# Role of rare damaging mutations in aging

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $555,217

## Abstract

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 statistica...

## Key facts

- **NIH application ID:** 10403519
- **Project number:** 5R01AG064223-03
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Vadim N. Gladyshev
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $555,217
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10403519

## Citation

> US National Institutes of Health, RePORTER application 10403519, Role of rare damaging mutations in aging (5R01AG064223-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10403519. Licensed CC0.

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