Another Way of Searching for Longevity-Related Mechanisms
Researchers are developing all sorts of methods for sifting through the mass of data on protein machinery used in our bodies, and some groups are finding novel ways to identify possible longevity-related proteins: "Despite a 10-100-fold difference in maximum lifespan (MLS), most known mammal species show similar phenotypes of aging. This observation suggests that the genetic determinants of mammalian aging and lifespan may be relatively plastic. The classical evolutionary theory of antagonistic pleiotropy posits that aging is an effect of the decrease in selection pressure that occurs after successful reproduction. Conversely, lifespan extension has been shown to occur when selection pressure increases in later age. Still relatively unexplored are the specific molecular mechanisms that determine differences in mammalian lifespan. Many mechanisms are possible and likely occur simultaneously, including changes in the sequence, structure, function, and expression of RNA and proteins. Here, we focus on changes in proteins caused by fixed substitutions. In this context, two recent studies predicted a simple consequence of the evolutionary theory: we might expect that proteins necessary for long mammalian lifespan would have fewer substitutions, i.e. show more conservation, in long-lived versus short-lived species. Thus, it may be possible to identify aging-related proteins [by] inferring and comparing some measure of such preferential substitutions, here called 'longevity-selected positions', among the several dozen mammal species whose proteomes are available. ... We analyzed 7,590 orthologous protein families in 33 mammalian species, accounting for body mass, phylogeny, and species-specific mutation rate. Overall, we found that the number of longevity-selected positions in the mammalian proteome is much higher than would be expected by chance. Further, these positions are enriched in domains of several proteins that interact with one another in inflammation and other aging-related processes, as well as in organismal development. We present as an example the kinase domain of anti-Müllerian hormone type-2 receptor (AMHR2). AMHR2 inhibits ovarian follicle recruitment and growth, and [its] longevity-selected positions cluster near a SNP associated with delayed human menopause. Distinct from its canonical role in development, this region of AMHR2 may function to regulate the protein's activity in a lifespan-specific manner."