Metabolic regulation of stem cell function in tissue homeostasis and organismal ageing (original) (raw)

• Chandel, N. Navigating Metabolism (Cold Spring Harbor Laboratory, 2015).
  Google Scholar
• Weissman, I. L. Stem cells: units of development, units of regeneration, and units in evolution. Cell 100, 157–168 (2000).
  CAS PubMed Google Scholar
• Shyh-Chang, N., Daley, G. Q. & Cantley, L. C. Stem cell metabolism in tissue development and aging. Development 140, 2535–4257 (2013).
  CAS PubMed PubMed Central Google Scholar
• Kohli, L. & Passegué, E. Surviving change: the metabolic journey of hematopoietic stem cells. Trends Cell Biol. 24, 479–487 (2014).
  CAS PubMed PubMed Central Google Scholar
• Folmes, C. D., Dzeja, P. P., Nelson, T. J & Terzic, A. Metabolic plasticity in stem cell homeostasis and differentiation. Cell Stem Cell 11, 596–606 (2012).
  CAS PubMed PubMed Central Google Scholar
• Zhang, J., Nuebel, E., Daley, G. Q., Koehler, C. M. & Teitell, M. A. Metabolic regulation in pluripotent stem cells during reprogramming and self-renewal. Cell Stem Cell 11, 589–595 (2012).
  CAS PubMed PubMed Central Google Scholar
• Xu, X. et al. Mitochondrial regulation in pluripotent stem cells. Cell Metab. 18, 325–332 (2013).
  CAS PubMed Google Scholar
• Teslaa, T. & Teitell, M. A. Pluripotent stem cell energy metabolism: an update. EMBO J. 34, 138–153 (2015).
  CAS PubMed Google Scholar
• Cho, Y. M. et al. Dynamic changes in mitochondrial biogenesis and antioxidant enzymes during the spontaneous differentiation of human embryonic stem cells. Biochem. Biophys. Res. Commun. 348, 1472–1478 (2006).
  CAS PubMed Google Scholar
• Hom, J. R. et al. The permeability transition pore controls cardiac mitochondrial maturation and myocyte differentiation. Dev. Cell 21, 469–478 (2011).
  CAS PubMed PubMed Central Google Scholar
• Tormos, K. V. et al. Mitochondrial complex III ROS regulate adipocyte differentiation. Cell Metab. 14, 537–544 (2011).
  CAS PubMed PubMed Central Google Scholar
• Folmes, C. D. et al. Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming. Cell Metab. 14, 264–271 (2011).
  CAS PubMed PubMed Central Google Scholar
• Zhang, J. et al. UCP2 regulates energy metabolism and differentiation potential of human pluripotent stem cells. EMBO J. 30, 4860–4873 (2011).
  CAS PubMed PubMed Central Google Scholar
• Facucho-Oliveira, J. M., Alderson, J., Spikings, E. C., Egginton, S. & St John, J. C. Mitochondrial DNA replication during differentiation of murine embryonic stem cells. J. Cell Sci. 120, 4025–4034 (2007).
  CAS PubMed Google Scholar
• Todd, L. R. et al. Growth factor erv1-like modulates Drp1 to preserve mitochondrial dynamics and function in mouse embryonic stem cells. Mol. Biol. Cell 21, 1225–1236 (2010).
  CAS PubMed PubMed Central Google Scholar
• Vazquez-Martin, A. et al. Mitochondrial fusion by pharmacological manipulation impedes somatic cell reprogramming to pluripotency: new insight into the role of mitophagy in cell stemness. Aging 4, 393–401 (2012).
  CAS PubMed PubMed Central Google Scholar
• Son, M. J. et al. Mitofusins deficiency elicits mitochondrial metabolic reprogramming to pluripotency. Cell Death Differ. 22, 1957–1969 (2015).
  CAS PubMed PubMed Central Google Scholar
• Kaelin, W. G. Jr & McKnight, S. L. Influence of metabolism on epigenetics and disease. Cell 153, 56–69 (2013).
  CAS PubMed PubMed Central Google Scholar
• Wang, J. et al. Dependence of mouse embryonic stem cells on threonine catabolism. Science 325, 435–439 (2009).
  CAS PubMed PubMed Central Google Scholar
• Sperber, H. et al. The metabolome regulates the epigenetic landscape during naive-to-primed human embryonic stem cell transition. Nat. Cell Biol. 17, 1523–1535 (2015).
  CAS PubMed PubMed Central Google Scholar
• Cheung, T. H. & Rando, T. A. Molecular regulation of stem cell quiescence. Nat. Rev. Mol. Cell Biol. 14, 329–340 (2013).
  CAS PubMed Google Scholar
• Rando, T. A. Stem cells, ageing and the quest for immortality. Nature 441, 1080–1086 (2006).
  CAS PubMed Google Scholar
• Rossi, D. J., Jamieson, C. H. & Weissman, I. L. Stems cells and the pathways to aging and cancer. Cell 132, 681–696 (2008).
  CAS PubMed Google Scholar
• López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).
  PubMed PubMed Central Google Scholar
• Adams, P. D., Jasper, H. & Rudolph, K. L. Aging-induced stem cell mutations as drivers for disease and cancer. Cell Stem Cell 16, 601–612 (2015).
  CAS PubMed PubMed Central Google Scholar
• Pietras, E. M., Warr, M. & Passegué, E. Cell cycle regulation in hematopoietic stem cells. J. Cell Biol. 195, 709–720 (2011).
  CAS PubMed PubMed Central Google Scholar
• Simsek, T. et al. The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell 7, 380–390 (2010).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Maryanovich, M. et al. An MTCH2 pathway repressing mitochondria metabolism regulates haematopoietic stem cell fate. Nat. Commun. 6, 7901 (2015).
  CAS PubMed Google Scholar
• Takubo, K. et al. Regulation of the HIF-1alpha level is essential for hematopoietic stem cells. Cell Stem Cell 7, 391–402 (2010).
  CAS PubMed Google Scholar
• Maltepe, E. et al. Abnormal angiogenesis and responses to glucose and oxygen deprivation in mice lacking the protein ARNT. Nature 386, 403–407 (1997).
  CAS PubMed Google Scholar
• Adelman, D. M. et al. Placental cell fates are regulated in vivo by HIF-mediated hypoxia responses. Genes Dev. 14, 3191–3203 (2000).
  CAS PubMed PubMed Central Google Scholar
• Mazumdar J. et al. O2 regulates stem cells through Wnt/β-catenin signalling. Nat. Cell Biol. 12, 1007–1013 (2010).
  CAS PubMed PubMed Central Google Scholar
• Miharada, K. et al. Cripto regulates hematopoietic stem cells as a hypoxic-niche-related factor through cell surface receptor GRP78. Cell Stem Cell 9, 330–344 (2011).
  CAS PubMed Google Scholar
• Kocabas, F. et al. Meis1 regulates the metabolic phenotype and oxidant defense of hematopoietic stem cells. Blood 120, 4963–4972 (2012).
  CAS PubMed PubMed Central Google Scholar
• Mohrin, M. et al. Stem cell aging: a mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging. Science 347, 1374–1377 (2015).
  CAS PubMed PubMed Central Google Scholar
• Mantel, C. R. et al. Enhancing hematopoietic stem cell transplantation efficacy by mitigating oxygen shock. Cell 161, 1553–1565 (2015).
  CAS PubMed PubMed Central Google Scholar
• Nakada, D., Saunders, T. L. & Morrison, S. J. Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature 468, 653–658 (2010).
  CAS PubMed PubMed Central Google Scholar
• Luchsinger, L. L. et al. Mitofusin 2 maintains haematopoietic stem cells with extensive lymphoid potential. Nature 529, 528–531 (2016).
  CAS PubMed PubMed Central Google Scholar
• Ito, K. et al. A PML–PPAR-δ pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance. Nat. Med. 18, 1350–1358 (2012).
  CAS PubMed PubMed Central Google Scholar
• Katajisto, P. et al. Stem cells: asymmetric apportioning of aged mitochondria between daughter cells is required for stemness. Science 348, 340–343 (2015).
  CAS PubMed PubMed Central Google Scholar
• Biteau, B., Hochmuth, C. E. & Jasper, H. Maintaining tissue homeostasis: dynamic control of somatic stem cell activity. Cell Stem Cell 9, 402–411 (2011).
  CAS PubMed PubMed Central Google Scholar
• O'Brien, L. E., Soliman, S. S., Li, X. & Bilder, D. Altered modes of stem cell division drive adaptive intestinal growth. Cell 147, 603–614 (2011).
  CAS PubMed PubMed Central Google Scholar
• Amcheslavsky, A., Jiang, J. & Ip, Y. T. Tissue damage-induced intestinal stem cell division in Drosophila. Cell Stem Cell 4, 49–61 (2009).
  CAS PubMed PubMed Central Google Scholar
• Buchon, N., Broderick, N. A., Chakrabarti, S. & Lemaitre, B. Invasive and indigenous microbiota impact intestinal stem cell activity through multiple pathways in Drosophila. Genes Dev. 23, 2333–2344 (2009).
  CAS PubMed PubMed Central Google Scholar
• Biteau, B., Hochmuth, C. E. & Jasper, H. JNK activity in somatic stem cells causes loss of tissue homeostasis in the aging Drosophila gut. Cell Stem Cell 3, 442–455 (2008).
  CAS PubMed PubMed Central Google Scholar
• Biteau, B. et al. Lifespan extension by preserving proliferative homeostasis in Drosophila. PLoS Genet. 6, 1001159 (2010).
  Google Scholar
• Rera, M., Clark, R. I. & Walker, D. W. Intestinal barrier dysfunction links metabolic and inflammatory markers of aging to death in Drosophila. Proc. Natl Acad. Sci. USA 109, 21528–21533 (2012).
  CAS PubMed PubMed Central Google Scholar
• Rera, M. et al. Modulation of longevity and tissue homeostasis by the Drosophila PGC-1 homolog. Cell Metab. 14, 623–634 (2011).
  CAS PubMed PubMed Central Google Scholar
• Hochmuth, C. E., Biteau, B., Bohmann, D. & Jasper, H. Redox regulation by Keap1 and Nrf2 controls intestinal stem cell proliferation in Drosophila. Cell Stem Cell 8, 1–12 (2011).
  Google Scholar
• Hur, J. H. et al. Increased longevity mediated by yeast NDI1 expression in Drosophila intestinal stem and progenitor cells. Aging 5, 662–681 (2013).
  CAS PubMed PubMed Central Google Scholar
• Chen, C. T., Shih, Y. R., Kuo, T. K., Lee, O. K. & Wei, Y. H. Coordinated changes of mitochondrial biogenesis and antioxidant enzymes during osteogenic differentiation of human mesenchymal stem cells. Stem Cells 26, 960–968 (2008).
  CAS PubMed Google Scholar
• Fu, X., Zhu, M. J., Dodson, M. V. & Du, M. AMP-activated protein kinase stimulates Warburg-like glycolysis and activation of satellite cells during muscle regeneration. J. Biol. Chem. 290, 26445–26456 (2015).
  CAS PubMed PubMed Central Google Scholar
• 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 Google Scholar
• Knobloch, M. et al. Metabolic control of adult neural stem cell activity by Fasn-dependent lipogenesis. Nature 493, 226–230 (2013).
  CAS PubMed Google Scholar
• Kenyon, C. J. The genetics of ageing. Nature 464, 504–512 (2010).
  CAS PubMed Google Scholar
• Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009).
  CAS PubMed PubMed Central Google Scholar
• Laplante, M. & Sabatini, D. M. mTOR signaling in growth control and disease. Cell 149, 274–293 (2012).
  CAS PubMed PubMed Central Google Scholar
• Huang, J. & Manning, B. D. The TSC1–TSC2 complex: a molecular switchboard controlling cell growth. Biochem. J. 412, 179–190 (2008).
  CAS PubMed Google Scholar
• Kapahi, P. et al. With TOR, less is more: a key role for the conserved nutrient-sensing TOR pathway in aging. Cell Metab. 11, 453–465 (2010).
  CAS PubMed PubMed Central Google Scholar
• Wilkinson, J. E. et al. Rapamycin slows aging in mice. Aging Cell 11, 675–682 (2012).
  CAS PubMed Google Scholar
• Jasper, H. & Jones, D. L. Metabolic regulation of stem cell behavior and implications for aging. Cell Metab. 12, 561–565 (2010).
  CAS PubMed PubMed Central Google Scholar
• Amcheslavsky, A., Ito, N., Jiang, J. & Ip, Y. T. Tuberous sclerosis complex and Myc coordinate the growth and division of Drosophila intestinal stem cells. J. Cell Biol. 193, 695–710 (2011).
  CAS PubMed PubMed Central Google Scholar
• Kapuria, S., Karpac, J., Biteau, B., Hwangbo, D. & Jasper, H. Notch-mediated suppression of TSC2 expression regulates cell differentiation in the Drosophila intestinal stem cell lineage. PLoS Genet. 8, e1003045 (2012).
  CAS PubMed PubMed Central Google Scholar
• Quan, Z., Sun, P., Lin, G. & Xi, R. TSC1/2 regulates intestinal stem cell maintenance and lineage differentiation via Rheb–TorC1–S6K but independent of nutrition status or Notch activation. J. Cell Sci. 126, 3884–3892 (2013).
  CAS PubMed Google Scholar
• Yilmaz, O. H. et al. mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 486, 490–495 (2012).
  CAS PubMed PubMed Central Google Scholar
• Beyaz, S. et al. High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature 531, 53–58 (2016).
  CAS PubMed PubMed Central Google Scholar
• Sampson, L. L., Davis, A. K., Grogg, M. W. & Zheng, Y. mTOR disruption causes intestinal epithelial cell defects and intestinal atrophy postinjury in mice. FASEB J. 30, 1263–1275 (2016).
  CAS PubMed Google Scholar
• Magri, L. et al. Sustained activation of mTOR pathway in embryonic neural stem cells leads to development of Tuberous Sclerosis Complex-associated lesions. Cell Stem Cell 9, 447–462 (2011).
  CAS PubMed Google Scholar
• Easley, C. A. et al. mTOR-mediated activation of p70 S6K induces differentiation of pluripotent human embryonic stem cells. Cell Reprogram. 12, 263–273 (2010).
  CAS PubMed PubMed Central Google Scholar
• Chen, T. et al. Rapamycin and other longevity-promoting compounds enhance the generation of mouse induced pluripotent stem cells. Aging Cell 10, 908–911 (2011).
  CAS PubMed Google Scholar
• Rodgers, J. T. et al. mTORC1 controls the adaptive transition of quiescent stem cells from G0 to GAlert . Nature 510, 393–396 (2014).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Kasahara, A., Cipolat, S., Chen, Y., Dorn, G. W. II & Scorrano, L. Mitochondrial fusion directs cardiomyocyte differentiation via calcineurin and Notch signaling. Science 342, 734–737 (2013).
  CAS PubMed Google Scholar
• Yilmaz, O. H. et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441, 475–482 (2006).
  CAS PubMed Google Scholar
• Kharas, M. G. et al. Constitutively active AKT depletes hematopoietic stem cells and induces leukemia in mice. Blood 115, 1406–1415 (2010).
  CAS PubMed PubMed Central Google Scholar
• Qian, P. et al. The Dlk1–Gtl2 locus preserves LT-HSC function by inhibiting the PI3K–mTOR pathway to restrict mitochondrial metabolism. Cell Stem Cell 18, 214–228 (2015).
  PubMed PubMed Central Google Scholar
• Juntilla, M. M. et al. AKT1 and AKT2 maintain hematopoietic stem cell function by regulating reactive oxygen species. Blood 115, 4030–4038 (2010).
  CAS PubMed PubMed Central Google Scholar
• Wilson, A., Laurenti, E. & Trumpp, A. Balancing dormant and self-renewing hematopoietic stem cells. Curr. Opin. Genet. Dev. 19, 461–468 (2009).
  CAS PubMed Google Scholar
• Mortensen, M. et al. The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance. J. Exp. Med. 208, 455–467 (2011).
  CAS PubMed PubMed Central Google Scholar
• Warr, M. R. et al. FOXO3A directs a protective autophagy program in haematopoietic stem cells. Nature 494, 323–327 (2013).
  CAS PubMed PubMed Central Google Scholar
• Malinska, D., Kudin, A. P., Bejtka, M. & Kunz, W. S. Changes in mitochondrial reactive oxygen species synthesis during differentiation of skeletal muscle cells. Mitochondrion 12, 144–148 (2012).
  CAS PubMed Google Scholar
• Biteau, B. & Jasper, H. EGF signaling regulates the proliferation of intestinal stem cells in Drosophila. Development 138, 1045–1055 (2011).
  CAS PubMed PubMed Central Google Scholar
• Hamanaka, R. B. et al. Mitochondrial reactive oxygen species promote epidermal differentiation and hair follicle development. Sci. Signal. 6, ra8 (2013).
  PubMed PubMed Central Google Scholar
• Morimoto, H. et al. ROS are required for mouse spermatogonial stem cell self-renewal. Cell Stem Cell 12, 774–786 (2013).
  CAS PubMed Google Scholar
• Le Belle, J. E. et al. Proliferative neural stem cells have high endogenous ROS levels that regulate self-renewal and neurogenesis in a PI3K/AKT-dependant manner. Cell Stem Cell 8, 59–71 (2011).
  CAS PubMed PubMed Central Google Scholar
• Paul, M. K. et al. Dynamic changes in intracellular ROS levels regulate airway basal stem cell homeostasis through Nrf2-dependent notch signaling. Cell Stem Cell 15, 199–214 (2014).
  CAS PubMed PubMed Central Google Scholar
• Bakker, S. T. & Passegué, E. Resilient and resourceful: genome maintenance strategies in hematopoietic stem cells. Exp. Hematol. 41, 915–923 (2013).
  CAS PubMed Google Scholar
• Owusu-Ansah, E. & Banerjee, U. Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation. Nature 461, 537–541 (2009).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed Google Scholar
• Rimmelé, P. et al. Mitochondrial metabolism in hematopoietic stem cells requires functional FOXO3. EMBO Rep. 16, 1164–1176 (2015).
  PubMed PubMed Central Google Scholar
• Lewandowski, D. et al. In vivo cellular imaging pinpoints the role of reactive oxygen species in the early steps of adult hematopoietic reconstitution. Blood 115, 443–452 (2010).
  CAS PubMed Google Scholar
• Ludin, A. et al. Reactive oxygen species regulate hematopoietic stem cell self-renewal, migration and development, as well as their bone marrow microenvironment. Antioxid. Redox Signal. 21, 1605–1619 (2014).
  CAS PubMed PubMed Central Google Scholar
• Jang, Y. Y. & Sharkis, S. J. 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).
  CAS PubMed PubMed Central Google Scholar
• Itkin, T. et al. FGF-2 expands murine hematopoietic stem and progenitor cells via proliferation of stromal cells, c-Kit activation, and CXCL12 down-regulation. Blood 120, 1843–1855 (2012).
  CAS PubMed Google Scholar
• Ludin, A. et al. Monocytes-macrophages that express alpha-smooth muscle actin preserve primitive hematopoietic cells in the bone marrow. Nat. Immunol. 13, 1072–1082 (2012).
  CAS PubMed Google Scholar
• Golan, K. et al. S1P promotes murine progenitor cell egress and mobilization via S1P1-mediated ROS signaling and SDF-1 release. Blood 119, 2478–2488 (2012).
  CAS PubMed PubMed Central Google Scholar
• Ishikawa, E. T. et al. Connexin-43 prevents hematopoietic stem cell senescence through transfer of reactive oxygen species to bone marrow stromal cells. Proc. Natl Acad. Sci. USA 109, 9071–9076 (2012).
  CAS Google Scholar
• Spencer, J. A. et al. Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature 508, 269–273 (2014).
  CAS PubMed PubMed Central Google Scholar
• Itkin, T. et al. Distinct bone marrow blood vessels differentially regulate haematopoiesis. Nature 532, 323–328 (2016).
  CAS PubMed PubMed Central Google Scholar
• Matsui, K. et al. NAD-dependent histone deacetylase, SIRT1, plays essential roles in the maintenance of hematopoietic stem cells. Biochem. Biophys. Res. Commun. 418, 811–817 (2012).
  CAS PubMed Google Scholar
• Rimmelé, P. et al. Aging-like phenotype and defective lineage specification in SIRT1-deleted hematopoietic stem and progenitor cells. Stem Cell Rep. 3, 44–59 (2014).
  Google Scholar
• Brown, K. et al. SIRT3 reverses aging-associated degeneration. Cell Rep. 3, 319–327 (2013).
  CAS PubMed PubMed Central Google Scholar
• Miyamoto, K. et al. FoxO3a regulates hematopoietic homeostasis through a negative feedback pathway in conditions of stress or aging. Blood 112, 4485–4493 (2008).
  CAS PubMed PubMed Central Google Scholar
• Mehta, A. et al. The microRNA-132 and microRNA-212 cluster regulates hematopoietic stem cell maintenance and survival with age by buffering FOXO3 expression. Immunity 42, 1021–1032 (2015).
  CAS PubMed PubMed Central Google Scholar
• Tothova, Z. et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128, 325–339 (2007).
  CAS PubMed Google Scholar
• Miyamoto, K. et al. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 1, 101–112 (2007).
  CAS PubMed Google Scholar
• Murakami, S. & Motohashi, H. Roles of Nrf2 in cell proliferation and differentiation. Free Radic. Biol. Med. 88, 168–178 (2015).
  CAS PubMed Google Scholar
• Sykiotis, G. P. & Bohmann, D. Keap1/Nrf2 signaling regulates oxidative stress tolerance and lifespan in Drosophila. Dev. Cell. 14, 76–85 (2008).
  CAS PubMed PubMed Central Google Scholar
• Harman, D. The free radical theory of aging. Antioxid. Redox Signal. 5, 557–561 (2003).
  CAS PubMed Google Scholar
• Park, C. B. & Larsson, N. G. Mitochondrial DNA mutations in disease and aging. J. Cell Biol. 193, 809–818 (2011).
  CAS PubMed PubMed Central Google Scholar
• Trifunovic, A. et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417–423 (2004).
  CAS PubMed Google Scholar
• Kujoth, G. C. et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309, 481–484 (2005).
  CAS PubMed Google Scholar
• Chen, M. L. et al. Erythroid dysplasia, megaloblastic anemia, and impaired lymphopoiesis arising from mitochondrial dysfunction. Blood 114, 4045–4053 (2009).
  CAS PubMed PubMed Central Google Scholar
• 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 (2011).
  Google Scholar
• Hämäläinen, R. H. et al. mtDNA mutagenesis disrupts pluripotent stem cell function by altering redox signaling. Cell Rep. 11, 1614–1624 (2015).
  PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed Google Scholar
• Cosentino, C. & Mostoslavsky, R. Metabolism, longevity and epigenetics. Cell Mol. Life Sci. 70, 1525–1541 (2013).
  CAS PubMed PubMed Central Google Scholar
• Lu, C. & Thompson, C. B. Metabolic regulation of epigenetics. Cell Metab. 16, 9–17 (2012).
  CAS PubMed PubMed Central Google Scholar
• Keating, S. T. & El-Osta, A. Epigenetics and metabolism. Circ. Res. 116, 715–736 (2015).
  CAS PubMed Google Scholar
• Greer, E. L. et al. Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature 479, 365–371 (2011).
  CAS PubMed PubMed Central Google Scholar
• Beerman, I. & Rossi, D. J. Epigenetic control of stem cell potential during homeostasis, aging, and disease. Cell Stem Cell 16, 613–625 (2015).
  CAS PubMed PubMed Central Google Scholar
• Chinopoulos, C. Which way does the citric acid cycle turn during hypoxia? The critical role of α-ketoglutarate dehydrogenase complex. J. Neurosci Res. 91, 1030–1043 (2013).
  CAS PubMed Google Scholar
• Koivunen, P. et al. Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF. J. Biol. Chem. 282, 4524–4532 (2007).
  CAS PubMed Google Scholar
• Beerman, I. et al. Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging. Cell Stem Cell 12, 413–425 (2013).
  CAS PubMed Google Scholar
• Salminen, A., Kauppinen, A., Hiltunen, M. & Kaarniranta, K. Krebs cycle intermediates regulate DNA and histone methylation: epigenetic impact on the aging process. Ageing Res Rev. 16, 45–65 (2014).
  CAS PubMed Google Scholar
• Chambers, S. M. et al. Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation. PLoS Biol. 5, 201 (2007).
  Google Scholar
• 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 Google Scholar
• Challen, G. A. et al. Dnmt3a is essential for hematopoietic stem cell differentiation. Nat. Genet. 44, 23–31 (2011).
  PubMed PubMed Central Google Scholar
• Imai, S. & Guarente, L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 24, 464–471 (2014).
  CAS PubMed PubMed Central Google Scholar
• Braidy, N. et al. Age related changes in NAD+ metabolism oxidative stress and Sirt1 activity in wistar rats. PLoS One 6, 19194 (2011).
  Google Scholar
• Florian, M. C. et al. Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation. Cell Stem Cell 10, 520–530 (2012).
  CAS PubMed PubMed Central Google Scholar
• Zhang, X. P. et al. Oxidized low-density lipoprotein induces hematopoietic stem cell senescence. Cell Biol Int. 37, 940–948 (2013).
  CAS PubMed Google Scholar
• Tie, G., Messina, K. E., Yan, J., Messina, J.A. & Messina, L. M. Hypercholesterolemia induces oxidant stress that accelerates the ageing of hematopoietic stem cells. J. Am. Heart Assoc. 3, 000241 (2014).
  Google Scholar
• Chen, J., Astle, C. M. & Harrison, D. E. Hematopoietic senescence is postponed and hematopoietic stem cell function is enhanced by dietary restriction. Exp. Hematol. 31, 1097–1103 (2003).
  CAS PubMed Google Scholar
• Cheng, C. W. et al. Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression. Cell Stem Cell 14, 810–823 (2014).
  CAS PubMed PubMed Central Google Scholar
• Passegué, E, Wagers, A. J., Giuriato, S., Anderson, W. C. & Weissman, I. L. Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates. J. Exp. Med. 202, 1599–1611 (2005).
  PubMed PubMed Central Google Scholar
• 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 Google Scholar
• Martin-Montalvo, A. & de Cabo, R. Mitochondrial metabolic reprogramming induced by calorie restriction. Antioxid. Redox Signal. 19, 310–320 (2013).
  CAS PubMed PubMed Central Google Scholar
• López-Lluch, G. et al. Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. Proc. Natl Acad. Sci. USA 103, 1768–1773 (2006).
  PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Hekimi, S., Lapointe, J. & Wen, Y. Taking a “good” look at free radicals in the aging process. Trends Cell Biol. 21, 569–576 (2011).
  CAS PubMed PubMed Central Google Scholar
• Tanaka, Y. et al. JmjC enzyme KDM2A is a regulator of rRNA transcription in response to starvation. EMBO J. 29, 1510–1522 (2010).
  CAS PubMed PubMed Central Google Scholar
• Shimazu, T. et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339, 211–214 (2013).
  CAS PubMed Google Scholar
• Boroughs, L. K. & DeBerardinis, R. J. Metabolic pathways promoting cancer cell survival and growth. Nat. Cell Biol. 17, 351–359 (2015).
  CAS PubMed PubMed Central Google Scholar
• Locasale, J. W. Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat. Rev. Cancer 13, 572–583 (2013).
  CAS PubMed PubMed Central Google Scholar