. Rare genetic coding variants associated with human longevity and protection against age-related diseases. Nature Aging, 1, 2021, pp.783–94. Nat Aging.


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  1. Lin et al. have conducted a rigorous evaluation of three independent cohorts (German, UK Biobank, and ADSP longevity cohorts) to investigate key factors in longevity and resilience to age-related diseases including Alzheimer’s. Their results indicate significant longevity associations of functional rare variants in insulin signaling in all three cohorts, and confirm in humans the results of numerous studies using rodent or invertebrate model systems.

    AMPK also showed similar associations in two of three cohorts, but interestingly no associations were observed for mTOR signaling. Further, lifespan was moderated by an interaction between reduced pathogenic rare variant counts and common polygenic disease risk for AD and Type 2 diabetes. This shows that the effects of common diseases related to dysregulation of insulin can be intensified by cumulative rare variant burden. Other findings of interest include the association of Wnt signaling and APOE4 status.

    The findings provide new insights into the architecture of longevity, and a rationale for ongoing therapeutic efforts targeting insulin signaling to enhance longevity and healthspan, and reduce risk of AD.

    View all comments by Suzanne Craft
  2. This is a carefully prepared study of a homogenous cohort of Ashkenazi Jewish centenarians and controls from the same households. The authors used whole-exome sequencing to study rare variant associations (and enrichment) with longevity. While single variant and region-based tests did not reach the Bonferroni-corrected significance level, they found an enrichment of rare coding variants in centenarians vs controls across insulin and AMPK signaling pathways.

    Particularly interesting was the identified interaction between the rare variant allele count in Wnt signaling and APOE4 status. Those variants showed a positive correlation with lifespan among APOE4+ non-centenarians and a general protective effect of rare exonic variants involved in the Wnt pathway.

    In agreement with these new findings, we have previously reported rare variants in the WNT signaling pathway gene, APC,  to be associated with AD (Prokopenko et al., 2020). 

    It is important to note that in their PRS analysis, the authors also show that centenarians have reduced genetic susceptibility to complex diseases such as AD, CAD, and T2D, showing that extreme longevity can largely be explained by reduced risk for multiple complex age-related diseases.


    . Whole-genome sequencing reveals new Alzheimer's disease-associated rare variants in loci related to synaptic function and neuronal development. medRxiv. 2020 Nov 4; PubMed.

    View all comments by Dmitry Prokopenko

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This paper appears in the following:


  1. In Oldest Old, Rare Longevity Variants Suppress Common Pathogenic Ones


  1. APOE C130R (ApoE4)