Gonzalez, Brenda, Tare, Archana, Ryu, Seungjin, Johnson, Simon, Atzmon, Gil, Barzilai, Nir, Kaeberlein, Matt and Suh, Yousin (2022) High-throughput sequencing analysis of nuclear-encoded mitochondrial genes reveals a genetic signature of human longevity. GeroScience, 45 (1). pp. 311-330. ISSN 2509-2715
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Abstract
Mitochondrial dysfunction is a well-known contributor to aging and age-related diseases. The precise mechanisms through which mitochondria impact human lifespan, however, remain unclear. We hypothesize that humans with exceptional longevity harbor rare variants in nuclear-encoded mitochondrial genes (mitonuclear genes) that confer resistance against age-related mitochondrial dysfunction. Here we report an integrated functional genomics study to identify rare functional variants in ~ 660 mitonuclear candidate genes discovered by target capture sequencing analysis of 496 centenarians and 572 controls of Ashkenazi Jewish descent. We identify and prioritize longevity-associated variants, genes, and mitochondrial pathways that are enriched with rare variants. We provide functional gene variants such as those in MTOR (Y2396Lfs*29), CPS1 (T1406N), and MFN2 (G548*) as well as LRPPRC (S1378G) that is predicted to affect mitochondrial translation. Taken together, our results suggest a functional role for specific mitonuclear genes and pathways in human longevity.
| Item Type: | Article |
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| Additional Information: | Funding Information: This work was supported by NIH grants AG069750, DK127778, AG057433, AG061521, HL150521, AG055501, AG057341, AG057706, AG057909, and AG17242 (Y.S), a grant from The Paul F. Glenn Center for the Biology of Human Aging (Y.S.), a grant GCRLE-1320 (Y.S.) from the Global Consortium for Reproductive Longevity and Equality at the Buck Institute, made possible by the Bia-Echo Foundation, and a grant from The Simons Foundation (Y.S.). B. G. was supported by NIH pre-doctoral aging training grant 6T32AG023475-13. S.R. is the recipient of a Glenn/AFAR Scholarships for Research in the Biology of Aging. M.K. was supported by NIH grant P30AG013280. |
| Uncontrolled Keywords: | Aging, Centenarian, Genetic variant, Longevity, Mitochondria |
| Subjects: | A300 Clinical Medicine C400 Genetics C700 Molecular Biology, Biophysics and Biochemistry |
| Department: | Faculties > Health and Life Sciences > Applied Sciences |
| Depositing User: | Rachel Branson |
| Date Deposited: | 07 Dec 2022 09:13 |
| Last Modified: | 03 Feb 2023 15:00 |
| URI: | https://nrl.northumbria.ac.uk/id/eprint/50819 |
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