Stem cell aging: mechanisms, regulators and therapeutic opportunities

Article metrics

Abstract

Aging tissues experience a progressive decline in homeostatic and regenerative capacities, which has been attributed to degenerative changes in tissue-specific stem cells, stem cell niches and systemic cues that regulate stem cell activity. Understanding the molecular pathways involved in this age-dependent deterioration of stem cell function will be critical for developing new therapies for diseases of aging that target the specific causes of age-related functional decline. Here we explore key molecular pathways that are commonly perturbed as tissues and stem cells age and degenerate. We further consider experimental evidence both suppoxrting and refuting the notion that modulation of these pathways per se can reverse aging phenotypes. Finally, we ask whether stem cell aging establishes an epigenetic 'memory' that is indelibly written or one that can be reset.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Common pathways contributing to stem cell loss and dysfunction in the aging process.

Debbie Maizels / Nature Publishing Group

Figure 2: The effects of DNA damage in the aging genome that may affect stem cell function.

Debbie Maizels / Nature Publishing Group

Figure 3: Signaling pathways involved in aging of stem cells.

Debbie Maizels / Nature Publishing Group

References

  1. 1

    Cheung, T.H. & Rando, T.A. Molecular regulation of stem cell quiescence. Nat. Rev. Mol. Cell Biol. 14, 329–340 (2013).

  2. 2

    Takubo, K. et al. Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells. Cell Stem Cell 12, 49–61 (2013).

  3. 3

    Harris, J.M. et al. Glucose metabolism impacts the spatiotemporal onset and magnitude of HSC induction in vivo. Blood 121, 2483–2493 (2013).

  4. 4

    Yu, W.-M. et al. Metabolic regulation by the mitochondrial phosphatase PTPMT1 is required for hematopoietic stem cell differentiation. Cell Stem Cell 12, 62–74 (2013).

  5. 5

    Pervaiz, S., Taneja, R. & Ghaffari, S. Oxidative stress regulation of stem and progenitor cells. Antioxid. Redox Signal. 11, 2777–2789 (2009).

  6. 6

    Harman, D. Free radical theory of aging: dietary implications. Am. J. Clin. Nutr. 25, 839–843 (1972).

  7. 7

    Clément, M.V. & Stamenkovic, I. Superoxide anion is a natural inhibitor of FAS-mediated cell death. EMBO J. 15, 216–225 (1996).

  8. 8

    Ahmad, K.A., Clement, M.-V.V. & Pervaiz, S. Pro-oxidant activity of low doses of resveratrol inhibits hydrogen peroxide-induced apoptosis. Ann. NY Acad. Sci. 1010, 365–373 (2003).

  9. 9

    Stolzing, A., Jones, E., McGonagle, D. & Scutt, A. Age-related changes in human bone marrow-derived mesenchymal stem cells: consequences for cell therapies. Mech. Ageing Dev. 129, 163–173 (2008).

  10. 10

    Jang, Y.Y. & Sharkis, S. A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche. Blood 110, 3056–3063 (2007).

  11. 11

    Ito, K. et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 431, 997–1002 (2004).

  12. 12

    Sahin, E. & Depinho, R.A. Linking functional decline of telomeres, mitochondria and stem cells during ageing. Nature 464, 520–528 (2010).

  13. 13

    Rossi, D.J., Jamieson, C.H. & Weissman, I.L. Stems cells and the pathways to aging and cancer. Cell 132, 681–696 (2008).

  14. 14

    Paik, J.H. et al. FoxOs cooperatively regulate diverse pathways governing neural stem cell homeostasis. Cell Stem Cell 5, 540–553 (2009).

  15. 15

    Tothova, Z. et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128, 325–339 (2007).

  16. 16

    Miyamoto, K. et al. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 1, 101–112 (2007).

  17. 17

    Yalcin, S. et al. Foxo3 is essential for the regulation of ataxia telangiectasia mutated and oxidative stress-mediated homeostasis of hematopoietic stem cells. J. Biol. Chem. 283, 25692–25705 (2008).

  18. 18

    Renault, V.M. et al. FoxO3 regulates neural stem cell homeostasis. Cell Stem Cell 5, 527–539 (2009).

  19. 19

    Zhang, J. et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature 441, 518–522 (2006).

  20. 20

    Chen, C. et al. TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species. J. Exp. Med. 205, 2397–2408 (2008).

  21. 21

    Juntilla, M.M. et al. AKT1 and AKT2 maintain hematopoietic stem cell function by regulating reactive oxygen species. Blood 115, 4030–4038 (2010).

  22. 22

    Melov, S. et al. Mitochondrial disease in superoxide dismutase 2 mutant mice. Proc. Natl. Acad. Sci. USA 96, 846–851 (1999).

  23. 23

    Sakata, H. et al. Interleukin 6-preconditioned neural stem cells reduce ischaemic injury in stroke mice. Brain 135, 3298–3310 (2012).

  24. 24

    Ito, K. et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat. Med. 12, 446–451 (2006).

  25. 25

    Liang, R. & Ghaffari, S. Stem cells, redox signaling, and stem cell aging. Antioxid. Redox Signal. 20, 1902–1916 (2014).

  26. 26

    Owusu-Ansah, E. & Banerjee, U. Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation. Nature 461, 537–541 (2009).

  27. 27

    Yuan, H.-F.F. et al. SIRT1 is required for long-term growth of human mesenchymal stem cells. J. Mol. Med. 90, 389–400 (2012).

  28. 28

    Chen, H. et al. Role of SIRT1 and AMPK in mesenchymal stem cells differentiation. Ageing Res. Rev. 13, 55–64 (2014).

  29. 29

    Kim, H.-S.S. et al. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell 17, 41–52 (2010).

  30. 30

    Brown, K. et al. SIRT3 reverses aging-associated degeneration. Cell Reports 3, 319–327 (2013).

  31. 31

    Sadowska, A.M., Manuel- y-Keenoy, B. & De Backer, W.A. Antioxidant and anti-inflammatory efficacy of NAC in the treatment of COPD: discordant in vitro and in vivo dose-effects: a review. Pulm. Pharmacol. Ther. 20, 9–22 (2007).

  32. 32

    Abe, M., Takiguchi, Y., Ichimaru, S., Tsuchiya, K. & Wada, K. Comparison of the protective effect of N-acetylcysteine by different treatments on rat myocardial ischemia-reperfusion injury. J. Pharmacol. Sci. 106, 571–577 (2008).

  33. 33

    Kondratov, R.V., Vykhovanets, O., Kondratova, A.A. & Antoch, M.P. Antioxidant N-acetyl-L-cysteine ameliorates symptoms of premature aging associated with the deficiency of the circadian protein BMAL1. Aging 1, 979–987 (2009).

  34. 34

    Drowley, L. et al. Cellular antioxidant levels influence muscle stem cell therapy. Mol. Ther. 18, 1865–1873 (2010).

  35. 35

    Kolosova, N.G., Stefanova, N.A Muraleva, N.A. & Skulachev, V.P. The mitochondria-targeted antioxidant SkQ1 but not N-acetylcysteine reverses aging-related biomarkers in rats. Aging 4, 689–694 (2012).

  36. 36

    Rossi, D.J. et al. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature 447, 725–729 (2007).

  37. 37

    Rübe, C.E. et al. Accumulation of DNA damage in hematopoietic stem and progenitor cells during human aging. PLoS ONE 6, e17487 (2011).

  38. 38

    Sinha, M. et al. Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science 344, 649–652 (2014).

  39. 39

    Rogakou, E.P., Pilch, D.R., Orr, A.H., Ivanova, V.S. & Bonner, W.M. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J. Biol. Chem. 273, 5858–5868 (1998).

  40. 40

    Beerman, I., Seita, J., Inlay, M.A., Weissman, I.L. & Rossi, D.J. Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle. Cell Stem Cell 15, 37–50 (2014).

  41. 41

    Flores, I. et al. The longest telomeres: a general signature of adult stem cell compartments. Genes Dev. 22, 654–667 (2008).

  42. 42

    Larsen, B.D. et al. Caspase 3/caspase-activated DNase promote cell differentiation by inducing DNA strand breaks. Proc. Natl. Acad. Sci. USA 107, 4230–4235 (2010).

  43. 43

    Charville, G.W. & Rando, T.A. Stem cell ageing and non-random chromosome segregation. Phil. Trans. R. Soc. Lond. B 366, 85–93 (2011).

  44. 44

    Ciccia, A. & Elledge, S. The DNA damage response: making it safe to play with knives. Mol. Cell 40, 179–204 (2010).

  45. 45

    Fortini, P., Ferretti, C. & Dogliotti, E. The response to DNA damage during differentiation: pathways and consequences. Mutat. Res. 743–744, 160–168 (2013).

  46. 46

    Behrens, A., van Deursen, J.M., Rudolph, K.L. & Schumacher, B. Impact of genomic damage and ageing on stem cell function. Nat. Cell Biol. 16, 201–207 (2014).

  47. 47

    Moskalev, A.A. et al. The role of DNA damage and repair in aging through the prism of Koch-like criteria. Ageing Res. Rev. 12, 661–684 (2013).

  48. 48

    Bernardes de Jesus, B. & Blasco, M.A. Telomerase at the intersection of cancer and aging. Trends Genet. 29, 513–520 (2013).

  49. 49

    Dupressoir, A., Puech, A. & Heidmann, T. IAP retrotransposons in the mouse liver as reporters of ageing. Biochim. Biophys. Acta 1264, 397–402 (1995).

  50. 50

    Li, W. et al. Activation of transposable elements during aging and neuronal decline in Drosophila. Nat. Neurosci. 16, 529–531 (2013).

  51. 51

    Maxwell, P.H., Burhans, W.C. & Curcio, M.J. Retrotransposition is associated with genome instability during chronological aging. Proc. Natl. Acad. Sci. USA 108, 20376–20381 (2011).

  52. 52

    Wong, K.-K. et al. Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature 421, 643–648 (2003).

  53. 53

    Nijnik, A. et al. DNA repair is limiting for haematopoietic stem cells during ageing. Nature 447, 686–690 (2007).

  54. 54

    Wilson, A. et al. Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell 135, 1118–1129 (2008).

  55. 55

    Foudi, A. et al. Analysis of histone 2B-GFP retention reveals slowly cycling hematopoietic stem cells. Nat. Biotechnol. 27, 84–90 (2009).

  56. 56

    Mohrin, M. et al. Hematopoietic stem cell quiescence promotes error-prone DNA repair and mutagenesis. Cell Stem Cell 7, 174–185 (2010).

  57. 57

    Fumagalli, M. et al. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat. Cell Biol. 14, 355–365 (2012).

  58. 58

    Hewitt, G. et al. Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. Nat. Commun. 3, 708 (2012).

  59. 59

    Salama, R., Sadaie, M., Hoare, M. & Narita, M. Cellular senescence and its effector programs. Genes Dev. 28, 99–114 (2014).

  60. 60

    Erol, A. Deciphering the intricate regulatory mechanisms for the cellular choice between cell repair, apoptosis or senescence in response to damaging signals. Cell. Signal. 23, 1076–1081 (2011).

  61. 61

    Mandal, P.K., Blanpain, C. & Rossi, D.J. DNA damage response in adult stem cells: pathways and consequences. Nat. Rev. Mol. Cell Biol. 12, 198–202 (2011).

  62. 62

    Kirkwood, T.B. Understanding the odd science of aging. Cell 120, 437–447 (2005).

  63. 63

    Jaskelioff, M. et al. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature 469, 102–106 (2011).

  64. 64

    Canela, A., Martín-Caballero, J., Flores, J.M. & Blasco, M.A. Constitutive expression of tert in thymocytes leads to increased incidence and dissemination of T-cell lymphoma in Lck-Tert mice. Mol. Cell. Biol. 24, 4275–4293 (2004).

  65. 65

    Artandi, S.E. et al. Constitutive telomerase expression promotes mammary carcinomas in aging mice. Proc. Natl. Acad. Sci. USA 99, 8191–8196 (2002).

  66. 66

    González-Suárez, E. et al. Increased epidermal tumors and increased skin wound healing in transgenic mice overexpressing the catalytic subunit of telomerase, mTERT, in basal keratinocytes. EMBO J. 20, 2619–2630 (2001).

  67. 67

    Tomás-Loba, A. et al. Telomerase reverse transcriptase delays aging in cancer-resistant mice. Cell 135, 609–622 (2008).

  68. 68

    Bucciantini, M. et al. Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 416, 507–511 (2002).

  69. 69

    Balch, W.E., Morimoto, R.I., Dillin, A. & Kelly, J.W. Adapting proteostasis for disease intervention. Science 319, 916–919 (2008).

  70. 70

    Powers, E.T., Morimoto, R.I., Dillin, A., Kelly, J.W. & Balch, W.E. Biological and chemical approaches to diseases of proteostasis deficiency. Annu. Rev. Biochem. 78, 959–991 (2009).

  71. 71

    Taylor, R.C. & Dillin, A. Aging as an event of proteostasis collapse. Cold Spring Harb. Perspect. Biol. 3, a004440 (2011).

  72. 72

    Moreno-Gonzalez, I. & Soto, C. Misfolded protein aggregates: mechanisms, structures and potential for disease transmission. Semin. Cell Dev. Biol. 22, 482–487 (2011).

  73. 73

    Morimoto, R.I. & Cuervo, A.M. Protein homeostasis and aging: taking care of proteins from the cradle to the grave. J. Gerontol. A Biol. Sci. Med. Sci. 64A, 167–170 (2009).

  74. 74

    Rubinsztein, D.C., Mariño, G. & Kroemer, G. Autophagy and aging. Cell 146, 682–695 (2011).

  75. 75

    Tomaru, U. et al. Decreased proteasomal activity causes age-related phenotypes and promotes the development of metabolic abnormalities. Am. J. Pathol. 180, 963–972 (2012).

  76. 76

    Warr, M.R. et al. FOXO3A directs a protective autophagy program in haematopoietic stem cells. Nature 494, 323–327 (2013).

  77. 77

    Cook, C. et al. Aging is not associated with proteasome impairment in UPS reporter mice. PLoS ONE 4, e5888 (2009).

  78. 78

    Mortensen, M. et al. The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance. J. Exp. Med. 208, 455–467 (2011).

  79. 79

    Yilmaz, Ö.H. et al. mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 486, 490–495 (2012).

  80. 80

    Laplante, M. & Sabatini, D.M. mTOR signaling in growth control and disease. Cell 149, 274–293 (2012).

  81. 81

    Vilchez, D. et al. Increased proteasome activity in human embryonic stem cells is regulated by PSMD11. Nature 489, 304–308 (2012).

  82. 82

    Murphy, C.T. et al. Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 424, 277–283 (2003).

  83. 83

    Oh, S.W. et al. Identification of direct DAF-16 targets controlling longevity, metabolism and diapause by chromatin immunoprecipitation. Nat. Genet. 38, 251–257 (2006).

  84. 84

    Demontis, F. & Perrimon, N. FOXO/4E-BP signaling in Drosophila muscles regulates organism-wide proteostasis during aging. Cell 143, 813–825 (2010).

  85. 85

    Tatar, M., Khazaeli, A.A. & Curtsinger, J.W. Chaperoning extended life. Nature 390, 30 (1997).

  86. 86

    Walker, G.A. & Lithgow, G.J. Lifespan extension in C. elegans by a molecular chaperone dependent upon insulin-like signals. Aging Cell 2, 131–139 (2003).

  87. 87

    Morley, J.F. & Morimoto, R.I. Regulation of longevity in Caenorhabditis elegans by heat shock factor and molecular chaperones. Mol. Biol. Cell 15, 657–664 (2004).

  88. 88

    Chen, C., Liu, Y., Liu, Y. & Zheng, P. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci. Signal. 2, ra75 (2009).

  89. 89

    Zhang, C. & Cuervo, A.M. Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function. Nat. Med. 14, 959–965 (2008).

  90. 90

    Cummings, C.J. et al. Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice. Hum. Mol. Genet. 10, 1511–1518 (2001).

  91. 91

    Feng, Y. et al. Heat shock improves Sca-1+ stem cell survival and directs ischemic cardiomyocytes toward a prosurvival phenotype via exosomal transfer: a critical role for HSF1/miR-34a/HSP70 pathway. Stem Cells 32, 462–472 (2014).

  92. 92

    McArdle, A., Dillmann, W.H., Mestril, R., Faulkner, J.A. & Jackson, M.J. Overexpression of HSP70 in mouse skeletal muscle protects against muscle damage and age-related muscle dysfunction. FASEB J. 18, 355–357 (2004).

  93. 93

    Bratic, A. & Larsson, N.-G.G. The role of mitochondria in aging. J. Clin. Invest. 123, 951–957 (2013).

  94. 94

    Miquel, J., Economos, A.C., Fleming, J. & Johnson, J.E. Mitochondrial role in cell aging. Exp. Gerontol. 15, 575–591 (1980).

  95. 95

    Zheng, W., Khrapko, K., Coller, H.A., Thilly, W.G. & Copeland, W.C. Origins of human mitochondrial point mutations as DNA polymerase gamma-mediated errors. Mutat. Res. 599, 11–20 (2006).

  96. 96

    Trifunovic, A. et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417–423 (2004).

  97. 97

    Kujoth, G.C. et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309, 481–484 (2005).

  98. 98

    Ahlqvist, K.J. et al. Somatic progenitor cell vulnerability to mitochondrial DNA mutagenesis underlies progeroid phenotypes in Polg mutator mice. Cell Metab. 15, 100–109 (2012).

  99. 99

    Fox, R.G., Magness, S., Kujoth, G.C., Prolla, T.A. & Maeda, N. Mitochondrial DNA polymerase editing mutation, PolgD257A, disturbs stem-progenitor cell cycling in the small intestine and restricts excess fat absorption. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G914–G924 (2012).

  100. 100

    Taylor, R.W. et al. Mitochondrial DNA mutations in human colonic crypt stem cells. J. Clin. Invest. 112, 1351–1360 (2003).

  101. 101

    McDonald, S.A. et al. Mechanisms of field cancerization in the human stomach: the expansion and spread of mutated gastric stem cells. Gastroenterology 134, 500–510 (2008).

  102. 102

    Fellous, T.G. et al. Locating the stem cell niche and tracing hepatocyte lineages in human liver. Hepatology 49, 1655–1663 (2009).

  103. 103

    Norddahl, G.L. et al. Accumulating mitochondrial DNA mutations drive premature hematopoietic aging phenotypes distinct from physiological stem cell aging. Cell Stem Cell 8, 499–510 (2011).

  104. 104

    Bonawitz, N.D., Chatenay-Lapointe, M., Pan, Y. & Shadel, G.S. Reduced TOR signaling extends chronological life span via increased respiration and upregulation of mitochondrial gene expression. Cell Metab. 5, 265–277 (2007).

  105. 105

    Holzenberger, M. et al. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421, 182–187 (2003).

  106. 106

    Nakada, D., Saunders, T.L. & Morrison, S.J. Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature 468, 653–658 (2010).

  107. 107

    Gross, D.N., van den Heuvel, A.P. & Birnbaum, M.J. The role of FoxO in the regulation of metabolism. Oncogene 27, 2320–2336 (2008).

  108. 108

    Peserico, A. et al. A novel AMPK-dependent FoxO3A-SIRT3 intramitochondrial complex sensing glucose levels. Cell. Mol. Life Sci. 70, 2015–2029 (2013).

  109. 109

    Rera, M. et al. Modulation of longevity and tissue homeostasis by the Drosophila PGC-1 homolog. Cell Metab. 14, 623–634 (2011).

  110. 110

    Cerletti, M., Jang, Y.C., Finley, L.W., Haigis, M.C. & Wagers, A.J. Short-term calorie restriction enhances skeletal muscle stem cell function. Cell Stem Cell 10, 515–519 (2012).

  111. 111

    Piper, M.D. & Bartke, A. Diet and aging. Cell Metab. 8, 99–104 (2008).

  112. 112

    Lee, J., Duan, W. & Mattson, M.P. Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J. Neurochem. 82, 1367–1375 (2002).

  113. 113

    Narala, S.R. et al. SIRT1 acts as a nutrient-sensitive growth suppressor and its loss is associated with increased AMPK and telomerase activity. Mol. Biol. Cell 19, 1210–1219 (2008).

  114. 114

    Yang, S.-A.A. et al. FOXO/Fringe is necessary for maintenance of the germline stem cell niche in response to insulin insufficiency. Dev. Biol. 382, 124–135 (2013).

  115. 115

    Schulz, T.J. et al. Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab. 6, 280–293 (2007).

  116. 116

    Gredilla, R., Sanz, A., Lopez-Torres, M. & Barja, G. Caloric restriction decreases mitochondrial free radical generation at complex I and lowers oxidative damage to mitochondrial DNA in the rat heart. FASEB J. 15, 1589–1591 (2001).

  117. 117

    Sohal, R.S., Agarwal, S., Candas, M., Forster, M.J. & Lal, H. Effect of age and caloric restriction on DNA oxidative damage in different tissues of C57BL/6 mice. Mech. Ageing Dev. 76, 215–224 (1994).

  118. 118

    Gomes, A.P. et al. Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 155, 1624–1638 (2013).

  119. 119

    Hur, J.H. et al. Increased longevity mediated by yeast NDI1 expression in Drosophila intestinal stem and progenitor cells. Aging 5, 662–681 (2013).

  120. 120

    Sousa-Victor, P. et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 506, 316–321 (2014).

  121. 121

    Molofsky, A.V. et al. Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443, 448–452 (2006).

  122. 122

    Boyle, M., Wong, C., Rocha, M. & Jones, D.L. Decline in self-renewal factors contributes to aging of the stem cell niche in the Drosophila testis. Cell Stem Cell 1, 470–478 (2007).

  123. 123

    Florian, M.C. et al. Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation. Cell Stem Cell 10, 520–530 (2012).

  124. 124

    Geiger, H., de Haan, G. & Florian, M.C. The ageing haematopoietic stem cell compartment. Nat. Rev. Immunol. 13, 376–389 (2013).

  125. 125

    Campisi, J. Cancer, aging and cellular senescence. In Vivo 14, 183–188 (2000).

  126. 126

    Campisi, J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120, 513–522 (2005).

  127. 127

    Coppé, J.-P.P., Desprez, P.-Y.Y., Krtolica, A. & Campisi, J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu. Rev. Pathol. 5, 99–118 (2010).

  128. 128

    Janzen, V. et al. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature 443, 421–426 (2006).

  129. 129

    Attema, J.L., Pronk, C.J., Norddahl, G.L., Nygren, J.M. & Bryder, D. Hematopoietic stem cell ageing is uncoupled from p16 INK4A-mediated senescence. Oncogene 28, 2238–2243 (2009).

  130. 130

    Cheng, T. et al. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science 287, 1804–1808 (2000).

  131. 131

    Kippin, T.E., Martens, D.J. & van der Kooy, D. p21 loss compromises the relative quiescence of forebrain stem cell proliferation leading to exhaustion of their proliferation capacity. Genes Dev. 19, 756–767 (2005).

  132. 132

    Chakkalakal, J.V., Jones, K.M., Basson, M.A. & Brack, A.S. The aged niche disrupts muscle stem cell quiescence. Nature 490, 355–360 (2012).

  133. 133

    Hamanaka, R.B. & Chandel, N.S. Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes. Trends Biochem. Sci. 35, 505–513 (2010).

  134. 134

    Sacco, A. et al. Short telomeres and stem cell exhaustion model Duchenne muscular dystrophy in mdx/mTR mice. Cell 143, 1059–1071 (2010).

  135. 135

    Copelan, E.A. Hematopoietic stem-cell transplantation. N. Engl. J. Med. 354, 1813–1826 (2006).

  136. 136

    Salani, S. et al. Generation of skeletal muscle cells from embryonic and induced pluripotent stem cells as an in vitro model and for therapy of muscular dystrophies. J. Cell. Mol. Med. 16, 1353–1364 (2012).

  137. 137

    Chhabra, P. & Brayman, K.L. Stem cell therapy to cure type 1 diabetes: from hype to hope. Stem Cells Transl. Med. 2, 328–336 (2013).

  138. 138

    Kim, S.U. & de Vellis, J. Stem cell-based cell therapy in neurological diseases: a review. J. Neurosci. Res. 87, 2183–2200 (2009).

  139. 139

    Cerletti, M. et al. Highly efficient, functional engraftment of skeletal muscle stem cells in dystrophic muscles. Cell 134, 37–47 (2008).

  140. 140

    Cosgrove, B.D. et al. Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nat. Med. 20, 255–264 (2014).

  141. 141

    Tabebordbar, M., Wang, E. & Wagers, A.J. Skeletal muscle degenerative diseases and strategies for therapeutic muscle repair. Annu. Rev. Pathol. 8, 441–475 (2013).

  142. 142

    Bernet, J.D. et al. p38 MAPK signaling underlies a cell-autonomous loss of stem cell self-renewal in skeletal muscle of aged mice. Nat. Med. 20, 265–271 (2014).

  143. 143

    Ding, Q. et al. Enhanced efficiency of human pluripotent stem cell genome editing through replacing TALENs with CRISPRs. Cell Stem Cell 12, 393–394 (2013).

  144. 144

    Ding, Q. et al. A TALEN genome-editing system for generating human stem cell-based disease models. Cell Stem Cell 12, 238–251 (2013).

  145. 145

    Xu, Y. et al. Integrating haplotypes and single genetic variability effects of the Pax7 gene on growth traits in two cattle breeds. Genome 56, 9–15 (2013).

  146. 146

    Borchin, B., Chen, J. & Barberi, T. Derivation and FACS-mediated purification of PAX3+/PAX7+ skeletal muscle precursors from human pluripotent stem cells. Stem Cell Reports 1, 620–631 (2013).

  147. 147

    Darabi, R. et al. Human ES- and iPS-derived myogenic progenitors restore DYSTROPHIN and improve contractility upon transplantation in dystrophic mice. Cell Stem Cell 10, 610–619 (2012).

  148. 148

    Kobayashi, Y. et al. Pre-evaluated safe human iPSC-derived neural stem cells promote functional recovery after spinal cord injury in common marmoset without tumorigenicity. PLoS ONE 7, e52787 (2012).

  149. 149

    Nakamura, M. & Okano, H. Cell transplantation therapies for spinal cord injury focusing on induced pluripotent stem cells. Cell Res. 23, 70–80 (2013).

  150. 150

    Kuhn, H.G., Dickinson-Anson, H. & Gage, F.H. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J. Neurosci. 16, 2027–2033 (1996).

  151. 151

    Maslov, A.Y., Barone, T.A., Plunkett, R.J. & Pruitt, S.C. Neural stem cell detection, characterization, and age-related changes in the subventricular zone of mice. J. Neurosci. 24, 1726–1733 (2004).

  152. 152

    Morrison, S.J. & Spradling, A.C. Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 132, 598–611 (2008).

  153. 153

    Pan, L. et al. Stem cell aging is controlled both intrinsically and extrinsically in the Drosophila ovary. Cell Stem Cell 1, 458–469 (2007).

  154. 154

    Ryu, B.-Y.Y., Orwig, K.E., Oatley, J.M., Avarbock, M.R. & Brinster, R.L. Effects of aging and niche microenvironment on spermatogonial stem cell self-renewal. Stem Cells 24, 1505–1511 (2006).

  155. 155

    Sato, T. et al. In vitro production of fertile sperm from murine spermatogonial stem cell lines. Nat. Commun. 2, 472 (2011).

  156. 156

    Sato, T. et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 469, 415–418 (2011).

  157. 157

    Schnoor, M. et al. Production of type VI collagen by human macrophages: a new dimension in macrophage functional heterogeneity. J. Immunol. 180, 5707–5719 (2008).

  158. 158

    Murphy, M.M., Lawson, J.A., Mathew, S.J., Hutcheson, D.A. & Kardon, G. Satellite cells, connective tissue fibroblasts and their interactions are crucial for muscle regeneration. Development 138, 3625–3637 (2011).

  159. 159

    Joe, A.W. et al. Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis. Nat. Cell Biol. 12, 153–163 (2010).

  160. 160

    Conboy, I.M., Conboy, M.J., Smythe, G.M. & Rando, T.A. Notch-mediated restoration of regenerative potential to aged muscle. Science 302, 1575–1577 (2003).

  161. 161

    Carlson, M.E. et al. Relative roles of TGF-b1 and Wnt in the systemic regulation and aging of satellite cell responses. Aging Cell 8, 676–689 (2009).

  162. 162

    Franceschi, C. et al. Inflamm-aging: an evolutionary perspective on immunosenescence. Ann. NY Acad. Sci. 908, 244–254 (2000).

  163. 163

    de Magalhães, J.P., Curado, J. & Church, G.M. Meta-analysis of age-related gene expression profiles identifies common signatures of aging. Bioinformatics 25, 875–881 (2009).

  164. 164

    Conboy, I.M. et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433, 760–764 (2005).

  165. 165

    Villeda, S.A. et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477, 90–94 (2011).

  166. 166

    Katsimpardi, L. et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 344, 630–634 (2014).

  167. 167

    Ruckh, J.M. et al. Rejuvenation of regeneration in the aging central nervous system. Cell Stem Cell 10, 96–103 (2012).

  168. 168

    Loffredo, F.S. et al. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell 153, 828–839 (2013).

  169. 169

    Elabd, C. et al. Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration. Nat. Commun. 5, 4082 (2014).

  170. 170

    Baker, D.J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011).

  171. 171

    Fraga, M.F. & Esteller, M. Epigenetics and aging: the targets and the marks. Trends Genet. 23, 413–418 (2007).

  172. 172

    Greer, E.L. et al. Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. Nature 466, 383–387 (2010).

  173. 173

    Han, S. & Brunet, A. Histone methylation makes its mark on longevity. Trends Cell Biol. 22, 42–49 (2012).

  174. 174

    Greer, E.L. et al. Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature 479, 365–371 (2011).

  175. 175

    Peleg, S. et al. Altered histone acetylation is associated with age-dependent memory impairment in mice. Science 328, 753–756 (2010).

  176. 176

    Krishnan, V. et al. Histone H4 lysine 16 hypoacetylation is associated with defective DNA repair and premature senescence in Zmpste24-deficient mice. Proc. Natl. Acad. Sci. USA 108, 12325–12330 (2011).

  177. 177

    Beerman, I. et al. Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging. Cell Stem Cell 12, 413–425 (2013).

  178. 178

    Sun, D. et al. Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal. Cell Stem Cell 14, 673–688 (2014).

  179. 179

    Gurdon, J.B. The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. J. Embryol. Exp. Morphol. 10, 622–640 (1962).

  180. 180

    Lanza, R.P. et al. Extension of cell life-span and telomere length in animals cloned from senescent somatic cells. Science 288, 665–669 (2000).

  181. 181

    Abramovich, A., Muradian, K.K. & Fraifeld, V.E. Have we reached the point for in vivo rejuvenation? Rejuvenation Res. 11, 489–492 (2008).

  182. 182

    Takahashi, K. & Yamanaka, S. Induced pluripotent stem cells in medicine and biology. Development 140, 2457–2461 (2013).

  183. 183

    Wahlestedt, M. et al. An epigenetic component of hematopoietic stem cell aging amenable to reprogramming into a young state. Blood 121, 4257–4264 (2013).

  184. 184

    Price, N.L. et al. SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab. 15, 675–690 (2012).

  185. 185

    Miller, R.A. Rebuttal to Hasty and Vijg: 'Accelerating aging by mouse reverse genetics: a rational approach to understanding longevity'. Aging Cell 3, 53–54 (2004).

  186. 186

    Burtner, C.R. & Kennedy, B.K. Progeria syndromes and ageing: what is the connection? Nat. Rev. Mol. Cell Biol. 11, 567–578 (2010).

  187. 187

    Hua, G. et al. Crypt base columnar stem cells in small intestines of mice are radioresistant. Gastroenterology 143, 1266–1276 (2012).

  188. 188

    Sotiropoulou, P.A. et al. Bcl-2 and accelerated DNA repair mediates resistance of hair follicle bulge stem cells to DNA-damage-induced cell death. Nat. Cell Biol. 12, 572–582 (2010).

  189. 189

    Cheung, H.-H.H. et al. Telomerase protects Werner syndrome lineage-specific stem cells from premature aging. Stem Cell Reports 2, 534–546 (2014).

  190. 190

    Zhang, J. et al. A human iPSC model of Hutchinson Gilford progeria reveals vascular smooth muscle and mesenchymal stem cell defects. Cell Stem Cell 8, 31–45 (2011).

  191. 191

    Mitchell, J.R., Wood, E. & Collins, K. A telomerase component is defective in the human disease dyskeratosis congenita. Nature 402, 551–555 (1999).

  192. 192

    Jones, M. et al. Hematopoietic stem cells are acutely sensitive to Acd shelterin gene inactivation. J. Clin. Invest. 124, 353–366 (2014).

Download references

Acknowledgements

We thank all members of the Wagers laboratory for advice and comments during the preparation of this article. This work was funded in part by US National Cancer Institute grant T32CA-0216 from the Massachusetts General Hospital Department of Pathology (Y.D.L.), by US National Institutes of Health (NIH) grant T32DK007260 (J.O.), and by NIH grants 1R01 AG033053 and 5U01 HL100402 and the Paul F. Glenn Laboratories for the Biological Mechanisms of Aging (A.J.W.). A.J.W. is an Early Career Scientist of the Howard Hughes Medical Institute. Content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other funding agencies.

Author information

Correspondence to Amy J Wagers.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Oh, J., Lee, Y. & Wagers, A. Stem cell aging: mechanisms, regulators and therapeutic opportunities. Nat Med 20, 870–880 (2014) doi:10.1038/nm.3651

Download citation

Further reading