{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T04:38:12Z","timestamp":1784954292227,"version":"3.55.0"},"reference-count":42,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2020,4,7]],"date-time":"2020-04-07T00:00:00Z","timestamp":1586217600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,4,7]],"date-time":"2020-04-07T00:00:00Z","timestamp":1586217600000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,4,7]],"date-time":"2020-04-07T00:00:00Z","timestamp":1586217600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["AG047745"],"award-info":[{"award-number":["AG047745"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Heritability of human lifespan is 23\u201333% 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 estimated 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.<\/jats:p>","DOI":"10.7554\/elife.53449","type":"journal-article","created":{"date-parts":[[2020,4,6]],"date-time":"2020-04-06T20:01:21Z","timestamp":1586203281000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.53449","source":"Crossref","is-referenced-by-count":20,"title":["Germline burden of rare damaging variants negatively affects human healthspan and lifespan"],"prefix":"10.7554","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7336-3086","authenticated-orcid":true,"given":"Anastasia V","family":"Shindyapina","sequence":"first","affiliation":[{"name":"Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1522-0359","authenticated-orcid":true,"given":"Aleksandr A","family":"Zenin","sequence":"additional","affiliation":[{"name":"Gero LLC, Moscow, Russian Federation"},{"name":"The Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russian Federation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3350-4785","authenticated-orcid":true,"given":"Andrei E","family":"Tarkhov","sequence":"additional","affiliation":[{"name":"Gero LLC, Moscow, Russian Federation"},{"name":"Skolkovo Institute of Science and Technology, Skolkovo Innovation Center, Moscow, Russian Federation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Didac","family":"Santesmasses","sequence":"additional","affiliation":[{"name":"Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter O","family":"Fedichev","sequence":"additional","affiliation":[{"name":"Gero LLC, Moscow, Russian Federation"},{"name":"Moscow Institute of Physics and Technology, Moscow, Russian Federation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0372-7016","authenticated-orcid":true,"given":"Vadim N","family":"Gladyshev","sequence":"additional","affiliation":[{"name":"Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2020,4,7]]},"reference":[{"key":"bib1","volume-title":"Picard Tools","author":"Broad Institute","year":"2018","unstructured":"Broad Institute. 2018. Picard Tools. http:\/\/broadinstitute.github.io\/picard\/."},{"key":"bib2","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1038\/s41586-018-0579-z","article-title":"The UK biobank resource with deep phenotyping and genomic data","volume":"562","author":"Bycroft","year":"2018","journal-title":"Nature"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"80","DOI":"10.4161\/fly.19695","article-title":"A program for annotating and predicting the effects of single Nucleotide Polymorphisms, SnpEff: snps in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3","volume":"6","author":"Cingolani","year":"2012","journal-title":"Fly"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41467-019-11558-2","article-title":"A meta-analysis of genome-wide association studies identifies multiple longevity genes","volume":"10","author":"Deelen","year":"2019","journal-title":"Nature Communications"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"1204","DOI":"10.1016\/j.ajhg.2018.05.002","article-title":"Quantifying the impact of rare and Ultra-rare coding variation across the phenotypic spectrum","volume":"102","author":"Ganna","year":"2018","journal-title":"The American Journal of Human Genetics"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1016\/S0140-6736(15)60175-1","article-title":"5 year mortality predictors in 498 103 UK Biobank participants: a prospective population-based study","volume":"386","author":"Ganna","year":"2015","journal-title":"The Lancet"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1111\/acel.12480","article-title":"Aging: progressive decline in fitness due to the rising deleteriome adjusted by genetic, environmental, and stochastic processes","volume":"15","author":"Gladyshev","year":"2016","journal-title":"Aging Cell"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1038\/nature24277","article-title":"Genetic effects on gene expression across human tissues","volume":"550","author":"GTEx Consortium","year":"2017","journal-title":"Nature"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1007\/BF02185763","article-title":"The heritability of human longevity: a population-based study of 2872 danish twin pairs born 1870-1900","volume":"97","author":"Herskind","year":"1996","journal-title":"Human Genetics"},{"key":"bib10","doi-asserted-by":"publisher","DOI":"10.1101\/572347","article-title":"Whole exome sequencing and characterization of coding variation in2 49,960 individuals in the UK biobank","volume-title":"bioRxiv","author":"Hout","year":"2019"},{"key":"bib11","doi-asserted-by":"publisher","first-page":"15054","DOI":"10.1073\/pnas.1613195113","article-title":"Increased burden of deleterious variants in essential genes in autism spectrum disorder","volume":"113","author":"Ji","year":"2016","journal-title":"PNAS"},{"key":"bib12","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11174","article-title":"Variants near CHRNA3\/5 and APOE have age- and sex-related effects on human lifespan","volume":"7","author":"Joshi","year":"2016","journal-title":"Nature Communications"},{"key":"bib13","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1101\/gr.210609.116","article-title":"Genetic compendium of 1511 human brains available through the UK medical research council brain banks network resource","volume":"27","author":"Keogh","year":"2017","journal-title":"Genome Research"},{"key":"bib14","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1002886","article-title":"Interpretation of genomic variants using a unified biological network approach","volume":"9","author":"Khurana","year":"2013","journal-title":"PLOS Computational Biology"},{"key":"bib15","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1038\/nature19057","article-title":"Analysis of protein-coding genetic variation in 60,706 humans","volume":"536","author":"Lek","year":"2016","journal-title":"Nature"},{"key":"bib16","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1016\/j.ebiom.2015.07.005","article-title":"Genome-wide polygenic burden of rare deleterious variants in sudden unexpected death in epilepsy","volume":"2","author":"Leu","year":"2015","journal-title":"EBioMedicine"},{"key":"bib17","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1038\/nature24267","article-title":"The impact of rare variation on gene expression across tissues","volume":"550","author":"Li","year":"2017","journal-title":"Nature"},{"key":"bib18","doi-asserted-by":"publisher","first-page":"M441","DOI":"10.1093\/gerona\/53A.6.M441","article-title":"The effect of genetic factors for longevity: a comparison of identical and fraternal twins in the swedish twin registry","volume":"53A","author":"Ljungquist","year":"1998","journal-title":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences"},{"key":"bib19","doi-asserted-by":"publisher","first-page":"1505","DOI":"10.1038\/s41588-018-0241-6","article-title":"Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps","volume":"50","author":"Mahajan","year":"2018","journal-title":"Nature Genetics"},{"key":"bib20","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1038\/nrm1310","article-title":"Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics","volume":"5","author":"Maquat","year":"2004","journal-title":"Nature Reviews Molecular Cell Biology"},{"key":"bib21","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-019-0648-4","article-title":"Somatic mutation and clonal expansions in human tissues","volume":"11","author":"Martincorena","year":"2019","journal-title":"Genome Medicine"},{"key":"bib22","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1038\/s41576-019-0183-6","article-title":"The genetics of human ageing","volume":"21","author":"Melzer","year":"2020","journal-title":"Nature Reviews Genetics"},{"key":"bib23","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.5685","article-title":"Age-related somatic mutations in the cancer genome","volume":"6","author":"Milholland","year":"2015","journal-title":"Oncotarget"},{"key":"bib24","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15183","article-title":"Differences between germline and somatic mutation rates in humans and mice","volume":"8","author":"Milholland","year":"2017","journal-title":"Nature Communications"},{"key":"bib25","doi-asserted-by":"publisher","first-page":"2061","DOI":"10.1534\/genetics.108.088526","article-title":"A theory of age-dependent mutation and senescence","volume":"179","author":"Moorad","year":"2008","journal-title":"Genetics"},{"key":"bib26","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2014-005663","article-title":"Do smoking habits differ between women and men in contemporary western populations? evidence from half a million people in the UK biobank study","volume":"4","author":"Peters","year":"2014","journal-title":"BMJ Open"},{"key":"bib27","doi-asserted-by":"publisher","first-page":"2504","DOI":"10.18632\/aging.101334","article-title":"Human longevity: 25 genetic loci associated in 389,166 UK biobank participants","volume":"9","author":"Pilling","year":"2017","journal-title":"Aging"},{"key":"bib28","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1023\/A:1017047212008","article-title":"Mutation and senescence: where genetics and demography meet","volume":"102-103","author":"Promislow","year":"1998","journal-title":"Genetica"},{"key":"bib29","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1086\/519795","article-title":"PLINK: a tool set for whole-genome association and population-based linkage analyses","volume":"81","author":"Purcell","year":"2007","journal-title":"The American Journal of Human Genetics"},{"key":"bib30","article-title":"R: A Language and Environment for Statistical Computing","author":"R Development Core Team","year":"2018","unstructured":"R Development Core Team. 2018. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing. http:\/\/www.r-project.org."},{"key":"bib31","doi-asserted-by":"publisher","first-page":"D886","DOI":"10.1093\/nar\/gky1016","article-title":"CADD: predicting the deleteriousness of variants throughout the human genome","volume":"47","author":"Rentzsch","year":"2019","journal-title":"Nucleic Acids Research"},{"key":"bib32","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1126\/science.1261877","article-title":"Human genomics. Effect of predicted protein-truncating genetic variants on the human transcriptome","volume":"348","author":"Rivas","year":"2015","journal-title":"Science"},{"key":"bib33","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1534\/genetics.118.301613","article-title":"Estimates of the heritability of human longevity are substantially inflated due to assortative mating","volume":"210","author":"Ruby","year":"2018","journal-title":"Genetics"},{"key":"bib34","volume-title":"National Life Tables","author":"Sanders","year":"2017","unstructured":"Sanders S. 2017. United Kingdom. National Life Tables. https:\/\/www.ons.gov.uk\/peoplepopulationandcommunity\/birthsdeathsandmarriages\/lifeexpectancies\/methodologies\/nationallifetablesqmi."},{"key":"bib35","doi-asserted-by":"publisher","first-page":"1167","DOI":"10.1038\/ng.3903","article-title":"The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability","volume":"49","author":"Singh","year":"2017","journal-title":"Nature Genetics"},{"key":"bib36","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv474","article-title":"Haploinsufficiency predictions without study Bias","volume":"43","author":"Steinberg","year":"2015","journal-title":"Nucleic Acids Research"},{"key":"bib37","doi-asserted-by":"publisher","first-page":"11.10.1","DOI":"10.1002\/0471250953.bi1110s43","article-title":"From FastQ data to high confidence variant calls: the genome analysis toolkit best practices pipeline","volume":"43","author":"Van der Auwera","year":"2013","journal-title":"Current Protocols in Bioinformatics"},{"key":"bib38","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/S0027-5107(99)00202-X","article-title":"Somatic mutations and aging: a re-evaluation","volume":"447","author":"Vijg","year":"2000","journal-title":"Mutation Research\/Fundamental and Molecular Mechanisms of Mutagenesis"},{"key":"bib39","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Research"},{"key":"bib40","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1007\/s10519-017-9838-2","article-title":"Phenotypic and genetic relationship between BMI and drinking in a sample of UK adults","volume":"47","author":"Wills","year":"2017","journal-title":"Behavior Genetics"},{"key":"bib41","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-019-0290-0","article-title":"Identification of 12 genetic loci associated with human healthspan","volume":"2","author":"Zenin","year":"2019","journal-title":"Communications Biology"},{"key":"bib42","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1146\/annurev-genet-120417-031501","article-title":"Somatic mutagenesis in mammals and its implications for human disease and aging","volume":"52","author":"Zhang","year":"2018","journal-title":"Annual Review of Genetics"}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/53449\/elife-53449-v2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/53449\/elife-53449-v2.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/53449","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T21:00:57Z","timestamp":1697058057000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/53449"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,7]]},"references-count":42,"alternative-id":["10.7554\/eLife.53449"],"URL":"https:\/\/doi.org\/10.7554\/elife.53449","archive":["CLOCKSS"],"relation":{"references":[{"id-type":"uri","id":"https:\/\/www.ukbiobank.ac.uk","asserted-by":"subject"}],"has-preprint":[{"id-type":"doi","id":"10.1101\/802082","asserted-by":"object"}],"has-review":[{"id-type":"doi","id":"10.7554\/eLife.53449.sa1","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.53449.sa2","asserted-by":"object"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,7]]},"article-number":"e53449"}}