Fight Aging!

Why are long-lived individuals long-lived? While some evidence suggests that cultural transmission of beneficial lifestyle choices across generations might explain much or all of the phenomenon of long-lived families, and continued examination of large databases of genetic information has tended to reduce the estimated contribution of genetic variants to life expectancy, there continue to be studies demonstrating that older cohorts exhibit fewer of the long list of mutations and variants known to be disadvantageous. The implication here is that small reductions in mortality add up over time and over large populations. The older the population, the greater the odds that any given member will have more beneficial gene variants and fewer harmful gene variants. The effect size for any given variant when it comes to mortality risk does not have to be large for this to be the case.

Given that the effect size for a given gene variant is typically small, and indeed the discovery of a variant that moves average life expectancy by a year or more is big news, is there really much to be gained from the exploration of the genetics of extremely long-lived people? So far the results seem to bear out the pessimistic viewpoint: that this is probably helpful to those working on the long, long road ahead to a complete map of metabolism, how it changes with age, and how that all maps to health outcomes, but that we should not expect useful therapies to slow aging to emerge from this part of the field.

Depletion of loss-of-function germline mutations in centenarians reveals longevity genes

While previous studies identified common genetic variants associated with longevity in centenarians, the role of the rare loss-of-function (LOF) mutation burden remains largely unexplored. Here, we investigated the burden of rare LOF mutations in Ashkenazi Jewish individuals from the Longevity Genes Project and LonGenity study cohorts using whole-exome sequencing data.

In this study, we have discovered that centenarians, within the large cohort we examined, possess a significantly lower burden of predicted deleterious LOF variants compared to controls. This finding suggests that a protective genetic background, characterized by the depletion of damaging coding mutations, contributes to the exceptional longevity of centenarians. Notably, we also observed a lower mutation burden in centenarian offspring, although the effect was less pronounced. These findings support the notion of a heritable component to longevity outside of protective and common variants and suggest that the combined genetic background, including protective variants and depletion of damaging variants, may be transmitted across generations to support exceptional longevity.

Our pathway analysis revealed that centenarian exomes are depleted of LOF variants in several pathways related to aging and disease, including Class A/1 (Rhodopsin-like receptors), hyaluronan metabolism, post-translational protein modification, and mitochondrial translation. Class A/1 (Rhodopsin-like) receptors are involved in various physiological processes and have been implicated in age-related diseases, suggesting their potential role in longevity. Hyaluronan is a key component of the extracellular matrix that has been shown to decline with age, and its increase contributes to the extension of lifespan. Variants that maintain hyaluronan homeostasis may, therefore, promote healthy aging in humans. Post-translational protein modifications play crucial roles in protein function and stability, and their dysregulation has been associated with various age-related diseases. Mitochondrial translation has also been linked to lifespan extension in model organisms.

To complement our analysis of rare LOF variants, we also investigated the causal role of identified longevity genes in aging-related traits using Mendelian randomization (MR) analyzes. This approach allows us to infer potential causal relationships between gene expression and phenotypes of interest by using expression quantitative trait loci, eQTLs (common variants that are associated with gene expression) as instrumental variables. Our MR analyzes provided evidence for the causal effects of several longevity-associated genes, including RGP1, PCNX2, and ANO9, on multiple aging-related traits. PCNX2 was identified to be associated with longevity in an independent genome-wide association study, while ANO9 was associated with various cancers. These findings suggest that these genes may directly influence the aging process and contribute to the extended healthspan and lifespan. The consistent causal effect estimates across different aging-related traits further support the robustness of these associations.