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  • Perspective
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Genetics of extreme human longevity to guide drug discovery for healthy ageing

Nature Metabolism volume 2, pages 663–672 (2020)Cite this article

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Abstract

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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Fig. 1: Examples of conserved pathways of ageing.
Fig. 2: Genetic architecture of human ageing.
Fig. 3: Discovery of causal variants and genes in genetic studies of complex human traits.
Fig. 4: An integrated approach to drug discovery for healthy human ageing, on the basis of the genomic analysis of extreme longevity.
Fig. 5: Schematic illustration of the InPOINT pipeline.

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Acknowledgements

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.

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Authors and Affiliations

  1. Department of Genetics, Albert Einstein College of Medicine, New York, NY, USA

    Zhengdong D. Zhang, Sofiya Milman, Jhih-Rong Lin, Nir Barzilai, Yousin Suh & Jan Vijg

  2. Department of Medicine, Albert Einstein College of Medicine, New York, NY, USA

    Sofiya Milman & Nir Barzilai

  3. Department of Computational Biology, Weill Institute for Cell and Molecular Biology, Cornell University, New York, NY, USA

    Shayne Wierbowski & Haiyuan Yu

  4. Department of Biology, University of Rochester, Rochester, NY, USA

    Vera Gorbunova

  5. Department of Comparative Medicine, School of Medicine, University of Washington, Seattle, WA, USA

    Warren C. Ladiges

  6. Institute on the Biology of Aging and Metabolism and Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA

    Laura J. Niedernhofer & Paul D. Robbins

  7. Departments of Obstetrics and Gynecology, Genetics and Development, Columbia University, New York, NY, USA

    Yousin Suh

  8. Center for Single-Cell Omics in Aging and Disease, School of Public Health, Shanghai, Jiao Tong University School of Medicine, Shanghai, China

    Jan Vijg

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Contributions

Z.D.Z., V.G., W.C.L., L.J.N., Y.S., P.D.R. and J.V. substantially contributed to the discussion and the writing of the content. Z.D.Z., S.M., J.-R.L., S.W., H.Y., N.B., V.G., W.C.L., L.J.N., Y.S., P.D.R. and J.V. researched content for the article, contributed to writing, and reviewed and edited the manuscript before submission.

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Correspondence to Zhengdong D. Zhang.

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Competing interests

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.

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Peer review information Primary Handling Editor: Pooja Jha.

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Zhang, Z.D., Milman, S., Lin, JR. 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

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