Rare genetic coding variants associated with human longevity and protection against age-related diseases

Autor: Vera Gorbunova, Joydeep Mitra, Tina Gao, M. Reza Jabalameli, Almut Nebel, Matthias Laudes, Paul D. Robbins, Siegfried Görg, Quanwei Zhang, Alan R. Shuldiner, Valerio Napolioni, Kenny Ye, Nir Barzilai, Gil Atzmon, Warren C. Ladiges, Sofiya Milman, Yousin Suh, Guillermo G. Torres, Nha Nguyen, Zhengdong Zhang, Michael D. Greicius, Zhen Wang, Jhih Rong Lin, Jan Vijg, Patrick Sin-Chan, Andre Franke, Laura J. Niedernhofer
Rok vydání: 2021
Předmět:
Zdroj: Nature Aging. 1:783-794
ISSN: 2662-8465
DOI: 10.1038/s43587-021-00108-5
Popis: Extreme longevity in humans has a strong genetic component, but whether this involves genetic variation in the same longevity pathways as found in model organisms is unclear. Using whole-exome sequences of a large cohort of Ashkenazi Jewish centenarians to examine enrichment for rare coding variants, we found most longevity-associated rare coding variants converge upon conserved insulin/insulin-like growth factor 1 signaling and AMP-activating protein kinase signaling pathways. Centenarians have a number of pathogenic rare coding variants similar to control individuals, suggesting that rare variants detected in the conserved longevity pathways are protective against age-related pathology. Indeed, we detected a pro-longevity effect of rare coding variants in the Wnt signaling pathway on individuals harboring the known common risk allele APOE4. The genetic component of extreme human longevity constitutes, at least in part, rare coding variants in pathways that protect against aging, including those that control longevity in model organisms. In this whole-exome sequencing study of the largest centenarian cohort to date, Lin et al. demonstrate that conserved pathways—for example, IIS and AMPK signaling—are as relevant to human longevity and healthy aging as they are in worms, flies and mice.
Databáze: OpenAIRE
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