Fight Aging!

In today's open access paper, researchers presented data on the pace at which random mutational damage accumulates in the nuclear DNA of somatic cells over a lifetime, covering a range of mammalian species with differing body sizes and life spans. They looked only at the lining of the gut, a tissue in which cells replicate rapidly, and thus one might expect to find more mutations and thus data that is more easily analyzed. The researchers found that the burden of mutations in late life is remarkably consistent, the rate of mutation inversely correlated with species life span. This is suggestive that somatic mutations are either an important contributing cause of aging, or a side-effect that is strongly connected to an important contributing cause of aging.

How could random mutational damage in cells throughout the body contribute to aging? Most of that damage is irrelevant, as it occurs in genes that are not active, or in cells that will reach the Hayflick limit and be removed from tissue in a matter of days to months. Present thought is focused on the effects of mutations in stem cells and progenitor cells, as these mutations can spread widely in tissue to produce what is known as somatic mosaicism. A growing body of evidence links specific forms of somatic mosaicism with conditions ranging from cardiovascular disease to specific cancers.

Another item for consideration is the comparatively recent discovery that DNA double strand break repair may produce characteristic age-related epigenetic changes regardless of where in the genome it occurs. Mutation rates determined by sequencing the genome, as in the study here, reflect the combination of rate of damage and rate of successful repair. If the important difference between species is the incidence of damage, and particularly incidence of double strand breaks, then the ability of DNA damage to drive age-related epigenetic change may be the important factor.

We can speculate, but at the end of the day the only way to robustly determine whether or not a given mechanism is important in aging is to fix it and see what happens. In the case of stochastic nuclear DNA damage that is something of a tall order. Reversing arbitrary changes in nuclear DNA, cell by cell throughout the body, will remain beyond the capabilities of medical science for some time to come. We can instead envisage relatively near-term approaches, still years distant, such as the complete replacement of a stem cell population supporting a tissue subject to somatic mosaicism, or ways to prevent DNA double strand break repair from causing epigenetic change, and perhaps these would produce compelling data.

Somatic mutation rates scale with lifespan across mammals

The rates and patterns of somatic mutation in normal tissues are largely unknown outside of humans. Comparative analyses can shed light on the diversity of mutagenesis across species, and on long-standing hypotheses about the evolution of somatic mutation rates and their role in cancer and ageing. Here we performed whole-genome sequencing of 208 intestinal crypts from 56 individuals to study the landscape of somatic mutation across 16 mammalian species. We found that somatic mutagenesis was dominated by seemingly endogenous mutational processes in all species, including 5-methylcytosine deamination and oxidative damage. With some differences, mutational signatures in other species resembled those described in humans, although the relative contribution of each signature varied across species.

Notably, the somatic mutation rate per year varied greatly across species and exhibited a strong inverse relationship with species lifespan, with no other life-history trait studied showing a comparable association. Despite widely different life histories among the species we examined-including variation of around 30-fold in lifespan and around 40,000-fold in body mass-the somatic mutation burden at the end of lifespan varied only by a factor of around 3.

The inverse scaling of somatic mutation rates and lifespan is consistent with somatic mutations contributing to ageing and with somatic mutation rates being evolutionarily constrained. This interpretation is also supported by studies reporting more efficient DNA repair in longer-lived species. Somatic mutations could contribute to ageing in different ways. Traditionally, they have been proposed to contribute to ageing through deleterious effects on cellular fitness, but recent findings question this assumption. Instead, the discovery of widespread clonal expansions in ageing human tissues raises the possibility that some somatic mutations contribute to ageing by driving clonal expansions of functionally altered cells at a cost to the organism. Examples include the possible links between clonal haematopoiesis and cardiovascular disease.

Alternative non-causal explanations for the observed anticorrelation between somatic mutation rates and lifespan need to be considered. One alternative explanation is that cell division rates could scale with lifespan and explain the observed somatic mutation rates. Available estimates of cell division rates, although imperfect and limited to a few species, do not readily support this argument. More importantly, studies in humans have shown that cell division rates are not a major determinant of somatic mutation rates across human tissues.

Another alternative explanation for the observed anticorrelation might be that selection acts to reduce germline mutation rates in species with longer reproductive spans, which in turn causes an anticorrelation of somatic mutation rates and lifespan. Although selective pressure on germline mutation rates could influence somatic mutation rates, it is unlikely that germline mutation rates tightly determine somatic mutation rates: somatic mutation rates in humans are 10-20 times higher than germline mutation rates, show variability across cell types and are influenced by additional mutational processes. Overall, the strong scaling of somatic mutation rates with lifespan across mammals suggests that somatic mutation rates themselves have been evolutionarily constrained, possibly through selection on multiple DNA repair pathways. Alternative explanations need to be able to explain the strength of the scaling despite these differences.