To be continued.

Carlos Lo´ pez-Otı´n,1,2,3,* Maria A. Blasco,4 Linda Partridge,5,6 Manuel Serrano,7,8,9 and Guido Kroemer10,11,12,*

1 Departamento de Bioquı´mica y Biologı´a Molecular, Instituto Universitario de Oncologı´a (IUOPA), Universidad de Oviedo, Oviedo, Spain

2 Instituto de Investigacio´ n Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain

3 Centro de Investigacio´ n Biome´ dica en Red de Ca´ ncer (CIBERONC), Madrid, Spain

4 Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Madrid, Spain

5 Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, University College London, London, UK

6 Max Planck Institute for Biology of Ageing, Cologne, Germany

7 Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain

8 Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain

9 Altos Labs, Cambridge, UK

10 Centre de Recherche des Cordeliers, Equipe labellise´ e par la Ligue contre le cancer, Universite´ de Paris, Sorbonne Universite´ , INSERM U1138, Institut Universitaire de France, Paris, France

11 Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France

12 Institut du Cancer Paris CARPEM, Department of Biology, Hoˆ pital Europe´ en Georges Pompidou, AP-HP, Paris, France

*Correspondence: 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。 (C.L.-O.), 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。 (G.K.)

https://doi.org/10.1016/j.cell.2022.11.001

SUMMARY

Aging is driven by hallmarks fulfilling the following three premises: (1) their age-associated manifestation, (2) the acceleration of aging by experimentally accentuating them, and (3) the opportunity to decelerate, stop, or reverse aging by therapeutic interventions on them. We propose the following twelve hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. These hallmarks are interconnected among each other, as well as to the recently proposed hallmarks of health, which include organizational features of spatial compartmentalization, maintenance of homeostasis, and adequate responses to strees.

Yuancheng Lu1, Benedikt Brommer2,3,11, Xiao Tian1,11, Anitha Krishnan3,4,11, Margarita Meer5,6,11, Chen Wang2,3, Daniel L. Vera1, Qiurui Zeng1, Doudou Yu1, Michael S. Bonkowski1, Jae-Hyun Yang1, Songlin Zhou2,3, Emma M. Hoffmann3,4, Margarete M. Karg3,4, Michael B. Schultz1, Alice E. Kane1, Noah Davidsohn7, Ekaterina Korobkina3,4, Karolina Chwalek1, Luis A. Rajman1, George M. Church7, Konrad Hochedlinger8, Vadim N. Gladyshev5, Steve Horvath9, Morgan E. Levine6, Meredith S. Gregory-Ksander3,4,* , Bruce R. Ksander3,4,* , Zhigang He2,3,* , David A. Sinclair1,10,*,#

1. Department of Genetics, Blavatnik Institute, Paul F. Glenn Center for Biology of Aging Research, Harvard Medical School, MA, USA;

2. Department of Neurology, Boston Children’s Hospital, Harvard Medical School, MA, USA;

3. Department of Ophthalmology, Harvard Medical School, Boston, MA, USA;

4. Schepens Eye Research Institute of Mass Eye & Ear, Harvard Medical School, MA, USA;

5. Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, MA, USA;

6. Department of Pathology, Yale School of Medicine, New Haven, CT, USA;

7. Department of Genetics, Wyss Institute for Biologically Inspired Engineering, Harvard University, MA, USA;

8. Department of Molecular Biology, Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, MA, USA;

9. Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, CA, USA;

10. Laboratory for Aging Research, Department of Pharmacology, School of Medical Sciences, The University of New South Wales, Sydney, Australia;

11. These authors contributed equally: B. B., X. T., A. K., M. M.;

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Senior authors;

Contributions

Y.L. and D.A.S. conceived the project. Y.L., X.T., and D.A.S. wrote the manuscript with input from all co-authors. Y.L. was involved in all experiments and analyses. M.S.B. and J.-H.Y. provided early training to Y.L.. B.B., C.W., Q.Z., D.Y., S.Z., and Z.H. contributed to the optic nerve crush studies and imaging. A.K., D.Y., Q.Z., E.M.H., E.K., M.S.G.-K., and B.R.K. contributed to the glaucoma and ageing studies. M.M.K. and B.R.K. performed OCT imaging and analysis. M.M. and V.N.G. conducted ribosomal DNAm age analysis for mouse RGCs. M.E.L. developed DNAm ageing signature. D.L.V. performed the RNA-seq and gene association analysis. X.T. conducted human neuron experiments. S.H. conducted human methylation clock analysis. X.T., J.-H.Y., and K.H. helped with transgenic mouse fibroblasts work. M.S.B., X.T., M.B.S., A.E.K., L.A.R., helped with systemic AAV9 experiments. N.D., and G.M.C. helped with plasmid constructs and AAV9 production. K.C. helped with grant applications and project management. M.S.G.-K., B.R.K., Z.H., and D.A.S. jointly supervised this work.

Conflict of interest

D.A.S. is a consultant to, inventor of patents licensed to, board member of and equity owner of Iduna Therapeutics, a Life Biosciences company developing epigenetic reprograming therapies. D.A.S. is an advisor to Zymo Research, an epigenetics tools company. Additional disclosures are at https://genetics.med.harvard.edu/sinclair/people/sinclair-other.php. Y.L., L.A.R. and S.H. are equity owners of Iduna Therapeutics, a Life Biosciences company. D.L.V. is an advisor to Liberty Biosecurity. M.S.B. is a shareholder in MetroBiotech. K.C. is an equity owner in Life Biosciences and affiliates. N.D. and G.M.C. are co-founders of Rejuvenate Bio. Disclosures for G.M.C. can be found at http://arep.med.harvard.edu/gmc/tech.html. M.E.L. is a bioinformatics advisor to Elysium Health. Y.L., N.D. and D.A.S. are inventors on patents arising from this work (WO/2020/069373 and WO/2020/069339), filed by the President and Fellows of Harvard College. The other authors declare no competing interests.