Footprints in the Sand: Deep Taxonomic Comparisons in Vertebrate Genomics to Unveil the Genetic Programs of Human Longevity

Abstract

With the modern quality, quantity, and availability of genomic sequencing across species, as well as across the expanse of human populations, we can screen for shared signatures underlying longevity and lifespan. Knowledge of these mechanisms would be medically invaluable in combating aging and age-related diseases. The diversity of longevities across vertebrates is an opportunity to look for patterns of genetic variation that may signal how this life history property is regulated, and ultimately how it can be modulated. Variation in human longevity provides a unique window to look for cases of extreme lifespan within a population, as well as associations across populations for factors that influence capacity to live longer. Current large cohort studies support the use of population level analyses to identify key factors associating with human lifespan. These studies are powerful in concept, but have demonstrated limited ability to resolve signals from background variation. In parallel, the expanding catalog of sequencing and annotation from diverse species, some of which have evolved longevities well past a human lifespan, provides independent cases to look at the genomic signatures of longevity. Recent comparative genomic work has shown promise in finding shared mechanisms associating with longevity among distantly related vertebrate groups. Given the genetic constraints between vertebrates, we posit that a combination of approaches, of parallel meta-analysis of human longevity along with refined analysis of other vertebrate clades having exceptional longevity, will aid in resolving key regulators of enhanced lifespan that have proven to be elusive when analyzed in isolation.

Refining Convergent Rate Analysis with Topology in Mammalian Longevity and Marine Transitions

“…Human GWAS indicates GSTO2 may be involved in both the risk and age-of-onset of Alzheimer’s Disease ( Allen et al 2012 ). Intersecting data sets in these ways can generate specific testable hypotheses regarding the function of genes that would not be conceived of in isolation ( Treaster et al 2021 ).…”

Thermodynamics and Inflammation: Insights into Quantum Biology and Ageing

“…This, therefore, suggests that one of the simplest explanations of the ageing process is that the loss of homeostasis, which is largely heritable, and involves failing proteostasis (the ability to detect and remove the normal production of damaged components, preventing death by garbage, much like the inefficient removal of rubbish in cities which starts to hinder every other function, such as traffic flow). Although multiple pathways are involved in ageing, and it appears that some are conserved in many species, such as those involving mTOR (mammalian target of rapamycin), DNA repair, resistance to oxidative stress, or telomere length, there are obviously differences in how some species achieve longevity, which makes it difficult to pin down the precise genetic programs that determine human longevity [97]. However, a key element in all life are functional proteins, which have to be correctly folded; if not, this can not only directly reduce the efficiency of a particular pathway, but the incorrectly folded/damaged ones can become toxic to the entire system if they are not cleared, which is why protein homeostasis, or proteostasis, is so important in the ageing process [98].…”

Convergent genomics of longevity in Rockfishes highlights the genetics of human lifespan variation

“…These life-history traits are shaped in evolution through changes in genetic controls, but disentangling these key variations from other species-specific changes is infeasible using isolated species genomes. However, with independent evolutionary occurrences, and analyses capable of bridging diverse genetic contexts, shared signatures within genomes can be identified across species (21). Here, we leverage the exceptional longevity and diversity of rockfishes to identify gene sets underlying the evolution of longevity.…”

“…The conservation of genetic mechanisms between vertebrates (17,18), particularly those regulating aging (19,20), suggests that the mechanisms underlying exceptional longevity may be consistent across species. This concept empowers meta-analyses, where broad evolutionary comparisons of exceptional longevity, within and between species, can refine our knowledge of fundamental mechanisms (21). Here, we leverage the rich diversity of rockfish longevities along with the extensive genome-wide association data available from long-lived humans (22).…”