Recent Research into Longevity-Associated Human Genes

Today I'll point out a couple of recent publications on the topic of longevity-associated genetic variants in humans. The research community devotes a lot of effort to the identification and confirmation of human genetic variants associated with greater longevity. The cost of obtaining genetic data continues to fall rapidly, and a few years from now will become small in comparison to the other costs of running a study. Ever more researchers are joining in as genetic studies fall within their budgets. In the world of pure scientific endeavor, the quest for knowledge, this is all good. There are few realms as large as that of genetics and cellular biochemistry, and the floodgates of data are opening as never before. Decades of work lie ahead to map even a sizable fraction of the intersection of aging and cellular metabolism at the detail level of molecular biology. In the long term, this is all useful: no data goes to waste, and whatever sort of comprehensive molecular nanotechnology that comes after medicine as we understand it today will require the complete map of human biochemistry as a starting point. That is a long way away, however.

From a practical point of view, in the context of producing ways to treat aging soon enough to matter, establishing the reasons why some people tend to live somewhat longer than others is a sideshow, however. It has little to no relevance to meaningfully extending the healthy human life span for everyone. For one, it is clear from work to date that (a) there are many, many contributing factors to the relationship between genetics and aging, (b) any single factor has a tiny, sometimes almost indistinguishable statistical effect on mortality, and (c) the vast majority of those factors are different for every study population. You can fill a book with the associations found to date and never replicated, while there are only a few genetic variants that hold up in multiple studies, such as APOE. Secondly, given drugs or other therapies that accurately alter genes and protein levels in a human to mimic those of a centenarian, what does that get you? A very small boost to your chances of living more years in a state of advanced aging and increasing frailty. The vast majority of those with the same genetic variants as long-lived study populations die on much the same schedule as the rest of us. If the research community is going to invest time and effort on treatments for aging, then they should at least be treatments with a large expectation value in terms of mortality reduction and healthy life extension.

These studies are representative of the range of work presently taking place: initial identification of possible associations with longevity; confirmation studies discarding the majority of associations found elsewhere; and studies outlining ways to improve the process of identifying genetic associations with longevity.

Genome-Wide Scan Informed by Age-Related Disease Identifies Loci for Exceptional Human Longevity

Longevity is a complex phenotype, and few genetic variants that affect lifespan have been identified. However, aging and disease are closely related, and a great deal is known about the genetic basis of disease risk. Here, we show using genome-wide association studies (GWAS) of longevity and disease that there is an overlap between loci involved in longevity and loci involved in several diseases, such as Alzheimer's disease and coronary artery disease. We then develop a new statistical framework to find genetic variants associated with extreme longevity. The method, informed GWAS (iGWAS), takes advantage of knowledge from 14 large studies of disease and disease-related traits in order to narrow the search for SNPs associated with longevity. Using iGWAS, we found eight SNPs that are significant in our discovery cohorts, and we were able to validate four of these in replication studies of long-lived subjects. Our results implicate new loci in longevity and reveal a genetic overlap between longevity and age-related diseases and traits. Beyond the study of human longevity, iGWAS can be applied to boost statistical power in any GWAS of a target phenotype by using larger GWAS of genetically-related conditions.

In a standard GWAS analysis, only one locus in these studies is significant (APOE/TOMM40). With iGWAS, we identify eight genetic loci to associate significantly with exceptional human longevity. We followed up the eight lead SNPs in independent cohorts, and found replication evidence of four loci and suggestive evidence for one more with exceptional longevity. The loci that replicated included APOE/TOMM40 (associated with Alzheimer's disease), CDKN2B/ANRIL (implicated in the regulation of cellular senescence), ABO (tags the O blood group), and SH2B3/ATXN2 (a signaling gene that extends lifespan in Drosophila and a gene involved in neurological disease).

Association study of polymorphisms in FOXO3, AKT1 and IGF-2R genes with human longevity in a Han Chinese population

FOXO3, AKT1 and IGF-2R are critical members of the insulin/IGF-1 signaling pathway. Previous studies showed that polymorphisms (SNPs) in FOXO3, AKT1 and IGF-2R were associated with human longevity in Caucasian population. However, the association of these SNPs in different ethnic groups is often inconsistent. Here, we investigated the association of genetic variants in three genes with human longevity in Han Chinese population. Twelve SNPs from FOXO3, AKT1 and IGF-2R were selected and genotyped in 1202 long-lived individuals (nonagenarians and centenarians) and younger individuals. Rs9486902 of FOXO3 was found to be associated with human longevity in both genders combined in this study. The other eleven SNPs were not significantly associated with human longevity in Han Chinese population.

Serum BPIFB4 levels classify health status in long-living individuals

People that reach extreme ages (Long-Living Individuals, LLIs) are object of intense investigation for increase/decrease of genetic variant frequencies, genetic methylation levels, protein abundance in serum and tissues. The aim of these studies is the discovery of the mechanisms behind LLIs extreme longevity and the identification of markers of well-being. Our recent multi-step genetic analysis of Italian (the screening set), and US and German LLIs (replication sets) and relative control populations, identified a variant in BPIFB4, down-regulated during aging and high in CD34+ of LLIs, and the codified protein (LAV-BPIFB4) to be a powerful boost for endothelial vasorelaxation and revascularization, two functions lost during aging and cause of human frailty.

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