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Peer-reviewedCC BY-NC-NDNature

Universal transcriptomic hallmarks of mammalian ageing and mortality

  • Alexander Tyshkovskiy1
  • Daria Kholdina2,3,4
  • Maria Davitadze2,3,4
  • Adrian Molière3,5
  • Alibek Moldakozhayev6,7,3,8
  • Yoshiyasu Tongu9,10
  • Tomoko Kasahara9,11
  • Dmitrii Glubokov3
  • Alec Eames3
  • Lauren Kats2
  • Anastasiya Vladimirova3,12
  • Kejun Ying3,13
10 more authors
  • Hanna Liu3,14
  • Bohan Zhang3
  • U.N. Khasanova2,4
  • Mahdi Moqri15,3
  • Jeremy M. Van Raamsdonk6,7,16,8
  • David E. Harrison17
  • Randy Strong18
  • Takaaki Abe9,11,19
  • Sergey E. Dmitriev2,4
  • Vadim N. Gladyshev20,21
21 affiliations
  1. 1Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. [email protected]
  2. 2Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, Russia
  3. 3Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
  4. 4Faculty of Bioengineering and Bioinformatics, Moscow State University, Moscow, Russia
  5. 5Institute of Molecular Health Sciences, Department of Biology, ETH Zürich, Zurich, Switzerland
  6. 6Brain Repair and Integrative Neuroscience Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
  7. 7Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
  8. 8Metabolic Disorders and Complications Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
  9. 9Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine, Sendai, Japan
  10. 10Tohoku University School of Medicine, Sendai, Japan
  11. 11Department of Nephrology, Tohoku University Graduate School of Medicine, Sendai, Japan
  12. 12Faculty of Engineering Sciences, Heidelberg University, Heidelberg, Germany
  13. 13T. H. Chan School of Public Health, Harvard University, Boston, MA, USA
  14. 14Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA
  15. 15Department of Genetics, School of Medicine, Stanford University, Stanford, CA, USA
  16. 16Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, Quebec, Canada
  17. 17The Jackson Laboratory, Bar Harbor, ME, USA
  18. 18Geriatric Research, Education and Clinical Center and Research Service, South Texas Veterans Health Care System, Department of Pharmacology, Barshop Institute for Longevity and Aging Studies at The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
  19. 19Division of Medical Science, Tohoku University Graduate School of Biomedical Engineering, Sendai, Japan
  20. 20Broad Institute of Harvard and MIT, Cambridge, MA, USA. [email protected]
  21. 21Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. [email protected]
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Abstract

, yet the underlying molecular mechanisms of this modulation remain unclear. Here we integrate more than 11,000 transcriptomes from more than 25 tissues across 4 mammals (mouse, rat, macaque and human) to develop accurate, interpretable rodent and multi-species biomarkers of chronological age and expected mortality, predicting lifespan-modulating interventions, time to death, chronic diseases and rejuvenation. Ageing-related changes were conserved across species and cell types, revealing universal transcriptomic signatures of mammalian ageing and mortality, including CDKN1A and LGALS3, whose protein levels were also associated with mortality and multimorbidity in UK Biobank. Mortality-associated features were recapitulated across in vivo and in vitro damage-accumulation models, including inflammation, replicative senescence, metabolic inhibition and γ-irradiation, and were attenuated or reversed by cell immortalization, reprogramming, heterochronic parabiosis and early embryogenesis. Network analysis uncovered a modular architecture of ageing- and mortality-associated hallmarks, encompassing inflammation, interferon signalling, mitochondrial function, chromatin modification and extracellular matrix organization. To quantify ageing of individual cellular components, we developed module-specific clocks, which revealed pathway-specific effects of interventions: chronic diseases primarily accelerated inflammatory-module ageing, whereas caloric restriction and Klotho (also known as Kl) deficiency targeted mitochondrial and metabolic modules. Transcriptomic and DNA methylation clocks showed correlated age acceleration in human blood, which was strongest for the chromatin-associated module clock, highlighting mechanistic links between molecular ageing modalities. This study reveals conserved signatures and a modular architecture of mortality regulation, providing a framework for quantifying and targeting ageing of cellular subsystems across species and tissues.

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Cite

BibTeXRIS
BibTeX
@article{tyshkovskiy2026universal,
  title = {{Universal transcriptomic hallmarks of mammalian ageing and mortality}},
  author = {Alexander Tyshkovskiy and Daria Kholdina and Maria Davitadze and Adrian Molière and Alibek Moldakozhayev and Yoshiyasu Tongu and Tomoko Kasahara and Dmitrii Glubokov and Alec Eames and Lauren Kats and Anastasiya Vladimirova and Kejun Ying and Hanna Liu and Bohan Zhang and U.N. Khasanova and Mahdi Moqri and Jeremy M. Van Raamsdonk and David E. Harrison and Randy Strong and Takaaki Abe and Sergey E. Dmitriev and Vadim N. Gladyshev},
  journal = {Nature},
  year = {2026},
  month = may,
  doi = {10.1038/s41586-026-10542-3},
  url = {https://doi.org/10.1038/s41586-026-10542-3},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Universal transcriptomic hallmarks of mammalian ageing and mortality
AU  - Alexander Tyshkovskiy
AU  - Daria Kholdina
AU  - Maria Davitadze
AU  - Adrian Molière
AU  - Alibek Moldakozhayev
AU  - Yoshiyasu Tongu
AU  - Tomoko Kasahara
AU  - Dmitrii Glubokov
AU  - Alec Eames
AU  - Lauren Kats
AU  - Anastasiya Vladimirova
AU  - Kejun Ying
AU  - Hanna Liu
AU  - Bohan Zhang
AU  - U.N. Khasanova
AU  - Mahdi Moqri
AU  - Jeremy M. Van Raamsdonk
AU  - David E. Harrison
AU  - Randy Strong
AU  - Takaaki Abe
AU  - Sergey E. Dmitriev
AU  - Vadim N. Gladyshev
PY  - 2026
DA  - 2026/05/27
JO  - Nature
DO  - 10.1038/s41586-026-10542-3
UR  - https://doi.org/10.1038/s41586-026-10542-3
AB  - , yet the underlying molecular mechanisms of this modulation remain unclear. Here we integrate more than 11,000 transcriptomes from more than 25 tissues across 4 mammals (mouse, rat, macaque and human) to develop accurate, interpretable rodent and multi-species biomarkers of chronological age and expected mortality, predicting lifespan-modulating interventions, time to death, chronic diseases and rejuvenation. Ageing-related changes were conserved across species and cell types, revealing universal transcriptomic signatures of mammalian ageing and mortality, including CDKN1A and LGALS3, whose protein levels were also associated with mortality and multimorbidity in UK Biobank. Mortality-associated features were recapitulated across in vivo and in vitro damage-accumulation models, including inflammation, replicative senescence, metabolic inhibition and γ-irradiation, and were attenuated or reversed by cell immortalization, reprogramming, heterochronic parabiosis and early embryogenesis. Network analysis uncovered a modular architecture of ageing- and mortality-associated hallmarks, encompassing inflammation, interferon signalling, mitochondrial function, chromatin modification and extracellular matrix organization. To quantify ageing of individual cellular components, we developed module-specific clocks, which revealed pathway-specific effects of interventions: chronic diseases primarily accelerated inflammatory-module ageing, whereas caloric restriction and Klotho (also known as Kl) deficiency targeted mitochondrial and metabolic modules. Transcriptomic and DNA methylation clocks showed correlated age acceleration in human blood, which was strongest for the chromatin-associated module clock, highlighting mechanistic links between molecular ageing modalities. This study reveals conserved signatures and a modular architecture of mortality regulation, providing a framework for quantifying and targeting ageing of cellular subsystems across species and tissues.
SN  - 0028-0836
SN  - 1476-4687
ER  -