DOI QR코드

DOI QR Code

우리는 다시 젊어질 수 있는가? 생물학적 노화 연구의 시사점

Can we rejuvenate? Implications of biological aging research

  • 손유림 (영남대학교 의과대학 생화학분자생물학교실, 스마트에이징융복합연구센터) ;
  • 김재룡 (영남대학교 의과대학 생화학분자생물학교실, 스마트에이징융복합연구센터)
  • Son, Youlim (Department of Biochemistry and Molecular Biology, Smart-Aging Convergence Research Center, Yeungnam University College of Medicine) ;
  • Kim, Jae-Ryong (Department of Biochemistry and Molecular Biology, Smart-Aging Convergence Research Center, Yeungnam University College of Medicine)
  • 투고 : 2017.04.29
  • 심사 : 2017.05.26
  • 발행 : 2017.06.30

초록

The life history of man is summarized as a birth-aging-disease-death. Man eventually ages and dies. How long can humans live? What is aging? Why do we age? Is aging inevitable? Can we rejuvenate? Recent researches on biological aging suggest that humans might overcome aging and rejuvenate. In this paper, we review the biologic characteristics of aging and the latest results of biological aging research, implicating that aging can be controlled, further treated, and that humans can ultimately be rejuvenated.

과제정보

연구 과제 주관 기관 : 한국연구재단

참고문헌

  1. Rose MR. Evolutionary biology of aging. New York: Oxford University Press; 1991.
  2. Kirkwood TB. Understanding the odd science of aging. Cell 2005;120:437-47. https://doi.org/10.1016/j.cell.2005.01.027
  3. Martin GM, Oshima J. Lessons from human progeroid syndromes. Nature 2000;408(6809):263-6. https://doi.org/10.1038/35041705
  4. Arking R. The biology of aging : observations and principles. 3rd ed. Oxford; New York: Oxford University Press; 2006. p. 3-25.
  5. Medvedev ZA. An attempt at a rational classification of theories of ageing. Biol Rev Camb Philos Soc 1990;65:375-98. https://doi.org/10.1111/j.1469-185X.1990.tb01428.x
  6. Ljubuncic P, Reznick AZ. The evolutionary theories of aging revisited--a mini-review. Gerontology 2009;55:205-16. https://doi.org/10.1159/000200772
  7. Rodier F, Campisi J, Bhaumik D. Two faces of p53: aging and tumor suppression. Nucleic Acids Res 2007;35:7475-84. https://doi.org/10.1093/nar/gkm744
  8. Weismann A, Poulton EB, Schoonland S, Shipley AE. Essays upon heredity and kindred biological problems. 2nd ed. Oxford: Clarendon press; 1891.
  9. Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol 1956;11:298-300. https://doi.org/10.1093/geronj/11.3.298
  10. Gerschman R, Gilbert DL, Nye SW, Dwyer P, Fenn WO. Oxygen poisoning and x-irradiation: a mechanism in common. Science 1954;119(3097):623-6. https://doi.org/10.1126/science.119.3097.623
  11. Alexander P. The role of DNA lesions in the processes leading to aging in mice. Symp Soc Exp Biol 1967;21:29-50.
  12. Gensler HL, Bernstein H. DNA damage as the primary cause of aging. Q Rev Biol 1981;56:279-303. https://doi.org/10.1086/412317
  13. Best BP. Nuclear DNA damage as a direct cause of aging. Rejuvenation Res 2009;12:199-208. https://doi.org/10.1089/rej.2009.0847
  14. Freitas AA, de Magalhaes JP. A review and appraisal of the DNA damage theory of ageing. Mutat Res 2011;728:12-22. https://doi.org/10.1016/j.mrrev.2011.05.001
  15. Chung HY, Sung B, Jung KJ, Zou Y, Yu BP. The molecular inflammatory process in aging. Antioxid Redox Signal 2006; 8:572-81. https://doi.org/10.1089/ars.2006.8.572
  16. Mortimer RK, Johnston JR. Life span of individual yeast cells. Nature 1959;183(4677):1751-2. https://doi.org/10.1038/1831751a0
  17. Arking R. The biology of aging : observations and principles. 3rd ed. Oxford; New York: Oxford University Press; 2006. p. 107-19.
  18. Yang J, McCormick MA, Zheng J, Xie Z, Tsuchiya M, Tsuchiyama S, et al. Systematic analysis of asymmetric partitioning of yeast proteome between mother and daughter cells reveals “aging factors” and mechanism of lifespan asymmetry. Proc Natl Acad Sci U S A 2015;112(38):11977-82. https://doi.org/10.1073/pnas.1506054112
  19. Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R. A C. elegans mutant that lives twice as long as wild type. Nature 1993;366(6454):461-4. https://doi.org/10.1038/366461a0
  20. Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 1997;277(5328):942-6. https://doi.org/10.1126/science.277.5328.942
  21. Kenyon C. The first long-lived mutants: discovery of the insulin/ IGF-1 pathway for ageing. Philos Trans R Soc Lond B Biol Sci 2011;366(1561):9-16. https://doi.org/10.1098/rstb.2010.0276
  22. Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res 1961;25:585-621. https://doi.org/10.1016/0014-4827(61)90192-6
  23. Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, et al. Extension of life-span by introduction of telomerase into normal human cells. Science 1998;279(5349):349-52. https://doi.org/10.1126/science.279.5349.349
  24. Collado M, Blasco MA, Serrano M. Cellular senescence in cancer and aging. Cell 2007;130:223-33. https://doi.org/10.1016/j.cell.2007.07.003
  25. Nakamura AJ, Chiang YJ, Hathcock KS, Horikawa I, Sedelnikova OA, Hodes RJ, et al. Both telomeric and non-telomeric DNA damage are determinants of mammalian cellular senescence. Epigenetics Chromatin 2008;1:6. https://doi.org/10.1186/1756-8935-1-6
  26. Lee JS, Ward WO, Ren H, Vallanat B, Darlington GJ, Han ES, et al. Meta-analysis of gene expression in the mouse liver reveals biomarkers associated with inflammation increased early during aging. Mech Ageing Dev 2012;133:467-78. https://doi.org/10.1016/j.mad.2012.05.006
  27. Fusenig NE, Boukamp P. Multiple stages and genetic alterations in immortalization, malignant transformation, and tumor progression of human skin keratinocytes. Mol Carcinog 1998; 23:144-58. https://doi.org/10.1002/(SICI)1098-2744(199811)23:3<144::AID-MC3>3.0.CO;2-U
  28. Alimonti A, Nardella C, Chen Z, Clohessy JG, Carracedo A, Trotman LC, et al. A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis. J Clin Invest 2010; 120:681-93. https://doi.org/10.1172/JCI40535
  29. Suzuki K, Mori I, Nakayama Y, Miyakoda M, Kodama S, Watanabe M. Radiation-induced senescence-like growth arrest requires TP53 function but not telomere shortening. Radiat Res 2001;155:248-53. https://doi.org/10.1667/0033-7587(2001)155[0248:RISLGA]2.0.CO;2
  30. Narita M, Nünez S, Heard E, Narita M, Lin AW, Hearn SA, et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 2003; 113:703-16. https://doi.org/10.1016/S0092-8674(03)00401-X
  31. Hampel B, Malisan F, Niederegger H, Testi R, Jansen-Dürr P. Differential regulation of apoptotic cell death in senescent human cells. Exp Gerontol 2004;39:1713-21. https://doi.org/10.1016/j.exger.2004.05.010
  32. Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A 1995;92:9363-7. https://doi.org/10.1073/pnas.92.20.9363
  33. Kuilman T, Michaloglou C, Mooi WJ, Peeper DS. The essence of senescence. Genes Dev 2010;24:2463-79. https://doi.org/10.1101/gad.1971610
  34. Alcorta DA, Xiong Y, Phelps D, Hannon G, Beach D, Barrett JC. Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Proc Natl Acad Sci U S A 1996;93(24):13742-7. https://doi.org/10.1073/pnas.93.24.13742
  35. Erusalimsky JD, Kurz DJ. Cellular senescence in vivo: its relevance in ageing and cardiovascular disease. Exp Gerontol 2005;40:634-42. https://doi.org/10.1016/j.exger.2005.04.010
  36. Price JS, Waters JG, Darrah C, Pennington C, Edwards DR, Donell ST, et al. The role of chondrocyte senescence in osteoarthritis. Aging Cell 2002;1:57-65. https://doi.org/10.1046/j.1474-9728.2002.00008.x
  37. Telgenhoff D, Shroot B. Cellular senescence mechanisms in chronic wound healing. Cell Death Differ 2005;12:695-8. https://doi.org/10.1038/sj.cdd.4401632
  38. Collado M, Serrano M. Senescence in tumours: evidence from mice and humans. Nat Rev Cancer 2010;10:51-7. https://doi.org/10.1038/nrc2772
  39. Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol 2013;75:685-705. https://doi.org/10.1146/annurev-physiol-030212-183653
  40. López-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell 2013;153:1194-217. https://doi.org/10.1016/j.cell.2013.05.039
  41. Munoz-Espin D, Canamero M, Maraver A, Gomez-Lopez G, Contreras J, Murillo-Cuesta S, et al. Programmed cell senescence during mammalian embryonic development. Cell 2013; 155:1104-18. https://doi.org/10.1016/j.cell.2013.10.019
  42. Krizhanovsky V, Yon M, Dickins RA, Hearn S, Simon J, Miething C, et al. Senescence of activated stellate cells limits liver fibrosis. Cell 2008;134:657-67. https://doi.org/10.1016/j.cell.2008.06.049
  43. Jun JI, Lau LF. The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nat Cell Biol 2010;12:676-85. https://doi.org/10.1038/ncb2070
  44. Kim KH, Chen CC, Monzon RI, Lau LF. Matricellular protein CCN1 promotes regression of liver fibrosis through induction of cellular senescence in hepatic myofibroblasts. Mol Cell Biol 2013;33:2078-90. https://doi.org/10.1128/MCB.00049-13
  45. Demaria M, Ohtani N, Youssef SA, Rodier F, Toussaint W, Mitchell JR, et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell 2014;31:722-33. https://doi.org/10.1016/j.devcel.2014.11.012
  46. van Deursen JM. The role of senescent cells in ageing. Nature 2014;509(7501):439-46. https://doi.org/10.1038/nature13193
  47. McCay CM, Crowell MF, Maynard LA. The effect of retarded growth upon the length of life span and upon the ultimate body size. 1935. Nutrition 1989;5:155-71.
  48. Fontana L, Partridge L, Longo VD. Extending healthy life span--from yeast to humans. Science 2010;328(5976):321-6. https://doi.org/10.1126/science.1172539
  49. Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 2009; 325(5937):201-4. https://doi.org/10.1126/science.1173635
  50. Mattison JA, Roth GS, Beasley TM, Tilmont EM, Handy AM, Herbert RL, et al. Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature 2012; 489(7415):318-21. https://doi.org/10.1038/nature11432
  51. Colman RJ, Beasley TM, Kemnitz JW, Johnson SC, Weindruch R, Anderson RM. Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. Nat Commun 2014;5: 3557. https://doi.org/10.1038/ncomms4557
  52. Mattison JA, Colman RJ, Beasley TM, Allison DB, Kemnitz JW, Roth GS, et al. Caloric restriction improves health and survival of rhesus monkeys. Nat Commun 2017;8:14063. https://doi.org/10.1038/ncomms14063
  53. Anderson RM, Weindruch R. Metabolic reprogramming, caloric restriction and aging. Trends Endocrinol Metab 2010;21:134-41. https://doi.org/10.1016/j.tem.2009.11.005
  54. Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 2005;434(7029):113-8. https://doi.org/10.1038/nature03354
  55. Kenyon CJ. The genetics of ageing. Nature 2010;464(7288):504-12. https://doi.org/10.1038/nature08980
  56. van Heemst D. Insulin, IGF-1 and longevity. Aging Dis 2010;1:147-57.
  57. Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, Wei M, Madia F, Cheng CW, et al. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med 2011;3(70):70ra13.
  58. Suh Y, Atzmon G, Cho MO, Hwang D, Liu B, Leahy DJ, et al. Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc Natl Acad Sci U S A 2008;105:3438-42. https://doi.org/10.1073/pnas.0705467105
  59. Cho CG, Kim HJ, Chung SW, Jung KJ, Shim KH, Yu BP, et al. Modulation of glutathione and thioredoxin systems by calorie restriction during the aging process. Exp Gerontol 2003;38:539-48. https://doi.org/10.1016/S0531-5565(03)00005-6
  60. Jung KJ, Lee EK, Kim JY, Zou Y, Sung B, Heo HS, et al. Effect of short term calorie restriction on pro-inflammatory NF-kB and AP-1 in aged rat kidney. Inflamm Res 2009;58:143-50. https://doi.org/10.1007/s00011-008-7227-2
  61. Trumbo P, Schlicker S, Yates AA, Poos M; Food and Nutrition Board of the Institute of Medicine, The National Academies. Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein and amino acids. J Am Diet Assoc 2002;102:1621-30. https://doi.org/10.1016/S0002-8223(02)90346-9
  62. Heilbronn LK, de Jonge L, Frisard MI, DeLany JP, Larson- Meyer DE, Rood J, et al. Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial. JAMA 2006;295:1539-48. https://doi.org/10.1001/jama.295.13.1539
  63. Ingram DK, Roth GS. Calorie restriction mimetics: can you have your cake and eat it, too? Ageing Res Rev 2015;20:46-62. https://doi.org/10.1016/j.arr.2014.11.005
  64. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009;460(7253):392-5. https://doi.org/10.1038/nature08221
  65. Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 2012;335(6076):1638-43. https://doi.org/10.1126/science.1215135
  66. Bannister CA, Holden SE, Jenkins-Jones S, Morgan CL, Halcox JP, Schernthaner G, et al. Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes Obes Metab 2014;16:1165-73. https://doi.org/10.1111/dom.12354
  67. Crandall J. Metformin in Longevity Study (MILES) [Internet]. Bethesda: National Libreary of Medicine; 2015 [cited 2017 April 29]. https://clinicaltrials.gov/ct2/show/NCT02432287
  68. Longo VD, Mattson MP. Fasting: molecular mechanisms and clinical applications. Cell Metab 2014;19:181-92. https://doi.org/10.1016/j.cmet.2013.12.008
  69. Cheng CW, Villani V, Buono R, Wei M, Kumar S, Yilmaz OH, et al. Fasting-mimicking diet promotes Ngn3-driven ${\beta}$-cell regeneration to reverse diabetes. Cell 2017;168:775-88.e12. https://doi.org/10.1016/j.cell.2017.01.040
  70. Wei M, Brandhorst S, Shelehchi M, Mirzaei H, Cheng CW, Budniak J, et al. Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease. Sci Transl Med 2017;9(377). pii: eaai8700.
  71. Herbig U, Ferreira M, Condel L, Carey D, Sedivy JM. Cellular senescence in aging primates. Science 2006;311(5765):1257. https://doi.org/10.1126/science.1122446
  72. Wang C, Jurk D, Maddick M, Nelson G, Martin-Ruiz C, von Zglinicki T. DNA damage response and cellular senescence in tissues of aging mice. Aging Cell 2009;8:311-23. https://doi.org/10.1111/j.1474-9726.2009.00481.x
  73. Davalos AR, Coppe JP, Campisi J, Desprez PY. Senescent cells as a source of inflammatory factors for tumor progression. Cancer Metastasis Rev 2010;29:273-83. https://doi.org/10.1007/s10555-010-9220-9
  74. Rodier F, Campisi J. Four faces of cellular senescence. J Cell Biol 2011;192:547-56. https://doi.org/10.1083/jcb.201009094
  75. Rudolph KL, Chang S, Lee HW, Blasco M, Gottlieb GJ, Greider C, et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 1999;96:701-12. https://doi.org/10.1016/S0092-8674(00)80580-2
  76. Jaskelioff M, Muller FL, Paik JH, Thomas E, Jiang S, Adams AC, et al. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature 2011;469(7328): 102-6. https://doi.org/10.1038/nature09603
  77. Yang HH, Son JK, Jung B, Zheng M, Kim JR. Epifriedelanol from the root bark of Ulmus davidiana inhibits cellular senescence in human primary cells. Planta Med 2011;77:441-9. https://doi.org/10.1055/s-0030-1250458
  78. Yang HH, Hwangbo K, Zheng MS, Son JK, Kim HY, Baek SH, et al. Inhibitory effects of juglanin on cellular senescence in human dermal fibroblasts. J Nat Med 2014;68:473-80. https://doi.org/10.1007/s11418-014-0817-0
  79. Yang HH, Hwangbo K, Zheng MS, Cho JH, Son JK, Kim HY, et al. Quercetin-3-O-beta-D-glucuronide isolated from Polygonum aviculare inhibits cellular senescence in human primary cells. Arch Pharm Res 2014;37:1219-33. https://doi.org/10.1007/s12272-014-0344-2
  80. Yang HH, Hwangbo K, Zheng MS, Cho JH, Son JK, Kim HY, et al. Inhibitory effects of (-)-loliolide on cellular senescence in human dermal fibroblasts. Arch Pharm Res 2015; 38:876-84. https://doi.org/10.1007/s12272-014-0435-0
  81. Bae YU, Choi JH, Nagy A, Sung HK, Kim JR. Antisenescence effect of mouse embryonic stem cell conditioned medium through a PDGF/FGF pathway. FASEB J 2016;30:1276-86. https://doi.org/10.1096/fj.15-278846
  82. Kang HT, Park JT, Choi K, Kim Y, Choi HJC, Jung CW, et al. Chemical screening identifies ATM as a target for alleviating senescence. Nat Chem Biol 2017;13:616-23. https://doi.org/10.1038/nchembio.2342
  83. Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, et al. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 2016;530(7589):184-9. https://doi.org/10.1038/nature16932
  84. Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 2015;14:644-58. https://doi.org/10.1111/acel.12344
  85. Chang J, Wang Y, Shao L, Laberge RM, Demaria M, Campisi J, et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med 2016;22: 78-83. https://doi.org/10.1038/nm.4010
  86. Yosef R, Pilpel N, Tokarsky-Amiel R, Biran A, Ovadya Y, Cohen S, et al. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat Commun 2016;7:11190. https://doi.org/10.1038/ncomms11190
  87. Jeon OH, Kim C, Laberge RM, Demaria M, Rathod S, Vasserot AP, et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med 2017;23:775-81. https://doi.org/10.1038/nm.4324
  88. Baar MP, Brandt RM, Putavet DA, Klein JD, Derks KW, Bourgeois BR, et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell 2017;169:132-47.e16. https://doi.org/10.1016/j.cell.2017.02.031
  89. Rebo J, Mehdipour M, Gathwala R, Causey K, Liu Y, Conboy MJ, et al. A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood. Nat Commun 2016;7:13363. https://doi.org/10.1038/ncomms13363
  90. Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J, et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med 2014;20:659-63. https://doi.org/10.1038/nm.3569
  91. Castellano JM, Mosher KI, Abbey RJ, McBride AA, James ML, Berdnik D, et al. Human umbilical cord plasma proteins revitalize hippocampal function in aged mice. Nature 2017; 544(7651):488-92. https://doi.org/10.1038/nature22067
  92. Brack AS, Conboy MJ, Roy S, Lee M, Kuo CJ, Keller C, et al. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 2007;317(5839): 807-10. https://doi.org/10.1126/science.1144090
  93. Carlson ME, Hsu M, Conboy IM. Imbalance between pSmad3 and Notch induces CDK inhibitors in old muscle stem cells. Nature 2008;454(7203):528-32. https://doi.org/10.1038/nature07034
  94. Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 2011;477(7362):90-4. https://doi.org/10.1038/nature10357
  95. Smith LK, He Y, Park JS, Bieri G, Snethlage CE, Lin K, et al. ${\beta}2$-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis. Nat Med 2015;21: 932-7. https://doi.org/10.1038/nm.3898
  96. Loffredo FS, Steinhauser ML, Jay SM, Gannon J, Pancoast JR, Yalamanchi P, et al. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell 2013;153:828-39. https://doi.org/10.1016/j.cell.2013.04.015
  97. Egerman MA, Cadena SM, Gilbert JA, Meyer A, Nelson HN, Swalley SE, et al. GDF11 increases with age and inhibits skeletal muscle regeneration. Cell Metab 2015;22:164-74. https://doi.org/10.1016/j.cmet.2015.05.010
  98. Hayflick L. Biological aging is no longer an unsolved problem. Ann N Y Acad Sci 2007;1100:1-13. https://doi.org/10.1196/annals.1395.001