Ageing is the greatest risk factor for most common chronic human diseases, and it therefore is a logical target for developing interventions to prevent, mitigate or reverse multiple age-related morbidities. Over the past two decades, genetic and pharmacologic interventions targeting conserved pathways of growth and metabolism have consistently led to substantial extension of the lifespan and healthspan in model organisms as diverse as nematodes, flies and mice. Recent genetic analysis of long-lived individuals is revealing common and rare variants enriched in these same conserved pathways that significantly correlate with longevity. In this Perspective, we summarize recent insights into the genetics of extreme human longevity and propose the use of this rare phenotype to identify genetic variants as molecular targets for gaining insight into the physiology of healthy ageing and the development of new therapies to extend the human healthspan.
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We thank M. Guo and R. Kohanski at NIA for their scientific input, which contributed to the concepts outlined in this Perspective. This work was supported by grant U19 AG056278 from the US National Institutes of Health.
J.V. is a founder of Singulomics Corp. P.R. and L.N. are co-founders of NRTK Biosciences. All other authors declare no competing interests.
Peer review information Primary Handling Editor: Pooja Jha.
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Zhang, Z.D., Milman, S., Lin, J. et al. Genetics of extreme human longevity to guide drug discovery for healthy ageing. Nat Metab 2, 663–672 (2020). https://doi.org/10.1038/s42255-020-0247-0