Metabolic Regulation: A Potential Strategy for Rescuing Stem Cell Senescence

Stem Cell Reviews and Reports - Tập 18 - Trang 1728-1742 - 2022
Wenxin Zhang1, Jiayu Li1, Yuchi Duan1, Yanlin Li1, Yanan Sun1, Hui Sun1, Xiao Yu1, Xingyu Gao1, Chang Zhang1, Haiying Zhang1, Yingai Shi1, Xu He1
1The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, China

Tóm tắt

Stem cell senescence and exhaustion are closely related to organ failure and individual aging, which not only induces age-related diseases, but also hinders stem cell applications in regenerative medicine. Thus, it’s imminent to find effective ways to delay and retrieve stem cell senescence. Metabolic abnormalities are one of the main characteristics of age-associated declines in stem cell function. Understanding the underlying mechanisms may reveal potential strategies for ameliorating age-associated phenotypes and treating age-related diseases. This review focuses on recent advances in the association between metabolism including glucose, lipid, glutamine and NAD+ metabolism and stem cell senescence, as well as the other properties like proliferation and differentiation. Layers of studies are summarized to demonstrate how metabolism varies in senescent stem cells and how metabolic reprogramming regulates stem cell senescence. Additionally, we mentioned some recent progress in therapeutic strategies to rejuvenate dysfunctional aged stem cells. Finally, a brief conclusion about the prospect of metabolic regulation as a potential strategy for rescuing stem cell senescence is displayed.

Tài liệu tham khảo

Campisi, J. (2013). Aging, cellular senescence, and cancer. Annual Review of Physiology, 75, 685–705. https://doi.org/10.1146/annurev-physiol-030212-183653 Ren, R., Ocampo, A., Liu, G. H., & Izpisua Belmonte, J. C. (2017). Regulation of Stem Cell Aging by Metabolism and Epigenetics. Cell Metabolism, 26(3), 460–474. https://doi.org/10.1016/j.cmet.2017.07.019 Muñoz-Espín, D., & Serrano, M. (2014). Cellular senescence: from physiology to pathology. Nature Reviews. Molecular Cell Biology, 15(7), 482–496. https://doi.org/10.1038/nrm3823 Kwon, S. M., Hong, S. M., Lee, Y. K., Min, S., & Yoon, G. (2019). Metabolic features and regulation in cell senescence. BMB Reports, 52(1), 5–12. https://doi.org/10.5483/BMBRep.2019.52.1.291 He, S., & Sharpless, N. E. (2017). Senescence in Health and Disease. Cell, 169(6), 1000–1011. https://doi.org/10.1016/j.cell.2017.05.015 Li, L., & Xie, T. (2005). Stem cell niche: structure and function. Annual Review of Cell and Developmental Biology, 21, 605–631. https://doi.org/10.1146/annurev.cellbio.21.012704.131525 Neves, J., Sousa-Victor, P., & Jasper, H. (2017). Rejuvenating Strategies for Stem Cell-Based Therapies in Aging. Cell Stem Cell, 20(2), 161–175. https://doi.org/10.1016/j.stem.2017.01.008 Khademi-Shirvan, M., Ghorbaninejad, M., Hosseini, S., & Baghaban Eslaminejad, M. (2020). The Importance of Stem Cell Senescence in Regenerative Medicine. Advances in Experimental Medicine and Biology, 1288, 87–102. https://doi.org/10.1007/5584_2020_489 Shyh-Chang, N., & Ng, H. H. (2017). The metabolic programming of stem cells. Genes & Development, 31(4), 336–346. https://doi.org/10.1101/gad.293167.116 Tatar, M., & Sedivy, J. M. (2016). Mitochondria: Masters of Epigenetics. Cell, 165(5), 1052–1054. https://doi.org/10.1016/j.cell.2016.05.021 Berger, S. L., & Sassone-Corsi, P. (2016). Metabolic Signaling to Chromatin. Cold Spring Harbor Perspectives in Biology, 8(11). https://doi.org/10.1101/cshperspect.a019463 Gray, L. R., Tompkins, S. C., & Taylor, E. B. (2014). Regulation of pyruvate metabolism and human disease. Cellular and Molecular Life Sciences, 71(14), 2577–2604. https://doi.org/10.1007/s00018-013-1539-2 Cliff, T. S., & Dalton, S. (2017). Metabolic switching and cell fate decisions: implications for pluripotency, reprogramming and development. Current Opinion in Genetics & Development, 46, 44–49. https://doi.org/10.1016/j.gde.2017.06.008 Nakamura-Ishizu, A., Ito, K., & Suda, T. (2020). Hematopoietic Stem Cell Metabolism during Development and Aging. Developmental Cell, 54(2), 239–255. https://doi.org/10.1016/j.devcel.2020.06.029 Rigaud, V. O. C., Hoy, R., Mohsin, S., & Khan, M. (2020). Stem Cell Metabolism. Powering Cell-Based Therapeutics. Cells, 9(11). https://doi.org/10.3390/cells9112490 Tsogtbaatar, E., Landin, C., Minter-Dykhouse, K., & Folmes, C. D. L. (2020). Energy Metabolism Regulates Stem Cell Pluripotency. Frontiers in Cell and Development Biology, 8, 87. https://doi.org/10.3389/fcell.2020.00087 Perales-Clemente, E., Folmes, C. D., & Terzic, A. (2014). Metabolic regulation of redox status in stem cells. Antioxidants & Redox Signaling, 21(11), 1648–1659. https://doi.org/10.1089/ars.2014.6000 Pouikli, A., & Tessarz, P. (2021). Metabolism and chromatin: A dynamic duo that regulates development and ageing: Elucidating the metabolism-chromatin axis in bone-marrow mesenchymal stem cell fate decisions. Bioessays, 43(5), e2000273. https://doi.org/10.1002/bies.202000273 Lunt, S. Y., & Vander Heiden, M. G. (2011). Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annual Review of Cell and Developmental Biology, 27, 441–464. https://doi.org/10.1146/annurev-cellbio-092910-154237 Hernandez-Segura, A., Nehme, J., & Demaria, M. (2018). Hallmarks of Cellular Senescence. Trends in Cell Biology, 28(6), 436–453. https://doi.org/10.1016/j.tcb.2018.02.001 James, E. L., Michalek, R. D., Pitiyage, G. N., de Castro, A. M., Vignola, K. S., Jones, J., Mohney, R. P., Karoly, E. D., Prime, S. S., & Parkinson, E. K. (2015). Senescent human fibroblasts show increased glycolysis and redox homeostasis with extracellular metabolomes that overlap with those of irreparable DNA damage, aging, and disease. Journal of Proteome Research, 14(4), 1854–1871. https://doi.org/10.1021/pr501221g Knobloch, M., Pilz, G. A., Ghesquière, B., Kovacs, W. J., Wegleiter, T., Moore, D. L., Hruzova, M., Zamboni, N., Carmeliet, P., & Jessberger, S. (2017). A Fatty Acid Oxidation-Dependent Metabolic Shift Regulates Adult Neural Stem Cell Activity. Cell Reports, 20(9), 2144–2155. https://doi.org/10.1016/j.celrep.2017.08.029 Smith, B., Schafer, X. L., Ambeskovic, A., Spencer, C. M., Land, H., & Munger, J. (2016). Addiction to Coupling of the Warburg Effect with Glutamine Catabolism in Cancer Cells. Cell Reports, 17(3), 821–836. https://doi.org/10.1016/j.celrep.2016.09.045 Semenza, G. L. (2017). Hypoxia-inducible factors: coupling glucose metabolism and redox regulation with induction of the breast cancer stem cell phenotype. The EMBO Journal, 36(3), 252–259. https://doi.org/10.15252/embj.201695204 Soto-Heredero, G., de Las, G., Heras, M. M., Gabandé-Rodríguez, E., Oller, J., & Mittelbrunn, M. (2020). Glycolysis - a key player in the inflammatory response. The FEBS Journal, 287(16), 3350–3369. https://doi.org/10.1111/febs.15327 Mylotte, L. A., Duffy, A. M., Murphy, M., O'Brien, T., Samali, A., Barry, F., & Szegezdi, E. (2008). Metabolic flexibility permits mesenchymal stem cell survival in an ischemic environment. Stem Cells, 26(5), 1325–1336. https://doi.org/10.1634/stemcells.2007-1072 Yang, F., Li, B., Yang, Y., Huang, M., Liu, X., Zhang, Y., Liu, H., Zhang, L., Pan, Y., Tian, S., Wu, Y., Wang, L., & Yang, L. (2019). Leptin enhances glycolysis via OPA1-mediated mitochondrial fusion to promote mesenchymal stem cell survival. International Journal of Molecular Medicine, 44(1), 301–312. https://doi.org/10.3892/ijmm.2019.4189 Flores, A., Schell, J., Krall, A. S., Jelinek, D., Miranda, M., Grigorian, M., Braas, D., White, A. C., Zhou, J. L., Graham, N. A., Graeber, T., Seth, P., Evseenko, D., Coller, H. A., Rutter, J., Christofk, H. R., & Lowry, W. E. (2017). Lactate dehydrogenase activity drives hair follicle stem cell activation. Nature Cell Biology, 19(9), 1017–1026. https://doi.org/10.1038/ncb3575 Guo, B., Huang, X., Lee, M. R., Lee, S. A., & Broxmeyer, H. E. (2018). Antagonism of PPAR-γ signaling expands human hematopoietic stem and progenitor cells by enhancing glycolysis. Nature Medicine, 24(3), 360–367. https://doi.org/10.1038/nm.4477 Hennrich, M. L., Romanov, N., Horn, P., Jaeger, S., Eckstein, V., Steeples, V., Ye, F., Ding, X., Poisa-Beiro, L., Lai, M. C., Lang, B., Boultwood, J., Luft, T., Zaugg, J. B., Pellagatti, A., Bork, P., Aloy, P., Gavin, A. C., & Ho, A. D. (2018). Cell-specific proteome analyses of human bone marrow reveal molecular features of age-dependent functional decline. Nature Communications, 9(1), 4004. https://doi.org/10.1038/s41467-018-06353-4 Morris, O., Deng, H., Tam, C., & Jasper, H. (2020). Warburg-like Metabolic Reprogramming in Aging Intestinal Stem Cells Contributes to Tissue Hyperplasia. Cell Reports, 33(8), 108423. https://doi.org/10.1016/j.celrep.2020.108423 Choi, S., Quan, X., Bang, S., Yoo, H., Kim, J., Park, J., Park, K. S., & Chung, J. (2017). Mitochondrial calcium uniporter in Drosophila transfers calcium between the endoplasmic reticulum and mitochondria in oxidative stress-induced cell death. The Journal of Biological Chemistry, 292(35), 14473–14485. https://doi.org/10.1074/jbc.M116.765578 von Stockum, S., Giorgio, V., Trevisan, E., Lippe, G., Glick, G. D., Forte, M. A., Da-Rè, C., Checchetto, V., Mazzotta, G., Costa, R., Szabò, I., & Bernardi, P. (2015). F-ATPase of Drosophila melanogaster forms 53-picosiemen (53-pS) channels responsible for mitochondrial Ca2+-induced Ca2+ release. The Journal of Biological Chemistry, 290(8), 4537–4544. https://doi.org/10.1074/jbc.C114.629766 Wu, K. K. (2021). Control of Mesenchymal Stromal Cell Senescence by Tryptophan Metabolites. International Journal of Molecular Sciences, 22(2). https://doi.org/10.3390/ijms22020697 Papaconstantinou, J. (2019). The Role of Signaling Pathways of Inflammation and Oxidative Stress in Development of Senescence and Aging Phenotypes in Cardiovascular Disease. Cells, 8(11). https://doi.org/10.3390/cells8111383 Sturchler, E., Feurstein, D., McDonald, P., & Duckett, D. (2010). Mechanism of oxidative stress-induced ASK1-catalyzed MKK6 phosphorylation. Biochemistry, 49(19), 4094–4102. https://doi.org/10.1021/bi100010j Hsieh, C. C., & Papaconstantinou, J. (2006). Thioredoxin-ASK1 complex levels regulate ROS-mediated p38 MAPK pathway activity in livers of aged and long-lived Snell dwarf mice. The FASEB Journal, 20(2), 259–268. https://doi.org/10.1096/fj.05-4376com Zhang, D., Lu, H., Chen, Z., Wang, Y., Lin, J., Xu, S., Zhang, C., Wang, B., Yuan, Z., Feng, X., Jiang, X., & Pan, J. (2017). High glucose induces the aging of mesenchymal stem cells via Akt/mTOR signaling. Molecular Medicine Reports, 16(2), 1685–1690. https://doi.org/10.3892/mmr.2017.6832 Kanatsu-Shinohara, M., Yamamoto, T., Toh, H., Kazuki, Y., Kazuki, K., Imoto, J., Ikeo, K., Oshima, M., Shirahige, K., Iwama, A., Nabeshima, Y., Sasaki, H., & Shinohara, T. (2019). Aging of spermatogonial stem cells by Jnk-mediated glycolysis activation. Proceedings of the National Academy of Sciences of the United States of America, 116(33), 16404–16409. https://doi.org/10.1073/pnas.1904980116 Mohyeldin, A., Garzón-Muvdi, T., & Quiñones-Hinojosa, A. (2010). Oxygen in stem cell biology: a critical component of the stem cell niche. Cell Stem Cell, 7(2), 150–161. https://doi.org/10.1016/j.stem.2010.07.007 Arthur, S. A., Blaydes, J. P., & Houghton, F. D. (2019). Glycolysis Regulates Human Embryonic Stem Cell Self-Renewal under Hypoxia through HIF-2α and the Glycolytic Sensors CTBPs. Stem Cell Reports, 12(4), 728–742. https://doi.org/10.1016/j.stemcr.2019.02.005 Forristal, C. E., Wright, K. L., Hanley, N. A., Oreffo, R. O., & Houghton, F. D. (2010). Hypoxia inducible factors regulate pluripotency and proliferation in human embryonic stem cells cultured at reduced oxygen tensions. Reproduction, 139(1), 85–97. https://doi.org/10.1530/rep-09-0300 Cacchiarelli, D., Trapnell, C., Ziller, M. J., Soumillon, M., Cesana, M., Karnik, R., Donaghey, J., Smith, Z. D., Ratanasirintrawoot, S., Zhang, X., Ho Sui, S. J., Wu, Z., Akopian, V., Gifford, C. A., Doench, J., Rinn, J. L., Daley, G. Q., Meissner, A., Lander, E. S., & Mikkelsen, T. S. (2015). Integrative Analyses of Human Reprogramming Reveal Dynamic Nature of Induced Pluripotency. Cell, 162(2), 412–424. https://doi.org/10.1016/j.cell.2015.06.016 Ma, T., Li, J., Xu, Y., Yu, C., Xu, T., Wang, H., Liu, K., Cao, N., Nie, B. M., Zhu, S. Y., Xu, S., Li, K., Wei, W. G., Wu, Y., Guan, K. L., & Ding, S. (2015). Atg5-independent autophagy regulates mitochondrial clearance and is essential for iPSC reprogramming. Nature Cell Biology, 17(11), 1379–1387. https://doi.org/10.1038/ncb3256 Li, L., Chen, K., Wang, T., Wu, Y., Xing, G., Chen, M., Hao, Z., Zhang, C., Zhang, J., Ma, B., Liu, Z., Yuan, H., Liu, Z., Long, Q., Zhou, Y., Qi, J., Zhao, D., Gao, M., Pei, D., et al. (2020). Glis1 facilitates induction of pluripotency via an epigenome-metabolome-epigenome signalling cascade. Nature Metabolism, 2(9), 882–892. https://doi.org/10.1038/s42255-020-0267-9 Liu, J., Guðmundsson, A., & Bäckvall, J. E. (2021). Efficient Aerobic Oxidation of Organic Molecules by Multistep Electron Transfer. Angewandte Chemie (International Ed. in English), 60(29), 15686–15704. https://doi.org/10.1002/anie.202012707 Christofk, H. R., Vander Heiden, M. G., Wu, N., Asara, J. M., & Cantley, L. C. (2008). Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature, 452(7184), 181–186. https://doi.org/10.1038/nature06667 Zhang, Y., Guo, L., Han, S., Chen, L., Li, C., Zhang, Z., Hong, Y., Zhang, X., Zhou, X., Jiang, D., Liang, X., Qiu, J., Zhang, J., Li, X., Zhong, S., Liao, C., Yan, B., Tse, H. F., & Lian, Q. (2020). Adult mesenchymal stem cell ageing interplays with depressed mitochondrial Ndufs6. Cell Death & Disease, 11(12), 1075. https://doi.org/10.1038/s41419-020-03289-w Ou, T., Yang, W., Li, W., Lu, Y., Dong, Z., Zhu, H., Sun, X., Dong, Z., Weng, X., Chang, S., Li, H., Li, Y., Qiu, Z., Hu, K., Sun, A., & Ge, J. (2020). SIRT5 deficiency enhances the proliferative and therapeutic capacities of adipose-derived mesenchymal stem cells via metabolic switching. Clinical and Translational Medicine, 10(5), e172. https://doi.org/10.1002/ctm2.172 Ren, L., Chen, X., Chen, X., Li, J., Cheng, B., & Xia, J. (2020). Mitochondrial Dynamics: Fission and Fusion in Fate Determination of Mesenchymal Stem Cells. Frontiers in Cell and Development Biology, 8, 580070. https://doi.org/10.3389/fcell.2020.580070 Lampert, M. A., Orogo, A. M., Najor, R. H., Hammerling, B. C., Leon, L. J., Wang, B. J., Kim, T., Sussman, M. A., Gustafsson, Å., & B. (2019). BNIP3L/NIX and FUNDC1-mediated mitophagy is required for mitochondrial network remodeling during cardiac progenitor cell differentiation. Autophagy, 15(7), 1182–1198. https://doi.org/10.1080/15548627.2019.1580095 Zhao, M., Liu, S., Wang, C., Wang, Y., Wan, M., Liu, F., Gong, M., Yuan, Y., Chen, Y., Cheng, J., Lu, Y., & Liu, J. (2021). Mesenchymal Stem Cell-Derived Extracellular Vesicles Attenuate Mitochondrial Damage and Inflammation by Stabilizing Mitochondrial DNA. ACS Nano, 15(1), 1519–1538. https://doi.org/10.1021/acsnano.0c08947 Sala, D., Cunningham, T. J., Stec, M. J., Etxaniz, U., Nicoletti, C., Dall'Agnese, A., Puri, P. L., Duester, G., Latella, L., & Sacco, A. (2019). The Stat3-Fam3a axis promotes muscle stem cell myogenic lineage progression by inducing mitochondrial respiration. Nature Communications, 10(1), 1796. https://doi.org/10.1038/s41467-019-09746-1 Kim, C. S., Ding, X., Allmeroth, K., Biggs, L. C., Kolenc, O. I., L'Hoest, N., Chacón-Martínez, C. A., Edlich-Muth, C., Giavalisco, P., Quinn, K. P., Denzel, M. S., Eming, S. A., & Wickström, S. A. (2020). Glutamine Metabolism Controls Stem Cell Fate Reversibility and Long-Term Maintenance in the Hair Follicle. Cell Metabolism, 32(4), 629–642.e628. https://doi.org/10.1016/j.cmet.2020.08.011 Stincone, A., Prigione, A., Cramer, T., Wamelink, M. M., Campbell, K., Cheung, E., Olin-Sandoval, V., Grüning, N. M., Krüger, A., Tauqeer Alam, M., Keller, M. A., Breitenbach, M., Brindle, K. M., Rabinowitz, J. D., & Ralser, M. (2015). The return of metabolism: biochemistry and physiology of the pentose phosphate pathway. Biological Reviews of the Cambridge Philosophical Society, 90(3), 927–963. https://doi.org/10.1111/brv.12140 Meyer, J., Salamon, A., Mispagel, S., Kamp, G., & Peters, K. (2018). Energy metabolic capacities of human adipose-derived mesenchymal stromal cells in vitro and their adaptations in osteogenic and adipogenic differentiation. Experimental Cell Research, 370(2), 632–642. https://doi.org/10.1016/j.yexcr.2018.07.028 Tokuda, K., Baron, B., Yamashiro, C., Kuramitsu, Y., Kitagawa, T., Kobayashi, M., et al. (2019). Up-regulation of the pentose phosphate pathway and HIF-1α expression during neural progenitor cell induction following glutamate treatment in rat ex vivo retina. Cell Biology International, 44(1), 137–144. https://doi.org/10.1002/cbin.11212. Dimmeler, S., & Leri, A. (2008). Aging and disease as modifiers of efficacy of cell therapy. Circulation Research, 102(11), 1319–1330. https://doi.org/10.1161/circresaha.108.175943 Katare, R., Oikawa, A., Cesselli, D., Beltrami, A. P., Avolio, E., Muthukrishnan, D., Munasinghe, P. E., Angelini, G., Emanueli, C., & Madeddu, P. (2013). Boosting the pentose phosphate pathway restores cardiac progenitor cell availability in diabetes. Cardiovascular Research, 97(1), 55–65. https://doi.org/10.1093/cvr/cvs291 Zhao, Y., Pan, X., Zhao, J., Wang, Y., Peng, Y., & Zhong, C. (2009). Decreased transketolase activity contributes to impaired hippocampal neurogenesis induced by thiamine deficiency. Journal of Neurochemistry, 111(2), 537–546. https://doi.org/10.1111/j.1471-4159.2009.06341.x Warburg, O. (1925). The Metabolism of Carcinoma Cells, 9(1), 148–163. Kathagen, A., Schulte, A., Balcke, G., Phillips, H. S., Martens, T., Matschke, J., Günther, H. S., Soriano, R., Modrusan, Z., Sandmann, T., Kuhl, C., Tissier, A., Holz, M., Krawinkel, L. A., Glatzel, M., Westphal, M., & Lamszus, K. (2013). Hypoxia and oxygenation induce a metabolic switch between pentose phosphate pathway and glycolysis in glioma stem-like cells. Acta Neuropathologica, 126(5), 763–780. https://doi.org/10.1007/s00401-013-1173-y Wang, Z., & Dong, C. (2019). Gluconeogenesis in Cancer: Function and Regulation of PEPCK, FBPase, and G6Pase. Trends Cancer, 5(1), 30–45. https://doi.org/10.1016/j.trecan.2018.11.003 Onken, B., Kalinava, N., & Driscoll, M. (2020). Gluconeogenesis and PEPCK are critical components of healthy aging and dietary restriction life extension. PLoS Genetics, 16(8), e1008982. https://doi.org/10.1371/journal.pgen.1008982 Koide, S., Oshima, M., Takubo, K., Yamazaki, S., Nitta, E., Saraya, A., Aoyama, K., Kato, Y., Miyagi, S., Nakajima-Takagi, Y., Chiba, T., Matsui, H., Arai, F., Suzuki, Y., Kimura, H., Nakauchi, H., Suda, T., Shinkai, Y., & Iwama, A. (2016). Setdb1 maintains hematopoietic stem and progenitor cells by restricting the ectopic activation of nonhematopoietic genes. Blood, 128(5), 638–649. https://doi.org/10.1182/blood-2016-01-694810 Zhang, C. Y., Yin, H. M., Wang, H., Su, D., Xia, Y., Yan, L. F., Fang, B., Liu, W., Wang, Y. M., Gu, A. H., & Zhou, Y. (2018). Transforming growth factor-β1 regulates the nascent hematopoietic stem cell niche by promoting gluconeogenesis. Leukemia, 32(2), 479–491. https://doi.org/10.1038/leu.2017.198 Küllenberg, D., Taylor, L. A., Schneider, M., & Massing, U. (2012). Health effects of dietary phospholipids. Lipids in Health and Disease, 11, 3. https://doi.org/10.1186/1476-511x-11-3 Wymann, M. P., & Schneiter, R. (2008). Lipid signalling in disease. Nature Reviews. Molecular Cell Biology, 9(2), 162–176. https://doi.org/10.1038/nrm2335 Ma, Y., Temkin, S. M., Hawkridge, A. M., Guo, C., Wang, W., Wang, X. Y., & Fang, X. (2018). Fatty acid oxidation: An emerging facet of metabolic transformation in cancer. Cancer Letters, 435, 92–100. https://doi.org/10.1016/j.canlet.2018.08.006 Ito, K., Carracedo, A., Weiss, D., Arai, F., Ala, U., Avigan, D. E., Schafer, Z. T., Evans, R. M., Suda, T., Lee, C. H., & Pandolfi, P. P. (2012). A PML–PPAR-δ pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance. Nature Medicine, 18(9), 1350–1358. https://doi.org/10.1038/nm.2882 Mergenthaler, P., Lindauer, U., Dienel, G. A., & Meisel, A. (2013). Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends in Neurosciences, 36(10), 587–597. https://doi.org/10.1016/j.tins.2013.07.001 Weindruch, R., Walford, R. L., Fligiel, S., & Guthrie, D. (1986). The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. The Journal of Nutrition, 116(4), 641–654. https://doi.org/10.1093/jn/116.4.641 Mihaylova, M. M., Cheng, C. W., Cao, A. Q., Tripathi, S., Mana, M. D., Bauer-Rowe, K. E., Abu-Remaileh, M., Clavain, L., Erdemir, A., Lewis, C. A., Freinkman, E., Dickey, A. S., La Spada, A. R., Huang, Y., Bell, G. W., Deshpande, V., Carmeliet, P., Katajisto, P., Sabatini, D. M., et al. (2018). Fasting Activates Fatty Acid Oxidation to Enhance Intestinal Stem Cell Function during Homeostasis and Aging. Cell Stem Cell, 22(5), 769–778.e764. https://doi.org/10.1016/j.stem.2018.04.001 Chen, L., Vasoya, R. P., Toke, N. H., Parthasarathy, A., Luo, S., Chiles, E., Flores, J., Gao, N., Bonder, E. M., Su, X., & Verzi, M. P. (2020). HNF4 Regulates Fatty Acid Oxidation and Is Required for Renewal of Intestinal Stem Cells in Mice. Gastroenterology, 158(4), 985–999.e989. https://doi.org/10.1053/j.gastro.2019.11.031 Ryall, J. G., Dell'Orso, S., Derfoul, A., Juan, A., Zare, H., Feng, X., Clermont, D., Koulnis, M., Gutierrez-Cruz, G., Fulco, M., & Sartorelli, V. (2015). The NAD(+)-dependent SIRT1 deacetylase translates a metabolic switch into regulatory epigenetics in skeletal muscle stem cells. Cell Stem Cell, 16(2), 171–183. https://doi.org/10.1016/j.stem.2014.12.004 Papsdorf, K., & Brunet, A. (2019). Linking Lipid Metabolism to Chromatin Regulation in Aging. Trends in Cell Biology, 29(2), 97–116. https://doi.org/10.1016/j.tcb.2018.09.004 Sabari, B. R., Zhang, D., Allis, C. D., & Zhao, Y. (2017). Metabolic regulation of gene expression through histone acylations. Nature Reviews. Molecular Cell Biology, 18(2), 90–101. https://doi.org/10.1038/nrm.2016.140 Wang, T., Fahrmann, J. F., Lee, H., Li, Y. J., Tripathi, S. C., Yue, C., Zhang, C., Lifshitz, V., Song, J., Yuan, Y., Somlo, G., Jandial, R., Ann, D., Hanash, S., Jove, R., & Yu, H. (2018). JAK/STAT3-Regulated Fatty Acid β-Oxidation Is Critical for Breast Cancer Stem Cell Self-Renewal and Chemoresistance. Cell Metabolism, 27(1), 136–150.e135. https://doi.org/10.1016/j.cmet.2017.11.001 Ali, A., Levantini, E., Teo, J. T., Goggi, J., Clohessy, J. G., Wu, C. S., Chen, L., Yang, H., Krishnan, I., Kocher, O., Zhang, J., Soo, R. A., Bhakoo, K., Chin, T. M., & Tenen, D. G. (2018). Fatty acid synthase mediates EGFR palmitoylation in EGFR mutated non-small cell lung cancer. EMBO Molecular Medicine, 10(3). https://doi.org/10.15252/emmm.201708313 Song, Z., Xiaoli, A. M., & Yang, F. (2018). Regulation and Metabolic Significance of De Novo Lipogenesis in Adipose Tissues. Nutrients, 10(10). https://doi.org/10.3390/nu10101383 Wang, L., Zhang, T., Wang, L., Cai, Y., Zhong, X., He, X., Hu, L., Tian, S., Wu, M., Hui, L., Zhang, H., & Gao, P. (2017). Fatty acid synthesis is critical for stem cell pluripotency via promoting mitochondrial fission. The EMBO Journal, 36(10), 1330–1347. https://doi.org/10.15252/embj.201695417 Knobloch, M., Braun, S. M., Zurkirchen, L., von Schoultz, C., Zamboni, N., Araúzo-Bravo, M. J., Kovacs, W. J., Karalay, O., Suter, U., Machado, R. A., Roccio, M., Lutolf, M. P., Semenkovich, C. F., & Jessberger, S. (2013). Metabolic control of adult neural stem cell activity by Fasn-dependent lipogenesis. Nature, 493(7431), 226–230. https://doi.org/10.1038/nature11689 Kinlaw, W. B., Baures, P. W., Lupien, L. E., Davis, W. L., & Kuemmerle, N. B. (2016). Fatty Acids and Breast Cancer: Make Them on Site or Have Them Delivered. Journal of Cellular Physiology, 231(10), 2128–2141. https://doi.org/10.1002/jcp.25332 Yi, M., Li, J., Chen, S., Cai, J., Ban, Y., Peng, Q., Zhou, Y., Zeng, Z., Peng, S., Li, X., Xiong, W., Li, G., & Xiang, B. (2018). Emerging role of lipid metabolism alterations in Cancer stem cells. Journal of Experimental & Clinical Cancer Research, 37(1), 118. https://doi.org/10.1186/s13046-018-0784-5 Pandey, P. R., Xing, F., Sharma, S., Watabe, M., Pai, S. K., Iiizumi-Gairani, M., Fukuda, K., Hirota, S., Mo, Y. Y., & Watabe, K. (2013). Elevated lipogenesis in epithelial stem-like cell confers survival advantage in ductal carcinoma in situ of breast cancer. Oncogene, 32(42), 5111–5122. https://doi.org/10.1038/onc.2012.519 Zhang, J., Pavlova, N. N., & Thompson, C. B. (2017). Cancer cell metabolism: the essential role of the nonessential amino acid, glutamine. The EMBO Journal, 36(10), 1302–1315. https://doi.org/10.15252/embj.201696151 Yoo, H. C., Yu, Y. C., Sung, Y., & Han, J. M. (2020). Glutamine reliance in cell metabolism. Experimental & Molecular Medicine, 52(9), 1496–1516. https://doi.org/10.1038/s12276-020-00504-8 Scalise, M., Pochini, L., Galluccio, M., Console, L., & Indiveri, C. (2017). Glutamine Transport and Mitochondrial Metabolism in Cancer Cell Growth. Frontiers in Oncology, 7, 306. https://doi.org/10.3389/fonc.2017.00306 Velickovic, K., Lugo Leija, H. A., Surrati, A., Kim, D. H., Sacks, H., Symonds, M. E., & Sottile, V. (2020). Targeting Glutamine Synthesis Inhibits Stem Cell Adipogenesis in Vitro. Cellular Physiology and Biochemistry, 54(5), 917–927. https://doi.org/10.33594/000000278 Yu, Y., Newman, H., Shen, L., Sharma, D., Hu, G., Mirando, A. J., Zhang, H., Knudsen, E., Zhang, G. F., Hilton, M. J., & Karner, C. M. (2019). Glutamine Metabolism Regulates Proliferation and Lineage Allocation in Skeletal Stem Cells. Cell Metabolism, 29(4), 966–978.e964. https://doi.org/10.1016/j.cmet.2019.01.016 Birsoy, K., Wang, T., Chen, W. W., Freinkman, E., Abu-Remaileh, M., & Sabatini, D. M. (2015). An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis. Cell, 162(3), 540–551. https://doi.org/10.1016/j.cell.2015.07.016 Sullivan, L. B., Gui, D. Y., Hosios, A. M., Bush, L. N., Freinkman, E., & Vander Heiden, M. G. (2015). Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells. Cell, 162(3), 552–563. https://doi.org/10.1016/j.cell.2015.07.017 Tohyama, S., Fujita, J., Hishiki, T., Matsuura, T., Hattori, F., Ohno, R., Kanazawa, H., Seki, T., Nakajima, K., Kishino, Y., Okada, M., Hirano, A., Kuroda, T., Yasuda, S., Sato, Y., Yuasa, S., Sano, M., Suematsu, M., & Fukuda, K. (2016). Glutamine Oxidation Is Indispensable for Survival of Human Pluripotent Stem Cells. Cell Metabolism, 23(4), 663–674. https://doi.org/10.1016/j.cmet.2016.03.001 Vardhana, S. A., Arnold, P. K., Rosen, B. P., Chen, Y., Carey, B. W., Huangfu, D., Carmona Fontaine, C., Thompson, C. B., & Finley, L. W. S. (2019). Glutamine independence is a selectable feature of pluripotent stem cells. Nature Metabolism, 1(7), 676–687. https://doi.org/10.1038/s42255-019-0082-3 Fang, E. F., Lautrup, S., Hou, Y., Demarest, T. G., Croteau, D. L., Mattson, M. P., & Bohr, V. A. (2017). NAD(+) in Aging: Molecular Mechanisms and Translational Implications. Trends in Molecular Medicine, 23(10), 899–916. https://doi.org/10.1016/j.molmed.2017.08.001 Ma, C., Pi, C., Yang, Y., Lin, L., Shi, Y., Li, Y., Li, Y., & He, X. (2017). Nampt Expression Decreases Age-Related Senescence in Rat Bone Marrow Mesenchymal Stem Cells by Targeting Sirt1. PLoS One, 12(1), e0170930. https://doi.org/10.1371/journal.pone.0170930 Neelakantan, H., Brightwell, C. R., Graber, T. G., Maroto, R., Wang, H. L., McHardy, S. F., Papaconstantinou, J., Fry, C. S., & Watowich, S. J. (2019). Small molecule nicotinamide N-methyltransferase inhibitor activates senescent muscle stem cells and improves regenerative capacity of aged skeletal muscle. Biochemical Pharmacology, 163, 481–492. https://doi.org/10.1016/j.bcp.2019.02.008 Kaeberlein, M., McVey, M., & Guarente, L. (1999). The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes & Development, 13(19), 2570–2580. https://doi.org/10.1101/gad.13.19.2570 Lim, C. J., Lee, Y. M., Kang, S. G., Lim, H. W., Shin, K. O., Jeong, S. K., Huh, Y. H., Choi, S., Kor, M., Seo, H. S., Park, B. D., Park, K., Ahn, J. K., Uchida, Y., & Park, K. (2017). Aquatide Activation of SIRT1 Reduces Cellular Senescence through a SIRT1-FOXO1-Autophagy Axis. Biomol Ther (Seoul), 25(5), 511–518. https://doi.org/10.4062/biomolther.2017.119 Lamichane, S., Baek, S. H., Kim, Y. J., Park, J. H., Dahal Lamichane, B., Jang, W. B., Ji, S., Lee, N. K., Dehua, L., Kim, D. Y., Kang, S., Seong, H. J., Yun, J., Lee, D. H., Moon, H. R., Chung, H. Y., & Kwon, S. M. (2019). MHY2233 Attenuates Replicative Cellular Senescence in Human Endothelial Progenitor Cells via SIRT1 Signaling. Oxidative Medicine and Cellular Longevity, 2019, 6492029. https://doi.org/10.1155/2019/6492029 Liu, S., Zheng, Z., Ji, S., Liu, T., Hou, Y., Li, S., & Li, G. (2018). Resveratrol reduces senescence-associated secretory phenotype by SIRT1/NF-κB pathway in gut of the annual fish Nothobranchius guentheri. Fish & Shellfish Immunology, 80, 473–479. https://doi.org/10.1016/j.fsi.2018.06.027 García-Aguilar, A., Guillén, C., Nellist, M., Bartolomé, A., & Benito, M. (2016). TSC2 N-terminal lysine acetylation status affects to its stability modulating mTORC1 signaling and autophagy. Biochimica et Biophysica Acta, 1863(11), 2658–2667. https://doi.org/10.1016/j.bbamcr.2016.08.006 Chen, P., Chen, F., Lei, J., Li, Q., & Zhou, B. (2019). Activation of the miR-34a-Mediated SIRT1/mTOR Signaling Pathway by Urolithin A Attenuates D-Galactose-Induced Brain Aging in Mice. Neurotherapeutics, 16(4), 1269–1282. https://doi.org/10.1007/s13311-019-00753-0 Kauppinen, A., Suuronen, T., Ojala, J., Kaarniranta, K., & Salminen, A. (2013). Antagonistic crosstalk between NF-κB and SIRT1 in the regulation of inflammation and metabolic disorders. Cellular Signalling, 25(10), 1939–1948. https://doi.org/10.1016/j.cellsig.2013.06.007 Kitada, M., Ogura, Y., Monno, I., & Koya, D. (2019). Sirtuins and Type 2 Diabetes: Role in Inflammation, Oxidative Stress, and Mitochondrial Function. Front Endocrinol (Lausanne), 10, 187. https://doi.org/10.3389/fendo.2019.00187 Wang, Y., Zhao, X., Lotz, M., Terkeltaub, R., & Liu-Bryan, R. (2015). Mitochondrial biogenesis is impaired in osteoarthritis chondrocytes but reversible via peroxisome proliferator-activated receptor γ coactivator 1α. Arthritis & Rhematology, 67(8), 2141–2153. https://doi.org/10.1002/art.39182 Brunet, A., Sweeney, L. B., Sturgill, J. F., Chua, K. F., Greer, P. L., Lin, Y., Tran, H., Ross, S. E., Mostoslavsky, R., Cohen, H. Y., Hu, L. S., Cheng, H. L., Jedrychowski, M. P., Gygi, S. P., Sinclair, D. A., Alt, F. W., & Greenberg, M. E. (2004). Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science, 303(5666), 2011–2015. https://doi.org/10.1126/science.1094637 Pi, C., Yang, Y., Sun, Y., Wang, H., Sun, H., Ma, M., Lin, L., Shi, Y., Li, Y., Li, Y., & He, X. (2019). Nicotinamide phosphoribosyltransferase postpones rat bone marrow mesenchymal stem cell senescence by mediating NAD(+)-Sirt1 signaling. Aging (Albany NY), 11(11), 3505–3522. https://doi.org/10.18632/aging.101993 Son, M. J., Kwon, Y., Son, T., & Cho, Y. S. (2016). Restoration of Mitochondrial NAD(+) Levels Delays Stem Cell Senescence and Facilitates Reprogramming of Aged Somatic Cells. Stem Cells, 34(12), 2840–2851. https://doi.org/10.1002/stem.2460 Meng, Y., Ren, Z., Xu, F., Zhou, X., Song, C., Wang, V. Y., Liu, W., Lu, L., Thomson, J. A., & Chen, G. (2018). Nicotinamide Promotes Cell Survival and Differentiation as Kinase Inhibitor in Human Pluripotent Stem Cells. Stem Cell Reports, 11(6), 1347–1356. https://doi.org/10.1016/j.stemcr.2018.10.023 Avalos, J. L., Bever, K. M., & Wolberger, C. (2005). Mechanism of sirtuin inhibition by nicotinamide: altering the NAD(+) cosubstrate specificity of a Sir2 enzyme. Molecular Cell, 17(6), 855–868. https://doi.org/10.1016/j.molcel.2005.02.022 Saldeen, J., & Welsh, N. (1998). Nicotinamide-induced apoptosis in insulin producing cells is associated with cleavage of poly(ADP-ribose) polymerase. Molecular and Cellular Endocrinology, 139(1-2), 99–107. https://doi.org/10.1016/s0303-7207(98)00068-9 Igarashi, M., Miura, M., Williams, E., Jaksch, F., Kadowaki, T., Yamauchi, T., & Guarente, L. (2019). NAD(+) supplementation rejuvenates aged gut adult stem cells. Aging Cell, 18(3), e12935. https://doi.org/10.1111/acel.12935 Luo, J., Mills, K., le Cessie, S., Noordam, R., & van Heemst, D. (2020). Ageing, age-related diseases and oxidative stress: What to do next? Ageing Research Reviews, 57, 100982. https://doi.org/10.1016/j.arr.2019.100982 Blommestein, H. M., Verelst, S. G., Huijgens, P. C., Blijlevens, N. M., Cornelissen, J. J., & Uyl-de Groot, C. A. (2012). Real-world costs of autologous and allogeneic stem cell transplantations for haematological diseases: a multicentre study. Annals of Hematology, 91(12), 1945–1952. https://doi.org/10.1007/s00277-012-1530-2