Aging is associated with a continuous accumulation of deleterious changes, consequential loss of function, and development of age-related diseases. The length of time organisms live is a complex trait, influenced by genetic, environmental and stochastic processes. Much effort has been placed at defining the genetic basis of lifespan variation. However, common genetic variants have low effect size and are responsible only for a fraction of human lifespan variation. On the other hand, human genomes also harbor highly damaging variants, such as highly deleterious alleles represented by loss-of-function variants in important genes. These damaging mutations are rare or ultra-rare, but they often have strong effect sizes. While these variants are missed by genotyping, they can be easily detected by exome sequencing, providing an opportunity to quantify their role in age-related diseases, mortality and longevity, if information on these phenotypes is available together with exome sequences. We hypothesize that burden of rare damaging variants influences lifespan and that this effect can be quantified. This would mean that long-lived individuals, especially centenarians, on average are depleted of these mutations, whereas mid-life mortality may be associated with their increased burden. To test this hypothesis, we propose the following: (1) Quantify the impact of burden of rare damaging mutations on human mortality and healthspan. We will examine if higher burden of damaging mutations is associated with increased mortality and an early onset of age-related diseases. To test this possibility, we will determine if longer life is associated with lower burden of rare variants that lead to stop or start codon gain/loss, frameshifting and splicing aberrations. We will apply the methods we developed in preliminary studies to larger cohorts, quantifying the role of rare mutation burden in men and women, determining their effect on the incidence of various age-related diseases as well as on healthspan, assessing the effect of mutation frequency, and identifying genes and pathways affected by damaging mutations. We will further determine if centenarians and other long-lived individuals are depleted of damaging mutations, whereas earlier mortality is associated with them. (2) Examine the association of burden of rare damaging variants with mouse lifespan. We will take advantage of genetically heterogeneous UM-HET3 mice with the known age at death. We will sequence their exomes and determine the effect of rare damaging mutations on longevity. As in humans, we hypothesize that burden of these variants negatively affects mouse lifespan. Comparative analysis of human and mouse damaging mutations will allow us to uncover common features at the level of mutations, genes and pathways. We will further characterize exomes of mice subjected to interventions that extend lifespan. Using this dataset, we will determine if adjusting for mutation burden offers a better statistical support for the observed effect of these interventions.
We propose to define the role of rare protein-truncating mutations in human lifespan and healthspan through state-of-the-art genomic technologies and mouse models. These analyses may pave the way for future aging strategies, targeting highly damaging mutations already in mid-life, thereby decreasing the incidence of age- related diseases in the late life. They may also improve assessment of age-related patterns, disease risks and interventions that extend lifespan and healthspan.
