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Circadian rhythms, nutrition and implications for longevity in urban environments

  • O. Froy (a1)


Presently, about 12% of the population is 65 years or older and by the year 2030 that figure is expected to reach 21%. In order to promote the well-being of the elderly and to reduce the costs associated with health care demands, increased longevity should be accompanied by ageing attenuation. Energy restriction, which limits the amount of energy consumed to 60–70% of the daily intake, and intermittent fasting, which allows the food to be available ad libitum every other day, extend the life span of mammals and prevent or delay the onset of major age-related diseases, such as cancer, diabetes and cataracts. Recently, we have shown that well-being can be achieved by resetting of the circadian clock and induction of robust catabolic circadian rhythms via timed feeding. In addition, the clock mechanism regulates metabolism and major metabolic proteins are key factors in the core clock mechanism. Therefore, it is necessary to increase our understanding of circadian regulation over metabolism and longevity and to design new therapies based on this regulation. This review will explore the present data in the field of circadian rhythms, ageing and metabolism.

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Corresponding author

Corresponding author: O. Froy, fax 972-8-936-3208, e-mail


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1.Reppert, SM & Weaver, DR (2002) Coordination of circadian timing in mammals. Nature 418, 935941.
2.Panda, S, Antoch, MP, Miller, BH et al. (2002) Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 109, 307320.
3.Schibler, U, Ripperger, J & Brown, SA (2003) Peripheral circadian oscillators in mammals: time and food. J Biol Rhythms 18, 250260.
4.Froy, O, Chang, DC & Reppert, SM (2002) Redox potential: differential roles in dCRY and mCRY1 functions. Curr Biol 12, 147152.
5.Davis, S & Mirick, DK (2006) Circadian disruption, shift work and the risk of cancer: a summary of the evidence and studies in Seattle. Cancer Causes Control 17, 539545.
6.Qureshi, IA & Mehler, MF (2014) Epigenetics of sleep and chronobiology. Curr Neurol Neurosci Rep 14, 432.
7.Hurd, MW & Ralph, MR (1998) The significance of circadian organization for longevity in the golden hamster. J Biol Rhythms 13, 430436.
8.Penev, PD, Kolker, DE, Zee, PC et al. (1998) Chronic circadian desynchronization decreases the survival of animals with cardiomyopathic heart disease. Am J Physiol 275, H2334H2337.
9.Hofman, MA & Swaab, DF (2006) Living by the clock: the circadian pacemaker in older people. Ageing Res Rev 5, 3351.
10.Froy, O & Miskin, R (2007) The interrelations among feeding, circadian rhythms and ageing. Prog Neurobiol 82, 142150.
11.Seyfarth, F, Schliemann, S, Antonov, D et al. (2011) Dry skin, barrier function, and irritant contact dermatitis in the elderly. Clin Dermatol 29, 3136.
12.Iroku-Malize, T & Kirsch, S (2016) Eye conditions in older adults: cataracts. FP Essent 445, 1723.
13.Dubrovsky, YV, Samsa, WE & Kondratov, RV (2010) Deficiency of circadian protein CLOCK reduces lifespan and increases age-related cataract development in mice. Aging (Albany NY) 2, 936944.
14.Kondratov, RV, Kondratova, AA, Gorbacheva, VY et al. (2006) Early aging and age-related pathologies in mice deficient in BMAL1, the core component of the circadian clock. Genes Dev 20, 18681873.
15.Lee, CC (2005) The circadian clock and tumor suppression by mammalian period genes. Methods Enzymol 393, 852861.
16.Froy, O (2011) Circadian rhythms, aging, and life span in mammals. Physiology 26, 225235.
17.Zhang, Y, Brainard, GC, Zee, PC et al. (1998) Effects of aging on lens transmittance and retinal input to the suprachiasmatic nucleus in golden hamsters. Neurosci Lett 258, 167170.
18.Wyse, CA, Coogan, AN, Selman, C et al. (2010) Association between mammalian lifespan and circadian free-running period: the circadian resonance hypothesis revisited. Biol Lett 6, 696698.
19.Gutman, R, Genzer, Y, Chapnik, N et al. (2011) Long-lived mice exhibit 24 h locomotor circadian rhythms at young and old age. Exp Gerontol 46, 606609.
20.Wyatt, SB, Winters, KP & Dubbert, PM (2006) Overweight and obesity: prevalence, consequences, and causes of a growing public health problem. Am J Med Sci 331, 166174.
21.Oishi, K, Shirai, H & Ishida, N (2005) CLOCK is involved in the circadian transactivation of peroxisome-proliferator-activated receptor alpha (PPARalpha) in mice. Biochem J 386, 575581.
22.Turek, FW, Joshu, C, Kohsaka, A et al. (2005) Obesity and metabolic syndrome in circadian Clock mutant mice. Science 308, 10431045.
23.Marcheva, B, Ramsey, KM, Buhr, ED et al. (2010) Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature 466, 627631.
24.Froy, O (2010) Metabolism and circadian rhythms–implications for obesity. Endocr Rev 31, 124.
25.Arble, DM, Bass, J, Laposky, AD et al. (2009) Circadian timing of food intake contributes to weight gain. Obesity (Silver Spring) 17, 21002102.
26.McHill, AW & Wright, KP Jr. (2017) Role of sleep and circadian disruption on energy expenditure and in metabolic predisposition to human obesity and metabolic disease. Obes Rev 18(Suppl 1), 1524.
27.Garaulet, M & Madrid, JA (2010) Chronobiological aspects of nutrition, metabolic syndrome and obesity. Adv Drug Deliv Rev 62, 967978.
28.Kuehn, BM (2017) Resetting the circadian clock might boost metabolic health. JAMA 317, 13031305.
29.Hirota, T & Fukada, Y (2004) Resetting mechanism of central and peripheral circadian clocks in mammals. Zool Sci 21, 359368.
30.Kohsaka, A & Bass, J (2007) A sense of time: how molecular clocks organize metabolism. Trends Endocrinol Metab 18, 411.
31.La Fleur, SE, Kalsbeek, A, Wortel, J et al. (1999) A suprachiasmatic nucleus generated rhythm in basal glucose concentrations. J Neuroendocrinol 11, 643652.
32.La Fleur, SE (2003) Daily rhythms in glucose metabolism: suprachiasmatic nucleus output to peripheral tissue. J Neuroendocrinol 15, 315322.
33.Davidson, AJ, Castanon-Cervantes, O & Stephan, FK (2004) Daily oscillations in liver function: diurnal vs circadian rhythmicity. Liver Int 24, 179186.
34.Ramsey, KM, Marcheva, B, Kohsaka, A et al. (2007) The clockwork of metabolism. Annu Rev Nutr 27, 219240.
35.Cailotto, C, La Fleur, SE, Van Heijningen, C et al. (2005) The suprachiasmatic nucleus controls the daily variation of plasma glucose via the autonomic output to the liver: are the clock genes involved? Eur J Neurosci 22, 25312540.
36.Kalsbeek, A, Ruiter, M, La Fleur, SE et al. (2006) The hypothalamic clock and its control of glucose homeostasis. Prog Brain Res 153, 283307.
37.Yamazaki, S, Ishida, Y & Inouye, S (1994) Circadian rhythms of adenosine triphosphate contents in the suprachiasmatic nucleus, anterior hypothalamic area and caudate putamen of the rat – negative correlation with electrical activity. Brain Res 664, 237240.
38.Ruiter, M, La Fleur, SE, van Heijningen, C et al. (2003) The daily rhythm in plasma glucagon concentrations in the rat is modulated by the biological clock and by feeding behavior. Diabetes 52, 17091715.
39.Ando, H, Yanagihara, H, Hayashi, Y et al. (2005) Rhythmic messenger ribonucleic acid expression of clock genes and adipocytokines in mouse visceral adipose tissue. Endocrinology 146, 56315636.
40.De Boer, SF & Van der Gugten, J (1987) Daily variations in plasma noradrenaline, adrenaline and corticosterone concentrations in rats. Physiol Behav 40, 323328.
41.Ahima, RS, Prabakaran, D & Flier, JS (1998) Postnatal leptin surge and regulation of circadian rhythm of leptin by feeding. Implications for energy homeostasis and neuroendocrine function. J Clin Invest 101, 10201027.
42.Bodosi, B, Gardi, J, Hajdu, I et al. (2004) Rhythms of ghrelin, leptin, and sleep in rats: effects of the normal diurnal cycle, restricted feeding, and sleep deprivation. Am J Physiol Regul Integr Comp Physiol 287, R1071R1079.
43.Oishi, K, Ohkura, N, Wakabayashi, M et al. (2006) CLOCK is involved in obesity-induced disordered fibrinolysis in ob/ob mice by regulating PAI-1 gene expression. J Thromb Haemost 4, 17741780.
44.Green, CB, Takahashi, JS & Bass, J (2008) The meter of metabolism. Cell 134, 728742.
45.Rudic, RD, McNamara, P, Curtis, AM et al. (2004) BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis. PLoS Biol 2, e377.
46.Preitner, N, Damiola, F, Lopez-Molina, L et al. (2002) The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110, 251260.
47.Chawla, A & Lazar, MA (1993) Induction of Rev-ErbA alpha, an orphan receptor encoded on the opposite strand of the alpha-thyroid hormone receptor gene, during adipocyte differentiation. J Biol Chem 268, 1626516269.
48.Sato, TK, Panda, S, Miraglia, LJ et al. (2004) A functional genomics strategy reveals Rorα as a component of the mammalian circadian clock. Neuron 43, 527537.
49.Canaple, L, Rambaud, J, Dkhissi-Benyahya, O et al. (2006) Reciprocal regulation of brain and muscle Arnt-like protein 1 and peroxisome proliferator-activated receptor alpha defines a novel positive feedback loop in the rodent liver circadian clock. Mol Endocrinol 20, 17151727.
50.Ueda, HR, Chen, W, Adachi, A et al. (2002) A transcription factor response element for gene expression during circadian night. Nature 418, 534539.
51.Inoue, I, Shinoda, Y, Ikeda, M et al. (2005) CLOCK/BMAL1 is involved in lipid metabolism via transactivation of the peroxisome proliferator-activated receptor (PPAR) response element. J Atheroscler Thromb 12, 169174.
52.Liu, C, Li, S, Liu, T et al. (2007) Transcriptional coactivator PGC-1alpha integrates the mammalian clock and energy metabolism. Nature 447, 477481.
53.Eide, EJ, Woolf, MF, Kang, H et al. (2005) Control of mammalian circadian rhythm by CKIepsilon-regulated proteasome-mediated PER2 degradation. Mol Cell Biol 25, 27952807.
54.Lamia, KA, Sachdeva, UM, DiTacchio, L et al. (2009) AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science 326, 437440.
55.Um, JH, Yang, S, Yamazaki, S et al. (2007) Activation of 5'-AMP-activated kinase with diabetes drug metformin induces casein kinase Iepsilon (CKIepsilon)-dependent degradation of clock protein mPER2. J Biol Chem 282, 2079420798.
56.Barnea, M, Madar, Z & Froy, O (2009) High-fat diet delays and fasting advances the circadian expression of adiponectin signaling components in mouse liver. Endocrinology 150, 161168.
57.Cao, R, Lee, B, Cho, HY et al. (2008) Photic regulation of the mTOR signaling pathway in the suprachiasmatic circadian clock. Mol Cell Neurosci 38, 312324.
58.Lipton, JO, Yuan, ED, Boyle, LM et al. (2015) The circadian protein BMAL1 regulates translation in response to S6K1-mediated phosphorylation. Cell 161, 11381151.
59.Asher, G, Gatfield, D, Stratmann, M et al. (2008) SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell 134, 317328.
60.Nakahata, Y, Sahar, S, Astarita, G et al. (2009) Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1. Science 324, 654657.
61.Nakahata, Y, Kaluzova, M, Grimaldi, B et al. (2008) The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 134, 329340.
62.Stephan, FK (2002) The ‘other’ circadian system: food as a Zeitgeber. J Biol Rhythms 17, 284292.
63.Cassone, VM & Stephan, FK (2002) Central and peripheral regulation of feeding and nutrition by the mammalian circadian clock: implications for nutrition during manned space flight. Nutrition 18, 814819.
64.Honma, KI, Honma, S & Hiroshige, T (1983) Critical role of food amount for prefeeding corticosterone peak in rats. Am J Physiol 245, R339R344.
65.Grasl-Kraupp, B, Bursch, W, Ruttkay-Nedecky, B et al. (1994) Food restriction eliminates preneoplastic cells through apoptosis and antagonizes carcinogenesis in rat liver. Proc Natl Acad Sci USA 91, 99959999.
66.Froy, O, Chapnik, N & Miskin, R (2006) Long-lived alphaMUPA transgenic mice exhibit pronounced circadian rhythms. Am J Physiol Endocrinol Metab 291, E1017E1024.
67.Saito, M, Murakami, E & Suda, M (1976) Circadian rhythms in disaccharidases of rat small intestine and its relation to food intake. Biochim Biophys Acta 421, 177179.
68.Comperatore, CA & Stephan, FK (1987) Entrainment of duodenal activity to periodic feeding. J Biol Rhythms 2, 227242.
69.Stephan, FK, Swann, JM & Sisk, CL (1979) Anticipation of 24-hr feeding schedules in rats with lesions of the suprachiasmatic nucleus. Behav Neural Biol 25, 346363.
70.Mistlberger, RE (1994) Circadian food-anticipatory activity: formal models and physiological mechanisms. Neurosci Biobehav Rev 18, 171195.
71.Hara, R, Wan, K, Wakamatsu, H et al. (2001) Restricted feeding entrains liver clock without participation of the suprachiasmatic nucleus. Genes Cells 6, 269278.
72.Oishi, K, Miyazaki, K & Ishida, N (2002) Functional CLOCK is not involved in the entrainment of peripheral clocks to the restricted feeding: entrainable expression of mPer2 and Bmal1 mRNAs in the heart of Clock mutant mice on Jcl:ICR background. Biochem Biophys Res Commun 298, 198202.
73.Horikawa, K, Minami, Y, Iijima, M et al. (2005) Rapid damping of food-entrained circadian rhythm of clock gene expression in clock-defective peripheral tissues under fasting conditions. Neuroscience 134, 335343.
74.Damiola, F, Le Minh, N, Preitner, N et al. (2000) Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes Dev 14, 29502961.
75.Stokkan, KA, Yamazaki, S, Tei, H et al. (2001) Entrainment of the circadian clock in the liver by feeding. Science 291, 490493.
76.Lin, JD, Liu, C & Li, S (2008) Integration of energy metabolism and the mammalian clock. Cell Cycle 7, 453457.
77.Sherman, H, Frumin, I, Gutman, R et al. (2011) Long-term restricted feeding alters circadian expression and reduces the level of inflammatory and disease markers. J Cell Mol Med 15, 27452759.
78.Ibrahim, WH, Habib, HM, Jarrar, AH et al. (2008) Effect of Ramadan fasting on markers of oxidative stress and serum biochemical markers of cellular damage in healthy subjects. Ann Nutr Metab 53, 175181.
79.Salehi, M & Neghab, M (2007) Effects of fasting and a medium calorie balanced diet during the holy month Ramadan on weight, BMI and some blood parameters of overweight males. Pak J Biol Sci 10, 968971.
80.Aksungar, FB, Topkaya, AE & Akyildiz, M (2007) Interleukin-6, C-reactive protein and biochemical parameters during prolonged intermittent fasting. Ann Nutr Metab 51, 8895.
81.Masoro, EJ, Shimokawa, I, Higami, Y et al. (1995) Temporal pattern food intake not a factor in the retardation of aging processes by dietary restriction. J Gerontol A Biol Sci Med Sci 50A, B48B53.
82.Koubova, J & Guarente, L (2003) How does calorie restriction work? Genes Dev 17, 313321.
83.Masoro, EJ (2005) Overview of caloric restriction and ageing. Mech Ageing Dev 126, 913922.
84.Weindruch, R & Sohal, RS (1997) Seminars in medicine of the Beth Israel Deaconess Medical Center. Caloric intake and aging. N Engl J Med 337, 986994.
85.Roth, GS, Lane, MA, Ingram, DK et al. (2002) Biomarkers of caloric restriction may predict longevity in humans. Science 297, 811.
86.Roth, GS, Mattison, JA, Ottinger, MA et al. (2004) Aging in rhesus monkeys: relevance to human health interventions. Science 305, 14231426.
87.Muller, FL, Lustgarten, MS, Jang, Y et al. (2007) Trends in oxidative aging theories. Free Radic Biol Med 43, 477503.
88.Challet, E, Caldelas, I, Graff, C et al. (2003) Synchronization of the molecular clockwork by light- and food-related cues in mammals. Biol Chem 384, 711719.
89.Challet, E, Solberg, LC & Turek, FW (1998) Entrainment in calorie-restricted mice: conflicting zeitgebers and free-running conditions. Am J Physiol 274, R1751R1761.
90.Mendoza, J, Graff, C, Dardente, H et al. (2005) Feeding cues alter clock gene oscillations and photic responses in the suprachiasmatic nuclei of mice exposed to a light/dark cycle. J Neurosci 25, 15141522.
91.Resuehr, D & Olcese, J (2005) Caloric restriction and melatonin substitution: effects on murine circadian parameters. Brain Res 1048, 146152.
92.Mendoza, J, Drevet, K, Pevet, P et al. (2008) Daily meal timing is not necessary for resetting the main circadian clock by calorie restriction. J Neuroendocrinol 20, 251260.
93.Froy, O, Chapnik, N & Miskin, R (2008) Relationship between calorie restriction and the biological clock: lessons from long-lived transgenic mice. Rejuvenation Res 11, 467471.
94.Froy, O & Miskin, R (2010) Effect of feeding regimens on circadian rhythms: implications for aging and longevity. Aging (Albany NY) 2, 727.
95.Mattson, MP (2008) Dietary factors, hormesis and health. Ageing Res Rev 7, 4348.
96.Anson, RM, Guo, Z, de Cabo, R et al. (2003) Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake. Proc Natl Acad Sci USA 100, 62166220.
97.Froy, O, Chapnik, N & Miskin, R (2009) Effect of intermittent fasting on circadian rhythms in mice depends on feeding time. Mech Ageing Dev 130, 154160.
98.Kohsaka, A, Laposky, AD, Ramsey, KM et al. (2007) High-fat diet disrupts behavioral and molecular circadian rhythms in mice. Cell Metab 6, 414421.
99.Havel, PJ, Townsend, R, Chaump, L et al. (1999) High-fat meals reduce 24-h circulating leptin concentrations in women. Diabetes 48, 334341.
100.Cha, MC, Chou, CJ & Boozer, CN (2000) High-fat diet feeding reduces the diurnal variation of plasma leptin concentration in rats. Metabolism 49, 503507.
101.Cano, P, Jimenez-Ortega, V, Larrad, A et al. (2008) Effect of a high-fat diet on 24-h pattern of circulating levels of prolactin, luteinizing hormone, testosterone, corticosterone, thyroid-stimulating hormone and glucose, and pineal melatonin content, in rats. Endocrine 33, 118125.
102.Barnea, M, Madar, Z & Froy, O (2010) High-fat diet followed by fasting disrupts circadian expression of adiponectin signaling pathway in muscle and adipose tissue. Obesity (Silver Spring) 18, 230238.
103.Sherman, H, Genzer, Y, Cohen, R et al. (2012) Timed high-fat diet resets circadian metabolism and prevents obesity. FASEB J 26, 34933502.
104.Mekary, RA, Giovannucci, E, Willett, WC et al. (2012) Eating patterns and type 2 diabetes risk in men: breakfast omission, eating frequency, and snacking. Am J Clin Nutr 95, 11821189.
105.Jakubowicz, D, Wainstein, J, Ahren, B et al. (2015) High-energy breakfast with low-energy dinner decreases overall daily hyperglycaemia in type 2 diabetic patients: a randomised clinical trial. Diabetologia 58, 912919.
106.Rabinovitz, HR, Boaz, M, Ganz, T et al. (2014) Big breakfast rich in protein and fat improves glycemic control in type 2 diabetics. Obesity (Silver Spring) 22, E46E54.
107.Jakubowicz, D, Barnea, M, Wainstein, J et al. (2013) High caloric intake at breakfast vs. dinner differentially influences weight loss of overweight and obese women. Obesity (Silver Spring) 21, 25042512.
108.Jakubowicz, D, Wainstein, J, Ahren, B et al. (2015) Fasting until noon triggers increased postprandial hyperglycemia and impaired insulin response after lunch and dinner in individuals with type 2 diabetes: a randomized clinical trial. Diabetes Care 38, 18201826.



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