Aging is generally associated with weakening of the circadian system. The circadian amplitude is reduced and the circadian acrophase becomes more labile, tending to occur earlier with advancing age. As originally noted by Franz Halberg, similar features are observed in the experimental laboratory after bilateral lesioning of the suprachiasmatic nuclei, suggesting the involvement of clock genes in the aging process as they are in various disease conditions. Recent work has been shedding light on underlying pathways involved in the aging process, with the promise of interventions to extend healthy life spans. Caloric restriction, which is consistently and reproducibly associated with prolonging life in different animal models, is associated with an increased circadian amplitude. These results indicate the critical importance of chronobiology in dealing with problems of aging, from the circadian clock machinery orchestrating metabolism to the development of geroprotectors. The quantitative estimation of circadian rhythm characteristics interpreted in the light of time-specified reference values helps (1) to distinguish effects of natural healthy aging from those associated with disease and predisease; (2) to detect alterations in rhythm characteristics as markers of increased risk before there is overt disease; and (3) to individually optimize by timing prophylactic and/or therapeutic interventions aimed at restoring a disturbed circadian system and/or enhancing a healthy life span. Mapping changes in amplitude and/or acrophase that may overshadow any change in average value also avoids drawing spurious conclusions resulting from data collected at a fixed clock hour. Timely risk detection combined with treatment optimization by timing (chronotherapy) is the goal of several ongoing comprehensive community-based studies focusing on the well-being of the elderly, so that longevity is not achieved at the cost of a reduced quality of life.

1.
Hufeland CW: Makrobiotik, the Art of Prolonging Life, 2nd English translation. London, printed for J Bell, 1797, p 201.
2.
Halberg F, Nelson W: Chronobiologic optimization of aging; in Samis H, Capobianco S (eds): Advances in Experimental Medicine and Biology. New York, Plenum Press, 1978, vol 108, pp 5-56.
3.
Weindruch R: The retardation of aging by caloric restriction: studies in rodents and primates. Toxicol Pathol 1996;24:742-745.
4.
McCay CM, Crowell MF, Maynard LA: The effect of retarded growth upon the length of life span and upon the ultimate body size. J Nutr 1935;10:63-79.
5.
Cornelissen G: When you eat matters: 60 years of Franz Halberg's nutrition chronomics. Open Nutraceuticals J 2012;5(suppl 1-M1):16-44.
6.
Halberg F, Visscher MB, Bittner JJ: Eosinophil rhythm in mice: range of occurrence; effects of illumination, feeding, and adrenalectomy. Am J Physiol 1953;174:109-122.
7.
Halberg F, Visscher MB: A difference between the effects of dietary calorie restriction on the estrous cycle and on the 24-hour adrenal cortical cycle in rodents. Endocrinology 1952;51:329-335.
8.
Tevy MF, Giebultowicz J, Pincus Z, Mazzoccoli G, Vinciguerra M: Aging signaling pathways and circadian clock-dependent metabolic derangements. Trends Endocrinol Metab 2013;24:229-237.
9.
Mattson MP, Allison DB, Fontana L, Harvie M, Longo VD, Malaisse WJ, Mosley M, Notterpek L, Ravussin E, Scheer FA, Seyfried TN, Varady KA, Panda S: Meal frequency and timing in health and disease. Proc Natl Acad Sci USA 2014;111:16647-16653.
10.
Halberg F, Bittner JJ, Gully RJ, Albrecht PG, Brackney EL: 24-Hour periodicity and audiogenic convulsions in I mice of various ages. Proc Soc Exp Biol Med 1955;88:169-173.
11.
Halberg J, Halberg E, Regal P, Halberg F: Changes with age characterize circadian rhythms in telemetered core temperature of stroke-prone rats. J Gerontol 1981;36: 28-30.
12.
Radha E, Shankaraiah K, Halberg F, Bhaskaran D: Developmental, circadian and aging aspects of dopamine, norepinephrine and 5-HT in rat brain regions; in Redfern PH, Campbell I, Xavier JA, Martin KF (eds): Circadian Rhythms in the Central Nervous System. Proc IX Conf IUPHAR, Sat Symp, Bath, England, August 4-5, 1984. London, Macmillan, 1985, pp 199-209.
13.
Descovich GC, Montalbetti N, Kühl JFW, Rimondi S, Halberg F, Ceredi C: Age and catecholamine rhythms. Chronobiologia 1974;1:163-171.
14.
Nelson W, Bingham C, Haus E, Lakatua DJ, Kawasaki T, Halberg F: Rhythm-adjusted age effects in a concomitant study of twelve hormones in blood plasma of women. J Gerontol 1980;35:512-519.
15.
Cugini P, Scavo D, Halberg F, Schramm A, Pusch H-J, Franke H: Methodologically critical interactions of circadian rhythms, sex and aging characterize serum aldosterone of the female adrenopause. J Gerontol 1982;37:403-411.
16.
Otsuka K, Cornelissen G, Halberg F: Chronomics and Continuous Ambulatory Blood Pressure Monitoring - Vascular Chronomics: From 7-Day/24-Hour to Lifelong Monitoring. Tokyo, Springer Japan, 2016.
17.
Cornelissen G, Otsuka K, Halberg F: Blood pressure and heart rate chronome mapping: a complement to the human genome initiative; in Otsuka K, Cornelissen G, Halberg F (eds): Chronocardiology and Chronomedicine: Humans in Time and Cosmos. Tokyo, Life Science Publishing, 1993, pp 16-48.
18.
Gubin D, Cornelissen G, Halberg F, Gubin G, Uezono K, Kawasaki T: The human blood pressure chronome: a biological gauge of aging. In Vivo 1997;11:485-494.
19.
Halberg F, Powell D, Otsuka K, Watanabe Y, Beaty LA, Rosch P, Czaplicki J, Hillman D, Schwartzkopff O, Cornelissen G: Diagnosing vascular variability anomalies, not only MESOR-hypertension. Am J Physiol Heart Circ Physiol 2013;305:H279-H294.
20.
Halberg F, Cornelissen G, Bakken EE, Sothern RB, Schwartzkopff O, Hamburger C: Transyears: new endpoints for gerontology and geriatrics or confusing sources of variability? J Gerontol A Biol Sci Med Sci 2004;59:1344-1347.
21.
Halberg F, Nelson W, Lakatua D, Cadotte L, Haus E: Circadian amplitude increase associated with caloric restriction of mice by single daily meal reduced by ‘pattern-feeding'; in Haus E, Halberg F (eds): Chronobiology 1982-1983. Basel, Karger, 1984, pp 490-492.
22.
Nelson W, Halberg F: Meal-timing, circadian rhythms and lifespan of mice. J Nutr 1986;116:2244-2253.
23.
Bo S, Fadda M, Castiglione A, Ciccone G, De Francesco A, Fedele D, Guggino A, Parasiliti Caprino M, Ferrara S, Vezio Boggio M, Mengozzi G, Ghigo E, Maccario M, Broglio F: Is the timing of caloric intake associated with variation in diet-induced thermogenesis and in the metabolic pattern? A randomized cross-over study. Int J Obes (Lond) 2015;39:1689-1695.
24.
Jennings JH, Ung RL, Resendez SL, Stamatakis AM, Taylor JG, Huang J, Veleta K, Kantak PA, Aita M, Schilling-Scrivo K, Ramakrishnan C, Deisseroth K, Otte S, Stuber GD: Visualizing hypothalamic network dynamics for appetitive and consummatory behaviors. Cell 2015;160:516-527.
25.
Nieh EH, Matthews GA, Allsop GA, Presbrey KN, Leppla CA, Wichmann R, Neve R, Wildes CP, Tye KM: Decoding neural circuits that control compulsive sucrose seeking. Cell 2015;160:528-541.
26.
Moskalev A, Chernyagina E, Tsvetkov V, Fedintsev A, Shaposhnikov M, Krut'ko V, Zhavoronkov A, Kennedy BK: Developing criteria for evaluation of geroprotectors as a key stage toward translation to the clinic. Aging Cell 2016;15:407-415.
27.
Longo VD, Antebi A, Bartke A, Barzilai N, Brown-Borg HM, Caruso C, Curiel TJ, de Cabo R, Franceschi C, Gems D, Ingram DK, Johnson TE, Kennedy BK, Kenyon C, Klein S, Kopchick JJ, Lepperdinger G, Madeo F, Mirisola MG, Mitchell JR, Passarino G, Rudolph KL, Sedivy JM, Shadel GS, Sinclair DA, Spindler SR, Suh Y, Vijg J, Vinciguerra M, Fontana L: Interventions to slow aging in humans: are we ready? Aging Cell 2015;14:497-510.
28.
Powell EW, Halberg F, Pasley JN, Lubanovic W, Ernsberger P, Scheving LE: Suprachiasmatic nucleus and circadian core temperature rhythm in the rat. J Therm Biol 1980;5:189-196.
29.
Scheving LE, Tsai TS, Powell EW, Pasley JN, Halberg F, Dunn J: Bilateral lesions of suprachiasmatic nuclei affect circadian rhythms in [3H]-thymidine incorporation into deoxyribonucleic acid in mouse intestinal tract, mitotic index of corneal epithelium, and serum corticosterone. Anat Rec (Hoboken) 1983;205:239-249.
30.
Tomita J, Nakajima M, Kondo T, Iwasaki H: No transcription-translation feedback in circadian rhythm of KaiC phosphorylation. Science 2005;307:251-254.
31.
Yang Y, Jiang Z, Cheng S, Wang Y, Liu Y, Xiao J, Guo H, Li S, Hou W, Wang Z: Nicotinamide adenine dinucleotide: a possible circadian zeitgeber functioning in nontranscription oscillation. Biol Rhythm Res 2013;45:429-440.
32.
Mazzoccoli G, Pazienza V, Vinciguerra M: Clock genes and clock-controlled genes in the regulation of metabolic rhythms. Chronobiol Int 2012;29:227-251.
33.
Shinoda H, Ohtsuka-Isoya M, Cornelissen G, Halberg F: Putative circaseptans or other infradians in murine dentin accretion and the suprachiasmatic nuclei. Neuroendocrinol Lett 2003;24(suppl 1):208-211.
34.
Fujitsuka N, Asakawa A, Morinaga A, Amitani MS, Amitani H, Katsuura G, Sawada Y, Sudo Y, Uezono Y, Mochiki E, Sakata I, Sakai T, Hanazaki K, Yada T, Yakabi K, Sakuma E, Ueki T, Niijima A, Nakagawa K, Okubo N, Takeda H, Asaka M, Inui A: Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1. Mol Psychiatry 2016, Epub ahead of print.
35.
Belden WJ, Dunlap JC: Aging well with a little wine and a good clock. Cell 2013;153:1421-1422.
36.
Zhang C, Li S, Yang L, Huang P, Li W, Wang S, Zhao G, Zhang M, Pang X, Yan Z, Liu Y, Zhao L: Structural modulation of gut microbiota in life-long calorie-restricted mice. Nat Commun 2013;4:2163.
37.
Zuurbier LA, Luik AI, Hofman A, Franco OH, Van Someren EJ, Tiemeier H: Fragmentation and stability of circadian activity rhythms predict mortality: the Rotterdam Study. Am J Epidemiol 2015;181:54-63.
38.
Khapre RV, Kondratova AA, Patel S, Dubrovsky Y, Wrobel M, Antoch MP, Kondratov RV: BMAL1-dependent regulation of the mTOR signaling pathway delays aging. Aging (Albany NY) 2014;6:48-57.
39.
Yang G, Chen L, Grant GR, Paschos G, Song WL, Musiek ES, Lee V, McLoughlin SC, Grosser T, Cotsarelis G, FitzGerald GA: Timing of expression of the core clock gene Bmal1 influences its effects on aging and survival. Sci Transl Med 2016;8:324ra16.
40.
Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, Saltness RA, Jeganathan KB, Casaclang Verzosa G, Pezeshki A, Khazaie K, Miller JD, van Deursen JM: Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature 2016;530:184-189.
41.
Pagani L, Schmitt K, Meier F, Izakovic J, Roemer K, Viola A, Cajochen C, Wirz-Justice A, Brown SA, Eckert A: Serum factors in older individuals change cellular clock properties. Proc Natl Acad Sci USA 2011;108:7218-7223.
42.
Chen CY, Logan RW, Ma T, Lewis DA, Tseng GC, Sibille E, McClung CA: Effects of aging on circadian patterns of gene expression in the human prefrontal cortex. Proc Natl Acad Sci USA 2016;113:206-211.
43.
Cornelissen G, Halberg F: Treatment with open eyes: markers-guided chronotheranostics; in Youan BC (ed): Chronopharmaceutics: Science and Technology for Biological Rhythm-Guided Therapy and Prevention of Diseases. Hoboken, Wiley, 2009, pp 257-323.
44.
Halberg F, Sothern RB, Cornelissen G, Czaplicki J: Chronomics, human time estimation, and aging. Clin Interv Aging 2008;3:749-760.
45.
Halberg E, Halberg J, Halberg F, Sothern RB, Levine H, Halberg F: Familial and individualized longitudinal autorhythmometry for 5 to 12 years and human age effects. J Gerontol 1981;36:31-33.
46.
Halberg F, Gupta BD, Haus E, Halberg E, Deka AC, Nelson W, Sothern RB, Cornelissen G, Lee JK, Lakatua DJ, Scheving LE, Burns ER: Steps toward a cancer chronopolytherapy; in Acar J, Bastin R (eds): XIV Congrès International de Thérapeutique, 7-10 septembre 1977, Montpellier, France, sous la présidence de J Mirouze. Paris, Expansion Scientifique Française, 1977, pp 151-196.
47.
Altman BJ, Hsieh AL, Sengupta A, Krishnanaiah SY, Stine ZE, Walton ZE, Gouw AM, Venkataraman A, Li B, Goraksha-Hicks P, Diskin SJ, Bellovin DI, Simon MC, Rathmell JC, Lazar MA, Maris JM, Felsher DW, Hogenesch JB, Weljie AM, Dang CV: MYC disrupts the circadian clock and metabolism in cancer cells. Cell Metab 2015;22:1009-1019.
48.
Watanabe Y, Halberg F, Otsuka K, Cornelissen G: Toward a personalized chronotherapy of high blood pressure and a circadian overswing. Clin Exp Hypertens 2013;35:257-266.
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