Many tissues and organ systems in metazoans have the intrinsic capacity to regenerate, which is driven and maintained largely by tissue-resident somatic stem cell populations. Ageing is accompanied by a deregulation of stem cell function and a decline in regenerative capacity, often resulting in degenerative diseases. The identification of strategies to maintain stem cell function and regulation is therefore a promising avenue to allay a wide range of age-related diseases. Studies in various organisms have revealed a central role for metabolic pathways in the regulation of stem cell function. Ageing is associated with extensive metabolic changes, and interventions that influence cellular metabolism have long been recognized as robust lifespan-extending measures. In this Review, we discuss recent advances in our understanding of the metabolic control of stem cell function, and how stem cell metabolism relates to homeostasis and ageing.
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Chandel, N. Navigating Metabolism (Cold Spring Harbor Laboratory, 2015).
Weissman, I. L. Stem cells: units of development, units of regeneration, and units in evolution. Cell 100, 157–168 (2000).
Shyh-Chang, N., Daley, G. Q. & Cantley, L. C. Stem cell metabolism in tissue development and aging. Development 140, 2535–4257 (2013).
Kohli, L. & Passegué, E. Surviving change: the metabolic journey of hematopoietic stem cells. Trends Cell Biol. 24, 479–487 (2014).
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).
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).
Xu, X. et al. Mitochondrial regulation in pluripotent stem cells. Cell Metab. 18, 325–332 (2013).
Teslaa, T. & Teitell, M. A. Pluripotent stem cell energy metabolism: an update. EMBO J. 34, 138–153 (2015).
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).
Hom, J. R. et al. The permeability transition pore controls cardiac mitochondrial maturation and myocyte differentiation. Dev. Cell 21, 469–478 (2011).
Tormos, K. V. et al. Mitochondrial complex III ROS regulate adipocyte differentiation. Cell Metab. 14, 537–544 (2011).
Folmes, C. D. et al. Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming. Cell Metab. 14, 264–271 (2011).
Zhang, J. et al. UCP2 regulates energy metabolism and differentiation potential of human pluripotent stem cells. EMBO J. 30, 4860–4873 (2011).
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).
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).
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).
Son, M. J. et al. Mitofusins deficiency elicits mitochondrial metabolic reprogramming to pluripotency. Cell Death Differ. 22, 1957–1969 (2015).
Kaelin, W. G. Jr & McKnight, S. L. Influence of metabolism on epigenetics and disease. Cell 153, 56–69 (2013).
Wang, J. et al. Dependence of mouse embryonic stem cells on threonine catabolism. Science 325, 435–439 (2009).
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).
Cheung, T. H. & Rando, T. A. Molecular regulation of stem cell quiescence. Nat. Rev. Mol. Cell Biol. 14, 329–340 (2013).
Rando, T. A. Stem cells, ageing and the quest for immortality. Nature 441, 1080–1086 (2006).
Rossi, D. J., Jamieson, C. H. & Weissman, I. L. Stems cells and the pathways to aging and cancer. Cell 132, 681–696 (2008).
López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).
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).
Pietras, E. M., Warr, M. & Passegué, E. Cell cycle regulation in hematopoietic stem cells. J. Cell Biol. 195, 709–720 (2011).
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).
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).
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).
Maryanovich, M. et al. An MTCH2 pathway repressing mitochondria metabolism regulates haematopoietic stem cell fate. Nat. Commun. 6, 7901 (2015).
Takubo, K. et al. Regulation of the HIF-1alpha level is essential for hematopoietic stem cells. Cell Stem Cell 7, 391–402 (2010).
Maltepe, E. et al. Abnormal angiogenesis and responses to glucose and oxygen deprivation in mice lacking the protein ARNT. Nature 386, 403–407 (1997).
Adelman, D. M. et al. Placental cell fates are regulated in vivo by HIF-mediated hypoxia responses. Genes Dev. 14, 3191–3203 (2000).
Mazumdar J. et al. O2 regulates stem cells through Wnt/β-catenin signalling. Nat. Cell Biol. 12, 1007–1013 (2010).
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).
Kocabas, F. et al. Meis1 regulates the metabolic phenotype and oxidant defense of hematopoietic stem cells. Blood 120, 4963–4972 (2012).
Mohrin, M. et al. Stem cell aging: a mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging. Science 347, 1374–1377 (2015).
Mantel, C. R. et al. Enhancing hematopoietic stem cell transplantation efficacy by mitigating oxygen shock. Cell 161, 1553–1565 (2015).
Nakada, D., Saunders, T. L. & Morrison, S. J. Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature 468, 653–658 (2010).
Luchsinger, L. L. et al. Mitofusin 2 maintains haematopoietic stem cells with extensive lymphoid potential. Nature 529, 528–531 (2016).
Ito, K. et al. A PML–PPAR-δ pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance. Nat. Med. 18, 1350–1358 (2012).
Katajisto, P. et al. Stem cells: asymmetric apportioning of aged mitochondria between daughter cells is required for stemness. Science 348, 340–343 (2015).
Biteau, B., Hochmuth, C. E. & Jasper, H. Maintaining tissue homeostasis: dynamic control of somatic stem cell activity. Cell Stem Cell 9, 402–411 (2011).
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).
Amcheslavsky, A., Jiang, J. & Ip, Y. T. Tissue damage-induced intestinal stem cell division in Drosophila. Cell Stem Cell 4, 49–61 (2009).
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).
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).
Biteau, B. et al. Lifespan extension by preserving proliferative homeostasis in Drosophila. PLoS Genet. 6, 1001159 (2010).
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).
Rera, M. et al. Modulation of longevity and tissue homeostasis by the Drosophila PGC-1 homolog. Cell Metab. 14, 623–634 (2011).
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).
Hur, J. H. et al. Increased longevity mediated by yeast NDI1 expression in Drosophila intestinal stem and progenitor cells. Aging 5, 662–681 (2013).
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).
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).
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).
Knobloch, M. et al. Metabolic control of adult neural stem cell activity by Fasn-dependent lipogenesis. Nature 493, 226–230 (2013).
Kenyon, C. J. The genetics of ageing. Nature 464, 504–512 (2010).
Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009).
Laplante, M. & Sabatini, D. M. mTOR signaling in growth control and disease. Cell 149, 274–293 (2012).
Huang, J. & Manning, B. D. The TSC1–TSC2 complex: a molecular switchboard controlling cell growth. Biochem. J. 412, 179–190 (2008).
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).
Wilkinson, J. E. et al. Rapamycin slows aging in mice. Aging Cell 11, 675–682 (2012).
Jasper, H. & Jones, D. L. Metabolic regulation of stem cell behavior and implications for aging. Cell Metab. 12, 561–565 (2010).
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).
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).
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).
Yilmaz, O. H. et al. mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 486, 490–495 (2012).
Beyaz, S. et al. High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature 531, 53–58 (2016).
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).
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).
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).
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).
Rodgers, J. T. et al. mTORC1 controls the adaptive transition of quiescent stem cells from G0 to GAlert . Nature 510, 393–396 (2014).
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).
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).
Yilmaz, O. H. et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441, 475–482 (2006).
Kharas, M. G. et al. Constitutively active AKT depletes hematopoietic stem cells and induces leukemia in mice. Blood 115, 1406–1415 (2010).
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).
Juntilla, M. M. et al. AKT1 and AKT2 maintain hematopoietic stem cell function by regulating reactive oxygen species. Blood 115, 4030–4038 (2010).
Wilson, A., Laurenti, E. & Trumpp, A. Balancing dormant and self-renewing hematopoietic stem cells. Curr. Opin. Genet. Dev. 19, 461–468 (2009).
Mortensen, M. et al. The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance. J. Exp. Med. 208, 455–467 (2011).
Warr, M. R. et al. FOXO3A directs a protective autophagy program in haematopoietic stem cells. Nature 494, 323–327 (2013).
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).
Biteau, B. & Jasper, H. EGF signaling regulates the proliferation of intestinal stem cells in Drosophila. Development 138, 1045–1055 (2011).
Hamanaka, R. B. et al. Mitochondrial reactive oxygen species promote epidermal differentiation and hair follicle development. Sci. Signal. 6, ra8 (2013).
Morimoto, H. et al. ROS are required for mouse spermatogonial stem cell self-renewal. Cell Stem Cell 12, 774–786 (2013).
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).
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).
Bakker, S. T. & Passegué, E. Resilient and resourceful: genome maintenance strategies in hematopoietic stem cells. Exp. Hematol. 41, 915–923 (2013).
Owusu-Ansah, E. & Banerjee, U. Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation. Nature 461, 537–541 (2009).
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).
Rimmelé, P. et al. Mitochondrial metabolism in hematopoietic stem cells requires functional FOXO3. EMBO Rep. 16, 1164–1176 (2015).
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).
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).
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).
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).
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).
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).
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).
Spencer, J. A. et al. Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature 508, 269–273 (2014).
Itkin, T. et al. Distinct bone marrow blood vessels differentially regulate haematopoiesis. Nature 532, 323–328 (2016).
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).
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).
Brown, K. et al. SIRT3 reverses aging-associated degeneration. Cell Rep. 3, 319–327 (2013).
Miyamoto, K. et al. FoxO3a regulates hematopoietic homeostasis through a negative feedback pathway in conditions of stress or aging. Blood 112, 4485–4493 (2008).
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).
Tothova, Z. et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128, 325–339 (2007).
Miyamoto, K. et al. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 1, 101–112 (2007).
Murakami, S. & Motohashi, H. Roles of Nrf2 in cell proliferation and differentiation. Free Radic. Biol. Med. 88, 168–178 (2015).
Sykiotis, G. P. & Bohmann, D. Keap1/Nrf2 signaling regulates oxidative stress tolerance and lifespan in Drosophila. Dev. Cell. 14, 76–85 (2008).
Harman, D. The free radical theory of aging. Antioxid. Redox Signal. 5, 557–561 (2003).
Park, C. B. & Larsson, N. G. Mitochondrial DNA mutations in disease and aging. J. Cell Biol. 193, 809–818 (2011).
Trifunovic, A. et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417–423 (2004).
Kujoth, G. C. et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309, 481–484 (2005).
Chen, M. L. et al. Erythroid dysplasia, megaloblastic anemia, and impaired lymphopoiesis arising from mitochondrial dysfunction. Blood 114, 4045–4053 (2009).
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).
Hämäläinen, R. H. et al. mtDNA mutagenesis disrupts pluripotent stem cell function by altering redox signaling. Cell Rep. 11, 1614–1624 (2015).
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).
Cosentino, C. & Mostoslavsky, R. Metabolism, longevity and epigenetics. Cell Mol. Life Sci. 70, 1525–1541 (2013).
Lu, C. & Thompson, C. B. Metabolic regulation of epigenetics. Cell Metab. 16, 9–17 (2012).
Keating, S. T. & El-Osta, A. Epigenetics and metabolism. Circ. Res. 116, 715–736 (2015).
Greer, E. L. et al. Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature 479, 365–371 (2011).
Beerman, I. & Rossi, D. J. Epigenetic control of stem cell potential during homeostasis, aging, and disease. Cell Stem Cell 16, 613–625 (2015).
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).
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).
Beerman, I. et al. Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging. Cell Stem Cell 12, 413–425 (2013).
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).
Chambers, S. M. et al. Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation. PLoS Biol. 5, 201 (2007).
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).
Challen, G. A. et al. Dnmt3a is essential for hematopoietic stem cell differentiation. Nat. Genet. 44, 23–31 (2011).
Imai, S. & Guarente, L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 24, 464–471 (2014).
Braidy, N. et al. Age related changes in NAD+ metabolism oxidative stress and Sirt1 activity in wistar rats. PLoS One 6, 19194 (2011).
Florian, M. C. et al. Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation. Cell Stem Cell 10, 520–530 (2012).
Zhang, X. P. et al. Oxidized low-density lipoprotein induces hematopoietic stem cell senescence. Cell Biol Int. 37, 940–948 (2013).
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).
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).
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).
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).
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).
Martin-Montalvo, A. & de Cabo, R. Mitochondrial metabolic reprogramming induced by calorie restriction. Antioxid. Redox Signal. 19, 310–320 (2013).
López-Lluch, G. et al. Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. Proc. Natl Acad. Sci. USA 103, 1768–1773 (2006).
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).
Hekimi, S., Lapointe, J. & Wen, Y. Taking a “good” look at free radicals in the aging process. Trends Cell Biol. 21, 569–576 (2011).
Tanaka, Y. et al. JmjC enzyme KDM2A is a regulator of rRNA transcription in response to starvation. EMBO J. 29, 1510–1522 (2010).
Shimazu, T. et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339, 211–214 (2013).
Boroughs, L. K. & DeBerardinis, R. J. Metabolic pathways promoting cancer cell survival and growth. Nat. Cell Biol. 17, 351–359 (2015).
Locasale, J. W. Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat. Rev. Cancer 13, 572–583 (2013).
N.S.C. is supported by NIH HL122062, AG049665 and HL071643; H.J. by NIH AG028127, GM100196, AG047497 and EY018177; T.T.H. by an AHA Predoctoral Fellowship; and E.P. by an LLS Scholar Award, PBBR and Glenn Foundation Research Awards, and NIH HL111266, HL092471 and CA184014.
The authors declare no competing financial interests.
About this article
Cite this article
Chandel, N., Jasper, H., Ho, T. et al. Metabolic regulation of stem cell function in tissue homeostasis and organismal ageing. Nat Cell Biol 18, 823–832 (2016). https://doi.org/10.1038/ncb3385
Nature Communications (2021)
Nature Metabolism (2021)
GPX4 and vitamin E cooperatively protect hematopoietic stem and progenitor cells from lipid peroxidation and ferroptosis
Cell Death & Disease (2021)
Cellular and Molecular Life Sciences (2021)
Nicotinamide riboside attenuates age-associated metabolic and functional changes in hematopoietic stem cells
Nature Communications (2021)