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.