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Basic knowledge of the mechanisms underlying the effects of DR could be applicable to extending the healthspan in humans. This review highlights the importance of forkhead box O (FoxO) transcription factors downstream of the growth hormone\u2010insulin\u2010like growth factor 1 signaling in the effects of DR. Our lifespan studies in mice with heterozygous <jats:italic>Foxo1<\/jats:italic> or <jats:italic>Foxo3<\/jats:italic> gene knockout indicated differential roles of FoxO1 and FoxO3 in the tumor\u2010inhibiting and life\u2010extending effects of DR. Subsequent studies suggested a critical role of FoxO3 in metabolic and mitochondrial bioenergetic adaptation to DR. Our studies also verified hypothalamic neuropeptide Y (Npy) as a vital neuropeptide showing pleiotropic and sexually dimorphic effects for extending the healthspan in the context of nutritional availability. Npy was necessary for DR to exert its effects in male and female mice; meanwhile, under AL conditions, the loss of Npy prevented obesity and insulin resistance only in female mice. Overnutrition disrupts FoxO\u2010 and Npy\u2010associated metabolic and mitochondrial bioenergetic adaptive processes, causing the acceleration of aging and related diseases.<\/jats:p>","DOI":"10.1111\/pin.13387","type":"journal-article","created":{"date-parts":[[2023,11,18]],"date-time":"2023-11-18T03:31:59Z","timestamp":1700278319000},"page":"579-592","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Mechanisms underlying retardation of aging by dietary energy restriction"],"prefix":"10.1111","volume":"73","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8901-1029","authenticated-orcid":false,"given":"Isao","family":"Shimokawa","sequence":"first","affiliation":[{"name":"Department of Pathology I Nagasaki University School of Medicine and Graduate School of Biomedical Sciences Nagasaki Japan"},{"name":"SAGL, LLC Fukuoka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,11,17]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.11.001"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4000"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2000.tb06651.x"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2017.116"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/10.1.63"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-63001-4_5"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2019.01.018"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/geronj\/43.2.B40"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/sageke.2003.8.re2"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2001.tb05658.x"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4557"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1173635"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11432"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14063"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11484"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/57.6.B211"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glv057"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/geronj\/43.4.B102"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/382536a0"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/366461a0"},{"key":"e_1_2_10_22_1","unstructured":"De Magalhaes J. 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