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Ageing and rejuvenation of tissue stem cells and their niches

Abstract

Most adult organs contain regenerative stem cells, often organized in specific niches. Stem cell function is critical for tissue homeostasis and repair upon injury, and it is dependent on interactions with the niche. During ageing, stem cells decline in their regenerative potential and ability to give rise to differentiated cells in the tissue, which is associated with a deterioration of tissue integrity and health. Ageing-associated changes in regenerative tissue regions include defects in maintenance of stem cell quiescence, differentiation ability and bias, clonal expansion and infiltration of immune cells in the niche. In this Review, we discuss cellular and molecular mechanisms underlying ageing in the regenerative regions of different tissues as well as potential rejuvenation strategies. We focus primarily on brain, muscle and blood tissues, but also provide examples from other tissues, such as skin and intestine. We describe the complex interactions between different cell types, non-cell-autonomous mechanisms between ageing niches and stem cells, and the influence of systemic factors. We also compare different interventions for the rejuvenation of old regenerative regions. Future outlooks in the field of stem cell ageing are discussed, including strategies to counter ageing and age-dependent disease.

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Fig. 1: Organs with stem cells and stem cell niches.
Fig. 2: Changes in stem cells and their niches during ageing.
Fig. 3: Cell-autonomous and non-cell-autonomous mechanisms of stem cell ageing.

References

  1. Rando, T. A. & Wyss-Coray, T. Asynchronous, contagious and digital aging. Nat. Aging 1, 29–35 (2021).

    PubMed  PubMed Central  Article  Google Scholar 

  2. Sender, R. & Milo, R. The distribution of cellular turnover in the human body. Nat. Med. 27, 45–48 (2021).

    CAS  PubMed  Article  Google Scholar 

  3. Goodell, M. A. & Rando, T. A. Stem cells and healthy aging. Science 350, 1199–1204 (2015).

    CAS  PubMed  Article  Google Scholar 

  4. Navarro Negredo, P., Yeo, R. W. & Brunet, A. Aging and rejuvenation of neural stem cells and their niches. Cell Stem Cell 27, 202–223 (2020).

    CAS  PubMed  Article  Google Scholar 

  5. Oh, J., Lee, Y. D. & Wagers, A. J. Stem cell aging: mechanisms, regulators and therapeutic opportunities. Nat. Med. 20, 870–880 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. Artegiani, B. et al. A single-cell RNA sequencing study reveals cellular and molecular dynamics of the hippocampal neurogenic niche. Cell Rep. 21, 3271–3284 (2017).

    CAS  PubMed  Article  Google Scholar 

  7. Dulken, B. W. et al. Single-cell analysis reveals T cell infiltration in old neurogenic niches. Nature 571, 205–210 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. Kalamakis, G. et al. Quiescence modulates stem cell maintenance and regenerative capacity in the aging brain. Cell 176, 1407–1419.e14 (2019).

    CAS  PubMed  Article  Google Scholar 

  9. Ibrayeva, A. et al. Early stem cell aging in the mature brain. Cell Stem Cell 28, 955–966.e7 (2021).

    CAS  PubMed  Article  Google Scholar 

  10. Lukjanenko, L. et al. Aging disrupts muscle stem cell function by impairing matricellular WISP1 secretion from fibro-adipogenic progenitors. Cell Stem Cell 24, 433–446.e7 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. Ge, Y. et al. The aging skin microenvironment dictates stem cell behavior. Proc. Natl Acad. Sci. USA 117, 5339–5350 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. Shcherbina, A. et al. Dissecting murine muscle stem cell aging through regeneration using integrative genomic analysis. Cell Rep. 32, 107964 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. Kimmel, J. C., Hwang, A. B., Scaramozza, A., Marshall, W. F. & Brack, A. S. Aging induces aberrant state transition kinetics in murine muscle stem cells. Development 147, dev183855 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. Aros, C. J. et al. Distinct spatiotemporally dynamic Wnt-secreting niches regulate proximal airway regeneration and aging. Cell Stem Cell 27, 413–429.e4 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. Chambers, S. M. et al. Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation. PLoS Biol. 5, e201 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  16. Brack, A. S. et al. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 317, 807–810 (2007).

    CAS  PubMed  Article  Google Scholar 

  17. Sorrells, S. F. et al. Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature 555, 377–381 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. Sorrells, S. F. et al. Positive controls in adults and children support that very few, if any, new neurons are born in the adult human hippocampus. J. Neurosci. 41, 2554–2565 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. Franjic, D. et al. Transcriptomic taxonomy and neurogenic trajectories of adult human, macaque, and pig hippocampal and entorhinal cells. Neuron 110, 452–469.e14 (2022).

    CAS  PubMed  Article  Google Scholar 

  20. Moreno-Jimenez, E. P. et al. Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nat. Med. 25, 554–560 (2019).

    CAS  PubMed  Article  Google Scholar 

  21. Boldrini, M. et al. Human hippocampal neurogenesis persists throughout aging. Cell Stem Cell 22, 589–599.e5 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. Durante, M. A. et al. Single-cell analysis of olfactory neurogenesis and differentiation in adult humans. Nat. Neurosci. 23, 323–326 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. Mann, M. et al. Heterogeneous responses of hematopoietic stem cells to inflammatory stimuli are altered with age. Cell Rep. 25, 2992–3005.e5 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. Leins, H. et al. Aged murine hematopoietic stem cells drive aging-associated immune remodeling. Blood 132, 565–576 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. Sawen, P. et al. Murine HSCs contribute actively to native hematopoiesis but with reduced differentiation capacity upon aging. Elife 7, e41258 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  26. Yamamoto, R. et al. Large-scale clonal analysis resolves aging of the mouse hematopoietic stem cell compartment. Cell Stem Cell 22, 600–607.e4 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. Obernier, K. et al. Adult neurogenesis is sustained by symmetric self-renewal and differentiation. Cell Stem Cell 22, 221–234.e8 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. Bast, L. et al. Increasing neural stem cell division asymmetry and quiescence are predicted to contribute to the age-related decline in neurogenesis. Cell Rep. 25, 3231–3240.e8 (2018).

    CAS  PubMed  Article  Google Scholar 

  29. Harris, L. et al. Coordinated changes in cellular behavior ensure the lifelong maintenance of the hippocampal stem cell population. Cell Stem Cell 28, 863–876.e6 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. Kuang, S., Kuroda, K., Le Grand, F. & Rudnicki, M. A. Asymmetric self-renewal and commitment of satellite stem cells in muscle. Cell 129, 999–1010 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. Rocheteau, P., Gayraud-Morel, B., Siegl-Cachedenier, I., Blasco, M. A. & Tajbakhsh, S. A subpopulation of adult skeletal muscle stem cells retains all template DNA strands after cell division. Cell 148, 112–125 (2012).

    CAS  PubMed  Article  Google Scholar 

  32. Garcia-Prat, L. et al. FoxO maintains a genuine muscle stem-cell quiescent state until geriatric age. Nat. Cell Biol. 22, 1307–1318 (2020).

    CAS  PubMed  Article  Google Scholar 

  33. Evano, B. et al. Transcriptome and epigenome diversity and plasticity of muscle stem cells following transplantation. PLoS Genet. 16, e1009022 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. Brett, J. O. et al. Exercise rejuvenates quiescent skeletal muscle stem cells in old mice through restoration of cyclin D1. Nat. Metab. 2, 307–317 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. Scaramozza, A. et al. Lineage tracing reveals a subset of reserve muscle stem cells capable of clonal expansion under stress. Cell Stem Cell 24, 944–957.e5 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. Collins, C. A., Zammit, P. S., Ruiz, A. P., Morgan, J. E. & Partridge, T. A. A population of myogenic stem cells that survives skeletal muscle aging. Stem Cell 25, 885–894 (2007).

    CAS  Article  Google Scholar 

  38. Sacma, M. et al. Haematopoietic stem cells in perisinusoidal niches are protected from ageing. Nat. Cell Biol. 21, 1309–1320 (2019).

    CAS  PubMed  Article  Google Scholar 

  39. Zhang, H. et al. NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 352, 1436–1443 (2016).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  41. Le Roux, I., Konge, J., Le Cam, L., Flamant, P. & Tajbakhsh, S. Numb is required to prevent p53-dependent senescence following skeletal muscle injury. Nat. Commun. 6, 8528 (2015).

    PubMed  Article  CAS  Google Scholar 

  42. Zhu, P. et al. The transcription factor Slug represses p16Ink4a and regulates murine muscle stem cell aging. Nat. Commun. 10, 2568 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  43. Chiche, A. et al. Injury-induced senescence enables in vivo reprogramming in skeletal muscle. Cell Stem Cell 20, 407–414.e4 (2017).

    CAS  PubMed  Article  Google Scholar 

  44. Yanai, H. & Beerman, I. Proliferation: driver of HSC aging phenotypes? Mech. Ageing Dev. 191, 111331 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. Zhao, X. et al. 4D imaging analysis of the aging mouse neural stem cell niche reveals a dramatic loss of progenitor cell dynamism regulated by the RHO-ROCK pathway. Stem Cell Rep. 17, 245–258 (2022).

    CAS  Article  Google Scholar 

  46. White, C. W. III et al. Age-related loss of neural stem cell O-GlcNAc promotes a glial fate switch through STAT3 activation. Proc. Natl Acad. Sci. USA 117, 22214–22224 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. Arai, F. et al. Machine learning of hematopoietic stem cell divisions from paired daughter cell expression profiles reveals effects of aging on self-renewal. Cell Syst. 11, 640–652.e5 (2020).

    CAS  PubMed  Article  Google Scholar 

  48. Challen, G. A. & Goodell, M. A. Clonal hematopoiesis: mechanisms driving dominance of stem cell clones. Blood 136, 1590–1598 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Jaiswal, S. & Ebert, B. L. Clonal hematopoiesis in human aging and disease. Science 366, eaan4673 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. Jeong, M. et al. Loss of Dnmt3a immortalizes hematopoietic stem cells in vivo. Cell Rep. 23, 1–10 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. Tovy, A. et al. Tissue-biased expansion of DNMT3A-mutant clones in a mosaic individual is associated with conserved epigenetic erosion. Cell Stem Cell 27, 326–335.e4 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. Lee-Six, H. et al. The landscape of somatic mutation in normal colorectal epithelial cells. Nature 574, 532–537 (2019).

    CAS  PubMed  Article  Google Scholar 

  53. Martincorena, I. et al. Somatic mutant clones colonize the human esophagus with age. Science 362, 911–917 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. Martincorena, I. et al. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880–886 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. Tierney, M. T., Stec, M. J., Rulands, S., Simons, B. D. & Sacco, A. Muscle stem cells exhibit distinct clonal dynamics in response to tissue repair and homeostatic aging. Cell Stem Cell 22, 119–127.e3 (2018).

    CAS  PubMed  Article  Google Scholar 

  56. Watson, C. J. et al. The evolutionary dynamics and fitness landscape of clonal hematopoiesis. Science 367, 1449–1454 (2020).

    CAS  PubMed  Article  Google Scholar 

  57. Hormaechea-Agulla, D. et al. Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNgamma signaling. Cell Stem Cell 28, 1428–1442.e6 (2021).

    CAS  PubMed  Article  Google Scholar 

  58. Dharan, N. J. et al. HIV is associated with an increased risk of age-related clonal hematopoiesis among older adults. Nat. Med. 27, 1006–1011 (2021).

    CAS  PubMed  Article  Google Scholar 

  59. Bhattacharya, R. et al. Association of diet quality with prevalence of clonal hematopoiesis and adverse cardiovascular events. JAMA Cardiol. 6, 1069–1077 (2021).

    PubMed  Article  Google Scholar 

  60. Blokzijl, F. et al. Tissue-specific mutation accumulation in human adult stem cells during life. Nature 538, 260–264 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. Heyde, A. et al. Increased stem cell proliferation in atherosclerosis accelerates clonal hematopoiesis. Cell 184, 1348–1361.e22 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. Yu, K. R. et al. The impact of aging on primate hematopoiesis as interrogated by clonal tracking. Blood 131, 1195–1205 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. Ximerakis, M. et al. Single-cell transcriptomic profiling of the aging mouse brain. Nat. Neurosci. 22, 1696–1708 (2019).

    CAS  PubMed  Article  Google Scholar 

  64. Leeman, D. S. et al. Lysosome activation clears aggregates and enhances quiescent neural stem cell activation during aging. Science 359, 1277–1283 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. Liu, L. et al. Chromatin modifications as determinants of muscle stem cell quiescence and chronological aging. Cell Rep. 4, 189–204 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. Schuler, S. C. et al. Extensive remodeling of the extracellular matrix during aging contributes to age-dependent impairments of muscle stem cell functionality. Cell Rep. 35, 109223 (2021).

    PubMed  Article  CAS  Google Scholar 

  67. Hernando-Herraez, I. et al. Ageing affects DNA methylation drift and transcriptional cell-to-cell variability in mouse muscle stem cells. Nat. Commun. 10, 4361 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  68. Svendsen, A. F. et al. A comprehensive transcriptome signature of murine hematopoietic stem cell aging. Blood 138, 439–451 (2021).

    Article  CAS  Google Scholar 

  69. Tabula Muris, C. A single-cell transcriptomic atlas characterizes ageing tissues in the mouse. Nature 583, 590–595 (2020).

    Article  CAS  Google Scholar 

  70. Moreno-Valladares, M. et al. CD8+ T cells are increased in the subventricular zone with physiological and pathological aging. Aging Cell 19, e13198 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. Gross, K. M. et al. Loss of slug compromises dna damage repair and accelerates stem cell aging in mammary epithelium. Cell Rep. 28, 394–407.e6 (2019).

    CAS  PubMed  Article  Google Scholar 

  72. Mogilenko, D. A. et al. Comprehensive profiling of an aging immune system reveals clonal GZMK+ CD8+ T cells as conserved hallmark of inflammaging. Immunity 54, 99–115.e12 (2021).

    CAS  PubMed  Article  Google Scholar 

  73. Groh, J. et al. Accumulation of cytotoxic T cells in the aged CNS leads to axon degeneration and contributes to cognitive and motor decline. Nat. Aging 1, 357–367 (2021).

    Article  Google Scholar 

  74. Gate, D. et al. Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease. Nature 577, 399–404 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. Gate, D. et al. CD4+ T cells contribute to neurodegeneration in Lewy body dementia. Science 374, 868–874 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. He, H. et al. Aging-induced IL27Ra signaling impairs hematopoietic stem cells. Blood 136, 183–198 (2020).

    PubMed  Article  Google Scholar 

  77. Valletta, S. et al. Micro-environmental sensing by bone marrow stroma identifies IL-6 and TGFbeta1 as regulators of hematopoietic ageing. Nat. Commun. 11, 4075 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. Ho, Y. H. et al. Remodeling of bone marrow hematopoietic stem cell niches promotes myeloid cell expansion during premature or physiological aging. Cell Stem Cell 25, e6 (2019).

    Article  CAS  Google Scholar 

  79. Frisch, B. J. et al. Aged marrow macrophages expand platelet-biased hematopoietic stem cells via interleukin-1B. JCI Insight 5, e124213 (2019).

    Article  Google Scholar 

  80. Segel, M. et al. Niche stiffness underlies the ageing of central nervous system progenitor cells. Nature 573, 130–134 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. Shen, B. et al. A mechanosensitive peri-arteriolar niche for osteogenesis and lymphopoiesis. Nature 591, 438–444 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. Stearns-Reider, K. M. et al. Aging of the skeletal muscle extracellular matrix drives a stem cell fibrogenic conversion. Aging Cell 16, 518–528 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. Xie, Y. et al. Hair shaft miniaturization causes stem cell depletion through mechanosensory signals mediated by a Piezo1-calcium-TNF-alpha axis. Cell Stem Cell 29, 70–85.e6 (2022).

    CAS  PubMed  Article  Google Scholar 

  84. Koester, J. et al. Niche stiffening compromises hair follicle stem cell potential during ageing by reducing bivalent promoter accessibility. Nat. Cell Biol. 23, 771–781 (2021).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. Gopinath, S. D., Webb, A. E., Brunet, A. & Rando, T. A. FOXO3 promotes quiescence in adult muscle stem cells during the process of self-renewal. Stem Cell Rep. 2, 414–426 (2014).

    CAS  Article  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  90. 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).

    CAS  PubMed  Article  Google Scholar 

  91. Schaffner, I. et al. FoxO function is essential for maintenance of autophagic flux and neuronal morphogenesis in adult neurogenesis. Neuron 99, e6 (2018).

    Article  CAS  Google Scholar 

  92. Audesse, A. J. et al. FOXO3 directly regulates an autophagy network to functionally regulate proteostasis in adult neural stem cells. PLoS Genet. 15, e1008097 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. Hwang, I. et al. Cellular stress signaling activates type-I IFN response through FOXO3-regulated lamin posttranslational modification. Nat. Commun. 12, 640 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. Wheatley, E. G. et al. Neuronal O-GlcNAcylation improves cognitive function in the aged mouse brain. Curr. Biol. 29, 3359–3369 e4 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. Liu, L. et al. Impaired notch signaling leads to a decrease in p53 activity and mitotic catastrophe in aged muscle stem cells. Cell Stem Cell 23, 544–556.e4 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. Gutierrez-Martinez, P. et al. Diminished apoptotic priming and ATM signalling confer a survival advantage onto aged haematopoietic stem cells in response to DNA damage. Nat. Cell Biol. 20, 413–421 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. Gontier, G. et al. Tet2 rescues age-related regenerative decline and enhances cognitive function in the adult mouse brain. Cell Rep. 22, 1974–1981 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. Maybury-Lewis, S. Y. et al. Changing and stable chromatin accessibility supports transcriptional overhaul during neural stem cell activation and is altered with age. Aging Cell 20, e13499 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. Sera, Y. et al. UTX maintains functional integrity of murine hematopoietic system by globally regulating aging-associated genes. Blood 137, 908–922 (2020).

    Article  CAS  Google Scholar 

  101. Khokhar, E. S. et al. Aging-associated decrease in the histone acetyltransferase KAT6B is linked to altered hematopoietic stem cell differentiation. Exp. Hematol. 82, 43–52.e4 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. Keenan, C. R. et al. Extreme disruption of heterochromatin is required for accelerated hematopoietic aging. Blood 135, 2049–2058 (2020).

    PubMed  Article  Google Scholar 

  103. Guerreiro, I. & Kind, J. Spatial chromatin organization and gene regulation at the nuclear lamina. Curr. Opin. Genet. Dev. 55, 19–25 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. Bin Imtiaz, M. K. et al. Declining lamin B1 expression mediates age-dependent decreases of hippocampal stem cell activity. Cell Stem Cell 28, 967–977.e8 (2021).

    Article  CAS  Google Scholar 

  105. Dall’Agnese, A. et al. Transcription factor-directed re-wiring of chromatin architecture for somatic cell nuclear reprogramming toward trans-differentiation. Mol. Cell 76, 453–472.e8 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  106. Ho, T. T. et al. Autophagy maintains the metabolism and function of young and old stem cells. Nature 543, 205–210 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. Wei, Q. et al. MAEA is an E3 ubiquitin ligase promoting autophagy and maintenance of haematopoietic stem cells. Nat. Commun. 12, 2522 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. Garcia-Prat, L. et al. Autophagy maintains stemness by preventing senescence. Nature 529, 37–42 (2016).

    CAS  PubMed  Article  Google Scholar 

  109. Tang, A. H. & Rando, T. A. Induction of autophagy supports the bioenergetic demands of quiescent muscle stem cell activation. EMBO J. 33, 2782–2797 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  110. White, J. P. et al. The AMPK/p27Kip1 axis regulates autophagy/apoptosis decisions in aged skeletal muscle stem cells. Stem Cell Rep. 11, 425–439 (2018).

    CAS  Article  Google Scholar 

  111. Dong, S. et al. Chaperone-mediated autophagy sustains haematopoietic stem-cell function. Nature (2021).

  112. Vonk, W. I. M. et al. Differentiation drives widespread rewiring of the neural stem cell chaperone network. Mol. Cell 78, 329–345 e9 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. Kruta, M. et al. Hsf1 promotes hematopoietic stem cell fitness and proteostasis in response to ex vivo culture stress and aging. Cell Stem Cell 28, 1950–1965.e6 (2021).

    CAS  PubMed  Article  Google Scholar 

  114. Chandel, N. S., Jasper, H., Ho, T. T. & Passegue, E. Metabolic regulation of stem cell function in tissue homeostasis and organismal ageing. Nat. Cell Biol. 18, 823–832 (2016).

    CAS  PubMed  Article  Google Scholar 

  115. Meacham, C. E., DeVilbiss, A. W. & Morrison, S. J. Metabolic regulation of somatic stem cells in vivo. Nat. Rev. Mol. Cell Biol. 23, 428–443 (2022).

    CAS  PubMed  Article  Google Scholar 

  116. Imai, S. & Guarente, L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 24, 464–471 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. Schultz, M. B. & Sinclair, D. A. Why NAD+ declines during aging: it’s destroyed. Cell Metab. 23, 965–966 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. Ryall, J. G. et al. The NAD+-dependent SIRT1 deacetylase translates a metabolic switch into regulatory epigenetics in skeletal muscle stem cells. Cell Stem Cell 16, 171–183 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. Luo, H. et al. Mitochondrial stress-initiated aberrant activation of the NLRP3 inflammasome regulates the functional deterioration of hematopoietic stem cell aging. Cell Rep. 26, 945–954.e4 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. Igarashi, M. et al. NAD+ supplementation rejuvenates aged gut adult stem cells. Aging Cell 18, e12935 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  121. Poisa-Beiro, L. et al. Glycogen accumulation, central carbon metabolism, and aging of hematopoietic stem and progenitor cells. Sci. Rep. 10, 11597 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  122. Pala, F. et al. Distinct metabolic states govern skeletal muscle stem cell fates during prenatal and postnatal myogenesis. J. Cell Sci. 131, jcs212977 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  123. Hennrich, M. L. et al. Cell-specific proteome analyses of human bone marrow reveal molecular features of age-dependent functional decline. Nat. Commun. 9, 4004 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  124. Yucel, N. et al. Glucose metabolism drives histone acetylation landscape transitions that dictate muscle stem cell function. Cell Rep. 27, 3939–3955.e6 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  125. Beckervordersandforth, R. et al. Role of mitochondrial metabolism in the control of early lineage progression and aging phenotypes in adult hippocampal neurogenesis. Neuron 93, 560–573.e6 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. Guitart, A. V. et al. Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions. J. Exp. Med. 214, 719–735 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. Wosczyna, M. N. et al. Mesenchymal stromal cells are required for regeneration and homeostatic maintenance of skeletal muscle. Cell Rep. 27, 2029–2035.e5 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  128. Ambrosi, T. H. et al. Aged skeletal stem cells generate an inflammatory degenerative niche. Nature 597, 256–262 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. Ambrosi, T. H. et al. Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration. Cell Stem Cell 20, 771–784 e6 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. Sampath, S. C. et al. Induction of muscle stem cell quiescence by the secreted niche factor Oncostatin M. Nat. Commun. 9, 1531 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  131. Kann, A. P., Hung, M. & Krauss, R. S. Cell-cell contact and signaling in the muscle stem cell niche. Curr. Opin. Cell Biol. 73, 78–83 (2021).

    CAS  PubMed  Article  Google Scholar 

  132. Pentinmikko, N. et al. Notum produced by Paneth cells attenuates regeneration of aged intestinal epithelium. Nature 571, 398–402 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  133. Young, K. et al. Decline in IGF1 in the bone marrow microenvironment initiates hematopoietic stem cell aging. Cell Stem Cell 28, 1473–1482.e7 (2021).

    CAS  PubMed  Article  Google Scholar 

  134. Maity, P. et al. Persistent JunB activation in fibroblasts disrupts stem cell niche interactions enforcing skin aging. Cell Rep. 36, 109634 (2021).

    CAS  PubMed  Article  Google Scholar 

  135. Zhu, C., Mahesula, S., Temple, S. & Kokovay, E. Heterogeneous expression of SDF1 retains actively proliferating neural progenitors in the capillary compartment of the niche. Stem Cell Rep. 12, 6–13 (2019).

    CAS  Article  Google Scholar 

  136. Yousef, H. et al. Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1. Nat. Med. 25, 988–1000 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  137. Baruch, K. et al. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science 346, 89–93 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  138. Martin-Suarez, S., Valero, J., Muro-Garcia, T. & Encinas, J. M. Phenotypical and functional heterogeneity of neural stem cells in the aged hippocampus. Aging Cell 18, e12958 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  139. Kjell, J. et al. Defining the adult neural stem cell niche proteome identifies key regulators of adult neurogenesis. Cell Stem Cell 26, 277–293.e8 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  140. Baror, R. et al. Transforming growth factor-beta renders ageing microglia inhibitory to oligodendrocyte generation by CNS progenitors. Glia 67, 1374–1384 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  141. Liu, N. et al. Stem cell competition orchestrates skin homeostasis and ageing. Nature 568, 344–350 (2019).

    CAS  PubMed  Article  Google Scholar 

  142. Petrik, D. et al. Epithelial sodium channel regulates adult neural stem cell proliferation in a flow-dependent manner. Cell Stem Cell 22, 865–878.e8 (2018).

    CAS  PubMed  Article  Google Scholar 

  143. Carlson, B. M. & Faulkner, J. A. Muscle transplantation between young and old rats: age of host determines recovery. Am. J. Physiol. 256, C1262–C1266 (1989).

    CAS  PubMed  Article  Google Scholar 

  144. Popplewell, L. L. & Forman, S. J. Is there an upper age limit for bone marrow transplantation? Bone Marrow Transpl. 29, 277–284 (2002).

    CAS  Article  Google Scholar 

  145. Kuribayashi, W. et al. Limited rejuvenation of aged hematopoietic stem cells in young bone marrow niche. J. Exp. Med. 218 (2021).

  146. De Miguel, Z. et al. Exercise plasma boosts memory and dampens brain inflammation via clusterin. Nature 600, 494–499 (2021).

    PubMed  Article  CAS  Google Scholar 

  147. Horowitz, A. M. et al. Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain. Science 369, 167–173 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  149. Smith, L. K. et al. The aged hematopoietic system promotes hippocampal-dependent cognitive decline. Aging Cell 19, e13192 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  150. Ergen, A. V., Boles, N. C. & Goodell, M. A. Rantes/Ccl5 influences hematopoietic stem cell subtypes and causes myeloid skewing. Blood 119, 2500–2509 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  151. Kalluri, R. & LeBleu, V. S. The biology, function, and biomedical applications of exosomes. Science 367, eaau6977 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  152. Sahu, A. et al. Regulation of aged skeletal muscle regeneration by circulating extracellular vesicles. Nat. Aging 1, 1148–1161 (2021).

    PubMed  PubMed Central  Article  Google Scholar 

  153. Grenier-Pleau, I. et al. Blood extracellular vesicles from healthy individuals regulate hematopoietic stem cells as humans age. Aging Cell 19, e13245 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  154. Gao, X. et al. Nociceptive nerves regulate haematopoietic stem cell mobilization. Nature 589, 591–596 (2021).

    CAS  PubMed  Article  Google Scholar 

  155. Riera, C. E. et al. TRPV1 pain receptors regulate longevity and metabolism by neuropeptide signaling. Cell 157, 1023–1036 (2014).

    CAS  PubMed  Article  Google Scholar 

  156. Maryanovich, M. et al. Adrenergic nerve degeneration in bone marrow drives aging of the hematopoietic stem cell niche. Nat. Med. 24, 782–791 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  157. Paul, A., Chaker, Z. & Doetsch, F. Hypothalamic regulation of regionally distinct adult neural stem cells and neurogenesis. Science 356, 1383–1386 (2017).

    CAS  PubMed  Article  Google Scholar 

  158. Liu, W. et al. Loss of adult skeletal muscle stem cells drives age-related neuromuscular junction degeneration. Elife 6, e26464 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  159. Larouche, J. A. et al. Murine muscle stem cell response to perturbations of the neuromuscular junction are attenuated with aging. Elife 10, e66749 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  160. Solanas, G. et al. Aged stem cells reprogram their daily rhythmic functions to adapt to stress. Cell 170, 678–692.e20 (2017).

    CAS  PubMed  Article  Google Scholar 

  161. Sato, S. et al. Circadian reprogramming in the liver identifies metabolic pathways of aging. Cell 170, 664–677.e11 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  162. Welz, P. S. et al. BMAL1-driven tissue clocks respond independently to light to maintain homeostasis. Cell 177, 1436–1447.e12 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  163. Gengatharan, A. et al. Adult neural stem cell activation in mice is regulated by the day/night cycle and intracellular calcium dynamics. Cell 184, 709–722.e13 (2021).

    CAS  PubMed  Article  Google Scholar 

  164. Chambers, S. M. et al. Hematopoietic fingerprints: an expression database of stem cells and their progeny. Cell Stem Cell 1, 578–591 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  165. Golan, K., Kollet, O., Markus, R. P. & Lapidot, T. Daily light and darkness onset and circadian rhythms metabolically synchronize hematopoietic stem cell differentiation and maintenance: the role of bone marrow norepinephrine, tumor necrosis factor, and melatonin cycles. Exp. Hematol. 78, 1–10 (2019).

    CAS  PubMed  Article  Google Scholar 

  166. Garcia-Garcia, A. et al. Dual cholinergic signals regulate daily migration of hematopoietic stem cells and leukocytes. Blood 133, 224–236 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  167. Puram, R. V. et al. Core Circadian clock genes regulate leukemia stem cells in AML. Cell 165, 303–316 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  168. Garcia-Garcia, A. & Mendez-Ferrer, S. The autonomic nervous system pulls the strings to coordinate circadian HSC functions. Front. Immunol. 11, 956 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  169. Fry, C. S. et al. Inducible depletion of satellite cells in adult, sedentary mice impairs muscle regenerative capacity without affecting sarcopenia. Nat. Med. 21, 76–80 (2015).

    CAS  PubMed  Article  Google Scholar 

  170. Adams, K. L. & Gallo, V. The diversity and disparity of the glial scar. Nat. Neurosci. 21, 9–15 (2018).

    CAS  PubMed  Article  Google Scholar 

  171. Kernie, S. G. & Parent, J. M. Forebrain neurogenesis after focal ischemic and traumatic brain injury. Neurobiol. Dis. 37, 267–274 (2010).

    PubMed  Article  Google Scholar 

  172. Jin, K. et al. Evidence for stroke-induced neurogenesis in the human brain. Proc. Natl Acad. Sci. USA 103, 13198–13202 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  173. de Haan, G. & Van Zant, G. Dynamic changes in mouse hematopoietic stem cell numbers during aging. Blood 93, 3294–3301 (1999).

    PubMed  Article  Google Scholar 

  174. Rossi, D. J. et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc. Natl Acad. Sci. USA 102, 9194–9199 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  175. Ruzankina, Y. et al. Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss. Cell Stem Cell 1, 113–126 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  176. Wang, B. et al. Transplanting cells from old but not young donors causes physical dysfunction in older recipients. Aging Cell 19, e13106 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Muto, T. et al. TRAF6 functions as a tumor suppressor in myeloid malignancies by directly targeting MYC oncogenic activity. Cell Stem Cell 29, 298–314.e9 (2022).

    CAS  PubMed  Article  Google Scholar 

  178. Beier, F., Foronda, M., Martinez, P. & Blasco, M. A. Conditional TRF1 knockout in the hematopoietic compartment leads to bone marrow failure and recapitulates clinical features of dyskeratosis congenita. Blood 120, 2990–3000 (2012).

    CAS  PubMed  Article  Google Scholar 

  179. Jaiswal, S. et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371, 2488–2498 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  180. Genovese, G. et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 371, 2477–2487 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  181. Kempermann, G. et al. Human adult neurogenesis: evidence and remaining questions. Cell Stem Cell 23, 25–30 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  182. Snyder, J. S. Recalibrating the relevance of adult neurogenesis. Trends Neurosci. 42, 164–178 (2019).

    CAS  PubMed  Article  Google Scholar 

  183. Terreros-Roncal, J. et al. Impact of neurodegenerative diseases on human adult hippocampal neurogenesis. Science 374, 1106–1113 (2021).

    CAS  PubMed  Article  Google Scholar 

  184. Babcock, K. R., Page, J. S., Fallon, J. R. & Webb, A. E. Adult Hippocampal neurogenesis in aging and Alzheimer’s disease. Stem Cell Rep. 16, 681–693 (2021).

    CAS  Article  Google Scholar 

  185. Hamilton, L. K. et al. Aberrant lipid metabolism in the forebrain niche suppresses adult neural stem cell proliferation in an animal model of Alzheimer’s disease. Cell Stem Cell 17, 397–411 (2015).

    CAS  PubMed  Article  Google Scholar 

  186. Sadick, J. S. et al. Astrocytes and oligodendrocytes undergo subtype-specific transcriptional changes in Alzheimer’s disease. Neuron 110, 1788–1805.e10 (2022).

    CAS  PubMed  Article  Google Scholar 

  187. Parhizkar, S. & Holtzman, D. M. APOE mediated neuroinflammation and neurodegeneration in Alzheimer’s disease. Semin Immunol. https://doi.org/10.1016/j.smim.2022.101594 (2022).

    Article  PubMed  Google Scholar 

  188. Dumont, N. A. et al. Dystrophin expression in muscle stem cells regulates their polarity and asymmetric division. Nat. Med. 21, 1455–1463 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  189. Wang, Y. X. et al. EGFR-Aurka signaling rescues polarity and regeneration defects in dystrophin-deficient muscle stem cells by increasing asymmetric divisions. Cell Stem Cell 24, 419–432.e6 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  190. Conboy, M. J., Conboy, I. M. & Rando, T. A. Heterochronic parabiosis: historical perspective and methodological considerations for studies of aging and longevity. Aging Cell 12, 525–530 (2013).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  192. Villeda, S. A. et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat. Med. 20, 659–663 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  194. Sinha, I., Sinha-Hikim, A. P., Wagers, A. J. & Sinha-Hikim, I. Testosterone is essential for skeletal muscle growth in aged mice in a heterochronic parabiosis model. Cell Tissue Res. 357, 815–821 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  195. Salpeter, S. J. et al. Systemic regulation of the age-related decline of pancreatic beta-cell replication. Diabetes 62, 2843–2848 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  196. Baht, G. S. et al. Exposure to a youthful circulaton rejuvenates bone repair through modulation of beta-catenin. Nat. Commun. 6, 7131 (2015).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  198. Rebo, J. et al. A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood. Nat. Commun. 7, 13363 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  199. Ashapkin, V. V., Kutueva, L. I. & Vanyushin, B. F. The effects of parabiosis on aging and age-related diseases. Adv. Exp. Med. Biol. 1260, 107–122 (2020).

    CAS  PubMed  Article  Google Scholar 

  200. Castellano, J. M. et al. Human umbilical cord plasma proteins revitalize hippocampal function in aged mice. Nature 544, 488–492 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  201. Ho, T. T. et al. Aged hematopoietic stem cells are refractory to bloodborne systemic rejuvenation interventions. J. Exp. Med. 218, e20210223 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  202. Palovics, R. et al. Molecular hallmarks of heterochronic parabiosis at single-cell resolution. Nature 603, 309–314 (2022).

    CAS  PubMed  Article  Google Scholar 

  203. Warburton, D. E., Nicol, C. W. & Bredin, S. S. Health benefits of physical activity: the evidence. CMAJ 174, 801–809 (2006).

    PubMed  PubMed Central  Article  Google Scholar 

  204. Neufer, P. D. et al. Understanding the cellular and molecular mechanisms of physical activity-induced health benefits. Cell Metab. 22, 4–11 (2015).

    CAS  PubMed  Article  Google Scholar 

  205. van Praag, H., Shubert, T., Zhao, C. & Gage, F. H. Exercise enhances learning and hippocampal neurogenesis in aged mice. J. Neurosci. 25, 8680–8685 (2005).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  206. McCay, C. M., Cromwell, M. F. & Maynard, L. A. The effect of retarded growth upon the length of life span and upon ultimate body size. J. Nutr. 10, 63–79 (1935).

    CAS  Article  Google Scholar 

  207. McDonald, R. B. & Ramsey, J. J. Honoring Clive McCay and 75 years of calorie restriction research. J. Nutr. 140, 1205–1210 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  208. Brandhorst, S. et al. A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance, and healthspan. Cell Metab. 22, 86–99 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  209. Green, C. L., Lamming, D. W. & Fontana, L. Molecular mechanisms of dietary restriction promoting health and longevity. Nat. Rev. Mol. Cell. Biol. 23, 56–73 (2021).

    PubMed  Article  CAS  Google Scholar 

  210. Ma, S. et al. Caloric restriction reprograms the single-cell transcriptional landscape of rattus norvegicus aging. Cell 180, 984–1001.e22 (2020).

    CAS  PubMed  Article  Google Scholar 

  211. Gebert, N. et al. Region-specific proteome changes of the intestinal epithelium during aging and dietary restriction. Cell Rep. 31, 107565 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  212. Tang, D. et al. Dietary restriction improves repopulation but impairs lymphoid differentiation capacity of hematopoietic stem cells in early aging. J. Exp. Med. 213, 535–553 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  213. Mattson, M. P., Longo, V. D. & Harvie, M. Impact of intermittent fasting on health and disease processes. Ageing Res. Rev. 39, 46–58 (2017).

    PubMed  Article  Google Scholar 

  214. Mihaylova, M. M. et al. Fasting activates fatty acid oxidation to enhance intestinal stem cell function during homeostasis and aging. Cell Stem Cell 22, 769–778 e4 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  215. Benjamin, D. I. et al. Fasting induces a highly resilient deep quiescent state in muscle stem cells via ketone body signaling. Cell Metab. 34, 902–918.e6 (2022).

    PubMed  Article  CAS  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  217. Neumann, B. et al. Metformin restores CNS remyelination capacity by rejuvenating aged stem cells. Cell Stem Cell 25, 473–485.e8 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  218. Covarrubias, A. J., Perrone, R., Grozio, A. & Verdin, E. NAD+ metabolism and its roles in cellular processes during ageing. Nat. Rev. Mol. Cell Biol. 22, 119–141 (2020).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  219. Yoshino, J., Baur, J. A. & Imai, S. I. NAD+ intermediates: the biology and therapeutic potential of NMN and NR. Cell Metab. 27, 513–528 (2018).

    CAS  PubMed  Article  Google Scholar 

  220. Johnson, S. C., Rabinovitch, P. S. & Kaeberlein, M. mTOR is a key modulator of ageing and age-related disease. Nature 493, 338–345 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  221. Vannini, N. et al. The NAD-booster nicotinamide riboside potently stimulates hematopoiesis through increased mitochondrial clearance. Cell Stem Cell 24, 405–418.e7 (2019).

    CAS  PubMed  Article  Google Scholar 

  222. Zong, L. et al. NAD+ augmentation with nicotinamide riboside improves lymphoid potential of Atm−/− and old mice HSCs. NPJ Aging Mech. Dis. 7, 25 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  223. Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).

    CAS  PubMed  Article  Google Scholar 

  224. Izpisua Belmonte, J. C. Reprogramming development and aging: cell differentiation as a malleable process. Curr. Opin. Cell Biol. 24, 713–715 (2012).

    CAS  PubMed  Article  Google Scholar 

  225. Mahmoudi, S. & Brunet, A. Aging and reprogramming: a two-way street. Curr. Opin. Cell Biol. 24, 744–756 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  226. Rando, T. A. & Chang, H. Y. Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. Cell 148, 46–57 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  227. Abad, M. et al. Reprogramming in vivo produces teratomas and iPS cells with totipotency features. Nature 502, 340–345 (2013).

    CAS  PubMed  Article  Google Scholar 

  228. Ocampo, A. et al. In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell 167, 1719–1733 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  229. Rodriguez-Matellan, A., Alcazar, N., Hernandez, F., Serrano, M. & Avila, J. In vivo reprogramming ameliorates aging features in dentate gyrus cells and improves memory in mice. Stem Cell Rep. 15, 1056–1066 (2020).

    CAS  Article  Google Scholar 

  230. Sarkar, T. J. et al. Transient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells. Nat. Commun. 11, 1545 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  231. Lu, Y. et al. Reprogramming to recover youthful epigenetic information and restore vision. Nature 588, 124–129 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  232. Wang, C. et al. In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche. Nat. Commun. 12, 3094 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  233. Chondronasiou, D. et al. Multi-omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming. Aging Cell 21, e13578 (2022).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  234. Isern, J. et al. Self-renewing human bone marrow mesenspheres promote hematopoietic stem cell expansion. Cell Rep. 3, 1714–1724 (2013).

    CAS  PubMed  Article  Google Scholar 

  235. Nakahara, F. et al. Engineering a haematopoietic stem cell niche by revitalizing mesenchymal stromal cells. Nat. Cell Biol. 21, 560–567 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  236. Guan, J. et al. Chemical reprogramming of human somatic cells to pluripotent stem cells. Nature 605, 325–331 (2022).

    CAS  PubMed  Article  Google Scholar 

  237. Mahmoudi, S., Xu, L. & Brunet, A. Turning back time with emerging rejuvenation strategies. Nat. Cell Biol. 21, 32–43 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  238. Seidel, J. & Valenzano, D. R. The role of the gut microbiome during host ageing. F1000Res https://doi.org/10.12688/f1000research.15121.1 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  239. Kim, J. A. et al. Neural stem cell transplantation at critical period improves learning and memory through restoring synaptic impairment in Alzheimer’s disease mouse model. Cell Death Dis. 6, e1789 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  240. McGinley, L. M. et al. Human neural stem cell transplantation improves cognition in a murine model of Alzheimer’s disease. Sci. Rep. 8, 14776 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  241. Eckert, A. et al. Bystander effect fuels human induced pluripotent stem cell-derived neural stem cells to quickly attenuate early stage neurological deficits after stroke. Stem Cell Transl. Med. 4, 841–851 (2015).

    Article  Google Scholar 

  242. Huang, L., Wong, S., Snyder, E. Y., Hamblin, M. H. & Lee, J. P. Human neural stem cells rapidly ameliorate symptomatic inflammation in early-stage ischemic-reperfusion cerebral injury. Stem Cell Res. Ther. 5, 129 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  243. Wang, Y. et al. 3K3A-activated protein C stimulates postischemic neuronal repair by human neural stem cells in mice. Nat. Med. 22, 1050–1055 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  244. Piao, J. et al. Preclinical efficacy and safety of a human embryonic stem cell-derived midbrain dopamine progenitor product, MSK-DA01. Cell Stem Cell 28, 217–229.e7 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  245. Barker, R. A., Parmar, M., Studer, L. & Takahashi, J. Human trials of stem cell-derived dopamine neurons for Parkinson’s disease: dawn of a new era. Cell Stem Cell 21, 569–573 (2017).

    CAS  PubMed  Article  Google Scholar 

  246. Sun, C., Serra, C., Lee, G. & Wagner, K. R. Stem cell-based therapies for Duchenne muscular dystrophy. Exp. Neurol. 323, 113086 (2020).

    CAS  PubMed  Article  Google Scholar 

  247. Biressi, S., Filareto, A. & Rando, T. A. Stem cell therapy for muscular dystrophies. J. Clin. Invest. 130, 5652–5664 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  248. Mihaly, E., Altamirano, D. E., Tuffaha, S. & Grayson, W. Engineering skeletal muscle: Building complexity to achieve functionality. Semin. Cell Dev. Biol. 119, 61–69 (2021).

    CAS  PubMed  Article  Google Scholar 

  249. Eugenis, I., Wu, D. & Rando, T. A. Cells, scaffolds, and bioactive factors: Engineering strategies for improving regeneration following volumetric muscle loss. Biomaterials 278, 121173 (2021).

    CAS  PubMed  Article  Google Scholar 

  250. Boyer, O. et al. Myogenic cell transplantation in genetic and acquired diseases of skeletal muscle. Front. Genet. 12, 702547 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  251. Boyer, O. et al. Autologous myoblasts for the treatment of fecal incontinence: results of a phase 2 randomized placebo-controlled study (MIAS). Ann. Surg. 267, 443–450 (2018).

    PubMed  Article  Google Scholar 

  252. Kwon, H. S. et al. Anti-human CD117 antibody-mediated bone marrow niche clearance in nonhuman primates and humanized NSG mice. Blood 133, 2104–2108 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  253. Chhabra, A. et al. Hematopoietic stem cell transplantation in immunocompetent hosts without radiation or chemotherapy. Sci. Transl. Med. 8, 351ra105 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  254. Choi, S. H. et al. Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer’s mouse model. Science 361, eaan8821 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

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Acknowledgements

The authors apologize for not including all relevant studies due to space constraints. They thank the reviewers for helpful comments. This work was supported by National Institutes of Health/National Institute on Aging P01AG036695 (A.B., M.A.G. and T.A.R.).

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The authors contributed equally to all aspects of the article.

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Correspondence to Anne Brunet, Margaret A. Goodell or Thomas A. Rando.

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Nature Reviews Molecular Cell Biology thanks Jennifer Trowbridge, who co-reviewed with Jayna Mistry; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Regenerative regions

Specific regions of the tissue that contain stem cells. In some tissues (for example, brain and intestine), these regions are well delineated. In other tissues (for example, muscle), stem cells are distributed throughout.

Neuroblasts

Progenitor cells that are committed to give rise to neurons.

Lymphoid cells

B lymphocytes, T lymphocytes and natural killer cells.

Myeloid lineage

Lineage giving rise to platelets, red blood cells, monocytes, neutrophils, basophils and eosinophils.

CD34

Sialomucin, a glycosylated transmembrane protein that is expressed by several stem cells, notably muscle stem cells and, in humans, haematopoietic stem cells.

Fibrogenic state

State characterized by abnormal deposition of extracellular matrix proteins and scarring of the tissue.

DNA methyltransferase 3A

(DNMT3A). Enzyme that adds methyl groups to cytosines in DNA.

Inflammatory cytokines

Signalling molecules secreted from immune cells or other cell types that promote inflammation.

Mechanosensitive cells

Cells that respond to mechanical stress or mechanical stimulation.

Bulge

Region of the outer root sheath of the hair which contains hair follicle stem cells.

Paracrine

Refers to the effect of factors in the vicinity of cells that secrete these factors.

ATM

Serine and threonine protein kinase that is recruited at and activated by double-strand breaks in DNA.

Extracellular vesicles

Lipid-bound vesicles, including exosomes, secreted into the extracellular space.

Nociceptive innervation

Innervation by sensory neurons that respond to damaging stimuli and send signals to the spinal cord and the brain.

ATR

Serine and threonine protein kinase that is activated by single-strand breaks in DNA.

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Brunet, A., Goodell, M.A. & Rando, T.A. Ageing and rejuvenation of tissue stem cells and their niches. Nat Rev Mol Cell Biol (2022). https://doi.org/10.1038/s41580-022-00510-w

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