Chapter 167
Changing Aging — 4
By the age of 65 years, 10 percent of the participants with pathogenic or likely pathogenic variants in cancer genes had died. In contrast, in the group of participants without such a variant, 10 percent had died by 73 years of age.
You’ll note the lack of overlap for most of the actionable genes here, which are disease causing, compared with the genomic underpinnings of the aging process, not actionable now, but some of which may be addressed with drugs or ultimately genome editing in the future.
Apolygenic risk score for common variants linked to lifespan was established in nearly seven hundred thousand multiancestry participants and in the UK Biobank separately. Common variants in lipid metabolism genes like LPA, for which medications are emerging; TP53, a DNA repair and when mutated a major cancer predisposition gene; and many others that are linked to risk of heart disease or cancer have been uncovered. Having a polygenic risk score is helpful to dissect the relative contribution of genetics and lifestyle to longevity.
Everything so far mentioned on genomics refers to germline DNA, what we’re conceived with. But there’s another group of genomic mutations that occur during life known as somatic mutations, in our body, not our germline. We’ve learned a lot about these variants from single-cell sequencing: we’re all mosaics! When we age, we accumulate DNA mutations throughout our tissues and cells; therefore, the sets of genes in the cells of our body are far from uniform. We are mosaics of slightly varying genetic codes. And it’s not just aging that does this. Our exposures to environmental factors such as UV light or exogenous chemical agents can cause genomic instability, and it’s not confined to single letter changes or any particular cell type. We’ve seen the importance of jumping genes (transposons) unleashed, moving from one place to another in the three-dimensional genome, and mutations in stem cells that can alter the aging process.
Acheckpoint for genes that are involved in the aging process is to see if evolution conserved them—that they are identical or similar across species. Indeed, many of the gene variants and pathways associated with human lifespan, or their ortholog counterparts, are seen across multiple species. That’s notable given the marked variability in maximum lifespan as seen in figure 12.2.
That differs for somatic mutations and is known as Peto’s paradox. Mammals that live longer accumulate mutations at a slower rate. Those mammals also tend to be larger, with considerably higher cell mass, such that this slower mutation rate may have evolved to protect against cancer. Within many species that have been assessed, smaller size has an associated advantage for longer lifespans.