Importance of circadian timing for aging and longevity

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Importance of circadian timing for aging and longevity
Metabolism
Abstract
Dietary restriction (DR) decreases body weight, improves health, and extends lifespan. DR can be achieved by controlling how much and/or when food is provided, as well as by adjusting nutritional composition. Because these factors are often combined during DR, it is unclear which are necessary for beneficial effects. Several drugs have been utilized that target nutrient-sensing gene pathways, many of which change expression throughout the day, suggesting that the timing of drug administration is critical. Here, we discuss how dietary and pharmacological interventions promote a healthy lifespan by influencing energy intake and circadian rhythms.
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Introduction
Aging is a major risk factor for chronic diseases, including obesity, diabetes, cancer, cardiovascular disease, and neurodegenerative disorders 1 . Improvements in healthcare have increased life expectancy worldwide, but as the aged population increases, frailty and morbidity have become a public health burden. Through the Healthy Life Expectancy (HALE) indicator, the World Health Organization estimates that worldwide humans spend >10% of our lives suffering from age-related diseases. Aging research currently focuses on closing the gap between lifespan (living longer) and healthspan (remaining healthier for longer). While lifespan can be easily determined with survival curves, healthspan is more complex to quantify. Several biomarkers of healthspan are used in animal models 2 , 3 and humans 4 , ranging from levels of metabolites (glucose, cholesterol, fatty acids), biological processes (inflammation, autophagy, senescence, blood pressure) to biological functions (behavior, cognition, cardiovascular performance, fitness, and frailty).
A major challenge is to understand, mechanistically, the progressive deregulation of metabolic function and to design interventions to delay the onset of age-related diseases. Research in animal models has revealed that the aging process can be targeted using genetic, nutritional, and pharmacological interventions 5 .
Dietary restriction widely improves lifespan and healthspan 1 , and some of its benefits could be mediated by the circadian system. Interactions between circadian clocks and aging-related pathways, such as the sirtuin 6 , 7 , 8 , insulin/IGF-1 9 , and mTOR 10 signaling pathways, support this hypothesis; yet, the mechanisms are not fully understood. Here, we review the literature from animal models and human trials assessing the effects of feeding paradigms and food quality on circadian rhythms, health, and lifespan. Finally, we discuss concepts of circadian medicine as an opportunity for tailoring antiaging interventions.
Circadian rhythms and aging
In mammals, the circadian system controls daily (~24 h) rhythms in behavior and physiology 11 . This evolutionarily conserved timekeeping mechanism allows organisms to synchronize internal processes with environmental timing cues, ensuring optimal organismal adaptation 12 .
The central clock, located in the hypothalamic suprachiasmatic nucleus (SCN), synchronizes peripheral clocks in tissues throughout the body via humoral and neural signals 13 . Peripheral clocks are cell-autonomous, and while synchronized by the central clock, do not require SCN inputs to generate rhythms. Rather, they are composed of transcriptional/translational negative feedback loops of transcriptional activators (CLOCK/BMAL1) and repressors (PER/CRY) driving their own oscillations 14 and regulating the rhythmic expression of genes involved in key cellular functions 15 , 16 (Fig.  1 ). Glucose, fatty acid, and cholesterol metabolic pathways are under circadian control, and the disruption of clock genes alters metabolism and worsens health status 11 . Moreover, components of nutrient-sensing pathways associated with aging exhibit tissue-specific oscillations due to a direct crosstalk with core clock genes 15 (Figs.  1 – 2 , see Caloric Restriction below).
Fig. 1: Crosstalk between molecular components of circadian clock, nutrient-sensing, and metabolic pathways.
Core clock proteins CLOCK/BMAL1 (transcriptional activators) and PER/CRY (repressors) are engaged in an autoregulatory transcriptional/translational feedback loop leading to 24 h oscillations in gene expression, activity and protein levels. The molecular clock also regulates the rhythmic expression of genes involved in several cellular functions and nutrient-sensing pathways, which in turn feedback to the core clock machinery. CLOCK (Clock), BMAL1 (Arntl), PER (Period), CRY (Cryptochrome), SIRT1 (Sirtuin 1), AMPK (5’ AMP-activated protein kinase), PGC-1α (PPARγ co-activator 1a), mTOR (Mammalian target of rapamycin), ROR (RAR- Related Orphan Receptor), Rev-Erb (Nr1d1), and PPAR (Peroxisome Proliferator Activated Receptor).
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The endocrine system is also regulated in a circadian manner 17 . In humans, insulin, ghrelin, adiponectin, and cortisol are elevated in the morning/afternoon, while melatonin, thyroid stimulating hormone, prolactin, leptin, growth hormone (GH), and fibroblast growth factor 21 (FGF-21), are elevated in the evening/night 17 . These rhythmic hormones regulate feeding and sleep, and also synchronize endogenous clocks 18 . Hormonal rhythms may be central to coordinate internal clocks during aging, as timed-administration of insulin, corticosterone, and prolactin mimicking the rhythmic pattern seen in young rats, is sufficient to reverse insulin resistance and reduce body fat in aged rats 19 . Circadian clocks can regulate metabolic and endocrine rhythms independently of feeding and sleep 20 , 21 . For example, while nutrients account for circulating glucose during feeding events, the liver clock provides the glucose required during the fasting phase, leading to nearly constant levels of glucose throughout the day 20 . Interestingly, aspects of aging are reversed in parabiosis experiments, in which the circulatory systems of aged and young mice are connected 22 . Although possible, whether humoral rhythms from young mice contribute to aging reversal is unknown.
The systemic influence of circadian rhythms on tissue homeostasis, sleep regulation, and behavior is well established; with direct links to aging 23 , 24 . High-amplitude circadian rhythms correlate with wellbeing and increased lifespan in animal models regardless of food composition 25 , 26 , 27 , while circadian rhythms decrease in amplitude with normal aging and often exhibit a shift in phase 23 , 28 . Additionally, aged animals have defects in entrainment/synchronization to light/dark cycles 8 , 29 , 30 , 31 , which impairs the ability of the organism to predict and adapt to environmental changes.
A mismatch between internal clocks and daily changes in the environment is detrimental to survival. Mice with free-running periods of ~24 h live 20% longer than mice whose periods deviate significantly from 24h 32 . Conversely, mice with internal period of ~24 h reduce their lifespan when exposed to a short day of 4 h light/4 h dark as compared to a 24 h day (12 h light/12 h dark) 33 . Furthermore, rodents deficient in clock genes have shortened lifespans, including Clock−/− mice 25 , Bmal1−/− mice 34 , and 20-h-period golden hamsters carrying a tau mutation 35 . Remarkably, interventions that restore proper circadian rhythmicity improve longevity. For instance, transplantation of fetal SCN into aged animals increases rhythmicity and extends lifespan 35 , 36 , 37 . Conversely, genetic perturbation of circadian genes in peripheral tissues in rodents is associated with metabolic disorders 20 , 38 , 39 , 40 , 41 . Disruption of the clock through lifestyle (i.e., jet lag, shift work) is associated with decreased lifespan in mice 42 as well as increased risk of cancer 43 , cardiovascular disease, and metabolic disruption in humans 44 . How aging perturbs the function of internal clocks remains an open question, but collectively these data suggest that understanding the circadian regulation of physiology and metabolism may provide novel insights for designing and implementing antiaging interventions.
Feeding paradigms in animal models
In the last two decades we have come to appreciate that, in addition to caloric content, timing of feeding and fasting periods between meals influence wellbeing 45 , 46 . Recent findings highlight the influence of dietary restriction (DR) on circadian clocks, yet the mechanisms linking circadian systems with metabolism, epigenetic signatures, and age-related diseases remain to be elucidated. Furthermore, the role of peripheral clocks in regulating metabolic homeostasis during aging is still unclear. Understanding the mechanistic links between circadian regulation during dietary interventions is an exciting avenue that may provide insights on how to achieve optimal health benefits throughout life. Here we discuss how health and lifespan are influenced by the most commonly used DR paradigms: caloric restriction (CR), time restriction (TR), and intermittent fasting (IF), as well as changes in dietary composition, in animal models (Fig.  3 ).
Fig. 3: Dietary interventions protect against chronic diseases and promote lifespan.
a Dietary restriction improves healthspan in several species by reducing the risk for obesity, diabetes, cardiovascular disease (CVD), hypertension, neurodegeneration, and inflammation. Although these benefits have been associated with a reduction in the number of calories consumed, extending fasting periods, and restricting the timing of food intake, the individual contribution of these factors remains unknown, since classical dietary restriction protocols often combines one or more of these parameters. b Dietary restriction extends lifespan in most model organisms used in aging research. Green circles labeled as “YES” represent dietary interventions that increase both maximum and median lifespan. Green circles with white centers labeled as “YES” represent the extension of median but not maximum lifespan. Red circles labeled as “NO” refer interventions that have no effect on median or maximum lifespan. Gray circles labeled as “?” indicate conditions that have not yet been tested. Although time-restricted feeding (TR) does not extend lifespan in flies 204 , caloric restriction (CR) protocols that promote longevity in monkeys, rats and mice also involve TR as well (shown as green outer circles with gray centers labeled with “?”). Dietary interventions: Caloric Restriction (CR) 27 , 77 , 205 , 206 . Intermittent Fasting (IF) 92 , 207 includes either periodic fasting (PF, also known as every-other-day feeding EOD) or 5 days fasting/low calories followed by 2 days unrestricted intake (Weekdays 5:2). Fasting Mimicking Diet (FMD) 100 with 5 days of a low-caloric diet every 3–4 months. Time-restricted feeding (TR) 204 , in which food is available ~8–12 h exclusively during the active period.
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Caloric restriction
CR extends lifespan and improves health in several organisms 1 . CR reduces oxidative stress, increases insulin sensitivity, modulates neuroendocrine responses, impacts central nervous system function 47 , reduces necroptosis 48 , and delays the onset of neoplasia 49 . Overall, CR ameliorates several hallmarks of aging, including deregulated nutrient-sensing pathways, mitochondrial dysfunction, impaired autophagy, stem cell senescence, DNA damage, and inflammation 1 .
CR promotes longevity by targeting highly conserved pathways across species 50 . These include inhibition of IGF-1 and mTOR as well as the activation of SIRT1, NAMPT, AMPK, FGF-21, and PGC-1α signaling pathways (Fig.  2a ). These molecules exhibit tissue-specific circadian oscillations (Fig.  2b and Supplementary Table  1 ), and some of them feedback to molecular components of the clock 14 , 15 , 23 (Fig.  1 ). For instance, CLOCK-BMAL1 rhythmically activate NAMPT, the rate-limiting enzyme in NAD+ biosynthesis, leading to circadian oscillations of NAD+ levels 7 . As a NAD+-dependent deacetylase, SIRT1 directly binds to CLOCK-BMAL1 and rhythmically deacetylates and promotes degradation of PER2, contributing to the maintenance of robust circadian rhythms 7 , 51 . Furthermore, AMPK, an energy sensor of AMP/ATP ratios, destabilizes the circadian transcriptional repressor CRY1 52 .
Inhibition of the insulin/IGF-1 signaling pathway increases lifespan from C. elegans 53 to mice 54 , and polymorphisms in this pathway have been found in centenarians 55 . Intriguingly, IGF-1 levels decline with both normal and premature aging, perhaps as a defensive response to energy scarcity 56 . Igf-1 expression oscillates in mouse tissues, including the liver, where most IGF-1 is produced 57 . Additionally, IGF-1 rhythms in the liver and blood are abolished in mice lacking core clock genes (Cry1/2−/− mice) 9 . Downstream targets of IGF-1 also display tissue-specific oscillations, suggesting that IGF-1 signaling throughout the body is under circadian control 57 . IGF-1 may be one of signals that synchronizes peripheral clocks to feeding time 58 ; however, circadian regulation of the IGF-1 pathway throughout the lifespan has been largely unexplored.
mTOR plays a critical role in energy metabolism, and regulates circadian period in flies 59 and mice 60 . It has been implicated in the entrainment of the circadian clock in the mouse brain 61 and the activity of the mTOR complex oscillates in several brain regions and in peripheral tissues 60 . CR restores the rhythmic activity of mTOR that is lost under ad lib feeding in arrhythmic mutant mice 62 , perhaps through self-imposed feeding/fasting cycles associated with CR protocols 63 . Moreover, mTOR inhibition upon fasting is driven by induction of the core clock protein PER2 64 . These studies indicate that both endogenous clocks and CR regulate the rhythmic activity of mTOR.
A genome-wide circadian analysis of liver 65 and epithelial stem cells 66 showed that CR rescues the age-related decline in circadian metabolic pathways in mice. These findings suggest that the aging process has minimal effect on core clock machinery, and instead promotes tissue-specific reprogramming of the transcriptome. Interestingly, BMAL1-deficient mice not only have reduced lifespan but also exhibit premature aging phenotypes such as sarcopenia, cataracts, less subcutaneous fat (aged skin), reduction in organ size, and impaired hair growth 34 , 67 . Surprisingly, CR decreases survival in Bmal1−/− mice, while failing to reduce IGF-1 and insulin levels 68 or to improve circadian rhythmicity of clock genes 69 . It is unclear whether this is a specific effect of BMAL1, or whether CR also has detrimental effects in other clock mutant mice.
Tissue-specific responses to CR add an extra layer of complexity in understanding the relative contributions of nutrient-sensing pathways to longevity. For example, activation of SIRT1 has been proposed to mediate the effects of CR on lifespan. Yet, although CR increases SIRT1 in most tissues, it decreases it in liver 70 . Moreover, while brain-specific expression of SIRT1 is sufficient to extend lifespan in mice 71 , whole-body overexpression of SIRT1 has no such beneficial effect 72 . Experimental disruption of mTOR signaling in mice also has tissue-specific effects: in adipose tissue mTOR inhibition is beneficial, but in muscle it is deleterious 73 . A recent study showed that tissue-specific nutritional memory impairs the full benefits of CR if applied late in life 74 . Switching 24-month-old female mice from ad lib to CR slightly increases lifespan as compared to ad lib controls, but does not reach the lifespan extension observed in the life-long CR cohort 74 . Genome-wide comparisons revealed that while the liver was mostly reprogrammed by CR, ~13% of the genes in the white adipose tissue involved in lipogenesis and inflammation, were unresponsive to late-onset CR 74 . Therefore, many questions remain about the beneficial effects of CR in different tissues, in which tissue-specific circadian rhythms may play a significant role (Fig.  2 and Supplementary Table  1 ).
Two independent studies demonstrated that CR improves metabolic fitness and healthspan in rhesus monkeys, but reported a discrepancy on longevity, with either no effect 75 or improvement 76 with CR. Survival results were reconciled by considering differences in feeding behavior, age of treatment, genetic background, and other variables, and concluded that CR improves longevity in non-human primates 77 . The timing of food access partly explains the discrepancy in survival: CR had no effect on survival in the study that allowed the control group to eat ad lib, but only during the daytime, as food was removed every night 77 . This study was later replicated in mice, in which animals eating a single meal ad lib with variable periods of fasting lived longer than mice with 24 h food access 49 . It remains unknown whether these mechanisms also apply to humans.
A major confounding aspect of most CR regimens is that they change both the amount of food eaten and the temporal pattern of food intake 23 . CR protocols are often constrained by human schedules, with food provided in the morning when nocturnal rodents would not normally eat. With limited food access, rodents tend to eat their allotment as soon as the food is available, thereby self-imposing daily cycles of feeding and fasting 63 . Because food intake synchronizes metabolic function and hormone production throughout the body, the timing of food intake is critical. An intriguing study found no differences in lifespan in calorically restricted female mice with access to a single meal during the daytime, a single meal at night, or 6 meals at night 78 , suggesting that long-term effects of CR could be independent of feeding time. However, an important consideration is that CR mice eat shortly after food is made available; 63 which allows the animal to remain close to its normal nocturnal behavior (driven by the light/dark cycle) by extending the active phase for 80% of the FDA-approved drugs exhibit daily rhythms 57 , 173 . Thus, dosage timing may help to optimize benefits of antiaging drugs, especially when acting on oscillating or moving targets (Figs.  2 ,  4 ).
Fig. 4: Model of how Circadian Medicine can be used as an optimized intervention to improve circadian rhythms and potentially promote lifespan.
The top panel reflects the current evidence that, (1) aging-related pathways oscillate throughout the day; (2) circadian rhythms decline with age and restoring rhythms improves healthspan; and (3) CR, the most robust lifespan-extending intervention, remarkably protects against the age-dependent dampening of circadian rhythms. Circadian medicine introduces a time-of-day concept for administration of drugs. Considering most aging-related genes are circadian, perhaps there is an optimal time for interventions such as CR mimetics (CRMs). The hypothesis behind this model is that there is an optimal time to administer antiaging drugs, which can restore the proper rhythms targets, and consequently boost survival. If there were an optimal time, we would expect robust circadian rhythms even in an aged individual resembling a young state, potentially leading to lifespan extension. On the contrary, a suboptimal time of administration would not be effective or would require a higher dose to reach similar beneficial effect. Tailoring the treatment for each drug as to how often and what time of the day is still required, as it depends on pharmacokinetic properties, tissue-specific pathways, potential sex-differences, and other factors.
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For practical reasons, most drugs tested in mice are supplemented in the diet or drinking water, which leads to voluntary night-time administration 174 . However, this may not be the best time to administer drugs whose targets have circadian rhythms of expression. Because numerous aspects of human physiology are under circadian control, there are windows of opportunity for interventions by simply administering drugs when their targets are at the right expression level to restore (Fig.  4 ). This is the basis of a concept known as Circadian Medicine, or Chronotherapy 173 (Fig.  4 ). Circadian medicine as a model for antiaging interventions is based on current evidence that: (1) circadian rhythms decline with age 8 , 27 , 28 , 29 , 30 , 31 , 65 , 66 , 175 , (2) disruption of circadian rhythms leads to metabolic disorders 20 , 38 , 39 , 40 , 43 , 44 , 90 and shortens lifespan 25 , 32 , 33 , 34 , 35 , 36 , 37 , 42 , while restoration of circadian rhythms promotes health 19 , 26 , 91 and longevity 35 , 36 , 37 , 175 , and (3) aging-related pathways oscillate throughout the day 6 , 7 , 8 , 9 , 10 , 51 , 57 . Therefore, a plausible hypothesis is that there is an optimal time to administer drugs, which can restore the proper rhythms of targets, and ultimately result in lifespan extension (Fig.  4 ), while a suboptimal time would not have any benefit. This would require further tailoring treatments for each drug as to how often and what time of day it is needed, as it depends on pharmacokinetic properties, tissue-specific pathways, and potential sex-differences. Thus, moving forward, it will be necessary to develop new tools for administering interventions at specific times while controlling for frequency and amounts given. For example, it would be useful to develop an automated computer-controlled device to control access to drugs administered in the water or food, such as a gate alternating access between treated and nontreated water. For food-supplemented drugs, a separate compartment could be designed to deliver drugs as pills independently of the food dispenser. In addition, other promising approaches, such as mini-pumps, could be adapted for drug delivery.
There are many examples of treatments for aging-related diseases that are more effective when given at specific times of day, including cancer 176 , 177 , 178 , T2D 179 , and hypertension 180 . Aspirin extends lifespan in male mice 181 and is used as a secondary prevention for cardiovascular disease (CVD) in humans 182 . The efficacy and outcome of aspirin treatment highly depends on dosing timing 183 , 184 , 185 , 186 , 187 , 188 . In humans, a randomized crossover trial showed that aspirin reduces blood clotting more effectively when taken at bedtime rather than in the morning 186 . Conversely, increased hemorrhage, risk of CVD and all-cause mortality was found in a placebo-controlled trial with healthy older adults (65+) receiving aspirin during breakfast 187 , 188 .
Polyamines are an interesting success story highlighting how a pharmacological intervention could mediate crosstalk between circadian clocks, metabolic pathways, and lifespan. Polyamines (e.g., putrescine, spermidine and spermine) are involved in cell growth, survival, and proliferation 189 . Despite an association of increased levels with cancer, both spermidine supplementation and high-polyamine diets increase lifespan in rodents 189 . Interestingly, polyamines show circadian oscillations and also influence circadian periodicity by regulating PER2/CRY1 interactions 175 . Remarkably, polyamine oscillations exhibit an age-dependent lengthening of period that can be reversed by dietary supplementation of polyamines in drinking water 175 .
Other potential drugs for delaying age-related diseases are those that target endogenous clocks. Screens to identify small molecules that modulate the clock have indeed proven useful at identifying clock-enhancing drugs 190 , 191 . One such molecule, a natural flavonoid compound called nobiletin (NOB) was found to mitigate body weight gain without altering food intake, stimulate energy expenditure and circadian activity, enhance glucose and insulin tolerance, diminish lipid content, and improve mitochondrial respiration in mice 26 , 192 . This study provided clear evidence that maintenance of a robust circadian organization within the organism protects against metabolic disruption.
Methods to infer individual internal timing
Internal circadian time varies among individuals, as it is influenced by many factors, including work schedules, feeding regimens, genetic predisposition, age, sex, environmental light levels, and seasons. Current efforts are dedicated for leveraging individual patient’s circadian clocks to personalize healthcare. Several algorithms have been developed to identify reliable markers of internal timing based on blood and brain transcriptomic datasets 193 , 194 , 195 , 196 , 197 , 198 , 199 , 200 . The first method developed to infer internal timing, called Molecular Timetable, is composed of ~100 time-indicating-genes identified from mouse liver microarray datasets 193 . Identifying circadian targets in humans has been challenging, since genome-wide datasets for most tissues rarely include time of day during which samples were collected. Some algorithms have been developed to this end: CYCLOPS that reveals human transcriptional rhythms in health and disease 198 ; BodyTime, a simple assay to determine the internal timing of an individual from a single blood sample taken at any time during the day 199 ; and more recently TimeSignature, a machine learning-based algorithm designed to accurately predict internal timing from blood samples (±2 h) using ~40 genes as predictor markers 200 . All of these provide promising tools for translational studies and individualized circadian medicine (Fig.  4 ).
In addition to individual variation in rhythms, the circadian system is highly amenable to resetting signals, including environmental changes (light/dark cycle, food availability), behavior (sleep, exercise, feeding), endogenous metabolites, and hormonal status. Moreover, pharmacological interventions to extend longevity in mice often exhibit sexual dimorphism 201 , 202 , 203 and depend at what age the treatment starts 112 , and thus are important factors to consider in addition to the timing of antiaging therapies. Incorporating these variables in assessing individual internal timing pushes the need for developing novel computational tools.
Final remarks
As the human population ages, the increased risk of chronic diseases has become a public health burden worldwide. Additionally, ~39% of the world adult population is overweight due to unrestricted access to food and sedentary lifestyle, increasing the incidence of cardiovascular disease, obesity, diabetes, and stroke. Dietary interventions, including regulation of the amount and timing of food intake and length of fasting periods, have become attractive methods for mitigating age-related physical decline and chronic diseases. Although the specific mechanisms are far from being fully understood, a periodic break in energy intake appears to improve multiple risk factors and, in some cases, reverse disease progression in mice and humans. Going forward, it will be important to elucidate to what degree the effects of caloric restriction regimes are due to calories, fasting, and feeding time. In addition, pharmacological interventions targeting pathways improved by DR have become promising alternatives to restricted diets. Understanding how metabolic pathways change throughout the day may provide insights into when and how often treatments should be applied in order to minimize drug resistance and side effects (Fig.  4 ). Additionally, systematic studies are required to determine at what age treatment can be applied to provide maximum benefits. Integrating tissue-specific circadian oscillations in these pathways could also prove critical for pinpointing the optimal time to administer interventions in order to promote healthy aging.
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Acknowledgements
We thank Dr. Kimberly Cox for helpful manuscript editing and Fernando Augusto for the art production of figures. We apologize for the omission of relevant work owing to space constraints. This work was supported by the Howard Hughes Medical Institute, NIH grant R01 AG045795 (J.S.T. and C.B.G.), NIH/NIGMS grant R35 GM127122 (C.B.G.), and NIH/NIGMS 1K99GM132557 (F.R.-F.). J.S.T. is an Investigator and F.R.F. is an Associate in the Howard Hughes Medical Institute.
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Department of Neuroscience, Peter O’Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
Victoria A. Acosta-Rodríguez, Filipa Rijo-Ferreira, Carla B. Green & Joseph S. Takahashi
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
Filipa Rijo-Ferreira & Joseph S. Takahashi
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The authors declare no competing interests.
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Acosta-Rodríguez, V.A., Rijo-Ferreira, F., Green, C.B. et al. Importance of circadian timing for aging and longevity. Nat Commun 12, 2862 (2021). https://doi.org/10.1038/s41467-021-22922-6