Universal DNA methylation age across mammalian tissues

A. T. Lu; Z. Fei; A. Haghani; T. R. Robeck; J. A. Zoller; C. Z. Li; R. Lowe; Q. Yan; J. Zhang; H. Vu; J. Ablaeva; V. A. Acosta-Rodriguez; D. M. Adams; J. Almunia; A. Aloysius; R. Ardehali; A. Arneson; C. S. Baker; G. Banks; K. Belov; N. C. Bennett; P. Black; D. T. Blumstein; E. K. Bors; C. E. Breeze; R. T. Brooke; J. L. Brown; G. G. Carter; A. Caulton; J. M. Cavin; L. Chakrabarti; I. Chatzistamou; H. Chen; K. Cheng; P. Chiavellini; O. W. Choi; S. M. Clarke; L. N. Cooper; M. L. Cossette; J. Day; J. DeYoung; S. DiRocco; C. Dold; E. E. Ehmke; C. K. Emmons; S. Emmrich; E. Erbay; C. Erlacher-Reid; C. G. Faulkes; S. H. Ferguson; C. J. Finno; J. E. Flower; J. M. Gaillard; E. Garde; L. Gerber; V. N. Gladyshev; V. Gorbunova; R. G. Goya; M. J. Grant; C. B. Green; E. N. Hales; M. B. Hanson; D. W. Hart; M. Haulena; K. Herrick; A. N. Hogan; C. J. Hogg; T. A. Hore; T. Huang; J. C. Izpisua Belmonte; A. J. Jasinska; G. Jones; E. Jourdain; O. Kashpur; H. Katcher; E. Katsumata; V. Kaza; H. Kiaris; M. S. Kobor; P. Kordowitzki; W. R. Koski; M. Krützen; S. B. Kwon; B. Larison; S. G. Lee; M. Lehmann; J. F. Lemaitre; A. J. Levine; C. Li; X. Li; A. R. Lim; D. T.S. Lin; D. M. Lindemann; T. J. Little; N. Macoretta; D. Maddox; C. O. Matkin; J. A. Mattison; M. McClure; J. Mergl; J. J. Meudt; G. A. Montano; K. Mozhui; J. Munshi-South; A. Naderi; M. Nagy; P. Narayan; P. W. Nathanielsz; N. B. Nguyen; C. Niehrs; J. K. O’Brien; P. O’Tierney Ginn; D. T. Odom; A. G. Ophir; S. Osborn; E. A. Ostrander; K. M. Parsons; K. C. Paul; M. Pellegrini; K. J. Peters; A. B. Pedersen; J. L. Petersen; D. W. Pietersen; G. M. Pinho; J. Plassais; J. R. Poganik; N. A. Prado; P. Reddy; B. Rey; B. R. Ritz; J. Robbins; M. Rodriguez; J. Russell; E. Rydkina; L. L. Sailer; A. B. Salmon; A. Sanghavi; K. M. Schachtschneider; D. Schmitt; T. Schmitt; L. Schomacher; L. B. Schook; K. E. Sears; A. W. Seifert; A. Seluanov; A. B.A. Shafer; D. Shanmuganayagam; A. V. Shindyapina; M. Simmons; K. Singh; I. Sinha; J. Slone; R. G. Snell; E. Soltanmaohammadi; M. L. Spangler; M. C. Spriggs; L. Staggs; N. Stedman; K. J. Steinman; D. T. Stewart; V. J. Sugrue; B. Szladovits; J. S. Takahashi; M. Takasugi; E. C. Teeling; M. J. Thompson; B. Van Bonn; S. C. Vernes; D. Villar; H. V. Vinters; M. C. Wallingford; N. Wang; R. K. Wayne; G. S. Wilkinson; C. K. Williams; R. W. Williams; X. W. Yang; M. Yao; B. G. Young; B. Zhang; Z. Zhang; P. Zhao; Y. Zhao; W. Zhou; J. Zimmermann; J. Ernst; K. Raj; S. Horvath

doi:10.1038/s43587-023-00462-6

Universal DNA methylation age across mammalian tissues

A. T. Lu, Z. Fei, A. Haghani, T. R. Robeck, J. A. Zoller, C. Z. Li, R. Lowe, Q. Yan, J. Zhang, H. Vu, J. Ablaeva, V. A. Acosta-Rodriguez, D. M. Adams, J. Almunia, A. Aloysius, R. Ardehali, A. Arneson, C. S. Baker, G. Banks, K. BelovN. C. Bennett, P. Black, D. T. Blumstein, E. K. Bors, C. E. Breeze, R. T. Brooke, J. L. Brown, G. G. Carter, A. Caulton, J. M. Cavin, L. Chakrabarti, I. Chatzistamou, H. Chen, K. Cheng, P. Chiavellini, O. W. Choi, S. M. Clarke, L. N. Cooper, M. L. Cossette, J. Day, J. DeYoung, S. DiRocco, C. Dold, E. E. Ehmke, C. K. Emmons, S. Emmrich, E. Erbay, C. Erlacher-Reid, C. G. Faulkes, S. H. Ferguson, C. J. Finno, J. E. Flower, J. M. Gaillard, E. Garde, L. Gerber, V. N. Gladyshev, V. Gorbunova, R. G. Goya, M. J. Grant, C. B. Green, E. N. Hales, M. B. Hanson, D. W. Hart, M. Haulena, K. Herrick, A. N. Hogan, C. J. Hogg, T. A. Hore, T. Huang, J. C. Izpisua Belmonte, A. J. Jasinska, G. Jones, E. Jourdain, O. Kashpur, H. Katcher, E. Katsumata, V. Kaza, H. Kiaris, M. S. Kobor, P. Kordowitzki, W. R. Koski, M. Krützen, S. B. Kwon, B. Larison, S. G. Lee, M. Lehmann, J. F. Lemaitre, A. J. Levine, C. Li, X. Li, A. R. Lim, D. T.S. Lin, D. M. Lindemann, T. J. Little, N. Macoretta, D. Maddox, C. O. Matkin, J. A. Mattison, M. McClure, J. Mergl, J. J. Meudt, G. A. Montano, K. Mozhui, J. Munshi-South, A. Naderi, M. Nagy, P. Narayan, P. W. Nathanielsz, N. B. Nguyen, C. Niehrs, J. K. O’Brien, P. O’Tierney Ginn, D. T. Odom, A. G. Ophir, S. Osborn, E. A. Ostrander, K. M. Parsons, K. C. Paul, M. Pellegrini, K. J. Peters, A. B. Pedersen, J. L. Petersen, D. W. Pietersen, G. M. Pinho, J. Plassais, J. R. Poganik, N. A. Prado, P. Reddy, B. Rey, B. R. Ritz, J. Robbins, M. Rodriguez, J. Russell, E. Rydkina, L. L. Sailer, A. B. Salmon, A. Sanghavi, K. M. Schachtschneider, D. Schmitt, T. Schmitt, L. Schomacher, L. B. Schook, K. E. Sears, A. W. Seifert, A. Seluanov, A. B.A. Shafer, D. Shanmuganayagam, A. V. Shindyapina, M. Simmons, K. Singh, I. Sinha, J. Slone, R. G. Snell, E. Soltanmaohammadi, M. L. Spangler, M. C. Spriggs, L. Staggs, N. Stedman, K. J. Steinman, D. T. Stewart, V. J. Sugrue, B. Szladovits, J. S. Takahashi, M. Takasugi, E. C. Teeling, M. J. Thompson, B. Van Bonn, S. C. Vernes, D. Villar, H. V. Vinters, M. C. Wallingford, N. Wang, R. K. Wayne, G. S. Wilkinson, C. K. Williams, R. W. Williams, X. W. Yang, M. Yao, B. G. Young, B. Zhang, Z. Zhang, P. Zhao, Y. Zhao, W. Zhou, J. Zimmermann, J. Ernst, K. Raj, S. Horvath

Animal Sciences

Research output: Contribution to journal › Article › peer-review

Abstract

Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.

Original language	English (US)
Pages (from-to)	1144-1166
Number of pages	23
Journal	Nature Aging
Volume	3
Issue number	9
Early online date	Aug 10 2023
DOIs	https://doi.org/10.1038/s43587-023-00462-6
State	Published - Sep 2023

ASJC Scopus subject areas

Neuroscience (miscellaneous)
Aging
Geriatrics and Gerontology

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10.1038/s43587-023-00462-6License: CC BY

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Lu, A. T., Fei, Z., Haghani, A., Robeck, T. R., Zoller, J. A., Li, C. Z., Lowe, R., Yan, Q., Zhang, J., Vu, H., Ablaeva, J., Acosta-Rodriguez, V. A., Adams, D. M., Almunia, J., Aloysius, A., Ardehali, R., Arneson, A., Baker, C. S., Banks, G., ... Horvath, S. (2023). Universal DNA methylation age across mammalian tissues. Nature Aging, 3(9), 1144-1166. https://doi.org/10.1038/s43587-023-00462-6

Lu, AT, Fei, Z, Haghani, A, Robeck, TR, Zoller, JA, Li, CZ, Lowe, R, Yan, Q, Zhang, J, Vu, H, Ablaeva, J, Acosta-Rodriguez, VA, Adams, DM, Almunia, J, Aloysius, A, Ardehali, R, Arneson, A, Baker, CS, Banks, G, Belov, K, Bennett, NC, Black, P, Blumstein, DT, Bors, EK, Breeze, CE, Brooke, RT, Brown, JL, Carter, GG, Caulton, A, Cavin, JM, Chakrabarti, L, Chatzistamou, I, Chen, H, Cheng, K, Chiavellini, P, Choi, OW, Clarke, SM, Cooper, LN, Cossette, ML, Day, J, DeYoung, J, DiRocco, S, Dold, C, Ehmke, EE, Emmons, CK, Emmrich, S, Erbay, E, Erlacher-Reid, C, Faulkes, CG, Ferguson, SH, Finno, CJ, Flower, JE, Gaillard, JM, Garde, E, Gerber, L, Gladyshev, VN, Gorbunova, V, Goya, RG, Grant, MJ, Green, CB, Hales, EN, Hanson, MB, Hart, DW, Haulena, M, Herrick, K, Hogan, AN, Hogg, CJ, Hore, TA, Huang, T, Izpisua Belmonte, JC, Jasinska, AJ, Jones, G, Jourdain, E, Kashpur, O, Katcher, H, Katsumata, E, Kaza, V, Kiaris, H, Kobor, MS, Kordowitzki, P, Koski, WR, Krützen, M, Kwon, SB, Larison, B, Lee, SG, Lehmann, M, Lemaitre, JF, Levine, AJ, Li, C, Li, X, Lim, AR, Lin, DTS, Lindemann, DM, Little, TJ, Macoretta, N, Maddox, D, Matkin, CO, Mattison, JA, McClure, M, Mergl, J, Meudt, JJ, Montano, GA, Mozhui, K, Munshi-South, J, Naderi, A, Nagy, M, Narayan, P, Nathanielsz, PW, Nguyen, NB, Niehrs, C, O’Brien, JK, O’Tierney Ginn, P, Odom, DT, Ophir, AG, Osborn, S, Ostrander, EA, Parsons, KM, Paul, KC, Pellegrini, M, Peters, KJ, Pedersen, AB, Petersen, JL, Pietersen, DW, Pinho, GM, Plassais, J, Poganik, JR, Prado, NA, Reddy, P, Rey, B, Ritz, BR, Robbins, J, Rodriguez, M, Russell, J, Rydkina, E, Sailer, LL, Salmon, AB, Sanghavi, A, Schachtschneider, KM, Schmitt, D, Schmitt, T, Schomacher, L, Schook, LB, Sears, KE, Seifert, AW, Seluanov, A, Shafer, ABA, Shanmuganayagam, D, Shindyapina, AV, Simmons, M, Singh, K, Sinha, I, Slone, J, Snell, RG, Soltanmaohammadi, E, Spangler, ML, Spriggs, MC, Staggs, L, Stedman, N, Steinman, KJ, Stewart, DT, Sugrue, VJ, Szladovits, B, Takahashi, JS, Takasugi, M, Teeling, EC, Thompson, MJ, Van Bonn, B, Vernes, SC, Villar, D, Vinters, HV, Wallingford, MC, Wang, N, Wayne, RK, Wilkinson, GS, Williams, CK, Williams, RW, Yang, XW, Yao, M, Young, BG, Zhang, B, Zhang, Z, Zhao, P, Zhao, Y, Zhou, W, Zimmermann, J, Ernst, J, Raj, K & Horvath, S 2023, 'Universal DNA methylation age across mammalian tissues', Nature Aging, vol. 3, no. 9, pp. 1144-1166. https://doi.org/10.1038/s43587-023-00462-6

@article{d5d8874524e74dc6942134c7f87a2bf5,

title = "Universal DNA methylation age across mammalian tissues",

abstract = "Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.",

author = "Lu, \{A. T.\} and Z. Fei and A. Haghani and Robeck, \{T. R.\} and Zoller, \{J. A.\} and Li, \{C. Z.\} and R. Lowe and Q. Yan and J. Zhang and H. Vu and J. Ablaeva and Acosta-Rodriguez, \{V. A.\} and Adams, \{D. M.\} and J. Almunia and A. Aloysius and R. Ardehali and A. Arneson and Baker, \{C. S.\} and G. Banks and K. Belov and Bennett, \{N. C.\} and P. Black and Blumstein, \{D. T.\} and Bors, \{E. K.\} and Breeze, \{C. E.\} and Brooke, \{R. T.\} and Brown, \{J. L.\} and Carter, \{G. G.\} and A. Caulton and Cavin, \{J. M.\} and L. Chakrabarti and I. Chatzistamou and H. Chen and K. Cheng and P. Chiavellini and Choi, \{O. W.\} and Clarke, \{S. M.\} and Cooper, \{L. N.\} and Cossette, \{M. L.\} and J. Day and J. DeYoung and S. DiRocco and C. Dold and Ehmke, \{E. E.\} and Emmons, \{C. K.\} and S. Emmrich and E. Erbay and C. Erlacher-Reid and Faulkes, \{C. G.\} and Ferguson, \{S. H.\} and Finno, \{C. J.\} and Flower, \{J. E.\} and Gaillard, \{J. M.\} and E. Garde and L. Gerber and Gladyshev, \{V. N.\} and V. Gorbunova and Goya, \{R. G.\} and Grant, \{M. J.\} and Green, \{C. B.\} and Hales, \{E. N.\} and Hanson, \{M. B.\} and Hart, \{D. W.\} and M. Haulena and K. Herrick and Hogan, \{A. N.\} and Hogg, \{C. J.\} and Hore, \{T. A.\} and T. Huang and \{Izpisua Belmonte\}, \{J. C.\} and Jasinska, \{A. J.\} and G. Jones and E. Jourdain and O. Kashpur and H. Katcher and E. Katsumata and V. Kaza and H. Kiaris and Kobor, \{M. S.\} and P. Kordowitzki and Koski, \{W. R.\} and M. Kr{\"u}tzen and Kwon, \{S. B.\} and B. Larison and Lee, \{S. G.\} and M. Lehmann and Lemaitre, \{J. F.\} and Levine, \{A. J.\} and C. Li and X. Li and Lim, \{A. R.\} and Lin, \{D. T.S.\} and Lindemann, \{D. M.\} and Little, \{T. J.\} and N. Macoretta and D. Maddox and Matkin, \{C. O.\} and Mattison, \{J. A.\} and M. McClure and J. Mergl and Meudt, \{J. J.\} and Montano, \{G. A.\} and K. Mozhui and J. Munshi-South and A. Naderi and M. Nagy and P. Narayan and Nathanielsz, \{P. W.\} and Nguyen, \{N. B.\} and C. Niehrs and O{\textquoteright}Brien, \{J. K.\} and \{O{\textquoteright}Tierney Ginn\}, P. and Odom, \{D. T.\} and Ophir, \{A. G.\} and S. Osborn and Ostrander, \{E. A.\} and Parsons, \{K. M.\} and Paul, \{K. C.\} and M. Pellegrini and Peters, \{K. J.\} and Pedersen, \{A. B.\} and Petersen, \{J. L.\} and Pietersen, \{D. W.\} and Pinho, \{G. M.\} and J. Plassais and Poganik, \{J. R.\} and Prado, \{N. A.\} and P. Reddy and B. Rey and Ritz, \{B. R.\} and J. Robbins and M. Rodriguez and J. Russell and E. Rydkina and Sailer, \{L. L.\} and Salmon, \{A. B.\} and A. Sanghavi and Schachtschneider, \{K. M.\} and D. Schmitt and T. Schmitt and L. Schomacher and Schook, \{L. B.\} and Sears, \{K. E.\} and Seifert, \{A. W.\} and A. Seluanov and Shafer, \{A. B.A.\} and D. Shanmuganayagam and Shindyapina, \{A. V.\} and M. Simmons and K. Singh and I. Sinha and J. Slone and Snell, \{R. G.\} and E. Soltanmaohammadi and Spangler, \{M. L.\} and Spriggs, \{M. C.\} and L. Staggs and N. Stedman and Steinman, \{K. J.\} and Stewart, \{D. T.\} and Sugrue, \{V. J.\} and B. Szladovits and Takahashi, \{J. S.\} and M. Takasugi and Teeling, \{E. C.\} and Thompson, \{M. J.\} and \{Van Bonn\}, B. and Vernes, \{S. C.\} and D. Villar and Vinters, \{H. V.\} and Wallingford, \{M. C.\} and N. Wang and Wayne, \{R. K.\} and Wilkinson, \{G. S.\} and Williams, \{C. K.\} and Williams, \{R. W.\} and Yang, \{X. W.\} and M. Yao and Young, \{B. G.\} and B. Zhang and Z. Zhang and P. Zhao and Y. Zhao and W. Zhou and J. Zimmermann and J. Ernst and K. Raj and S. Horvath",

note = "This work was mainly supported by the Paul G. Allen Frontiers Group (S.H.). Additional support was also provided by the Open Philanthropy–Silicon Valley Fund (S.H. and K.R.). J.E. was supported by UCLA Jonsson Comprehensive Cancer Center and Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research Ablon Scholars Program. J.A.M. and the NHP Core were supported by the Intramural Research Program, National Institute on Aging, NIH. Plains zebra sample collection was supported by National Geographic Society grant 8941-11. We acknowledge the Museum of Vertebrate Zoology and C.J. Conroy from the University of California, Berkeley. We acknowledge R. Miller and his laboratory (http://www.richmillerlab.com/long-lived-mutants) for providing dwarf mice and controls (Snell dwarf mouse, GHRKO experiments). Lemur sample collections were supported by Duke Lemur Center. N.C.B. was funded by a DST-NRF SARChI chair of Mammalian Behavioural Ecology and Physiology (GUN 64756). V.N.G., A.S. and V.G. were supported by NIA grants. V.G. was supported by the Milky Way Research Foundation. D.T.O. was supported by European Research Council (788937) and Cancer Research UK (20412). The FHS is funded by National Institutes of Health contracts N01-HC-25195 and HHSN268201500001I. The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health. The analytical component of this project was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute and the Center for Information Technology, National Institutes of Health. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C and HHSN268201600004C. We thank the WHI investigators and staff for their dedication and the study participants for making the program possible. A full listing of WHI investigators can be found at https://www.whi.org/doc/WHI-Investigator-Long-List.pdf. The views expressed in this study are those of the authors and do not necessarily represent the views of funding bodies such as the National Heart, Lung, and Blood Institute, the National Institutes of Health or the U.S. Department of Health and Human Services. This work was mainly supported by the Paul G. Allen Frontiers Group (S.H.). Additional support was also provided by the Open Philanthropy–Silicon Valley Fund (S.H. and K.R.). J.E. was supported by UCLA Jonsson Comprehensive Cancer Center and Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research Ablon Scholars Program. J.A.M. and the NHP Core were supported by the Intramural Research Program, National Institute on Aging, NIH. Plains zebra sample collection was supported by National Geographic Society grant 8941-11. We acknowledge the Museum of Vertebrate Zoology and C.J. Conroy from the University of California, Berkeley. We acknowledge R. Miller and his laboratory ( http://www.richmillerlab.com/long-lived-mutants ) for providing dwarf mice and controls (Snell dwarf mouse, GHRKO experiments). Lemur sample collections were supported by Duke Lemur Center. N.C.B. was funded by a DST-NRF SARChI chair of Mammalian Behavioural Ecology and Physiology (GUN 64756). V.N.G., A.S. and V.G. were supported by NIA grants. V.G. was supported by the Milky Way Research Foundation. D.T.O. was supported by European Research Council (788937) and Cancer Research UK (20412). The FHS is funded by National Institutes of Health contracts N01-HC-25195 and HHSN268201500001I. The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health. The analytical component of this project was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute and the Center for Information Technology, National Institutes of Health. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C and HHSN268201600004C. We thank the WHI investigators and staff for their dedication and the study participants for making the program possible. A full listing of WHI investigators can be found at https://www.whi.org/doc/WHI-Investigator-Long-List.pdf . The views expressed in this study are those of the authors and do not necessarily represent the views of funding bodies such as the National Heart, Lung, and Blood Institute, the National Institutes of Health or the U.S. Department of Health and Human Services.",

year = "2023",

month = sep,

doi = "10.1038/s43587-023-00462-6",

language = "English (US)",

volume = "3",

pages = "1144--1166",

journal = "Nature Aging",

issn = "2662-8465",

publisher = "Springer",

number = "9",

}

TY - JOUR

T1 - Universal DNA methylation age across mammalian tissues

AU - Lu, A. T.

AU - Fei, Z.

AU - Haghani, A.

AU - Robeck, T. R.

AU - Zoller, J. A.

AU - Li, C. Z.

AU - Lowe, R.

AU - Yan, Q.

AU - Zhang, J.

AU - Vu, H.

AU - Ablaeva, J.

AU - Acosta-Rodriguez, V. A.

AU - Adams, D. M.

AU - Almunia, J.

AU - Aloysius, A.

AU - Ardehali, R.

AU - Arneson, A.

AU - Baker, C. S.

AU - Banks, G.

AU - Belov, K.

AU - Bennett, N. C.

AU - Black, P.

AU - Blumstein, D. T.

AU - Bors, E. K.

AU - Breeze, C. E.

AU - Brooke, R. T.

AU - Brown, J. L.

AU - Carter, G. G.

AU - Caulton, A.

AU - Cavin, J. M.

AU - Chakrabarti, L.

AU - Chatzistamou, I.

AU - Chen, H.

AU - Cheng, K.

AU - Chiavellini, P.

AU - Choi, O. W.

AU - Clarke, S. M.

AU - Cooper, L. N.

AU - Cossette, M. L.

AU - Day, J.

AU - DeYoung, J.

AU - DiRocco, S.

AU - Dold, C.

AU - Ehmke, E. E.

AU - Emmons, C. K.

AU - Emmrich, S.

AU - Erbay, E.

AU - Erlacher-Reid, C.

AU - Faulkes, C. G.

AU - Ferguson, S. H.

AU - Finno, C. J.

AU - Flower, J. E.

AU - Gaillard, J. M.

AU - Garde, E.

AU - Gerber, L.

AU - Gladyshev, V. N.

AU - Gorbunova, V.

AU - Goya, R. G.

AU - Grant, M. J.

AU - Green, C. B.

AU - Hales, E. N.

AU - Hanson, M. B.

AU - Hart, D. W.

AU - Haulena, M.

AU - Herrick, K.

AU - Hogan, A. N.

AU - Hogg, C. J.

AU - Hore, T. A.

AU - Huang, T.

AU - Izpisua Belmonte, J. C.

AU - Jasinska, A. J.

AU - Jones, G.

AU - Jourdain, E.

AU - Kashpur, O.

AU - Katcher, H.

AU - Katsumata, E.

AU - Kaza, V.

AU - Kiaris, H.

AU - Kobor, M. S.

AU - Kordowitzki, P.

AU - Koski, W. R.

AU - Krützen, M.

AU - Kwon, S. B.

AU - Larison, B.

AU - Lee, S. G.

AU - Lehmann, M.

AU - Lemaitre, J. F.

AU - Levine, A. J.

AU - Li, C.

AU - Li, X.

AU - Lim, A. R.

AU - Lin, D. T.S.

AU - Lindemann, D. M.

AU - Little, T. J.

AU - Macoretta, N.

AU - Maddox, D.

AU - Matkin, C. O.

AU - Mattison, J. A.

AU - McClure, M.

AU - Mergl, J.

AU - Meudt, J. J.

AU - Montano, G. A.

AU - Mozhui, K.

AU - Munshi-South, J.

AU - Naderi, A.

AU - Nagy, M.

AU - Narayan, P.

AU - Nathanielsz, P. W.

AU - Nguyen, N. B.

AU - Niehrs, C.

AU - O’Brien, J. K.

AU - O’Tierney Ginn, P.

AU - Odom, D. T.

AU - Ophir, A. G.

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N1 - This work was mainly supported by the Paul G. Allen Frontiers Group (S.H.). Additional support was also provided by the Open Philanthropy–Silicon Valley Fund (S.H. and K.R.). J.E. was supported by UCLA Jonsson Comprehensive Cancer Center and Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research Ablon Scholars Program. J.A.M. and the NHP Core were supported by the Intramural Research Program, National Institute on Aging, NIH. Plains zebra sample collection was supported by National Geographic Society grant 8941-11. We acknowledge the Museum of Vertebrate Zoology and C.J. Conroy from the University of California, Berkeley. We acknowledge R. Miller and his laboratory (http://www.richmillerlab.com/long-lived-mutants) for providing dwarf mice and controls (Snell dwarf mouse, GHRKO experiments). Lemur sample collections were supported by Duke Lemur Center. N.C.B. was funded by a DST-NRF SARChI chair of Mammalian Behavioural Ecology and Physiology (GUN 64756). V.N.G., A.S. and V.G. were supported by NIA grants. V.G. was supported by the Milky Way Research Foundation. D.T.O. was supported by European Research Council (788937) and Cancer Research UK (20412). The FHS is funded by National Institutes of Health contracts N01-HC-25195 and HHSN268201500001I. The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health. The analytical component of this project was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute and the Center for Information Technology, National Institutes of Health. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C and HHSN268201600004C. We thank the WHI investigators and staff for their dedication and the study participants for making the program possible. A full listing of WHI investigators can be found at https://www.whi.org/doc/WHI-Investigator-Long-List.pdf. The views expressed in this study are those of the authors and do not necessarily represent the views of funding bodies such as the National Heart, Lung, and Blood Institute, the National Institutes of Health or the U.S. Department of Health and Human Services. This work was mainly supported by the Paul G. Allen Frontiers Group (S.H.). Additional support was also provided by the Open Philanthropy–Silicon Valley Fund (S.H. and K.R.). J.E. was supported by UCLA Jonsson Comprehensive Cancer Center and Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research Ablon Scholars Program. J.A.M. and the NHP Core were supported by the Intramural Research Program, National Institute on Aging, NIH. Plains zebra sample collection was supported by National Geographic Society grant 8941-11. We acknowledge the Museum of Vertebrate Zoology and C.J. Conroy from the University of California, Berkeley. We acknowledge R. Miller and his laboratory ( http://www.richmillerlab.com/long-lived-mutants ) for providing dwarf mice and controls (Snell dwarf mouse, GHRKO experiments). Lemur sample collections were supported by Duke Lemur Center. N.C.B. was funded by a DST-NRF SARChI chair of Mammalian Behavioural Ecology and Physiology (GUN 64756). V.N.G., A.S. and V.G. were supported by NIA grants. V.G. was supported by the Milky Way Research Foundation. D.T.O. was supported by European Research Council (788937) and Cancer Research UK (20412). The FHS is funded by National Institutes of Health contracts N01-HC-25195 and HHSN268201500001I. The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health. The analytical component of this project was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute and the Center for Information Technology, National Institutes of Health. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C and HHSN268201600004C. We thank the WHI investigators and staff for their dedication and the study participants for making the program possible. A full listing of WHI investigators can be found at https://www.whi.org/doc/WHI-Investigator-Long-List.pdf . The views expressed in this study are those of the authors and do not necessarily represent the views of funding bodies such as the National Heart, Lung, and Blood Institute, the National Institutes of Health or the U.S. Department of Health and Human Services.

PY - 2023/9

Y1 - 2023/9

N2 - Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.

AB - Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.

UR - http://www.scopus.com/inward/record.url?scp=85165881383&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85165881383&partnerID=8YFLogxK

U2 - 10.1038/s43587-023-00462-6

DO - 10.1038/s43587-023-00462-6

M3 - Article

C2 - 37563227

AN - SCOPUS:85165881383

SN - 2662-8465

VL - 3

SP - 1144

EP - 1166

JO - Nature Aging

JF - Nature Aging

IS - 9

ER -

Universal DNA methylation age across mammalian tissues

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