Cheng, C. W. & Yilmaz Ã, H. 100 Years of exploiting diet and nutrition for tissue regeneration. Cell Stem Cell 28, 370â373 (2021).
Nencioni, A., Caffa, I., Cortellino, S. & Longo, V. D. Fasting and cancer: molecular mechanisms and clinical application. Nat. Rev. Cancer 18, 707â719 (2018).
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, 810â823 (2014).
Longo, V. D. & Mattson, M. P. Fasting: molecular mechanisms and clinical applications. Cell Metab. 19, 181â192 (2014).
Weindruch, R., Walford, R. L., Fligiel, S. & Guthrie, D. The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. J. Nutr. 116, 641â654 (1986).
Mattison, J. A. et al. Caloric restriction improves health and survival of rhesus monkeys. Nat. Commun. 8, 14063 (2017).
Calibasi-Kocal, G. et al. Nutritional control of intestinal stem cells in homeostasis and tumorigenesis. Trends Endocrinol. Metab. 32, 20â35 (2021).
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, 515â519 (2012).
Mihaylova, M. M. et al. Fasting activates fatty acid oxidation to enhance intestinal stem cell function during homeostasis and aging. Cell Stem Cell 22, 769â778.e4 (2018).
Yilmaz Ã, H. et al. mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 486, 490â495 (2012).
Vernieri, C. et al. Fasting-mimicking diet is safe and reshapes metabolism and antitumor immunity in cancer patients. Cancer Discov. https://doi.org/10.1158/2159-8290.Cd-21-0030 (2021).
Salvadori, G. et al. Fasting-mimicking diet blocks triple-negative breast cancer and cancer stem cell escape. Cell Metab. 33, 2247â2259.e6 (2021).
Alonso, S. & Yilmaz Ã, H. Nutritional regulation of intestinal stem cells. Annu. Rev. Nutr. 38, 273â301 (2018).
Beumer, J. & Clevers, H. Cell fate specification and differentiation in the adult mammalian intestine. Nat. Rev. Mol. Cell Biol. 22, 39â53 (2021).
Goto, N. et al. Lymphatics and fibroblasts support intestinal stem cells in homeostasis and injury. Cell Stem Cell 29, 1246â1261.e6 (2022).
Niec, R. E. et al. Lymphatics act as a signaling hub to regulate intestinal stem cell activity. Cell Stem Cell 29, 1067â1082.e18 (2022).
Palikuqi, B. et al. Lymphangiocrine signals are required for proper intestinal repair after cytotoxic injury. Cell Stem Cell 29, 1262â1272.e5 (2022).
Gehart, H. & Clevers, H. Tales from the crypt: new insights into intestinal stem cells. Nat. Rev. Gastroenterol. Hepatol. 16, 19â34 (2019).
Cheng, C. W. et al. Ketone body signaling mediates intestinal stem cell homeostasis and adaptation to diet. Cell 178, 1115â1131.e15 (2019).
Beyaz, S. et al. High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature 531, 53â58 (2016).
Igarashi, M. & Guarente, L. mTORC1 and SIRT1 cooperate to foster expansion of gut adult stem cells during calorie restriction. Cell 166, 436â450 (2016).
Zismanov, V. et al. Phosphorylation of eIF2α is a translational control mechanism regulating muscle stem cell quiescence and self-renewal. Cell Stem Cell 18, 79â90 (2016).
Llorens-Bobadilla, E. et al. Single-cell transcriptomics reveals a population of dormant neural stem cells that become activated upon brain injury. Cell Stem Cell 17, 329â340 (2015).
Signer, R. A., Magee, J. A., Salic, A. & Morrison, S. J. Haematopoietic stem cells require a highly regulated protein synthesis rate. Nature 509, 49â54 (2014).
Morral, C. et al. Zonation of ribosomal DNA transcription defines a stem cell hierarchy in colorectal cancer. Cell Stem Cell 26, 845â861.e12 (2020).
Benitah, S. A. & Welz, P. S. Circadian regulation of adult stem cell homeostasis and aging. Cell Stem Cell 26, 817â831 (2020).
Huch, M. et al. In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature 494, 247â250 (2013).
Liu, G. Y. & Sabatini, D. M. mTOR at the nexus of nutrition, growth, ageing and disease. Nat. Rev. Mol. Cell Biol. 21, 183â203 (2020).
Manning, B. D. & Toker, A. AKT/PKB signaling: navigating the network. Cell 169, 381â405 (2017).
Mulvihill, M. J. et al. Discovery of OSI-906: a selective and orally efficacious dual inhibitor of the IGF-1 receptor and insulin receptor. Future Med. Chem. 1, 1153â1171 (2009).
Burger, M. T. et al. Identification of NVP-BKM120 as a potent, selective, orally bioavailable class I PI3 kinase inhibitor for treating cancer. ACS Med. Chem. Lett. 2, 774â779 (2011).
Haber, A. L. et al. A single-cell survey of the small intestinal epithelium. Nature 551, 333â339 (2017).
Biton, M. et al. T helper cell cytokines modulate intestinal stem cell renewal and differentiation. Cell 175, 1307â1320.e22 (2018).
Ginguay, A., Cynober, L., Curis, E. & Nicolis, I. Ornithine aminotransferase, an important glutamate-metabolizing enzyme at the crossroads of multiple metabolic pathways. Biology 6, 18 (2017).
Daune, G., Gerhart, F. & Seiler, N. 5-Fluoromethylornithine, an irreversible and specific inhibitor of l-ornithine:2-oxo-acid aminotransferase. Biochem. J. 253, 481â488 (1988).
Poulin, R., Lu, L., Ackermann, B., Bey, P. & Pegg, A. E. Mechanism of the irreversible inactivation of mouse ornithine decarboxylase by α-difluoromethylornithine. Characterization of sequences at the inhibitor and coenzyme binding sites. J. Biol. Chem. 267, 150â158 (1992).
Puleston, D. J. et al. Polyamine metabolism is a central determinant of helper T cell lineage fidelity. Cell 184, 4186â4202.e20 (2021).
Park, M. H. & Wolff, E. C. Hypusine, a polyamine-derived amino acid critical for eukaryotic translation. J. Biol. Chem. 293, 18710â18718 (2018).
Puleston, D. J. et al. Polyamines and eIF5A hypusination modulate mitochondrial respiration and macrophage activation. Cell Metab. 30, 352â363.e8 (2019).
Zabala-Letona, A. et al. mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer. Nature 547, 109â113 (2017).
Mandal, S., Mandal, A., Johansson, H. E., Orjalo, A. V. & Park, M. H. Depletion of cellular polyamines, spermidine and spermine, causes a total arrest in translation and growth in mammalian cells. Proc. Natl Acad. Sci. USA 110, 2169â2174 (2013).
Abbruzzese, A., Park, M. H. & Folk, J. E. Deoxyhypusine hydroxylase from rat testis. Partial purification and characterization. J. Biol. Chem. 261, 3085â3089 (1986).
Gobert, A. P. et al. Hypusination orchestrates the antimicrobial response of macrophages. Cell Rep. 33, 108510 (2020).
Bruens, L. et al. Calorie restriction increases the number of competing stem cells and decreases mutation retention in the intestine. Cell Rep. 32, 107937 (2020).
Fontana, L., Partridge, L. & Longo, V. D. Extending healthy life span â from yeast to humans. Science 328, 321â326 (2010).
Mai, V. et al. Calorie restriction and diet composition modulate spontaneous intestinal tumorigenesis in Apc(Min) mice through different mechanisms. Cancer Res. 63, 1752â1755 (2003).
Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003â1007 (2007).
Faller, W. J. et al. mTORC1-mediated translational elongation limits intestinal tumour initiation and growth. Nature 517, 497â500 (2015).
Erdman, S. H. et al. APC-dependent changes in expression of genes influencing polyamine metabolism, and consequences for gastrointestinal carcinogenesis, in the Min mouse. Carcinogenesis 20, 1709â1713 (1999).
Oliver, E. R., Saunders, T. L., Tarlé, S. A. & Glaser, T. Ribosomal protein L24 defect in belly spot and tail (Bst), a mouse Minute. Development 131, 3907â3920 (2004).
Knight, J. R. et al. Rpl24(Bst) mutation suppresses colorectal cancer by promoting eEF2 phosphorylation via eEF2K. eLife 10, e69729 (2021).
Nagai, M. et al. Fastingârefeeding impacts immune cell dynamics and mucosal immune responses. Cell 178, 1072â1087.e14 (2019).
Napolitano, G. et al. mTOR-dependent phosphorylation controls TFEB nuclear export. Nat. Commun. 9, 3312 (2018).
Tinkum, K. L. et al. Fasting protects mice from lethal DNA damage by promoting small intestinal epithelial stem cell survival. Proc. Natl Acad. Sci. USA 112, E7148âE7154 (2015).
Kim, T. H., Escudero, S. & Shivdasani, R. A. Intact function of Lgr5 receptor-expressing intestinal stem cells in the absence of Paneth cells. Proc. Natl Acad. Sci. USA 109, 3932â3937 (2012).
Zoumas-Morse, C. et al. Development of a polyamine database for assessing dietary intake. J. Am. Diet Assoc. 107, 1024â1027 (2007).
Pegg, A. E. Functions of polyamines in mammals. J. Biol. Chem. 291, 14904â14912 (2016).
Allmeroth, K. et al. N1-acetylspermidine is a determinant of hair follicle stem cell fate. J. Cell Sci. 134, jcs252767 (2021).
Fritsch, S. D. et al. Metabolic support by macrophages sustains colonic epithelial homeostasis. Cell Metab. 35, 1931â1943.e8 (2023).
Brandhorst, S. et al. A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance, and healthspan. Cell Metab. 22, 86â99 (2015).
el Marjou, F. et al. Tissue-specific and inducible Cre-mediated recombination in the gut epithelium. Genesis 39, 186â193 (2004).
Colnot, S. et al. Colorectal cancers in a new mouse model of familial adenomatous polyposis: influence of genetic and environmental modifiers. Lab Invest. 84, 1619â1630 (2004).
Sato, T. et al. Single Lgr5 stem cells build cryptâvillus structures in vitro without a mesenchymal niche. Nature 459, 262â265 (2009).
Ootani, A. et al. Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche. Nat. Med. 15, 701â706 (2009).
Fuhrer, T., Heer, D., Begemann, B. & Zamboni, N. High-throughput, accurate mass metabolome profiling of cellular extracts by flow injection-time-of-flight mass spectrometry. Anal. Chem. 83, 7074â7080 (2011).
Sellick, C. A., Hansen, R., Stephens, G. M., Goodacre, R. & Dickson, A. J. Metabolite extraction from suspension-cultured mammalian cells for global metabolite profiling. Nat. Protoc. 6, 1241â1249 (2011).
Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545â15550 (2005).
