Reviewing the DNA Damage Response in Aging

Nuclear DNA damage is considered a contributing cause of aging, though at this stage the research community is still proposing and debating processes by which this damage might cause metabolic dysfunction throughout the body. Mutations to nuclear DNA evidently increase cancer risk, but setting this aside, how does random damage to random cells contribute to the declines of age?

There are a few possibilities; firstly that the vast majority of nuclear DNA damage, occurring as it does in somatic cells, or in unusued portions of the genome, is irrelevant. Harms are done when mutations affecting function occur in stem cells and progenitor cells, allowing that mutation to spread widely throughout a tissue. The second possibility, more recently proposed, is that all nuclear DNA damage systemically affects cell function wherever it occurs in the genome, because the processes of DNA repair have the side-effect of causing epigenetic changes characteristic of aging. Thirdly, higher levels of mutational damage may generate a greater burden of cellular senescence. Relative effect sizes of these processes are an open question, and much more work must be done to confirm that they are relevant in each case.

One important aspect of the ageing process is the accumulation of DNA damage through time. While containing the entire genetic information (except for mitochondria-encoded genes), the nuclear genome is constantly threatened by genotoxic insults, with an estimated frequency of the order of tens of thousands per day. These hazards can arise from exogenous or endogenous sources. Exogenous sources are, to some extent, avoidable; these include ultraviolet (UV) and ionizing radiation and a variety of genotoxic chemicals. Endogenous sources, on the other hand, are unavoidable as they include metabolic by-products, such as reactive oxygen species (ROS), and spontaneous chemical reactions that target DNA molecules (including alkylation and hydrolysis of DNA chemical bonds). The lesion type inflicted on the DNA greatly depends on the source of the damage. Lesions caused by endogenous sources tend to arise stochastically at a higher rate.

DNA damage can have distinctive consequences for cells. Persistent nucleotide substitutions, due to erroneous repair followed by misreplication, lead to the accumulation of permanent mutations and chromosomal aberrations, which increase the risk of cancer development. By contrast, bulky types of DNA lesions can block transcription and replication, triggering the arrest of the normal cell cycle, ultimately leading to cell senescence or cell death, both states preventing the cell from transforming into tumour cells but ultimately contributing to ageing. Nuclear DNA requires constant maintenance to be kept intact and error-free in order to avoid the aforementioned consequences. For this, cells evolved intricate, evolutionarily highly conserved machineries mediating cellular responses to DNA damage-termed the DNA damage response (DDR). These highly complex systems include not only several repair pathways specific for different types of lesion but also distinct signalling cascades of damage sensors, signal boosters and effectors responsible for deciding the cell's fate.

This system has two immediate goals: (i) arrest the cell cycle to prevent the propagation of corrupted genetic information, while providing time to repair the damage, and (ii) actually coordinate the repair of the DNA lesion. Depending on the success of these previous steps, the cell's fate is then decided: after lesions are successfully repaired, the DDR signalling ceases, cells survive and return to their original state; however, impossible to repair lesions trigger a persistent DDR signalling which can then engender cellular senescence or apoptosis. Given the harmful consequences of irreparable DNA damage, it is not surprising that defects in DNA repair pathways are associated with severe human pathological conditions.

Research over past decades has elucidated the role of genomic instability as a root cause of ageing. The observed age-dependent accumulation of somatic mutations in the genome and the accelerated ageing phenotypes caused by deficiencies in DNA repair systems provide compelling evidence supporting an active role for intrinsic DNA damage in mediating loss of tissue functionality with ageing. Still, the broad range of phenotypic variability within ageing populations strongly suggests that complex signalling pathways might coordinate specific systemic responses to DNA damage. These systemic responses have become increasingly apparent in multiple species and appear to have a major role not only during the physiological ageing process but also in response to acute stress. Importantly, these responses represent perfect examples of the intricate connection between DNA damage and other hallmarks of ageing, such as cellular senescence, stem cell exhaustion, and altered intercellular communication, which can all occur as a consequence of the DDR. Nevertheless, the interplay between cell-autonomous and these non-cell-autonomous responses is still somewhat poorly understood.

Link: https://doi.org/10.1098/rsob.190168

Comments

DNA breaks mess up the epigenome according to Sinclair and mutations can cause senescence and cancer. In the long run we probably will put stem cells back into us who have an improved dna damage repair machinery among other things (like enzymes that break down waste products that your body is currently not able to get rid of). But that is in the future, right now we need to make stem cells work at all, before we contemplate what cool things we could do with them.

Posted by: Tom at December 6th, 2019 5:59 AM

@Tom
Fasting is superior to calorie restriction and periodic fast can be adhered to much easier than a permanent CR diet. Still quite hard to do. And even harder to do it properly. I do think that a senolitics course followed by a fast can be much better than senolitics alone.
There people practicing fasting for decades. None of them is 130 old, though.

My longest fast was 20 days and there I have seen some improvements, getting better , better and smoother skin. No undoing the grey and receding hairline, though... So it has it limits

Posted by: Cuberat at December 6th, 2019 7:14 PM

I made a 13 day water fast and relapsed yesterday, intermittent fasting is, I think, a good thing, much easier than a CR diet and you enjoy your meals so much more.

Posted by: Tom at December 6th, 2019 9:33 PM

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