Aging is under genetic control in the sense that species have different genomes, different life spans, and different manifestations of aging within those life spans. Within any given species, it is far from clear that genetic variation has a large enough influence to care about. Individuals vary, but the evidence strongly suggests that this is near all due to environmental rather than genetic differences. Where there are genetic differences, the old who survive to benefit from them are still old people, greatly impacted by aging and trapped in a downward spiral of dysfunction.
The author of this commentary uses the gene PTTG1 as a starting point for a discussion of the genetics and evolution of aging across species, but again, this really doesn't have to mean that PTTG1 and its effects on metabolism are necessarily a place to start the development of therapies to treat aging in humans. Relevance in the former does not automatically lead to relevance in the latter. The research community should look less to differences between individuals and more to addressing the known causes of aging, mechanisms that are the same in all individuals of a given species.
Why do we get old? How much of aging is genetic? And in what genes? There is clearly a genetic basis of aging, as demonstrated from yeast to worms to humans. As one example, different mouse strains have different potential lifespans. Much effort has been invested in understanding the genetic underpinnings of lifespan differences between the long-lived C57Bl/6 strain and the short-lived DBA/2 strain, with 50% mortality in captivity by 914 and 687 days, respectively. Quantitative trait loci mapping in C57Bl/6 X DBA/2 (BXD) recombinant inbred strains identified a locus on chromosome 11 that is linked to lifespan. Subsequent analyses revealed that this locus confers differential expression of the pituitary tumor-transforming gene-1 (Pttg1)/Securin gene. PTTG1 level-dependent impacts on chromosomal segregation during mitosis could influence longevity.
Natural selection only acts to promote longevity to the extent that it benefits the passage of genetic material to subsequent generations. Different animals have evolved different strategies for somatic maintenance that maximize reproductive success, and the extension of youth through additional investment in tissue maintenance would be disfavored if the costs (often manifested through reduced investment in reproduction) outweigh benefits. For a small vulnerable animal like a field mouse that faces high extrinsic hazards (such as predation), natural selection has favored a "fast" life history - a breed early, breed often strategy with little investment in longevity. For larger animals like humans, elephants, and whales, or for animals like tortoises, moles, bats and birds that have evolved other strategies to greatly reduce extrinsic hazards, natural selection has favored a "slow" life history, with greater and/or prolonged tissue maintenance leading to longer potential lifespans.
While we understand how natural selection has shaped the pathways that control longevity, we know less about what these pathways actually are. Studies from model organisms have clearly demonstrated that modulation of the insulin-like growth factor-1 (IGF-1) pathway, which positively regulates the mTOR pathway and negatively regulates autophagy, can significantly impact longevity. Decreases in IGF-1 and mTOR, or increases in autophagy, have been shown to prolong lifespans in organisms ranging from yeast to mammals. Additional studies have shown how inflammation can contribute to aging-associated phenotypes, and polymorphisms in genes controlling the IGF-1 pathway and inflammation are enriched in human centenarians, but the extent to which these polymorphisms and their impact on inflammation are contributing to differences in longevity has not been established.
While genetic screens in model organisms have revealed key pathways that regulate lifespan, the mechanisms employed by natural selection in the evolution of lifespans largely remain a mystery. Although one could argue that the selective breeding to generate different mouse strains over the last couple of centuries may not qualify as "natural" selection, the studies focused on PTTG1 reveal at least one potential (and novel) mediator of lifespan control. Key questions remain: Do variations in PTTG1 expression or activity contribute to lifespan differences across species, and perhaps within a species (including variability in the human population)? Would modulation of PTTG1 expression or activity promote the extension of healthspan or lifespan? How do activities known to modulate lifespan, such as dietary restriction and exercise, influence PTTG1 activity? Are there links between known aging pathways such as via IGF-1 and PTTG1? Good science generates good questions, leading to new insights (and sometimes even solutions). As a senior colleague once told me after I had told him that I worked on aging - "Hurry up".