DNA damage is typically repaired on a timescale of hours or faster, depending on the type. If DNA damage levels increase with age, that is due to an increase in rate of damage or decrease in rate of repair, not permanent accumulation.
Edit: I now see from your post on homeostasis that you’re using “DNA damage” for forms of damage that do not cause a change of sequence, and “DNA mutations” for damage that does cause a permanent change of sequence. A lot of this is not really a critique then of your statement here—just a misreading of your specific terminology.
DNA damage repair mechanisms do not have a 100% chance of resolving the damage, and when this fails, permanent damage does accumulate in that cell and its lineage. A rare but highly cytotoxic example are double-strand breaks. While most DNA damage allows the cell to use information stored in the complementary nucleotide to repair the break accurately, double-strand breaks sever the chromosome and lose the ability to exploit the complementary nucleotide to guide repair. Normal processes of transcription and DNA replication during mitosis have been estimated to cause about 50 double-stranded breaks per cell per cell cycle (1).
It is true that mechanisms such as apoptosis and senescence can eliminate cells that have accumulated high levels of DNA damage. But setting those mechanisms aside, permanent accumulation of DNA damage does result from spontaneous double-strand breaks. And even taking those mechanisms into account, we will see selection for forms of DNA damage that evade the self-control mechanisms of apoptosis and senescence, and we may also see accumulated DNA damage leading to progressive degredation of the ability of immune cells to actively trigger apoptosis in damaged cells.
Edit: Note also that the proposed mechanism by which transposons cause aging is that they are a second form of accumulated, irreparable, and therefore permanent DNA damage within a particular cell lineage. While we can appeal to higher-order mechanisms to eliminate this accumulated damage, such as cell turnover, DNA damage most certainly does permanently accumulate within particular cell lineages.
I have not yet looked into the literature on senolytics, but if it typically wears off quickly, that may be because at a given age, all cells are likely to have accumulated DNA damage, among other dysregulations. Senolytics kills some of them, but other near-senescent cells on the verge of senescence that are not killed by senolytics quickly generate replacement senescent cells. If this were the case, it would be necessary to complement senolytics with transplant of young and healthy stem cells.
If this paper is right in positing that senescent cell accumulation is explained by saturation of the native senolytic capacity of the body and a linear increase of senescent cell production rate over time, then this tackles both aspects of the problem. If we only ablate senescent cells, we clear up the body’s removal capacity, but do not deal with the linear increase in production rates. The latter may be dealt with by the addition of young cells, which would then be responsible for responding to growth signals and would lead to proliferation of a population of cells that does not become senescent. We might expect even a small number of these cells to do the trick, since they would be more proliferative as they are not rapidly becoming senescent and non-proliferative, while their nearly-senescent competitors are constantly blocked by growth arrest.
Overall, I see a guiding metaphore here as a game of telephone. The body does not have a mechanism for very long-term storage and refreshment of the fundamental message, which is probably due mainly to a lack of evolutionary pressure and antagonistic pleiotropy to emphasize reproductive success at the age of puberty. The age of puberty in turn was targeted in the ancestral environment to give a factor of safety of several decades before the average pubescent human would be killed by extrinsic factors. We have evolved a set of native repair mechanisms that equalize the risk of intrinsict causes of death with the risk of extrinsic causes of death, as there is no point in investing resources to prolong the lives of humans much beyond the age at which they’d typically be killed by factors in the environment.
However, we have many extrinsic biomedical mechanisms by which an individual’s biological data can be stored, retrieved, amplified, and reorganized. Figuring out the minimal intervention that restores the original telephone message that cells are conveying to each other, that tells them what sort of cell to be, what sort of tissue architecture to form, and so on, could potentially prolong life indefinitely. This is probably more or less what “immortal” organisms are doing: they have found a set of mechanisms that preserves a particular biological telephone message for a very long period of time.
Edit 2: Senescent cells don’t proliferate, but they do create an inflammatory environment that seems to trigger additional cellular senescence. And mitochondria can be transferred between cells. If mitochondria attain a proliferative advantage, this gives them an opportunity to be a fundamental driver of aging—a sort of “mitochondrial cancer.”
(1) Mehta, A., & Haber, J. E. (2014). Sources of DNA double-strand breaks and models of recombinational DNA repair. Cold Spring Harbor perspectives in biology, 6(9), a016428.
(2) Torralba, D., Baixauli, F., & Sánchez-Madrid, F. (2016). Mitochondria know no boundaries: mechanisms and functions of intercellular mitochondrial transfer. Frontiers in cell and developmental biology, 4, 107.
Edit: I now see from your post on homeostasis that you’re using “DNA damage” for forms of damage that do not cause a change of sequence, and “DNA mutations” for damage that does cause a permanent change of sequence. A lot of this is not really a critique then of your statement here—just a misreading of your specific terminology.
DNA damage repair mechanisms do not have a 100% chance of resolving the damage, and when this fails, permanent damage does accumulate in that cell and its lineage. A rare but highly cytotoxic example are double-strand breaks. While most DNA damage allows the cell to use information stored in the complementary nucleotide to repair the break accurately, double-strand breaks sever the chromosome and lose the ability to exploit the complementary nucleotide to guide repair. Normal processes of transcription and DNA replication during mitosis have been estimated to cause about 50 double-stranded breaks per cell per cell cycle (1).
It is true that mechanisms such as apoptosis and senescence can eliminate cells that have accumulated high levels of DNA damage. But setting those mechanisms aside, permanent accumulation of DNA damage does result from spontaneous double-strand breaks. And even taking those mechanisms into account, we will see selection for forms of DNA damage that evade the self-control mechanisms of apoptosis and senescence, and we may also see accumulated DNA damage leading to progressive degredation of the ability of immune cells to actively trigger apoptosis in damaged cells.
Edit: Note also that the proposed mechanism by which transposons cause aging is that they are a second form of accumulated, irreparable, and therefore permanent DNA damage within a particular cell lineage. While we can appeal to higher-order mechanisms to eliminate this accumulated damage, such as cell turnover, DNA damage most certainly does permanently accumulate within particular cell lineages.
I have not yet looked into the literature on senolytics, but if it typically wears off quickly, that may be because at a given age, all cells are likely to have accumulated DNA damage, among other dysregulations. Senolytics kills some of them, but other near-senescent cells on the verge of senescence that are not killed by senolytics quickly generate replacement senescent cells. If this were the case, it would be necessary to complement senolytics with transplant of young and healthy stem cells.
If this paper is right in positing that senescent cell accumulation is explained by saturation of the native senolytic capacity of the body and a linear increase of senescent cell production rate over time, then this tackles both aspects of the problem. If we only ablate senescent cells, we clear up the body’s removal capacity, but do not deal with the linear increase in production rates. The latter may be dealt with by the addition of young cells, which would then be responsible for responding to growth signals and would lead to proliferation of a population of cells that does not become senescent. We might expect even a small number of these cells to do the trick, since they would be more proliferative as they are not rapidly becoming senescent and non-proliferative, while their nearly-senescent competitors are constantly blocked by growth arrest.
Overall, I see a guiding metaphore here as a game of telephone. The body does not have a mechanism for very long-term storage and refreshment of the fundamental message, which is probably due mainly to a lack of evolutionary pressure and antagonistic pleiotropy to emphasize reproductive success at the age of puberty. The age of puberty in turn was targeted in the ancestral environment to give a factor of safety of several decades before the average pubescent human would be killed by extrinsic factors. We have evolved a set of native repair mechanisms that equalize the risk of intrinsict causes of death with the risk of extrinsic causes of death, as there is no point in investing resources to prolong the lives of humans much beyond the age at which they’d typically be killed by factors in the environment.
However, we have many extrinsic biomedical mechanisms by which an individual’s biological data can be stored, retrieved, amplified, and reorganized. Figuring out the minimal intervention that restores the original telephone message that cells are conveying to each other, that tells them what sort of cell to be, what sort of tissue architecture to form, and so on, could potentially prolong life indefinitely. This is probably more or less what “immortal” organisms are doing: they have found a set of mechanisms that preserves a particular biological telephone message for a very long period of time.
Edit 2: Senescent cells don’t proliferate, but they do create an inflammatory environment that seems to trigger additional cellular senescence. And mitochondria can be transferred between cells. If mitochondria attain a proliferative advantage, this gives them an opportunity to be a fundamental driver of aging—a sort of “mitochondrial cancer.”
(1) Mehta, A., & Haber, J. E. (2014). Sources of DNA double-strand breaks and models of recombinational DNA repair. Cold Spring Harbor perspectives in biology, 6(9), a016428.
(2) Torralba, D., Baixauli, F., & Sánchez-Madrid, F. (2016). Mitochondria know no boundaries: mechanisms and functions of intercellular mitochondrial transfer. Frontiers in cell and developmental biology, 4, 107.