Skip to main content

Energy restriction and potential energy restriction mimetics

  • Sibylle Nikolai (a1), Kathrin Pallauf (a1), Patricia Huebbe (a1) and Gerald Rimbach (a1)

Energy restriction (ER; also known as caloric restriction) is the only nutritional intervention that has repeatedly been shown to increase lifespan in model organisms and may delay ageing in humans. In the present review we discuss current scientific literature on ER and its molecular, metabolic and hormonal effects. Moreover, criteria for the classification of substances that might induce positive ER-like changes without having to reduce energy intake are summarised. Additionally, the putative ER mimetics (ERM) 2-deoxy-d-glucose, metformin, rapamycin, resveratrol, spermidine and lipoic acid and their suggested molecular targets are discussed. While there are reports on these ERM candidates that describe lifespan extension in model organisms, data on longevity-inducing effects in higher organisms such as mice remain controversial or are missing. Furthermore, some of these candidates produce detrimental side effects such as immunosuppression or lactic acidosis, or have not been tested for safety in long-term studies. Up to now, there are no known ERM that could be recommended without limitations for use in humans.

Corresponding author
*Corresponding author: Sibylle Nikolai, fax +49 431 880 2628, email
Hide All
1.World Heath Organization (2005) Preventing chronic diseases: a vital investment. (accessed November 2014).
2.Berghofer, A, Pischon, T, Reinhold, T, et al. (2008) Obesity prevalence from a European perspective: a systematic review. BMC Public Health 8, 200.
3.Stevens, GA, Singh, GM, Lu, Y, et al. (2012) National, regional, and global trends in adult overweight and obesity prevalences. Popul Health Metr 10, 22.
4.Alberti, KG, Eckel, RH, Grundy, SM, et al. (2009) Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 120, 16401645.
5.Krauss, RM, Deckelbaum, RJ, Ernst, N, et al. (1996) Dietary guidelines for healthy American adults. A statement for health professionals from the Nutrition Committee, American Heart Association. Circulation 94, 17951800.
6.Martin-Montalvo, A, Mercken, EM, Mitchell, SJ, et al. (2013) Metformin improves healthspan and lifespan in mice. Nat Commun 4, 2192.
7.Ford, ES, Giles, WH & Dietz, WH (2002) Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 287, 356359.
8.Morselli, E, Galluzzi, L, Kepp, O, et al. (2009) Autophagy mediates pharmacological lifespan extension by spermidine and resveratrol. Aging 1, 961970.
9.Toth, MJ & Tchernof, A (2000) Lipid metabolism in the elderly. Eur J Clin Nutr 54, Suppl. 3, S121S125.
10.Kim, HJ, Jung, KJ, Yu, BP, et al. (2002) Modulation of redox-sensitive transcription factors by calorie restriction during aging. Mech Ageing Dev 123, 15891595.
11.Rae, MJ, Butler, RN, Campisi, J, et al. (2010) The demographic and biomedical case for late-life interventions in aging. Sci Transl Med 2, 40cm21.
12.Merry, BJ, Kirk, AJ & Goyns, MH (2008) Dietary lipoic acid supplementation can mimic or block the effect of dietary restriction on life span. Mech Ageing Dev 129, 341348.
13.Minor, RK, Smith, DL Jr, Sossong, AM, et al. (2010) Chronic ingestion of 2-deoxy-d-glucose induces cardiac vacuolization and increases mortality in rats. Toxicol Appl Pharmacol 243, 332339.
14.Yu, BP (1994) How diet influences the aging process of the rat. Proc Soc Exp Biol Med 205, 97105.
15.Weindruch, R (1996) The retardation of aging by caloric restriction: studies in rodents and primates. Toxicol Pathol 24, 742745.
16.McCay, CM, Crowell, MF & Maynard, LA (1989) The effect of retarded growth upon the length of life span and upon the ultimate body size. 1935. Nutrition 5, 155171; discussion 172.
17.Wu, Z, Liu, SQ & Huang, D (2013) Dietary restriction depends on nutrient composition to extend chronological lifespan in budding yeast Saccharomyces cerevisiae. PLOS ONE 8, e64448.
18.Lakowski, B & Hekimi, S (1998) The genetics of caloric restriction in Caenorhabditis elegans. Proc Natl Acad Sci U S A 95, 1309113096.
19.Min, KJ, Yamamoto, R, Buch, S, et al. (2008) Drosophila lifespan control by dietary restriction independent of insulin-like signaling. Aging Cell 7, 199206.
20.Weindruch, R, Walford, RL, Fligiel, S, et al. (1986) The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. J Nutr 116, 641654.
21.McShane, TM & Wise, PM (1996) Life-long moderate caloric restriction prolongs reproductive life span in rats without interrupting estrous cyclicity: effects on the gonadotropin-releasing hormone/luteinizing hormone axis. Biol Reprod 54, 7075.
22.Colman, RJ, Anderson, RM, Johnson, SC, et al. (2009) Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325, 201204.
23.McCay, CM, Crowell, MF & Maynard, LA (1935) The effect of retarded growth upon the length of life span and upon the ultimate body size. J Nutr 10, 6379.
24.Swindell, WR (2012) Dietary restriction in rats and mice: a meta-analysis and review of the evidence for genotype-dependent effects on lifespan. Ageing Res Rev 11, 254270.
25.Sohal, RS & Forster, MJ (2014) Caloric restriction and the aging process: a critique. Free Radic Biol Med 73, 366382.
26.Mattison, JA, Roth, GS, Beasley, TM, et al. (2012) Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature 489, 318321.
27.Walford, RL, Harris, SB & Gunion, MW (1992) The calorically restricted low-fat nutrient-dense diet in Biosphere 2 significantly lowers blood glucose, total leukocyte count, cholesterol, and blood pressure in humans. Proc Natl Acad Sci U S A 89, 1153311537.
28.Walford, RL, Mock, D, Verdery, R, et al. (2002) Calorie restriction in biosphere 2, alterations in physiologic, hematologic, hormonal, and biochemical parameters in humans restricted for a 2-year period. J Gerontol A Biol Sci Med Sci 57, B211B224.
29.Walford, RL, Weber, L & Panov, S (1995) Caloric restriction and aging as viewed from Biosphere 2. Receptor 5, 2933.
30.Willcox, BJ, Willcox, DC, He, Q, et al. (2006) Siblings of Okinawan centenarians share lifelong mortality advantages. J Gerontol A Biol Sci Med Sci 61, 345354.
31.Willcox, DC, Willcox, BJ, Todoriki, H, et al. (2009) The Okinawan diet: health implications of a low-calorie, nutrient-dense, antioxidant-rich dietary pattern low in glycemic load. J Am Coll Nutr 28, Suppl, 500S516S.
32.Lane, MA, Mattison, J, Ingram, DK, et al. (2002) Caloric restriction and aging in primates: relevance to humans and possible CR mimetics. Microsc Res Tech 59, 335338.
33.Duffy, PH, Feuers, RJ, Leakey, JA, et al. (1989) Effect of chronic caloric restriction on physiological variables related to energy metabolism in the male Fischer 344 rat. Mech Ageing Dev 48, 117133.
34.Mattison, JA, Lane, MA, Roth, GS, et al. (2003) Calorie restriction in rhesus monkeys. Exp Gerontol 38, 3546.
35.Chen, D, Steele, AD, Lindquist, S, et al. (2005) Increase in activity during calorie restriction requires Sirt1. Science 310, 1641.
36.Speakman, JR & Mitchell, SE (2011) Caloric restriction. Mol Aspects Med 32, 159221.
37.Hwangbo, DS, Gershman, B, Tu, MP, et al. (2004) Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nature 429, 562566.
38.Pires, RC, Souza, EE, Vanzela, EC, et al. (2014) Short-term calorie restriction improves glucose homeostasis in old rats: involvement of AMPK. Appl Physiol Nutr Metab 39, 895901.
39.Zhu, M, Miura, J, Lu, LX, et al. (2004) Circulating adiponectin levels increase in rats on caloric restriction: the potential for insulin sensitization. Exp Gerontol 39, 10491059.
40.Weindruch, R, Keenan, KP, Carney, JM, et al. (2001) Caloric restriction mimetics: metabolic interventions. J Gerontol A Biol Sci Med Sci 56, Spec no. 1, 2033.
41.Lim, EL, Hollingsworth, KG, Aribisala, BS, et al. (2011) Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia 54, 25062514.
42.Takatsu, M, Nakashima, C, Takahashi, K, et al. (2013) Calorie restriction attenuates cardiac remodeling and diastolic dysfunction in a rat model of metabolic syndrome. Hypertension 62, 957965.
43.Lezcano, EJ, Inigo, P, Larraga, AM, et al. (2014) Caloric restriction or telmisartan control dyslipidemia and nephropathy in obese diabetic Zucker rats. Diabetol Metab Syndr 6, 10.
44.Hagopian, K, Ramsey, JJ & Weindruch, R (2003) Caloric restriction increases gluconeogenic and transaminase enzyme activities in mouse liver. Exp Gerontol 38, 267278.
45.Feuers, RJ, Duffy, PH, Leakey, JA, et al. (1989) Effect of chronic caloric restriction on hepatic enzymes of intermediary metabolism in the male Fischer 344 rat. Mech Ageing Dev 48, 179189.
46.Hipkiss, AR (2007) Dietary restriction, glycolysis, hormesis and ageing. Biogerontology 8, 221224.
47.Anisimov, VN, Berstein, LM, Egormin, PA, et al. (2005) Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp Gerontol 40, 685693.
48.Guo, Z, Mitchell-Raymundo, F, Yang, H, et al. (2002) Dietary restriction reduces atherosclerosis and oxidative stress in the aorta of apolipoprotein E-deficient mice. Mech Ageing Dev 123, 11211131.
49.Yang, F, Chu, X, Yin, M, et al. (2014) mTOR and autophagy in normal brain aging and caloric restriction ameliorating age-related cognition deficits. Behav Brain Res 264, 8290.
50.Weindruch, R & Walford, RL (1982) Dietary restriction in mice beginning at 1 year of age: effect on life-span and spontaneous cancer incidence. Science 215, 14151418.
51.Hursting, SD, Lavigne, JA, Berrigan, D, et al. (2003) Calorie restriction, aging, and cancer prevention: mechanisms of action and applicability to humans. Annu Rev Med 54, 131152.
52.Sabatino, F, Masoro, EJ, McMahan, CA, et al. (1991) Assessment of the role of the glucocorticoid system in aging processes and in the action of food restriction. J Gerontol 46, B171B179.
53.Redman, LM & Ravussin, E (2009) Endocrine alterations in response to calorie restriction in humans. Mol Cell Endocrinol 299, 129136.
54.Cangemi, R, Friedmann, AJ, Holloszy, JO, et al. (2010) Long-term effects of calorie restriction on serum sex-hormone concentrations in men. Aging Cell 9, 236242.
55.Redman, LM, Martin, CK, Williamson, DA, et al. (2008) Effect of caloric restriction in non-obese humans on physiological, psychological and behavioral outcomes. Physiol Behav 94, 643648.
56.Smiarowska, M, Safranow, K, Dziedziejko, V, et al. (2014) Association of plasma hormones, nutritional status, and stressful life events in anorexia nervosa patients. Postepy Hig Med Dosw (Online) 68, 162171.
57.Sohal, RS & Weindruch, R (1996) Oxidative stress, caloric restriction, and aging. Science 273, 5963.
58.Roth, GS, Handy, AM, Mattison, JA, et al. (2002) Effects of dietary caloric restriction and aging on thyroid hormones of rhesus monkeys. Horm Metab Res 34, 378382.
59.Fontana, L, Klein, S, Holloszy, JO, et al. (2006) Effect of long-term calorie restriction with adequate protein and micronutrients on thyroid hormones. J Clin Endocrinol Metab 91, 32323235.
60.Heilbronn, LK, de Jonge, L, Frisard, MI, et al. (2006) Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial. JAMA 295, 15391548.
61.Wikstrom, L, Johansson, C, Salto, C, et al. (1998) Abnormal heart rate and body temperature in mice lacking thyroid hormone receptor α1. EMBO J 17, 455461.
62.Brown-Borg, HM, Borg, KE, Meliska, CJ, et al. (1996) Dwarf mice and the ageing process. Nature 384, 33.
63.Cadenas, S, Buckingham, JA, Samec, S, et al. (1999) UCP2 and UCP3 rise in starved rat skeletal muscle but mitochondrial proton conductance is unchanged. FEBS Lett 462, 257260.
64.Samec, S, Seydoux, J & Dulloo, AG (1998) Role of UCP homologues in skeletal muscles and brown adipose tissue: mediators of thermogenesis or regulators of lipids as fuel substrate? FASEB J 12, 715724.
65.Duval, C, Negre-Salvayre, A, Dogilo, A, et al. (2002) Increased reactive oxygen species production with antisense oligonucleotides directed against uncoupling protein 2 in murine endothelial cells. Biochem Cell Biol 80, 757764.
66.Fontana, L (2009) Neuroendocrine factors in the regulation of inflammation: excessive adiposity and calorie restriction. Exp Gerontol 44, 4145.
67.Mattson, MP (2008) Hormesis defined. Ageing Res Rev 7, 17.
68.Masoro, EJ (2007) The role of hormesis in life extension by dietary restriction. Interdiscip Top Gerontol 35, 117.
69.Ristow, M & Zarse, K (2010) How increased oxidative stress promotes longevity and metabolic health: the concept of mitochondrial hormesis (mitohormesis). Exp Gerontol 45, 410418.
70.Sharma, S & Kaur, G (2007) Intermittent dietary restriction as a practical intervention in aging. Ann N Y Acad Sci 1114, 419427.
71.Castello, L, Froio, T, Cavallini, G, et al. (2005) Calorie restriction protects against age-related rat aorta sclerosis. FASEB J 19, 18631865.
72.Lakatta, EG & Levy, D (2003) Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part I: aging arteries: a “set up” for vascular disease. Circulation 107, 139146.
73.Valko, M, Rhodes, CJ, Moncol, J, et al. (2006) Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact 160, 140.
74.Markesbery, WR (1997) Oxidative stress hypothesis in Alzheimer’s disease. Free Radic Biol Med 23, 134147.
75.Browne, SE, Ferrante, RJ & Beal, MF (1999) Oxidative stress in Huntington’s disease. Brain Pathol 9, 147163.
76.Gredilla, R & Barja, G (2005) Minireview: the role of oxidative stress in relation to caloric restriction and longevity. Endocrinology 146, 37133717.
77.Giller, K, Huebbe, P, Hennig, S, et al. (2013) Beneficial effects of a 6-month dietary restriction are time-dependently abolished within 2 weeks or 6 months of refeeding-genome-wide transcriptome analysis in mouse liver. Free Radic Biol Med 61C, 170178.
78.Zhang, Y & Gordon, GB (2004) A strategy for cancer prevention: stimulation of the Nrf2-ARE signaling pathway. Mol Cancer Ther 3, 885893.
79.Martin-Montalvo, A, Villalba, JM, Navas, P, et al. (2011) NRF2, cancer and calorie restriction. Oncogene 30, 505520.
80.Chan, K & Kan, YW (1999) Nrf2 is essential for protection against acute pulmonary injury in mice. Proc Natl Acad Sci U S A 96, 1273112736.
81.Wasserman, WW & Fahl, WE (1997) Functional antioxidant responsive elements. Proc Natl Acad Sci U S A 94, 53615366.
82.Suh, JH, Shenvi, SV, Dixon, BM, et al. (2004) Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid. Proc Natl Acad Sci U S A 101, 33813386.
83.Shih, PH & Yen, GC (2007) Differential expressions of antioxidant status in aging rats: the role of transcriptional factor Nrf2 and MAPK signaling pathway. Biogerontology 8, 7180.
84.Pearson, KJ, Lewis, KN, Price, NL, et al. (2008) Nrf2 mediates cancer protection but not prolongevity induced by caloric restriction. Proc Natl Acad Sci U S A 105, 23252330.
85.Sykiotis, GP, Habeos, IG, Samuelson, AV, et al. (2011) The role of the antioxidant and longevity-promoting Nrf2 pathway in metabolic regulation. Current Opin Clin Nutr Metab Care 14, 4148.
86.Faulks, SC, Turner, N, Else, PL, et al. (2006) Calorie restriction in mice: effects on body composition, daily activity, metabolic rate, mitochondrial reactive oxygen species production, and membrane fatty acid composition. J Gerontol A Biol Sci Med Sci 61, 781794.
87.Elchuri, S, Oberley, TD, Qi, W, et al. (2005) CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life. Oncogene 24, 367380.
88.Huang, TT, Carlson, EJ, Gillespie, AM, et al. (2000) Ubiquitous overexpression of CuZn superoxide dismutase does not extend life span in mice. J Gerontol A Biol Sci Med Sci 55, B5B9.
89.Van Remmen, H, Ikeno, Y, Hamilton, M, et al. (2003) Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging. Physiol Genomics 16, 2937.
90.Lipman, RD, Bronson, RT, Wu, D, et al. (1998) Disease incidence and longevity are unaltered by dietary antioxidant supplementation initiated during middle age in C57BL/6 mice. Mech Ageing Dev 103, 269284.
91.Selman, C, McLaren, JS, Meyer, C, et al. (2006) Life-long vitamin C supplementation in combination with cold exposure does not affect oxidative damage or lifespan in mice, but decreases expression of antioxidant protection genes. Mech Ageing Dev 127, 897904.
92.Lee, CK, Pugh, TD, Klopp, RG, et al. (2004) The impact of α-lipoic acid, coenzyme Q10 and caloric restriction on life span and gene expression patterns in mice. Free Radic Biol Med 36, 10431057.
93.Schriner, SE, Linford, NJ, Martin, GM, et al. (2005) Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308, 19091911.
94.Chung, HY, Kim, HJ, Jung, KJ, et al. (2000) The inflammatory process in aging. Rev Clin Gerontol 10, 207222.
95.Baldwin, AS Jr (2001) Series introduction: the transcription factor NF-κB and human disease. J Clin Invest 107, 36.
96.Helenius, M, Hanninen, M, Lehtinen, SK, et al. (1996) Aging-induced up-regulation of nuclear binding activities of oxidative stress responsive NF-κB transcription factor in mouse cardiac muscle. J Mol Cell Cardiol 28, 487498.
97.Chung, HY, Kim, HJ, Kim, JW, et al. (2001) The inflammation hypothesis of aging: molecular modulation by calorie restriction. Ann N Y Acad Sci 928, 327335.
98.Kang, MJ, Kim, HJ, Kim, HK, et al. (2005) The effect of age and calorie restriction on HIF-1-responsive genes in aged liver. Biogerontology 6, 2737.
99.Jung, KJ, Lee, EK, Kim, JY, et al. (2009) Effect of short term calorie restriction on pro-inflammatory NF-κB and AP-1 in aged rat kidney. Inflamm Res 58, 143150.
100.Horrillo, D, Gallardo, N, Lauzurica, N, et al. (2013) Development of liver fibrosis during aging: effects of caloric restriction. J Biol Regul Homeost Agents 27, 377388.
101.Li, N & Karin, M (1999) Is NF-κB the sensor of oxidative stress? FASEB J 13, 11371143.
102.Franceschi, C & Campisi, J (2014) Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci 69, Suppl. 1, S4S9.
103.Varol, C, Zvibel, I, Spektor, L, et al. (2014) Long-acting glucose-dependent insulinotropic polypeptide ameliorates obesity-induced adipose tissue inflammation. J Immunol 193, 40024009.
104.Chung, HY, Cesari, M, Anton, S, et al. (2009) Molecular inflammation: underpinnings of aging and age-related diseases. Ageing Res Rev 8, 1830.
105.Sung, B, Park, S, Yu, BP, et al. (2004) Modulation of PPAR in aging, inflammation, and calorie restriction. J Gerontol A Biol Sci Med Sci 59, 9971006.
106.Swindell, WR (2009) Genes and gene expression modules associated with caloric restriction and aging in the laboratory mouse. BMC Genomics 10, 585.
107.Higami, Y, Barger, JL, Page, GP, et al. (2006) Energy restriction lowers the expression of genes linked to inflammation, the cytoskeleton, the extracellular matrix, and angiogenesis in mouse adipose tissue. J Nutr 136, 343352.
108.Kim, JW, Zou, Y, Yoon, S, et al. (2004) Vascular aging: molecular modulation of the prostanoid cascade by calorie restriction. J Gerontol A Biol Sci Med Sci 59, B876B885.
109.Cadenas, E & Davies, KJ (2000) Mitochondrial free radical generation, oxidative stress, and aging. Free Radic Biol Med 29, 222230.
110.Turrens, JF (2003) Mitochondrial formation of reactive oxygen species. J Physiol 552, 335344.
111.Murphy, MP (2009) How mitochondria produce reactive oxygen species. Biochem J 417, 113.
112.Harper, ME, Monemdjou, S, Ramsey, JJ, et al. (1998) Age-related increase in mitochondrial proton leak and decrease in ATP turnover reactions in mouse hepatocytes. Am J Physiol 275, E197E206.
113.Hulbert, AJ, Pamplona, R, Buffenstein, R, et al. (2007) Life and death: metabolic rate, membrane composition, and life span of animals. Physiol Rev 87, 11751213.
114.Alexeyev, MF, Ledoux, SP & Wilson, GL (2004) Mitochondrial DNA and aging. Clin Sci (Lond) 107, 355364.
115.Pansarasa, O, Bertorelli, L, Vecchiet, J, et al. (1999) Age-dependent changes of antioxidant activities and markers of free radical damage in human skeletal muscle. Free Radic Biol Med 27, 617622.
116.Zhu, J, Wang, KZ & Chu, CT (2013) After the banquet: mitochondrial biogenesis, mitophagy, and cell survival. Autophagy 9, 16631676.
117.Palikaras, K & Tavernarakis, N (2014) Mitochondrial homeostasis: the interplay between mitophagy and mitochondrial biogenesis. Exp Gerontol 56, 182188.
118.Dominy, JE & Puigserver, P (2013) Mitochondrial biogenesis through activation of nuclear signaling proteins. Cold Spring Harb Perspect Biol 5, a015008.
119.Scarpulla, RC (2008) Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol Rev 88, 611638.
120.Picca, A, Pesce, V, Fracasso, F, et al. (2013) Aging and calorie restriction oppositely affect mitochondrial biogenesis through TFAM binding at both origins of mitochondrial DNA replication in rat liver. PLOS ONE 8, e74644.
121.Srivastava, S, Diaz, F, Iommarini, L, et al. (2009) PGC-1α/β induced expression partially compensates for respiratory chain defects in cells from patients with mitochondrial disorders. Human Mol Genet 18, 18051812.
122.Cantó, C & Auwerx, J (2009) PGC-1α, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr Opin Lipidol 20, 98105.
123.Massey, AC, Kiffin, R & Cuervo, AM (2006) Autophagic defects in aging: looking for an ‘emergency exit’? Cell Cycle 5, 12921296.
124.Miwa, S, Lawless, C & von Zglinicki, T (2008) Mitochondrial turnover in liver is fast in vivo and is accelerated by dietary restriction: application of a simple dynamic model. Aging Cell 7, 920923.
125.Parzych, KR & Klionsky, DJ (2014) An overview of autophagy: morphology, mechanism, and regulation. Antioxid Redox Signal 20, 460473.
126.Ravikumar, B, Sarkar, S, Davies, JE, et al. (2010) Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev 90, 13831435.
127.Yang, Z & Klionsky, DJ (2009) An overview of the molecular mechanism of autophagy. Curr Top Microbiol Immunol 335, 132.
128.Levine, B & Klionsky, DJ (2004) Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 6, 463477.
129.Powell, MJ, Casimiro, MC, Cordon-Cardo, C, et al. (2011) Disruption of a Sirt1-dependent autophagy checkpoint in the prostate results in prostatic intraepithelial neoplasia lesion formation. Cancer Res 71, 964975.
130.Fleming, A, Noda, T, Yoshimori, T, et al. (2011) Chemical modulators of autophagy as biological probes and potential therapeutics. Nat Chem Biol 7, 917.
131.Alers, S, Loffler, AS, Wesselborg, S, et al. (2012) Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol Cell Biol 32, 211.
132.Bergamini, E, Cavallini, G, Donati, A, et al. (2007) The role of autophagy in aging: its essential part in the anti-aging mechanism of caloric restriction. Ann N Y Acad Sci 1114, 6978.
133.Eisenberg, T, Knauer, H, Schauer, A, et al. (2009) Induction of autophagy by spermidine promotes longevity. Nat Cell Biol 11, 13051314.
134.Rubinsztein, DC, Marino, G & Kroemer, G (2011) Autophagy and aging. Cell 146, 682695.
135.LaRocca, TJ, Henson, GD, Thorburn, A, et al. (2012) Translational evidence that impaired autophagy contributes to arterial ageing. J Physiol 590, 33053316.
136.Donati, A (2006) The involvement of macroautophagy in aging and anti-aging interventions. Mol Aspects Med 27, 455470.
137.Salminen, A, Kaarniranta, K, Kauppinen, A, et al. (2013) Impaired autophagy and APP processing in Alzheimer’s disease: the potential role of Beclin 1 interacto. Prog Neurobiol 106–107, 3354.
138.Wolfe, DM, Lee, JH, Kumar, A, et al. (2013) Autophagy failure in Alzheimer’s disease and the role of defective lysosomal acidificati. Eur J Neurosci 37, 19491961.
139.Lynch-Day, MA, Mao, K, Wang, K, et al. (2012) The role of autophagy in Parkinson’s disease. Cold Spring Harb Perspect Med 2, a009357.
140.Cortes, CJ & La Spada, AR (2014) The many faces of autophagy dysfunction in Huntington’s disease: from mechanism to therapy. Drug Discov Today 19, 963971.
141.Hardie, DG (2007) AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 8, 774785.
142.Zhu, Z, Jiang, W, McGinley, JN, et al. (2005) 2-Deoxyglucose as an energy restriction mimetic agent: effects on mammary carcinogenesis and on mammary tumor cell growth in vitro. Cancer Res 65, 70237030.
143.Lee, IH, Cao, L, Mostoslavsky, R, et al. (2008) A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc Natl Acad Sci U S A 105, 33743379.
144.Pimentel, GD, Ropelle, ER, Rocha, GZ, et al. (2013) The role of neuronal AMPK as a mediator of nutritional regulation of food intake and energy homeostasis. Metabolism 62, 171178.
145.Greer, EL, Oskoui, PR, Banko, MR, et al. (2007) The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J Biol Chem 282, 3010730119.
146.Jager, S, Handschin, C, St-Pierre, J, et al. (2007) AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α. Proc Natl Acad Sci U S A 104, 1201712022.
147.Canto, C, Jiang, LQ, Deshmukh, AS, et al. (2010) Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab 11, 213219.
148.Tohyama, D & Yamaguchi, A (2010) A critical role of SNF1A/dAMPKα (Drosophila AMP-activated protein kinase α) in muscle on longevity and stress resistance in Drosophila melanogaster. Biochem Biophys Res Comm 394, 112118.
149.Apfeld, J, O’Connor, G, McDonagh, T, et al. (2004) The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes Dev 18, 30043009.
150.Palacios, OM, Carmona, JJ, Michan, S, et al. (2009) Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-1α in skeletal muscle. Aging 1, 771783.
151.Edwards, AG, Donato, AJ, Lesniewski, LA, et al. (2010) Life-long caloric restriction elicits pronounced protection of the aged myocardium: a role for AMPK. Mech Ageing Dev 131, 739742.
152.Miller, BF, Robinson, MM, Bruss, MD, et al. (2012) A comprehensive assessment of mitochondrial protein synthesis and cellular proliferation with age and caloric restriction. Aging Cell 11, 150161.
153.Gonzalez, AA, Kumar, R, Mulligan, JD, et al. (2004) Metabolic adaptations to fasting and chronic caloric restriction in heart, muscle, and liver do not include changes in AMPK activity. Am J Physiol Endocrinol Metab 287, E1032E1037.
154.Um, JH, Park, SJ, Kang, H, et al. (2010) AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol. Diabetes 59, 554563.
155.Price, NL, Gomes, AP, Ling, AJ, et al. (2012) SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab 15, 675690.
156.Han, L, Zhao, G, Wang, H, et al. (2014) Calorie restriction upregulated sirtuin 1 by attenuating its ubiquitin degradation in cancer cells. Clin Exp Pharmacol Physiol 41, 165168.
157.Silvestre, MF, Viollet, B, Caton, PW, et al. (2014) The AMPK–SIRT signaling network regulates glucose tolerance under calorie restriction conditions. Life Sci 100, 5560.
158.Yu, W, Zhou, HF, Lin, RB, et al. (2014) Short-term calorie restriction activates SIRT14 and 7 in cardiomyocytes in vivo and in vitro. Mol Med Rep 9, 12181224.
159.Lagouge, M, Argmann, C, Gerhart-Hines, Z, et al. (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127, 11091122.
160.Morselli, E, Maiuri, MC, Markaki, M, et al. (2010) Caloric restriction and resveratrol promote longevity through the sirtuin-1-dependent induction of autophagy. Cell Death Dis 1, e10.
161.Guarente, L (2006) Sirtuins as potential targets for metabolic syndrome. Nature 444, 868874.
162.Hoff, KG & Wolberger, C (2005) Getting a grip on O-acetyl-ADP-ribose. Nat Struct Mol Biol 12, 560561.
163.Vaquero, A, Scher, M, Lee, D, et al. (2004) Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin. Mol Cell 16, 93105.
164.Cameron, EE, Bachman, KE, Myöhänen, S, et al. (1999) Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet 21, 103107.
165.Rodgers, JT, Lerin, C, Haas, W, et al. (2005) Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature 434, 113118.
166.Lopez-Lluch, G, Irusta, PM, Navas, P, et al. (2008) Mitochondrial biogenesis and healthy aging. Exp Gerontol 43, 813819.
167.Morselli, E, Maiuri, MC, Markaki, M, et al. (2010) The life span-prolonging effect of sirtuin-1 is mediated by autophagy. Autophagy 6, 186188.
168.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 Dev 13, 25702580.
169.Tissenbaum, HA & Guarente, L (2001) Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410, 227230.
170.Wood, JG, Rogina, B, Lavu, S, et al. (2004) Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430, 686689.
171.Satoh, A, Brace, CS, Rensing, N, et al. (2013) Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH. Cell Metab 18, 416430.
172.Liang, F, Kume, S & Koya, D (2009) SIRT1 and insulin resistance. Nat Rev Endocrinol 5, 367373.
173.Pfluger, PT, Herranz, D, Velasco-Miguel, S, et al. (2008) Sirt1 protects against high-fat diet-induced metabolic damage. Proc Natl Acad Sci U S A 105, 97939798.
174.Herranz, D, Muñoz-Martin, M, Cañamero, M, et al. (2010) Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat Commun 1, 3.
175.Tamori, Y, Masugi, J, Nishino, N, et al. (2002) Role of peroxisome proliferator-activated receptor-γ in maintenance of the characteristics of mature 3T3-L1 adipocytes. Diabetes 51, 20452055.
176.Picard, F, Kurtev, M, Chung, N, et al. (2004) Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ. Nature 429, 771776.
177.Jiang, JC, Wawryn, J, Shantha Kumara, HM, et al. (2002) Distinct roles of processes modulated by histone deacetylases Rpd3p, Hda1p, and Sir2p in life extension by caloric restriction in yeast. Exp Gerontol 37, 10231030.
178.Smith, DL Jr, McClure, JM, Matecic, M, et al. (2007) Calorie restriction extends the chronological lifespan of Saccharomyces cerevisiae independently of the sirtuins. Aging Cell 6, 649662.
179.Kanfi, Y, Peshti, V, Gozlan, YM, et al. (2008) Regulation of SIRT1 protein levels by nutrient availability. FEBS Lett 582, 24172423.
180.Lopez-Lluch, G, Hunt, N, Jones, B, et al. (2006) Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. Proc Natl Acad Sci U S A 103, 17681773.
181.Hepple, RT, Baker, DJ, McConkey, M, et al. (2006) Caloric restriction protects mitochondrial function with aging in skeletal and cardiac muscles. Rejuvenation Res 9, 219222.
182.Anderson, R & Prolla, T (2009) PGC-1α in aging and anti-aging interventions. Biochim Biophys Acta 1790, 10591066.
183.Lin, J, Wu, H, Tarr, PT, et al. (2002) Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibres. Nature 418, 797801.
184.Puigserver, P, Wu, Z, Park, CW, et al. (1998) A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92, 829839.
185.Lee, CK, Allison, DB, Brand, J, et al. (2002) Transcriptional profiles associated with aging and middle age-onset caloric restriction in mouse hearts. Proc Natl Acad Sci U S A 99, 1498814993.
186.Hancock, CR, Han, DH, Higashida, K, et al. (2011) Does calorie restriction induce mitochondrial biogenesis? A reevaluation. FASEB J 25, 785791.
187.Calnan, DR & Brunet, A (2008) The FoxO code. Oncogene 27, 22762288.
188.Finkel, T, Deng, CX & Mostoslavsky, R (2009) Recent progress in the biology and physiology of sirtuins. Nature 460, 587591.
189.Brunet, A, Sweeney, LB, Sturgill, JF, et al. (2004) Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303, 20112015.
190.Zhao, Y, Yang, J, Liao, W, et al. (2010) Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity. Nat Cell Biol 12, 665675.
191.Plas, DR & Thompson, CB (2003) Akt activation promotes degradation of tuberin and FOXO3a via the proteasome. J Biol Chem 278, 1236112366.
192.Tazearslan, C, Cho, M & Suh, Y (2012) Discovery of functional gene variants associated with human longevity: opportunities and challenges. J Gerontol A Biol Sci Med Sci 67, 376383.
193.Bluher, M, Kahn, BB & Kahn, CR (2003) Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299, 572574.
194.Berryman, DE, Christiansen, JS, Johannsson, G, et al. (2008) Role of the GH/IGF-1 axis in lifespan and healthspan: lessons from animal models. Growth Horm IGF Res 18, 455471.
195.Dunn, SE, Kari, FW, French, J, et al. (1997) Dietary restriction reduces insulin-like growth factor I levels, which modulates apoptosis, cell proliferation, and tumor progression in p53-deficient mice. Cancer Res 57, 46674672.
196.Steger, RW, Bartke, A & Cecim, M (1993) Premature ageing in transgenic mice expressing different growth hormone genes. J Reprod Fertil Suppl 46, 6175.
197.Suh, Y, Atzmon, G, Cho, MO, et al. (2008) Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc Natl Acad Sci U S A 105, 34383442.
198.Holzenberger, M, Dupont, J, Ducos, B, et al. (2003) IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421, 182187.
199.Ikeno, Y, Bronson, RT, Hubbard, GB, et al. (2003) Delayed occurrence of fatal neoplastic diseases in Ames dwarf mice: correlation to extended longevity. J Gerontol A Biol Sci Med Sci 58, 291296.
200.Milman, S, Atzmon, G, Huffman, DM, et al. (2014) Low insulin-like growth factor-1 level predicts survival in humans with exceptional longevity. Aging Cell 13, 769771.
201.Facchini, FS, Hua, NW, Reaven, GM, et al. (2000) Hyperinsulinemia: the missing link among oxidative stress and age-related diseases? Free Radic Biol Med 29, 13021306.
202.Liu, HY, Han, J, Cao, SY, et al. (2009) Hepatic autophagy is suppressed in the presence of insulin resistance and hyperinsulinemia: inhibition of FoxO1-dependent expression of key autophagy genes by insulin. J Biol Chem 284, 3148431492.
203.Fleming-Waddell, JN, Olbricht, GR, Taxis, TM, et al. (2009) Effect of DLK1 and RTL1 but not MEG3 or MEG8 on muscle gene expression in Callipyge lambs. PloS ONE 4, e7399.
204.Hay, N & Sonenberg, N (2004) Upstream and downstream of mTOR. Genes Dev 18, 19261945.
205.Ciuffreda, L, Di Sanza, C, Incani, UC, et al. (2010) The mTOR pathway: a new target in cancer therapy. Curr Cancer Drug Targets 10, 484495.
206.Powers, RW III, Kaeberlein, M, Caldwell, SD, et al. (2006) Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev 20, 174184.
207.Kaeberlein, M, Powers, RW III, Steffen, KK, et al. (2005) Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310, 11931196.
208.Jia, K, Chen, D & Riddle, DL (2004) The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development 131, 38973906.
209.Vellai, T, Takacs-Vellai, K, Zhang, Y, et al. (2003) Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 426, 620.
210.Kapahi, P, Zid, BM, Harper, T, et al. (2004) Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol 14, 885890.
211.Sharp, ZD & Bartke, A (2005) Evidence for down-regulation of phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR)-dependent translation regulatory signaling pathways in Ames dwarf mice. J Gerontol A Biol Sci Med Sci 60, 293300.
212.Sun, L, Sadighi Akha, AA, Miller, RA, et al. (2009) Life-span extension in mice by preweaning food restriction and by methionine restriction in middle age. J Gerontol A Biol Sci Med Sci 64, 711722.
213.Ravikumar, B, Vacher, C, Berger, Z, et al. (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36, 585595.
214.Toth, ML, Sigmond, T, Borsos, E, et al. (2008) Longevity pathways converge on autophagy genes to regulate life span in Caenorhabditis elegans. Autophagy 4, 330338.
215.Duffy, PH, Seng, JE, Lewis, SM, et al. (2001) The effects of different levels of dietary restriction on aging and survival in the Sprague–Dawley rat: implications for chronic studies. Aging (Milano) 13, 263272.
216.Villareal, DT, Kotyk, JJ, Armamento-Villareal, RC, et al. (2011) Reduced bone mineral density is not associated with significantly reduced bone quality in men and women practicing long-term calorie restriction with adequate nutrition. Aging Cell 10, 96102.
217.Hunt, ND, Li, GD, Zhu, M, et al. (2012) Effect of calorie restriction and refeeding on skin wound healing in the rat. Age (Dordr) 34, 14531458.
218.Goldberg, EL, Romero-Aleshire, MJ, Renkema, KR, et al. (2015) Lifespan-extending caloric restriction or mTOR inhibition impair adaptive immunity of old mice by distinct mechanisms. Aging Cell 14, 130138.
219.Goodrick, CL, Ingram, DK, Reynolds, MA, et al. (1982) Effects of intermittent feeding upon growth and life span in rats. Gerontology 28, 233241.
220.Johnson, JB, Laub, DR & John, S (2006) The effect on health of alternate day calorie restriction: eating less and more than needed on alternate days prolongs life. Med Hypotheses 67, 209211.
221.Descamps, O, Riondel, J, Ducros, V, et al. (2005) Mitochondrial production of reactive oxygen species and incidence of age-associated lymphoma in OF1 mice: effect of alternate-day fasting. Mech Ageing Dev 126, 11851191.
222.Ahmet, I, Wan, R, Mattson, MP, et al. (2005) Cardioprotection by intermittent fasting in rats. Circulation 112, 31153121.
223.Mager, DE, Wan, R, Brown, M, et al. (2006) Caloric restriction and intermittent fasting alter spectral measures of heart rate and blood pressure variability in rats. FASEB J 20, 631637.
224.Chung, KW, Kim, DH, Park, MH, et al. (2013) Recent advances in calorie restriction research on aging. Exp Gerontol 48, 10491053.
225.Ingram, DK, Zhu, M, Mamczarz, J, et al. (2006) Calorie restriction mimetics: an emerging research field. Aging Cell 5, 97108.
226.Smith, DL Jr, Nagy, TR & Allison, DB (2010) Calorie restriction: what recent results suggest for the future of ageing research. Eur J Clin Invest 40, 440450.
227.Selman, C (2014) Dietary restriction and the pursuit of effective mimetics. Proc Nutr Soc 73, 260270.
228.Lane, MA, Roth, GS & Ingram, DK (2007) Caloric restriction mimetics: a novel approach for biogerontology. Methods Mol Biol 371, 143149.
229.Weimer, S, Priebs, J, Kuhlow, D, et al. (2014) d-Glucosamine supplementation extends life span of nematodes and of ageing mice. Nat Comm 5, 3563.
230.Ingram, DK, Anson, RM, de Cabo, R, et al. (2004) Development of calorie restriction mimetics as a prolongevity strategy. Ann N Y Acad Sci 1019, 412423.
231.Smith, DL Jr, Elam, CF Jr, Mattison, JA, et al. (2010) Metformin supplementation and life span in Fischer-344 rats. J Gerontol A Biol Sci Med Sci 65, 468474.
232.Ingram, DK & Roth, GS (2015) Calorie restriction mimetics: can you have your cake and eat it, too? Ageing Res Rev 20C, 4662.
233.Donati, A, Cavallini, G, Carresi, C, et al. (2004) Anti-aging effects of anti-lipolytic drugs. Exp Gerontol 39, 10611067.
234.Straniero, S, Cavallini, G, Donati, A, et al. (2009) Stimulation of autophagy by antilipolytic drugs may rescue rodents from age-associated hypercholesterolemia. Rejuvenation Res 12, 7784.
235.Alcaín, FJ & Villalba, JM (2009) Sirtuin activators. Expert Opin Ther Pat 19, 403414.
236.Marino, G, Pietrocola, F, Madeo, F, et al. (2014) Caloric restriction mimetics: natural/physiological pharmacological autophagy inducers. Autophagy 10, 18791882.
237.Navarro-Alarcón, M, Ruiz-Ojeda, FJ, Blanca-Herrera, RM, et al. (2014) Melatonin and metabolic regulation: a review. Food Funct 5, 28062832.
238.Lane, MA, Ingram, DK & Roth, GS (1998) 2-Deoxy-d-glucose feeding in rats mimics physiologic effects of calorie restriction. J Anti Aging Med 1, 327337.
239.Brown, J (1962) Effects of 2-deoxyglucose on carbohydrate metablism: review of the literature and studies in the rat. Metabolism 11, 10981112.
240.Yao, J, Chen, S, Mao, Z, et al. (2011) 2-Deoxy-d-glucose treatment induces ketogenesis, sustains mitochondrial function, and reduces pathology in female mouse model of Alzheimer’s disea. PloS ONE 6, e21788.
241.Wan, R, Camandola, S & Mattson, MP (2003) Intermittent fasting and dietary supplementation with 2-deoxy-d-glucose improve functional and metabolic cardiovascular risk factors in rats. FASEB J 17, 11331134.
242.Ingram, DK & Roth, GS (2011) Glycolytic inhibition as a strategy for developing calorie restriction mimetics. Exp Gerontol 46, 148154.
243.Lee, J, Bruce-Keller, AJ, Kruman, Y, et al. (1999) 2-Deoxy-d-glucose protects hippocampal neurons against excitotoxic and oxidative injury: evidence for the involvement of stress proteins. J Neurosci Res 57, 4861.
244.Canto, C, Gerhart-Hines, Z, Feige, JN, et al. (2009) AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activi. Nature 458, 10561060.
245.Schulz, TJ, Zarse, K, Voigt, A, et al. (2007) Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab 6, 280293.
246.Correia, S, Carvalho, C, Santos, MS, et al. (2008) Mechanisms of action of metformin in type 2 diabetes and associated complications: an overview. Mini Rev Med Chem 8, 13431354.
247.Radziuk, J, Bailey, CJ, Wiernsperger, NF, et al. (2003) Metformin and its liver targets in the treatment of type 2 diabetes. Curr Drug Targets Immune Endocr Metabol Disord 3, 151169.
248.Testa, G, Biasi, F, Poli, G, et al. (2014) Calorie restriction and dietary restriction mimetics: a strategy for improving healthy aging and longevity. Curr Pharm Des 20, 29502977.
249.Libby, G, Donnelly, LA, Donnan, PT, et al. (2009) New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 32, 16201625.
250.Berstein, LM (2012) Metformin in obesity, cancer and aging: addressing controversies. Aging 4, 320329.
251.Nagi, DK & Yudkin, JS (1993) Effects of metformin on insulin resistance, risk factors for cardiovascular disease, and plasminogen activator inhibitor in NIDDM subjects. A study of two ethnic groups. Diabetes Care 16, 621629.
252.Anisimov, VN, Berstein, LM, Egormin, PA, et al. (2008) Metformin slows down aging and extends life span of female SHR mice. Cell Cycle 7, 27692773.
253.Ben Sahra, I, Le Marchand-Brustel, Y, Tanti, JF, et al. (2010) Metformin in cancer therapy: a new perspective for an old antidiabetic drug? Mol Cancer Ther 9, 10921099.
254.Dhahbi, JM, Mote, PL, Fahy, GM, et al. (2005) Identification of potential caloric restriction mimetics by microarray profiling. Physiol Genomics 23, 343350.
255.Onken, B & Driscoll, M (2010) Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans healthspan via AMPK, LKB1, and SKN-1. PloS ONE 5, e8758.
256.Holst, H, Eldrup, E, Guldstad, NH, et al. (2012) Metformin associated with lactic acidosis in treatment of type 2 diabetes (article in Danish). Ugeskr Laeger 174, 15981602.
257.Salpeter, SR, Greyber, E, Pasternak, GA, et al. (2003) Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus: systematic review and meta-analysis. Arch Intern Med 163, 25942602.
258.Kruse, JA (2004) Review: metformin does not increase risk for lactic acidosis or increase lactate levels in type 2 diabetes. ACP J Club 141, 7.
259.Nisbet, JC, Sturtevant, JM & Prins, JB (2004) Metformin and serious adverse effects. M J Aust 180, 5354.
260.Wullschleger, S, Loewith, R & Hall, MN (2006) TOR signaling in growth and metabolism. Cell 124, 471484.
261.Garber, K (2001) Rapamycin’s resurrection: a new way to target the cancer cell cyc. J Natl Cancer Inst 93, 15171519.
262.Crespo, JL & Hall, MN (2002) Elucidating TOR signaling and rapamycin action: lessons from Saccharomyces cerevisiae. Microbiol Mol Biol Rev 66, 579591, table of contents.
263.Heitman, J, Movva, NR & Hall, MN (1991) Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253, 905909.
264.Alvers, AL, Wood, MS, Hu, D, et al. (2009) Autophagy is required for extension of yeast chronological life span by rapamycin. Autophagy 5, 847849.
265.Fontana, L, Partridge, L & Longo, VD (2010) Extending healthy life span – from yeast to humans. Science 328, 321326.
266.Cuervo, AM (2008) Autophagy and aging: keeping that old broom working. Trends Genet 24, 604612.
267.Harrison, DE, Strong, R, Sharp, ZD, et al. (2009) Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392395.
268.Miller, RA, Harrison, DE, Astle, CM, et al. (2011) Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci 66, 191201.
269.Stanfel, MN, Shamieh, LS, Kaeberlein, M, et al. (2009) The TOR pathway comes of age. Biochim Biophys Acta 1790, 10671074.
270.Mizushima, N (2010) The role of the Atg1/ULK1 complex in autophagy regulation. Curr Opin Cell Biol 22, 132139.
271.Calabrese, V, Cornelius, C, Dinkova-Kostova, AT, et al. (2012) Cellular stress responses, hormetic phytochemicals and vitagenes in aging and longevity. Biochim Biophys Acta 1822, 753783.
272.Bove, J, Martinez-Vicente, M & Vila, M (2011) Fighting neurodegeneration with rapamycin: mechanistic insights. Nat Rev Neurosci 12, 437452.
273.Blagosklonny, MV (2009) Validation of anti-aging drugs by treating age-related diseases. Aging 1, 281288.
274.Afaq, F & Mukhtar, H (2006) Botanical antioxidants in the prevention of photocarcinogenesis and photoaging. Exp Dermatol 15, 678684.
275.Agarwal, B & Baur, JA (2011) Resveratrol and life extension. Ann N Y Acad Sci 1215, 138143.
276.Vuong, TV, Franco, C & Zhang, W (2014) Treatment strategies for high resveratrol induction in Vitis vinifera L. cell suspension culture. Biotechnol Rep 1–2, 1521.
277.Baur, JA & Sinclair, DA (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5, 493506.
278.Zou, S, Carey, JR, Liedo, P, et al. (2009) The prolongevity effect of resveratrol depends on dietary composition and calorie intake in a tephritid fruit fly. Exp Gerontol 44, 472476.
279.Howitz, KT, Bitterman, KJ, Cohen, HY, et al. (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425, 191196.
280.Valenzano, DR, Terzibasi, E, Genade, T, et al. (2006) Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate. Curr Biol 16, 296300.
281.Baur, JA, Pearson, KJ, Price, NL, et al. (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337342.
282.Bass, TM, Weinkove, D, Houthoofd, K, et al. (2007) Effects of resveratrol on lifespan in Drosophila melanogaster and Caenorhabditis elegans. Mech Ageing Dev 128, 546552.
283.Pearson, KJ, Baur, JA, Lewis, KN, et al. (2008) Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 8, 157168.
284.Strong, R, Miller, RA, Astle, CM, et al. (2013) Evaluation of resveratrol, green tea extract, curcumin, oxaloacetic acid, and medium-chain triglyceride oil on life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci 68, 616.
285.Pan, M, Yuan, H, Brent, M, et al. (2012) SIRT1 contains N- and C-terminal regions that potentiate deacetylase activity. J Biol Chem 287, 24682476.
286.Pacholec, M, Bleasdale, JE, Chrunyk, B, et al. (2010) SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J Biol Chem 285, 83408351.
287.Kaeberlein, M, McDonagh, T, Heltweg, B, et al. (2005) Substrate-specific activation of sirtuins by resveratrol. J Biol Chem 280, 1703817045.
288.Park, SJ, Ahmad, F, Philp, A, et al. (2012) Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell 148, 421433.
289.Sajish, M & Schimmel, P (2015) A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol. Nature 519, 370373.
290.Crowell, JA, Korytko, PJ, Morrissey, RL, et al. (2004) Resveratrol-associated renal toxicity. Toxicol Sci 82, 614619.
291.Soda, K, Dobashi, Y, Kano, Y, et al. (2009) Polyamine-rich food decreases age-associated pathology and mortality in aged mice. Exp Gerontol 44, 727732.
292.Scalabrino, G & Ferioli, ME (1984) Polyamines in mammalian ageing: an oncological problem, too? A review. Mech Ageing Dev 26, 149164.
293.Paik, MJ, Ahn, YH, Lee, PH, et al. (2010) Polyamine patterns in the cerebrospinal fluid of patients with Parkinson’s disease and multiple system atrop. Clin Chim Acta 411, 15321535.
294.Jin, HT, Raty, S, Minkkinen, M, et al. (2009) Changes in blood polyamine levels in human acute pancreatitis. Scand J Gastroenterol 44, 10041011.
295.ter Steege, JC, Forget, PP & Buurman, WA (1999) Oral spermine administration inhibits NO-mediated intestinal damage and levels of systemic inflammatory mediators in a mouse endotoxin model. Shock 11, 115119.
296.Soda, K, Kano, Y, Nakamura, T, et al. (2005) Spermine, a natural polyamine, suppresses LFA-1 expression on human lymphocyte. J Immunol 175, 237245.
297.Seidl, R, Beninati, S, Cairns, N, et al. (1996) Polyamines in frontal cortex of patients with Down syndrome and Alzheimer disease. Neurosci Lett 206, 193195.
298.Guo, X, Harada, C, Namekata, K, et al. (2011) Spermidine alleviates severity of murine experimental autoimmune encephalomyelitis. Invest Ophthalmol Vis Sci 52, 26962703.
299.Zhu, S, Ashok, M, Li, J, et al. (2009) Spermine protects mice against lethal sepsis partly by attenuating surrogate inflammatory markers. Mol Med 15, 275282.
300.Morgan, DM (1998) Polyamines. An introduction. Methods Mol Biol 79, 330.
301.Minois, N, Carmona-Gutierrez, D & Madeo, F (2011) Polyamines in aging and disease. Aging 3, 716732.
302.Bardócz, S, Grant, G, Brown, DS, et al. (1993) Polyamines in food – implications for growth and health. J Nutr Biochem 4, 6671.
303.Amendola, R, Cervelli, M, Fratini, E, et al. (2009) Spermine metabolism and anticancer therapy. Curr Cancer Drug Targets 9, 118130.
304.Binh, PNT, Soda, K, Maruyama, C, et al. (2010) Relationship between food polyamines and gross domestic product in association with longevity in Asian countries. Health 2, 13901396.
305.Binh, PNT, Soda, K & Kawakami, M (2011) Mediterranean diet and polyamine intake: possible contribution of increased polyamine intake to inhibition of age-associated disease. Nutr Diet Suppl 3, 17.
306.Pucciarelli, S, Moreschini, B, Micozzi, D, et al. (2012) Spermidine and spermine are enriched in whole blood of nona/centenarians. Rejuvenation Res 15, 590595.
307.Jia, K & Levine, B (2007) Autophagy is required for dietary restriction-mediated life span extension in C. elegans. Autophagy 3, 597599.
308.Melendez, A, Talloczy, Z, Seaman, M, et al. (2003) Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 301, 13871391.
309.Jenuwein, T & Allis, CD (2001) Translating the histone code. Science 293, 10741080.
310.Minois, N, Carmona-Gutierrez, D, Bauer, MA, et al. (2012) Spermidine promotes stress resistance in Drosophila melanogaster through autophagy-dependent and -independent pathways. Cell Death Dis 3, e401.
311.LaRocca, TJ, Gioscia-Ryan, RA, Hearon, CM Jr, et al. (2013) The autophagy enhancer spermidine reverses arterial aging. Mech Ageing Dev 134, 314320.
312.Sarhan, S, Knodgen, B & Seiler, N (1992) Polyamine deprivation, malnutrition and tumor growth. Anticancer Res 12, 457466.
313.Quemener, V, Blanchard, Y, Chamaillard, L, et al. (1994) Polyamine deprivation: a new tool in cancer treatment. Anticancer Res 14, 443448.
314.Clifford, A, Morgan, D, Yuspa, SH, et al. (1995) Role of ornithine decarboxylase in epidermal tumorigenesis. Cancer Res 55, 16801686.
315.Packer, L, Witt, EH & Tritschler, HJ (1995) α-Lipoic acid as a biological antioxidant. Free Radic Biol Med 19, 227250.
316.Packer, L, Tritschler, HJ & Wessel, K (1997) Neuroprotection by the metabolic antioxidant α-lipoic acid. Free Radic Biol Med 22, 359378.
317.Packer, L, Kraemer, K & Rimbach, G (2001) Molecular aspects of lipoic acid in the prevention of diabetes complications. Nutrition 17, 888895.
318.Bauer, JH, Goupil, S, Garber, GB, et al. (2004) An accelerated assay for the identification of lifespan-extending interventions in Drosophila melanogaster. Proc Natl Acad Sci U S A 101, 1298012985.
319.Brown, MK, Evans, JL & Luo, Y (2006) Beneficial effects of natural antioxidants EGCG and α-lipoic acid on life span and age-dependent behavioral declines in Caenorhabditis elegans. Pharmacol Biochem Behav 85, 620628.
320.Benedetti, MG, Foster, AL, Vantipalli, MC, et al. (2008) Compounds that confer thermal stress resistance and extended lifespan. Exp Gerontol 43, 882891.
321.Farr, SA, Price, TO, Banks, WA, et al. (2012) Effect of α-lipoic acid on memory, oxidation, and lifespan in SAMP8 mice. J Alzheimers Dis 32, 447455.
322.Freisleben, HJ, Neeb, A, Lehr, F, et al. (1997) Influence of selegiline and lipoic acid on the life expectancy of immunosuppressed mice. ArzneimittelForschung 47, 776780.
323.Arivazhagan, P, Juliet, P & Panneerselvam, C (2000) Effect of dl-α-lipoic acid on the status of lipid peroxidation and antioxidants in aged rats. Pharmacol Res 41, 299303.
324.Arivazhagan, P, Thilakavathy, T, Ramanathan, K, et al. (2002) Effect of dl-α-lipoic acid on the status of lipid peroxidation and protein oxidation in various brain regions of aged rats. J Nutr Biochem 13, 619624.
325.Hagen, TM, Liu, J, Lykkesfeldt, J, et al. (2002) Feeding acetyl-l-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proc Natl Acad Sci U S A 99, 18701875.
326.Liu, J, Killilea, DW & Ames, BN (2002) Age-associated mitochondrial oxidative decay: improvement of carnitine acetyltransferase substrate-binding affinity and activity in brain by feeding old rats acetyl-l-carnitine and/or R-α-lipoic acid. Proc Natl Acad Sci U S A 99, 18761881.
327.Dicter, N, Madar, Z & Tirosh, O (2002) α-Lipoic acid inhibits glycogen synthesis in rat soleus muscle via its oxidative activity and the uncoupling of mitochondria. J Nutr 132, 30013006.
328.Bayir, H & Kagan, VE (2008) Bench-to-bedside review: mitochondrial injury, oxidative stress and apoptosis – there is nothing more practical than a good theory. Crit Care 12, 206.
329.Nedergaard, J, Golozoubova, V, Matthias, A, et al. (2001) UCP1, the only protein able to mediate adaptive non-shivering thermogenesis and metabolic inefficiency. Biochim Biophys Acta 1504, 82106.
330.Shabalina, IG, Jacobsson, A, Cannon, B, et al. (2004) Native UCP1 displays simple competitive kinetics between the regulators purine nucleotides and fatty acids. J Biol Chem 279, 3823638248.
331.Takahashi, H, Bungo, Y & Mikuni, K (2011) The aqueous solubility and thermal stability of α-lipoic acid are enhanced by cyclodextrin. Biosci Biotechnol Biochem 75, 633637.
332.Ikuta, N, Sugiyama, H, Shimosegawa, H, et al. (2013) Analysis of the enhanced stability of R(+)-α lipoic acid by the complex formation with cyclodextrins. Int J Mol Sci 14, 36393655.
333.Nikolai, S, Huebbe, P, Metges, CC, et al. (2014) R-α lipoic acid γ-cyclodextrin complex increases energy expenditure: a 4-month feeding study in mice. Nutrition 30, 228233.
334.Speakman, JR, Talbot, DA, Selman, C, et al. (2004) Uncoupled and surviving: individual mice with high metabolism have greater mitochondrial uncoupling and live longer. Aging Cell 3, 8795.
335.Pallauf, K, Giller, K, Huebbe, P, et al. (2013) Nutrition and healthy ageing: calorie restriction or polyphenol-rich “MediterrAsian” diet? Oxid Med Cell Longev 2013, 707421.
336.Chen, T, Shen, L, Yu, J, et al. (2011) Rapamycin and other longevity-promoting compounds enhance the generation of mouse induced pluripotent stem cells. Aging Cell 10, 908911.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Nutrition Research Reviews
  • ISSN: 0954-4224
  • EISSN: 1475-2700
  • URL: /core/journals/nutrition-research-reviews
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Altmetric attention score

Full text views

Total number of HTML views: 33
Total number of PDF views: 203 *
Loading metrics...

Abstract views

Total abstract views: 1533 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 25th March 2018. This data will be updated every 24 hours.