1. Human Biology and Medicine
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Germline burden of rare damaging variants negatively affects human healthspan and lifespan

  1. Anastasia V Shindyapina
  2. Aleksandr A Zenin
  3. Andrei E Tarkhov
  4. Didac Santesmasses
  5. Peter O Fedichev  Is a corresponding author
  6. Vadim N Gladyshev  Is a corresponding author
  1. Brigham and Women's Hospital, Harvard Medical School, United States
  2. Gero LLC, Russian Federation
Research Article
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Cite this article as: eLife 2020;9:e53449 doi: 10.7554/eLife.53449

Abstract

Heritability of human lifespan is 23-33% as evident from twin studies. Genome-wide association studies explored this question by linking particular alleles to lifespan traits. However, genetic variants identified so far can explain only a small fraction of lifespan heritability in humans. Here, we report that the burden of rarest protein-truncating variants (PTVs) in two large cohorts is negatively associated with human healthspan and lifespan, accounting for 0.4 and 1.3 years of their variability, respectively. In addition, longer-living individuals possess both fewer rarest PTVs and less damaging PTVs. We further find that somatic accumulation of PTVs accounts for only a small fraction of mortality and morbidity acceleration and hence is unlikely to be causal in aging. We conclude that rare damaging mutations, both inherited and accumulated throughout life, contribute to the aging process, and that burden of ultra-rare variants in combination with common alleles better explain apparent heritability of human lifespan.

Article and author information

Author details

  1. Anastasia V Shindyapina

    Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  2. Aleksandr A Zenin

    Research Division, Gero LLC, Moscow, Russian Federation
    Competing interests
    Aleksandr A Zenin, Employed by Gero LLC.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1522-0359
  3. Andrei E Tarkhov

    Research Division, Gero LLC, Moscow, Russian Federation
    Competing interests
    Andrei E Tarkhov, Employed by Gero LLC.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3350-4785
  4. Didac Santesmasses

    Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  5. Peter O Fedichev

    Research Division, Gero LLC, Moscow, Russian Federation
    For correspondence
    peter.fedichev@gero.ai
    Competing interests
    Peter O Fedichev, Founder of Gero LLC.
  6. Vadim N Gladyshev

    Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States
    For correspondence
    vgladyshev@rics.bwh.harvard.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0372-7016

Funding

National Institute on Aging (AG047745)

  • Vadim N Gladyshev

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Deidentified exome sequences were analyzed

Reviewing Editor

  1. Sara Hagg, Karolinska Institutet, Sweden

Publication history

  1. Received: November 8, 2019
  2. Accepted: March 20, 2020
  3. Accepted Manuscript published: April 7, 2020 (version 1)

Copyright

© 2020, Shindyapina et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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