1. Genetic signature of human longevity in PKC and NF‐κB signaling
- Author
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Ryu, Seungjin, Han, Jeehae, Norden‐Krichmar, Trina M, Zhang, Quanwei, Lee, Seunggeun, Zhang, Zhengdong, Atzmon, Gil, Niedernhofer, Laura J, Robbins, Paul D, Barzilai, Nir, Schork, Nicholas J, and Suh, Yousin
- Subjects
Brain Disorders ,Biotechnology ,Alzheimer's Disease ,Aging ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Acquired Cognitive Impairment ,Dementia ,Neurodegenerative ,Genetics ,Clinical Research ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Genetic Variation ,Humans ,Longevity ,NF-kappa B ,Peptide Fragments ,Protein Kinase C ,Signal Transduction ,centenarian ,genetic variant ,longevity ,PKC ,rare variant ,NF-κB ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
Gene variants associated with longevity are also associated with protection against cognitive decline, dementia and Alzheimer's disease, suggesting that common physiologic pathways act at the interface of longevity and cognitive function. To test the hypothesis that variants in genes implicated in cognitive function may promote exceptional longevity, we performed a comprehensive 3-stage study to identify functional longevity-associated variants in ~700 candidate genes in up to 450 centenarians and 500 controls by target capture sequencing analysis. We found an enrichment of longevity-associated genes in the nPKC and NF-κB signaling pathways by gene-based association analyses. Functional analysis of the top three gene variants (NFKBIA, CLU, PRKCH) suggests that non-coding variants modulate the expression of cognate genes, thereby reducing signaling through the nPKC and NF-κB. This matches genetic studies in multiple model organisms, suggesting that the evolutionary conservation of reduced PKC and NF-κB signaling pathways in exceptional longevity may include humans.
- Published
- 2021