Genetic signature of human longevity in PKC and NF-κB signaling

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 similar to 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-kappa B 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-kappa B. This matches genetic studies in multiple model organisms, suggesting that the evolutionary conservation of reduced PKC and NF-kappa B signaling pathways in exceptional longevity may include humans.

Automated summary

Gene variants associated with longevity were found to be enriched in the nPKC and NF-kappa B signaling pathways, with non-coding variants modulating the expression of cognate genes to reduce signaling. This matches genetic studies in other model organisms and suggests evolutionary conservation of reduced PKC and NF-kappa B signaling in exceptional longevity, possibly including humans.