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  3. Distinct longevity mechanisms across and within species and their association with aging

Distinct longevity mechanisms across and within species and their association with aging

  • Cell. 2023 May 26;S0092-8674(23)00476-2. doi: 10.1016/j.cell.2023.05.002.
Alexander Tyshkovskiy 1,  Siming Ma 2,  Anastasia V Shindyapina 2,  Stanislav Tikhonov 3,  Sang-Goo Lee 2,  Perinur Bozaykut 4,  José P Castro 5,  Andrei Seluanov 6,  Nicholas J Schork 7,  Vera Gorbunova 6,  Sergey E Dmitriev 3,  Richard A Miller 8,  Vadim N Gladyshev 9
Affiliations

Affiliations

  • 1 Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow 119234, Russia.
  • 2 Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 3 Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow 119234, Russia.
  • 4 Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Turkey.
  • 5 Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; Aging and Aneuploidy Laboratory, IBMC, Instituto de Biologia Molecular e Celular, Universidade do Porto, 4200-135 Porto, Portugal.
  • 6 Departments of Biology and Medicine, University of Rochester, Rochester, NY, USA.
  • 7 Quantitative Medicine and Systems Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA.
  • 8 Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI 48109, USA.
  • 9 Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute, Cambridge, MA, USA. Electronic address: vgladyshev@rics.bwh.harvard.edu.
PMID: 37269831 DOI: 10.1016/j.cell.2023.05.002
Abstract

Lifespan varies within and across species, but the general principles of its control remain unclear. Here, we conducted multi-tissue RNA-seq analyses across 41 mammalian species, identifying longevity signatures and examining their relationship with transcriptomic biomarkers of aging and established lifespan-extending interventions. An integrative analysis uncovered shared longevity mechanisms within and across species, including downregulated Igf1 and upregulated mitochondrial translation genes, and unique features, such as distinct regulation of the innate immune response and cellular respiration. Signatures of long-lived species were positively correlated with age-related changes and enriched for evolutionarily ancient essential genes, involved in proteolysis and PI3K-Akt signaling. Conversely, lifespan-extending interventions counteracted aging patterns and affected younger, mutable genes enriched for energy metabolism. The identified biomarkers revealed longevity interventions, including KU0063794, which extended mouse lifespan and healthspan. Overall, this study uncovers universal and distinct strategies of lifespan regulation within and across species and provides tools for discovering longevity interventions.

Keywords

Igf1, KU0063794; aging; bowhead whale; gene expression; lifespan extension; longevity; longevity signatures; mSALT; naked mole rat.

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