Fight Aging!

It is evident and settled that stochastic nuclear DNA damage contributes to cancer. The more of it that you have, the worse your risk. What is still very much debated is whether nuclear DNA damage contributes meaningfully to degenerative aging, and how it does so. Most mutational damage to DNA occurs in regions that are inactive, in cells that have comparatively few divisions remaining before reaching the Hayflick limit. Even if damage alters the function of such a cell, in some non-cancerous way, it is unclear as to how this could amount to a meaningful contribution to loss of tissue function.

The one school of thought is focused on somatic mosaicism, the spread of mutations throughout a tissue when mutational damage occurs in stem cells. In this case subtle dysfunctions could accumulate and interact with the spread of mutated cells over time. While there is evidence for somatic mosaicism to contribute to the risk of some forms of cancer, evidence is still lacking for it to meaningfully affect tissue function to the degree that aging does.

A second school of thought is focused on unexpected consequences of the repeated operation of DNA repair machinery. Double strand break repair can apparently deplete factors needed for maintaining the correct structure and epigenetic control of nuclear DNA, leading to age-related changes in epigenetics and gene expression. This is a comparatively recent discovery, and not yet fully digested, replicated, and risen to the status of consensus. It is an attractive proposition, however, a way to explain how stochastic mutational damage to inactive regions of the genome can somehow produce a consistent, systemic outcome throughout tissue, while forms of mutational damage other than double strand breaks can occur in greater amounts without strongly impacting age-related degeneration.

Somatic mutations in human ageing: New insights from DNA sequencing and inherited mutations

Taken together, recent DNA sequencing experiments focused on quantifying mutations with age reveal a gradual increase in mutations, and widespread evidence of clonal expansion of rapidly dividing mutant clones. These observations are consistent with the age-related increase in cancer observed in most tissues. However, the levels of mutations reported so far are difficult to reconcile with most ageing phenotypes. Whether and how somatic mutations in ageing tissues, affecting mostly non-coding regions and overwhelmingly different genes in different cells, can cause dysfunction is unclear. Likewise, while clonal expansion may be a factor in ageing and result in tissue dysfunction, so far this is not directly supported by experimental data and remains an open question.

As such, there is a stark contrast between cancer and ageing: while cancer can originate from mutations in a single cell and subsequent clonal expansion, shown empirically to occur, age-related dysfunction would need, we suggest, many mutations in a very large number of cells in a tissue. Evolutionarily this has led others to suggest that the evolutionary pressure to prevent cancer will result in levels of somatic mutations in tissues across the lifespan that will be lower than the number of mutations needed to cause most other age-related conditions.

Recent evidence from inherited mutations in patients with increased somatic mutation burden and no symptoms of accelerated ageing also cast doubt on the role of somatic mutations in most ageing phenotypes - even if it is not well understood why hypermutator phenotypes sometimes do and sometimes do not result in progeroid phenotypes. Perhaps other forms of DNA damage and/or genome instability may accumulate at much greater rates in human tissues, but these have not been studied in detail and have thus far limited empirical support. The impact of clonal expansion, somatic copy-number alteration (SCNAs), and structural variations (SVs) on ageing phenotypes, in fact, remains to be further investigated. Advances in genome sequencing technology together with the development of computational methods to reliably detect large-scale structural alterations at a single-cell level should shed light on the potential role of SVs and SCNAs on human ageing.

After the idea that somatic mutations could be the main cause of ageing was first proposed in the late 1950's, Maynard-Smith questioned it by arguing that the number of mutations necessary would be too high to be consistent with the data available at the time. Decades and numerous technological advances in genetics and genomics later, which have produced quantitative data on mutation load in aged tissues, and yet we are no closer to empirically showing a role for somatic mutations in ageing and, in fact, have grounds to question it.