For a while, people hypothesized that senescent cells accumulate with age without turning over, acting as a root cause. As mentioned earlier, the actual evidence suggests that senescent cells turn over on a timescale of days to weeks, which would mean this theory is wrong—senescent cell accumulation is not a root cause.
However, there is a saving throw: maybe a small subset of senescent cells are longer-lived, and the experiments measuring senescent cell turnover time just weren’t capturing the long-lived subset in particular. Results from senolytics (drugs which kill senescent cells) suggest this is also wrong: the effects of senolytics rapidly wear off once the drug stops being administered, whereas reversing a root cause should set an organism back to a youthful state longer-term.
Edit: I’m not sure that the claim that senolytics rapidly wear off is accurate. [1]
Senolytics do not have to be continuously present to exert their effect. Brief disruption of pro-survival pathways is adequate to kill senescent cells. Thus, senolytics can be effective when administered intermittently.22 For example, dasatinib and quercetin have an elimination half-life of a few hours, yet a single short course alleviates effects of leg radiation for at least 7 months.
An alternative possibility is that senolytics kill senescent cells in a tissue-selective manner. We see this here.
Briefly, the team uses a mouse breed in which senescent cells can be killed with a drug called AP. In the skeletal muscle, eye, kidney, lung, heart, and spleen, AP works better in some tissues, worse in others. AP doesn’t work at all in the colon or liver.
Decreasing the overall senescent cell burden seems to increase lifespan. But if the colon and liver are reservoires for senescent cells, allowing the cells to rapidly take over once AP administration stops, that would explain why senescent cells bounce back rapidly. Take Afghanistan as an analogy: America was able to suppress the Taliban for decades, as long as it maintained a constant military presence. But there were regions they couldn’t touch, which became safe harbor for the Taliban. As soon as America withdrew its military, the Taliban were able to take over the country immediately.
If senescent cells stimulate their own production and dampen their own removal in a way that’s concentration dependent, and if most senolytics are tissue-specific and therefore leave highly concentrated reservoires of senescent cells behind, this leaves intact the possibility that stem cells are a root cause of aging.
Fortunately, combination senolytics that cover the full range of tissues may be more tractable than chemotherapy for cancer. With cancer, we primarily target cells undergoing mitosis.[2] That impacts human cells as well, just somewhat less. And cancer’s constant growth means that it’s got lots of opportunities to evolve evasion to chemotherapies. But with senolytics, we may be able to target biomarkers that don’t especially impact healthy cells. And since senescent cells don’t proliferate, they don’t have the same opportunities to evolve mechanisms to evade senolytics (1).
Another advantage of senolytics is that cell division– dependent drug resistance is unlikely to occur, because senescent cells do not divide and therefore cannot acquire advantageous mutations, unlike the situation in treating cancers or infectious agents.
Kirkland, J. L., Tchkonia, T., Zhu, Y., Niedernhofer, L. J., & Robbins, P. D. (2017). The clinical potential of senolytic drugs. Journal of the American Geriatrics Society, 65(10), 2297-2301.
Although new strategies are emerging, such as pH-based drug delivery and immune modulation, since cancer creates an acidic and anti-inflammatory microenvironment.
I’d be careful about taking the claims in these sorts of papers at face value.
One problem is just the usual statistical abuse. For instance, this:
Briefly, the team uses a mouse breed in which senescent cells can be killed with a drug called AP. In the skeletal muscle, eye, kidney, lung, heart, and spleen, AP works better in some tissues, worse in others. AP doesn’t work at all in the colon or liver.
I haven’t looked carefully at that paper, but on the face of it, it sounds like a “garden of forking paths” situation. I wouldn’t be surprised if the colon/liver were just noise due to testing lots of different things.
Aside from that, the other problem which comes up all the time is:
Team does some experiment
Their abstract summarizes the result in a way which isn’t really backed by the data
Review articles or other future citers then repeat the claim from the abstract
This one happens a lot with cellular senescence, largely because people use the word “accumulate” to indicate that senescent cell counts are going up, and it’s easy to misintepret that as a claim that the cells are sticking around. Or, sometimes people just don’t have”senescent cell counts are going up without the individual cells sticking around” in their hypothesis space at all, so they do an experiment which finds that counts go up, and then interpret that as evidence that senescent cells stick around. Or, even worse:
Somebody outright speculates
Review articles and other future citers repeat the speculative claim, but fail to mention that it’s pure speculation
Later review articles cite the earlier review articles, and vaguely claim that there’s some kind of empirical evidence
That’s what happened in the case of the collagen:elastin ratio hypothesis for vascular stiffening (mentioned in the OP).
Point is, if you see a claim in a review article (like the one you cited), and it’s not extremely obvious where that claim came from, you should be extremely skeptical. You do actually need to follow the citations, not only to the abstract but all the way to the methods and data.
OK, let’s take a look. Note that the claim about senescent cells being protected from AP in the colon and liver is not from a review article—the citation is to an orginal research article on Nature. They don’t talk about correcting for multiple comparisons, although it’s possible that this was left unstated or is dealt with automatically via Prism, the software they used for analysis. I’ll contact the authors and ask.
This is the relevant figure (extended data figure 3). Red bars are no AP treatment, pink bars are with AP treatment (which ought to kill senescent cells). Eyeballing it, we see fairly consistent equal or higher expression levels across the range of senescence markers in the no AP group, and then this pattern vanishes in the liver and colon with the exception of p21 in the liver, which seems like it’s “trending toward significance” (my words, not theirs). Based on my visual spot-checking, I would have said that the liver and colon really do seem to respond differently to AP than other organs. And that’s a perfectly normal, expected outcome for any drug.
Error bars indicate s.e.m. *P < 0.05; **P < 0.01; ***P < 0.001 (unpaired two-tailed t-tests). Asterisks above individual bars in a denote significant changes to 2-month-old mice; asterisks above brackets denote significant differences between 18-month-old vehicle and AP-treated mice.
In the statistical analysis section, we have:
Prism software was used for statistical analysis and generation of survival, cataract and tumour latency curves… Investigators were blinded to allocation during experiments and outcome assessment, except for rare instances where blinding was not possible.
I agree with you that we are probably seeing AP being selectively broken down by the liver and colon. It therefore fails to reach the normal senescent cells in these tissues, and does not trigger their destruction. This causes a higher level of senescent cells to remain in these tissues after AP administration stops. If those liver and colon senescent cells can go on to trigger senescence in neighboring cells, that may explain why a temporary administration of senolytics fails to provide lasting protection against aging, despite the accumulation of senescent cells being a root cause of aging.
Under this hypothesis, senescent cells are a root cause of aging, as they trigger conversion of other cells to senescence—as suggested in the ODE model paper you linked—but this root cause can only be controlled in a lasting way by ensuring that senolytics eliminates senescent cells in a non-tissue selective manner. We can’t leave any pockets of them hanging out in the liver and colon, for example, or they’ll start spreading senescence to other nearby organs again as soon as you stop senolytics. Or alternatively, they might simply leave the mouse with an aged liver and colon, which might be enough to kill the mouse consistently, so that there’s no real lifespan benefit.
Edit: Sorry if I’m responding to a rebuttal you changed your mind about :)
Edit: Sorry if I’m responding to a rebuttal you changed your mind about :)
Yeah, sorry, I went back and looked at the context of the earlier comments and was like “oh, right, I see what the claim is” and then updated my comment.
Edit: I’m not sure that the claim that senolytics rapidly wear off is accurate. [1]
An alternative possibility is that senolytics kill senescent cells in a tissue-selective manner. We see this here.
Briefly, the team uses a mouse breed in which senescent cells can be killed with a drug called AP. In the skeletal muscle, eye, kidney, lung, heart, and spleen, AP works better in some tissues, worse in others. AP doesn’t work at all in the colon or liver.
Decreasing the overall senescent cell burden seems to increase lifespan. But if the colon and liver are reservoires for senescent cells, allowing the cells to rapidly take over once AP administration stops, that would explain why senescent cells bounce back rapidly. Take Afghanistan as an analogy: America was able to suppress the Taliban for decades, as long as it maintained a constant military presence. But there were regions they couldn’t touch, which became safe harbor for the Taliban. As soon as America withdrew its military, the Taliban were able to take over the country immediately.
If senescent cells stimulate their own production and dampen their own removal in a way that’s concentration dependent, and if most senolytics are tissue-specific and therefore leave highly concentrated reservoires of senescent cells behind, this leaves intact the possibility that stem cells are a root cause of aging.
Fortunately, combination senolytics that cover the full range of tissues may be more tractable than chemotherapy for cancer. With cancer, we primarily target cells undergoing mitosis.[2] That impacts human cells as well, just somewhat less. And cancer’s constant growth means that it’s got lots of opportunities to evolve evasion to chemotherapies. But with senolytics, we may be able to target biomarkers that don’t especially impact healthy cells. And since senescent cells don’t proliferate, they don’t have the same opportunities to evolve mechanisms to evade senolytics (1).
Although new strategies are emerging, such as pH-based drug delivery and immune modulation, since cancer creates an acidic and anti-inflammatory microenvironment.
I’d be careful about taking the claims in these sorts of papers at face value.
One problem is just the usual statistical abuse. For instance, this:
I haven’t looked carefully at that paper, but on the face of it, it sounds like a “garden of forking paths” situation. I wouldn’t be surprised if the colon/liver were just noise due to testing lots of different things.
Aside from that, the other problem which comes up all the time is:
Team does some experiment
Their abstract summarizes the result in a way which isn’t really backed by the data
Review articles or other future citers then repeat the claim from the abstract
This one happens a lot with cellular senescence, largely because people use the word “accumulate” to indicate that senescent cell counts are going up, and it’s easy to misintepret that as a claim that the cells are sticking around. Or, sometimes people just don’t have”senescent cell counts are going up without the individual cells sticking around” in their hypothesis space at all, so they do an experiment which finds that counts go up, and then interpret that as evidence that senescent cells stick around. Or, even worse:
Somebody outright speculates
Review articles and other future citers repeat the speculative claim, but fail to mention that it’s pure speculation
Later review articles cite the earlier review articles, and vaguely claim that there’s some kind of empirical evidence
That’s what happened in the case of the collagen:elastin ratio hypothesis for vascular stiffening (mentioned in the OP).
Point is, if you see a claim in a review article (like the one you cited), and it’s not extremely obvious where that claim came from, you should be extremely skeptical. You do actually need to follow the citations, not only to the abstract but all the way to the methods and data.
OK, let’s take a look. Note that the claim about senescent cells being protected from AP in the colon and liver is not from a review article—the citation is to an orginal research article on Nature. They don’t talk about correcting for multiple comparisons, although it’s possible that this was left unstated or is dealt with automatically via Prism, the software they used for analysis. I’ll contact the authors and ask.
This is the relevant figure (extended data figure 3). Red bars are no AP treatment, pink bars are with AP treatment (which ought to kill senescent cells). Eyeballing it, we see fairly consistent equal or higher expression levels across the range of senescence markers in the no AP group, and then this pattern vanishes in the liver and colon with the exception of p21 in the liver, which seems like it’s “trending toward significance” (my words, not theirs). Based on my visual spot-checking, I would have said that the liver and colon really do seem to respond differently to AP than other organs. And that’s a perfectly normal, expected outcome for any drug.
In the statistical analysis section, we have:
Cool, I buy the basic result.
I agree with you that we are probably seeing AP being selectively broken down by the liver and colon. It therefore fails to reach the normal senescent cells in these tissues, and does not trigger their destruction. This causes a higher level of senescent cells to remain in these tissues after AP administration stops. If those liver and colon senescent cells can go on to trigger senescence in neighboring cells, that may explain why a temporary administration of senolytics fails to provide lasting protection against aging, despite the accumulation of senescent cells being a root cause of aging.
Under this hypothesis, senescent cells are a root cause of aging, as they trigger conversion of other cells to senescence—as suggested in the ODE model paper you linked—but this root cause can only be controlled in a lasting way by ensuring that senolytics eliminates senescent cells in a non-tissue selective manner. We can’t leave any pockets of them hanging out in the liver and colon, for example, or they’ll start spreading senescence to other nearby organs again as soon as you stop senolytics. Or alternatively, they might simply leave the mouse with an aged liver and colon, which might be enough to kill the mouse consistently, so that there’s no real lifespan benefit.
Edit: Sorry if I’m responding to a rebuttal you changed your mind about :)
Yeah, sorry, I went back and looked at the context of the earlier comments and was like “oh, right, I see what the claim is” and then updated my comment.