​​Aubrey_de_Grey#Criticism

[JackH]

SENS Research Foundation aren’t the only source of funding for research into the hallmarks of aging. The research into the hallmarks of aging labs at NUS, the Buck Institute, Oxford, Harvard and many other institutions is largely funded through the traditional route of national medical research councils. SENS Research Foundation funds some of the research, but by no means most of it. That said, they have a good track record of selecting some of the most important projects to fund despite a small budget of $5-10 million. For a point of comparison, the National Institute of Aging which as a $3 billion budget allocates around $100 million to geroscience.

[emanuele ascani]

The thing that’s very unclear to me is why SENS has so little funding if that’s framework is now consensus

Because they choose the most neglected (long-term/​difficult/​high-risk high-reward) projects within the Hallmark framework (I talked extensively about this in my posts if you want to take a peek).

[ChristianKl]

Why wouldn’t billionaires (outside of Thiel and Greeves) that donate money for improving health outcomes want to fund long-term/​difficult/​high-risk high-reward projects?

Do you know whether SENS request a grant from OpenPhil?

[JackH]

Yes, and there are some signs that more billionaires (at least, the progressive-minded ones) are taking this seriously. For example, Elon Musk in an interview 3 weeks ago (timestamp: 24:03) mentioned the feasibility of ‘stop[ping] aging’ when asked about the biggest threats to the future of humanity, for the first time on the public record.

Two scientific advisors from OpenPhil conducted a ‘medium’ depth investigation into anti-aging in 2017 and seemed to understand the problem, though were less optimistic about anti-aging timelines, and funding this research area. They made the following forecast:

Our program officer Nick Beckstead offers the following forecast to make the above more precise/​accountable: By January 1, 2067, there will be no collection of medical interventions for adults that are healthy apart from normal aging, which, according to conventional wisdom in the medical community, have been shown to increase the average lifespan of such adults by at least 25 years (compared with not taking the interventions). (Subjective probability: ≥93%)

However, I would strongly disagree with this timeline, based on my knowledge of the field, today. I would go so far as to say that some combination of therapies available today—including metformin, senolytics, blood plasma exchange and epigenetic reprogramming—could already extend lifespan 25 years (compared to not taking the therapies) if personalised and multi-omics-biomarker-optimised. It’s just that we need more research to know how, when, where and how much of these therapies are required for each individual. With another 46 years of research in a field that is already expanding, I have no doubt that 25-year lifespan extension will be available by 2067.

They also summarised what a few of the anti-aging approaches (senolytics, stem cell therapies) but neglected many of the most promising approaches such as plasma exchange, partial epigenetic reprogramming, and mTOR inhibition.

They also made a big mistake, in my opinion, by overevaluating the amount of funding that geroscience (i.e. research that is relevant to the development of anti-aging therapies) receives:

The NIH reports spending $2.7 billion per year on aging research in 2015.16 In the 2015 budget request, $510 million per year is tagged as “neuroscience” and $177 million per year is tagged as “aging biology.”17 We have heard in various conversations that this research is mainly relevant to addressing particular symptoms associated with widely-recognized diseases (e.g., Alzheimer’s disease), rather than on understanding the basic mechanisms that cause aging. This is plausible to us, but we haven’t seen any convincing evidence for it and we do not take it for granted.

It is clear to almost everyone working in the field that the amount of funding going towards geroscience—i.e. targeting aging therapeutically—is drastically lower than that of age-related diseases—which employ completely different research methods and experimental protocols (i.e. do not perform lifespan studies with geroprotective interventions prior to disease onset). A list of most of the researchers working in the field is here (last updated April 2020) though I don’t think OpenPhil cared to look deeply enough into the field to recognise the lack of researchers and funding for geoscience in particular.

There are other flaws in their analysis. For example, they mentioned the large funding that Google-backed Calico receives, here:

Some aging-focused companies working in this area that we became aware of in the course of this investigation include Calico ($500 million in disclosed investment and agreed upon potential for $1B more);24

However, as Aubrey de Grey explains in this interview, Calico—despite having a huge budget—have a poor organisational structure that has so far precluded any meaningful research advances in the field.

As Aubrey de Grey puts it in the interview (from ~1:14:00 onwards):

They [Calico] have created a vast valley of death internally....they’ve got this paradise of research where they’ve hired fanastically good researchers in large numbers paid large salaries to find stuff out; to increase our understanding of what aging is. And on the other end they’ve got these people who know all these people who know all about how to turn proof of concept into a product—and they’ve got zero in the middle. They’ve got nothing that turns knowledge into proof of concept.

So overall, I believe OpenPhil are inaccurate in their assessment of the geroscience field based on their ‘medium’ depth investigation into it. There are numerous other examples of statements in their write-up that demonstrate a poor or incomplete knowledge of the state of the field—both scientifically and economically. I can go into these if you like, and I’ll probably write up a post about this in the future.

[ChristianKl]

Elon Musk in an interview 3 weeks ago (timestamp: 24:03)

Youtube allows you to link to specific timestamps when you click on the share button.

Yes, and there are some signs that more billionaires (at least, the progressive-minded ones) are taking this seriously.

I think there are two separate issues. One is about aging being taking seriously and the other is about SENS being taken seriously.

However, as Aubrey de Grey explains in this interview, Calico—despite having a huge budget—have a poor organisational structure that has so far precluded any meaningful research advances in the field.

I think you have the wrong link. In any case Aubrey de Grey basically here that hiring credentialed people is not enough to get results but that if he would organize the research it would produce better results. While that might be true it’s hard to assess.

I would go so far as to say that some combination of therapies available today—including metformin, senolytics, blood plasma exchange and epigenetic reprogramming—could already extend lifespan 25 years (compared to not taking the therapies) if personalised and multi-omics-biomarker-optimised.

That sounds like the people in the 1970s that they thought they could cure cancer by the end of the decade if they declare war on it.

[JackH]

Youtube allows you to link to specific timestamps when you click on the share button.

Thanks for the tip.

I think you have the wrong link. In any case Aubrey de Grey basically here that hiring credentialed people is not enough to get results but that if he would organize the research it would produce better results. While that might be true it’s hard to assess.

Sorry, here is the link. It’s not that hard to assess, given he has many informal chats with people affiliated with Calico. His point is that Calico has a huge budget but terrible internal structure that has essentially created an internal valley of death—many good aging researchers on good salaries, and many good pharma guys, but no-one who is actually developing and translating the technologies to solve aging (i.e. by repairing the hallmarks of aging).

That sounds like the people in the 1970s that they thought they could cure cancer by the end of the decade if they declare war on it.

It’s not an apt comparison for at two reasons:

• Scientists were nowhere near understanding cancer in mice let alone curing it in 1970. By contrast, with anti-aging technologies such as senolytics we can already delay cancer (which kills 80% of mice typically) and extend healthy lifespan 30%.

• Solving cancer is a potentially harder than slowing aging, since it involves intervening in the process further downstream i.e. when more damage has accumulated, rather than nipping it in the bud.

[emanuele ascani]

I dont’t know actually (for both questions). And I’m not sure how many billionaires like this there are.

[Florin]

If you want further evidence, consider that the original paper, The Hallmarks of Aging (2013) published in the journal Cell is the most highly cited academic paper in the entire field—with over 6800+ citations. Although it was Aubrey de Grey who first conceived of the Hallmarks (which he called the ‘7 deadly SENS’ and categorised them slightly differently in his 2007 book, Ending Aging) it has now become the framework used by researchers in the field, and even included in academic courses—such as the lectures I was invited to give to clinical neuroscience students here at Oxford University about aging and neurodegeneration.

SENS and Hallmarks shouldn’t be mixed as was done here and in the OP; although both sometimes overlap, they’re separate and distinct. Aubrey de Grey was the first to categorize aging damage and strategies to repair that damage (SENS) back in 2002 and published Ending Aging in 2007 to further popularize it. But he didn’t publish Hallmarks, and Hallmarks doesn’t always overlap with SENS (e.g., no cure for cancer, ignores crosslinks). Hallmarks also advocates lots of messing-with-metabolism (gerontology rather than the engineering/​maintenance/​damage repair approach), which is a big no-no from the SENS perspective. And while Hallmarks is popular in academia, SENS is not, unfortunately. It all boils down to this: the SENS approach has a decent chance of reaching LEV in the not-too-distant future, whereas Hallmarks doesn’t and never claimed to.

[ViktoriaMalyasova]

Hi! The link under the “Processes of Cellular reprogramming to pluripotency and rejuvenation” diagram is broken.

[YimbyGeorge]

I apologize for tldr. I think the most important thing is to prevent death of cells from low oxygen. If you solve he problem of nervous tissue dying from lack of oxygen, then you solve all coom problems like drowning, heart attacks, etc. Anything that cuts off oxygen will not kill you and. You will be invincible like a cockroach.

[Astynax]

For me, the case for doing this has not sufficiently been made. I read two sets of arguments for it. On this page, essentially, “aging is the leading cause of death,” which is funny—like engagement is the leading cause of marriage—but more seriously: to attempt to abolish aging is largely about fighting death. Pointing out aging kills doesn’t take us anywhere until we’ve shown death needs to go.

On the linked page about “pro-aging trance,” it was that if I’m still asking that question, I must be in a trance, and that’s not exactly sound.

I don’t have convincing arguments for death that I’ve thought through. The ecosystem would collapse, but maybe we could prevent that by almost never having children, if we can figure a way to convince everyone. It used to be said that a new paradigm in science takes hold when all the old scientists die, but maybe we can make scientists more flexible. And more creative, as they say a new physicist (say) does all his important work in his 20′s. Anyway, it seems there are a lot of problems to address.

[Florin]

Partial reprogramming in mice has shown promising results in alleviating age-related symptoms without increasing the risk of cancer.

Actually, it’s not really known whether or not partial reprogramming increases the risk of cancer.

[icemtel]

Is there any way for a small private investor to invest in this? By amount of risk, this is probably more of a charity than an investment, but with a small chance of hitting a jackpot.

Maybe some fund which invests into longevity projects? I could not find individual companies, which would be publicly traded.

[JackH]

Hi icemtel,

There are a number of publicly-traded longevity biotechnology companies. You could invest in Unity Biotechnology (NASDAQ:UBX) or Proteostasis Therapeutics (NASDAQ:PTI), for example.

I also recommend the Longevity Market Cap newsletter.

For larger investments, you could also look into longevity biotech VC’s such as Apollo Health Ventures.

Here are some links that may be useful:
https://​​investoraccess.masterinvestor.co.uk/​​events/​​investing-in-the-age-of-longevity/​​
https://​​transhumanplus.com/​​investments-on-antiaging/​​
https://​​investingnews.com/​​daily/​​life-science-investing/​​longevity-investing/​​longevity-research-companies/​​
https://​​www.nanalyze.com/​​2019/​​08/​​top-10-companies-longevity/​​

[icemtel]

Thank you for your time! I will take a look at these companies

[Victorel Petrovich]

On “Call to Action” :
Besides sharing, learning and donation, why don’t you encourage research-minded people to actually participate in /​ join the research?

First, students or young researchers in position to choose or change their research direction.

Second, others: since the audience that will fully read such an article is likely to have useful research skills (biology, science, computer science etc ). Some may be willing to volunteer with their skills and join some project.

[JackH]

Thanks for the tip—just added ‘become a researcher’ and ‘work for a longevity biotech company’ as additional ways to help the field.

[Victorel Petrovich]

Thanks, the way you have included links to possible laboratories and companies is great!

[Victorel Petrovich]

Thank you for the great article!
One possible minor correction: turtles do senesce https://​​www.ncbi.nlm.nih.gov/​​pmc/​​articles/​​PMC4988574/​​

[JackH]

You’re welcome!
I mentioned ‘tortoises’ rather than ‘turtles’ in the OP and was referring to species such as the Aldabra giant tortoise (Aldabrachelys gigantea). https://​​www.ncbi.nlm.nih.gov/​​pmc/​​articles/​​PMC5743229/​​

[Victorel Petrovich]

Thanks for correcting me, I didn’t know turtles and tortoises are different!
Another example, at least as good, of negligibly senescent tortoise, is Gopherus agassizii https://​​www.ncbi.nlm.nih.gov/​​pmc/​​articles/​​PMC4157354/​​

[AABoyles]

Without aging, COVID-19 would not be a global pandemic, since the death rate in individuals below 30 years old is extremely low.

A pandemic is an epidemic that occurs across multiple continents. Note that we can accordingly envision a pandemic with a death rate of zero, but a pandemic none-the-less. Accordingly, I think you’ve somewhat overstated the punchline about aging and COVID-19, though I agree with the broader point that if aging were effectively halted at 30, the death rates would be much, much lower.

[JackH]

That’s a reasonable challenge. However, the definition you cited (from Wikipedia) is the classical definition of a pandemic, and according to the WHO, does not take into account disease severity and transmissability, and would imply relatively harmless influenza outbreaks would also classified as pandemics—which is somewhat controversial in terms of definition. So depending on how you define a ‘pandemic’ (i.e. with or without disease severity and transmissibility taken into consideration) my original claim may be true.

[AABoyles]

Fair point. It does seems like “pandemic” is a more useful category if it doesn’t include a whole bunch of “things that happened but didn’t kill a lot of people.”

[AcurB]

“Recently, a group of Russian biohackers recently performed...”

Just reporting a little mistake here.

Good overview.

[JackH]

Thank-you, fixed.

[jmh]

Regarding parabiosis, are you familiar with the Conboy’s research on diluted blood plasma? I know they are trying to get a trial going—but suspect the effort has been a bit delayed due on the main event for 2020.

[JackH]

Yes, the Conboy lab are doing some of the best research in the field. The Brunet 2019 review I linked in the OP cites work from Conboy’s lab on plasma dilution /​ parabiosis. I know that the company affiliated with Wyss-Coray’s company Alkahest have plasma trials for Alzheimer’s.

[NunoSempere]

The evidence is promising that in the next 5-10 years, we will start seeing robust evidence that aging can be therapeutically slowed or reversed in humans

Are you willing to bet on this? If so, how much?

[JackH]

Definitely. There are over 50 therapies in clinical trials for aging today, addressing various components of cellular aging (i.e. all 9 hallmarks), and many have shown life extension effects in mice, and amelioration of the decline associated with age-related conditions in humans. I’m convinced some of these therapies, when administered from mid-life onwards, would extend human lifespan by 5 years or more. Especially if their delivery is personalised and biomarker-optimised. I expect some combination of these therapies, in tandem, to extend healthy human lifespan by 10 years or more.

The challenge lies in proving this within the next 10 years, since it would take up to 50 years to run a full-length human lifespan study. So it comes down to how we define robust evidence that aging can be slowed therapeutically. For this, we need accurate biomarkers of aging, and unfortunately, we don’t have the best aging biomarkers yet.

On the other hand, one could argue we already have robust evidence that aging can be slowed from thymic rejuvenation (using GH+DHEA+Metformin) demonstrated in 2019 to reverse biological age by 2.5 years with 1 year of treatment. However, the extent to which this can be considered robust evidence that aging can be slowed depends on who you are talking to in the field, and their familiarity with aging clocks.

If we are using epigenetic aging as the measurement, I’d bet all the money in my bank that at least one additional pharmacological compound will be shown to slow or reverse epigenetic aging in the next 10 years. That said, this measurement is likely to become redundant very soon, due to the development of multi-omics biomarkers of aging that will be more accurate in measuring aging.

So overall, I’m very confident that some of the 50 compounds being trialed today, and certainly some of those that will be discovered in the next 10 years, will slow aging—which is a less controversial claim than many people realize since some of these therapies (such as mTOR inhibitors like metformin) replicate the beneficial effects of lifestyle factors we know already increase healthy lifespan and slow aging as measured by epigenetic markers, like intermittent fasting.

[ChristianKl]

It might be worthwhile to formulate some of those predictions into Metaculus questions.

[JackH]

It’s a good idea.

There is already one on essentially this topic:

Will there be a culturally significant development in aging research by 2030?

The median is 65% so it seems most people (at least, out of those who have responded here) seem to agree with my 10-year timeline for important discoveries.

And this is another one anti-aging-related:

Will a senolytic therapy be approved for commercial sale by the United States Food and Drug Administration before January 1 2030?

The median is 58% for this one.

I haven’t used Metaculus before and I don’t know what value I could bring by signing up for Metaculus and adding new questions. I intuit that my time would be better spent progressing the research forward so the optimistic predictions actually occur, rather than endless forecasting.

That said, I don’t know much about how Metaculus works. If you think it’s a good platform for outreach and educating people about the field then I would consider it. Or, if you think there are certain kinds of questions I should ask (e.g. regarding the success of individual anti-aging approaches, maybe?). Let me know.

[ChristianKl]

When it comes to good long-term strategy and investment of resources understanding how the future likely looks like can be helpful. The act of writing a good Metaculus question is about operationalizing thinking about the future.

A question on the likelihood that research that’s spun out of SENS leads to an FDA approved drug might be useful for outreach. Both getting people to seriously think about the likelihood is useful and also to be able to use it when talking about the value of donating to SENS to rationalists.

For people outside the field it’s hard to evaluate the value of SENS by reading papers on their website. On the other hand likelihood to lead to a FDA approved drug is a metric that’s a lot easier to think about. Maybe you also have a better idea then likelihood of a FDA approved drug for your vision of the effect that SENS will have.

It seems to me like your thoughts about the importance of biomarkers of aging could also form the basis for questions. Thinking about good questions is about thinking what kind of events will be important in the next 20 years and building clarity about that is useful.

[JackH]

That seems like it could be a good idea. A few more questions though:

How would writing the question help to convince people? Would it not only be convincing in 5-10 years’ time if some of the predictions turn out to be accurate? Or, do you think if consensus on a Metaculus question that prediction X will occur is in and of itself convincing for rationalists?

I’m still a little uncertain about the practical benefit of writing questions, in helping to advance the technologies.

[Neel Nanda]

How would writing the question help to convince people? Would it not only be convincing in 5-10 years’ time if some of the predictions turn out to be accurate? Or, do you think if consensus on a Metaculus question that prediction X will occur is in and of itself convincing for rationalists?

I would personally find a consensus on Metaculus pretty convincing (at least, conditional on there being a significant amount of predictions for the question). I find it hard to gauge other people’s expertise and how much to defer to them, especially when I just see their point of view. Aggregating many people’s predictions is much more persuasive to me, and many of the top Metaculus predictors seem to have good epistemics.

[JackH]

Great—have you seen the existing Metaculus questions on anti-aging by Matthew Barnett and others?

[Neel Nanda]

Ooh, no. That’s super interesting, thanks!

[NunoSempere]

Thoughtful answer, thanks

[bardstale]

A very long article about anti-aging and not a single mention of the effect of insulin and carbohydrates on ageing. No mention of the use of a ketogenic diet as an anti-ageing strategy.

At least you mentioned Metformin…

[JackH]

Hi bardstale,

‘Deregulated nutrient sensing’ is one of the 9 hallmarks of aging covered in the article, and includes insulin signaling (IGF-1, etc) - that is, insulin signaling pathways.

Dietary protocols such as the fasting-mimicking diet (FMD) and ketogenic diets attenuate IGF-1 which is potentially beneficial for longevity. However, lifestyle protocols were not the focus of this article, since ultimately, lifestyle interventions alone are not likely sufficient to extend maximal lifespan beyond 125 years. Another way to phrase this, is that these diets are ‘anti-aging’ insofar as they slow the rate of aging, but not reverse it to a level that could potentially be achieved with therapies.

The goal of anti-aging research is to provide new therapies that can allow us to live much longer than is available with the best approaches today (diet/​exercise/​meditation/​low stress etc.).

[icemtel]

Why don’t you provide some references for other readers?

[Pedro Sachs]

It seems to me that unlike say, GAI research very little attention has been paid to the consequences of such work. I do not see how this would not result in a tiered society where at least at first those with access to longevity will be the wealthy and resourceful and thus able to tyrannise those that dont.

There are then of course a myriad of psychological/​existential implications which someone like Scott Alexander would have a field day with. How can we give our time meaning if we have an unlimited amount of it? What about personal relationships? Or vocational callings not to speak of parenthood or the environmental costs. Finally the arc of human life has been argued to have evolutionary purpose, our time is limited for good reason it is in a way the ultimate motivator to do good and build. Why would anyone want to take that away?

Indeed how are we to differentiate between supposed moral motivations and a thinly veiled fear of the shedding of our mortal coil?

Just playin the advocate. Fantastic post btw.

[JackH]

It seems to me that unlike say, GAI research very little attention has been paid to the consequences of such work.

This is true, and indeed there has been very little social sciences research on longevity that I am aware of, besides public attitudes towards longevity. Given the highly probable rise of anti-aging technologies in the near future, social science should focus its attention on modeling the impacts of longevity on social systems, political systems, and so on.

I do not see how this would not result in a tiered society where at least at first those with access to longevity will be the wealthy and resourceful and thus able to tyrannise those that dont.

Distributional justice is a very common objection to life extension that has been addressed at length by many in the field. This article and this site do a good job at laying out the arguments, and David Wood who I recently interviewed discusses this point, as he does in great depth in his book, The Abolition of Aging.

I’ll summarise some of the responses to distributional justice (i.e. ‘only for the rich’) arguments below:

• Anti-aging therapies are in principle no different from existing medical treatments such as anti-viral or anti-cancer therapies. For example, there is little philosophically difference between a cancer therapy (e.g. molecules that kill cancer cells) to extend healthy lifespan and a senolytic drug (e.g. molecules that kill senescent cells) to extend healthy lifespan. In the same way that few would object to the development of better cancer therapies today (e.g. CAR T-cell therapies) that only the rich can afford (and are not, for example, currently available to people in Africa), few should object to anti-aging drugs that extend healthy lifespan, even if only the rich can initially afford them too. Basically, many lifesaving medical interventions are initially expensive, and therefore only available to the rich, but this isn’t a reason to inhibit research. An additional point: if you support current medical research—which functions essentially to extend healthy lifespan, you should also support anti-aging, which also aims to extend healthy lifespan, though through prevention rather than cures. The only difference between the two is the approach, and the likely effectiveness—anti-aging is likely to be more effective at accomplishing the goal. Hence, we should be more enthusiastic about this approach, if anything.

• Therapies are unlikely to stay expensive for long. When patents expire after 10-20 years, drugs usually become ridiculously cheap, and so any distributional inequality is unlikely to last long. Metformin, a life-saving diabetes drug (that is also being studied for its anti-aging properties) is a good example—it was initially expensive but the price has now plummeted to 31 cents per tablet in 2013. There are numerous economic forces that will drive low prices—governments are incentivised to subsidise these therapies, to populations healthy and stave off the diseases of old age that cost healthcare systems trillions of dollars worldwide annually (e.g. dementia alone costs over $1 trillion), which is otherwise set to grow due to an aging population. Insurance companies will similarly be incentivized to subside these therapies, to keep their clients healthier and able to avoid the chronic diseases of old age for longer. A good analogy is car sales—cars used to be too expensive for most people but are now ubiquitous and largely affordable. Since the market size for anti-aging therapies (i.e. all humans on Earth) is huge, as it is for cars, we would expect the huge demand to result in lower prices. Food technology is another, more recent example. In 2013 the first lab-grown burger was $325,000, and two years later the cost fell to $12.

• Not developing anti-aging technology doesn’t help the poor. Anti-aging technologies only available for the rich would not help the poor, but not having these technologies available to the rich—that is, allowing the rich to age and die like the rest of us—also wouldn’t help the poor. What matters is not only that the gap between rich and poor is closed, but also how it is closed. For example, those in Western countries could give up all their comforts and wealth to be economically equal to the lowest African countries. But this is not the goal—the goal is to bring the African countries up in wealth, not bring economically prosperous nations down. The same applies to anti-aging: the goal is to bring everyone’s healthspans up (even if it means there will exist some inequality, initially), not keep everyone’s healthspans down.

There are then of course a myriad of psychological/​existential implications which someone like Scott Alexander would have a field day with. How can we give our time meaning if we have an unlimited amount of it? What about personal relationships? Or vocational callings not to speak of parenthood or the environmental costs. Finally the arc of human life has been argued to have evolutionary purpose, our time is limited for good reason it is in a way the ultimate motivator to do good and build. Why would anyone want to take that away?

This alludes to the ‘death brings meaning to life’ and ‘boredom’ arguments—i.e. that we need death in order to achieve some kind of meaning and psychological stability in our lives.

But the argument, upon closer inspection, is utterly absurd, as this article explains. Life gives meaning to life, not death. The meaning of life is whatever you want it to be, and is determined while you are alive to think, reflect, and plan—not when you are dead. When lifespans were extended from 40 years to 80 years, did people psychologically and existentially cripple at the newfound time on their hands? No, they found new ways to use the time. Humans are incredibly adaptable and will find new ways to spend the time. We have no reason to think this will change if lifespans are extended by 1 year, or 1000 years. Half of workers over 50 engage in 3 or more careers, and a longer lifespan simply allows more time to start new careers, pursue passions, spend time with loved ones and anything else that the person wants to do.

‘Death brings meaning to life’ is a nonsensical argument for death is really just another facet of the naturalistic fallacy coupled with the lazy conservatism inherent in human nature.