1 Midnight snacks might shorten your life - lifespan and healthspan

2 advantages of eating less and at the right time

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4 Monika M. Gladka1*, David G. Le Couteur2, Stephen J. Simpson2
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6 Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University

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7 Medical Center, Amsterdam, The Netherlands.
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8 The University of Sydney, Charles Perkins Centre, Sydney, New South Wales, Australia; The
9 University of Sydney, Faculty of Science, School of Life and Environmental Sciences, Sydney,

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10 New South Wales, Australia.
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12 Corresponding author

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14 Keywords: caloric restriction, circadian rhythm, longevity
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16 Commentary on: “Circadian alignment of early onset caloric restriction promotes longevity in
male C57BL/6J mice” by Victoria Acosta-Rodriguez et al. Science 2022;376:1192-1202.
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19 Healthy aging is a shared goal of most, if not all humans, but the body and brain deteriorate
20 inexorably over time. Numerous studies imply that it is feasible to create dietary and lifestyle
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21 modifications that can slow down the aging process and increase both lifespan and health span.
22 For example, caloric restriction (CR) has been shown to successfully reduce age-related
23 biological function decline and increase longevity in animal models, including rats and
nonhuman primates.1, 2 Nevertheless, more than 80 years after its discovery, the underlying
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25 mechanisms by which caloric restriction prolongs lifespan are not yet fully resolved.
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27 CR is described as a decrease of 30-40% in calorie intake below unrestricted ad libitum (AL)
28 intake.3 Numerous clinical and experimental studies have shown that CR can slow down the
29 aging process and the progression of many diseases, including diabetes mellitus,
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30 neurodegenerative diseases, autoimmune disorders, and cancer and decrease the incidence of
31 cardiovascular diseases.
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33 Another important aspect to nutrition and aging is when during the day food is consumed and
34 the periods of fasting in between. There are two aspects to this – the length of time across 24
35 hours during when food is eaten, and the time at which food is eaten relative to circadian
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36 biology. Hence, adopting a feeding schedule that includes extended periods without eating
37 across the day (time-restricted feeding) has been associated with longevity benefits and overall
38 improvements in health, whereas appropriate meal timing prevents circadian
39 desynchronization and reduces metabolic dysregulation.
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41 The ability of organisms to synchronize behaviour and physiology with ambient timing signals,
42 such as dawn and dusk, has been conserved throughout evolution and has been crucial to
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 1 Darwinian fitness. The circadian system orchestrates the daily (24 h) rhythms in physiology and
2 behaviour, including food consumption, which underpin optimal health and wellbeing. A
3 network of circadian clocks determines the best times of day to eat, which typically overlap
4 with the active period (e.g., daytime in humans; night-time in rodents).
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6 Although health and longevity benefits have been attributed to CR, time-restricted feeding, and

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7 appropriate circadian alignment of feeding, until now the interactions between these factors

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8 have not been studied.
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10 Acosta-Rodrigues and colleagues from the Department of Neuroscience at the University of

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11 Texas recently reported in the journal Science studies in which they explored the interaction of
12 CR and the timing of feeding in mice.4 They investigated fasting intervals and the alignment of

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13 eating with an animal's circadian clock (Figure 1a) and discovered that while CR is sufficient to
14 prolong life, the pattern and circadian timing of eating interacts with CR to further prolong life.
15 The lifespan of the AL-fed control group had a median lifespan of 792 days. CR-fed mice lived 10
16 -35% longer than AL-fed mice, depending on the CR group. CR-speard group lived 10.5% longer

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17 than the AL-fed group, demonstrating that caloric restriction alone without time limitation or
18 fasting is sufficient to extend longevity. The CR-day-12h and CR-day-2h groups had median
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lifespans of 18.9% and 21.1% longer than the lifespan of AL mice. Thus, in addition to reducing
calories, a minimum of 12 hours of fasting increases its benefits on longevity. CR-night-fed mice
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21 outlived both CR-day groups: the CR-night-12h and CR-night-2h mice had median lifespans of
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22 33.6% and 34.8% longer than the lifespan of AL mice. Hence, the processing of calories varies
23 depending on when they are consumed and the periods of fasting between feeds. Combining a
24 low-calorie diet with a nightly eating pattern allowed the animals to live an additional nine
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25 months past their average two-year median lifetime. It seems that longevity-extending
26 strategies like CR can be made more effective by timing them to a particular time of day.
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28 The authors discovered that independent of fasting duration (2 vs 22 hours) and body weight,
29 circadian alignment of eating boosts CR-mediated benefits for survival. In the livers of mice with
30 continuous access to food, aging promoted increases in inflammation and dysregulated
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31 metabolism, whereas a CR provided at night ameliorated most of these aging-related

32 alterations. As a result, eating solely at specific times of the day seems to increase longevity in
33 animals. A comparable strategy for people would limit eating to daylight hours only.
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35 The discovery that eating at a particular time of the day can affect lifespan is one of its most
36 intriguing findings from the study, setting up the question “what are the underlying molecular
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37 mechanisms?” In the livers of AL-fed mice aging led to increases in the expression of genes
38 related to inflammation and decreases in the expression of genes related to key metabolic
39 pathways. CR at night reversed these age-related alterations. These findings demonstrate that
40 circadian manipulations of diet can increase longevity.
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42 There are multiple lines of evidence that the cardiovascular system benefits enormously from
43 CR. One important finding reported by Acosta-Rodrigues and colleagues is that the longest-lived
44 CR groups had improved hormonal profiles, insulin sensitivity and glucose homeostasis as they

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 1 aged. In fact, current therapies aim to lower insulin resistance to lower the risk of
2 cardiovascular disease.5
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4 Additionally data from humans and experimental animals have shown that CR lowers basal
5 heart rate, which is associated with better cardiac performance.6 In addition to controlling
6 heart rate, CR may also control blood pressure. It was reported that rats and monkeys on a CR

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7 diet have significantly lower systolic and diastolic blood pressure.7 CR diminishes levels of

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8 oxidative stress in the cardiovascular system by ameliorating oxidative modifications of proteins
9 and DNA in the heart.8 Leukocyte counts, tumour necrosis factor alpha (TNFα) levels, and other
10 inflammatory cytokines are reduced in CR, indicating a reduction in the inflammatory processes

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11 that lead to atherosclerosis.9 Therefore, CR ultimately lowers the incidence of cardiovascular
12 disease and stroke by decreasing atherosclerosis. In various models of aging and obese animals,

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13 CR improves endothelial function in arteries, and nitric oxide (NO) bioavailability is one of the
14 underlying mechanisms. Furthermore, in various models of aging and obese animals, CR
15 improves endothelial function in arteries, and NO bioavailability is one of the underlying
16 mechanisms.10 The ability to tolerate ischemia declines with aging. Therefore many

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17 cardioprotective measures, such as ischemic preconditioning and postconditioning, are less
18 effective in older individuals.11 Interestingly, short- and long-term CR enhances ischemic
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ad libitum11 (Figure 1b).
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tolerance in young and elderly rat hearts with food restrictions but not in hearts from rats fed
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22 CR can robustly prevent a variety of age-related alterations in the structure and function of the
23 cardiovascular system. Studies in humans have shown that CR may be able to undo some of the
24 impairments caused by aging in the cardiovascular system. CR protects against the progressive
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25 decline in cardiovascular function that comes with aging and significantly impacts preventing
26 cardiovascular disorders. The work by Acosta-Rodrigues et al. also raises the possibility that CR
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27 may have considerable positive effects on lifespan, quality of life, and health that can be
28 translated to humans. Undeniable CR continues to be the most effective intervention to delay
29 aging progression or the development of age‐related chronic diseases.
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31 The challenge remains to devise interventions based on CR that are better accepted and
32 complied with by human subjects. The study of Acosta-Rodrigues et al. suggests that solutions
33 to these problems might lie in combining elements of calorie restriction, time-restricted feeding
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34 and the circadian timing of feeding.

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3 Figure 1. (a) Experimental design showing feeding conditions for each of the six groups. On the
4 right are the results, showing the percentage of increase in lifespan from timed feeding, with
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5 the most significant increase when food is restricted to night. (b) Some benefits of CR on the
6 cardiovascular system. CR = caloric restriction.
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8 Funding:
9 M.M.G. is supported by a Dr. Dekker Senior Scientist fellowship from the Dutch Heart
10 Foundation (NHS2020T041). D.J.L.C. and S.J.S. are supported by the Australian National Health
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11 and Medical Research Council (NHMRC) “Nutrition and Complexity” Program Grant
12 (GNT1149976).
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14 Conflict of interest:
15 The authors declare no conflict of interest.
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17 1. Hwangbo DS, Lee HY, Abozaid LS, Min KJ. Mechanisms of Lifespan Regulation by Calorie
18 Restriction and Intermittent Fasting in Model Organisms. Nutrients 2020;12.
19 2. Le Couteur DG, Raubenheimer D, Solon-Biet S, de Cabo R, Simpson SJ. Does diet
20 influence aging? Evidence from animal studies. J Intern Med 2022.

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 1 3. Han X, Ren J. Caloric restriction and heart function: is there a sensible link? Acta
2 Pharmacol Sin 2010;31:1111-1117.
3 4. Acosta-Rodriguez V, Rijo-Ferreira F, Izumo M, Xu P, Wight-Carter M, Green CB,
4 Takahashi JS. Circadian alignment of early onset caloric restriction promotes longevity in
5 male C57BL/6J mice. Science 2022;376:1192-1202.
6 5. Wang T, Li M, Zeng T, Hu R, Xu Y, Xu M, Zhao Z, Chen Y, Wang S, Lin H, Yu X, Chen G, Su

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9 Bi Y, Wang W, Lu J. Association Between Insulin Resistance and Cardiovascular Disease
10 Risk Varies According to Glucose Tolerance Status: A Nationwide Prospective Cohort

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14 7. Mattison JA, Lane MA, Roth GS, Ingram DK. Calorie restriction in rhesus monkeys. Exp
15 Gerontol 2003;38:35-46.
16 8. Pamplona R, Portero-Otin M, Requena J, Gredilla R, Barja G. Oxidative, glycoxidative and

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17 lipoxidative damage to rat heart mitochondrial proteins is lower after 4 months of
18 caloric restriction than in age-matched controls. Mech Ageing Dev 2002;123:1437-1446.
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Muthukumar A, Zaman K, Lawrence R, Barnes JL, Fernandes G. Food restriction and fish
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25 2009;83:247-261.
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 1 Biographies:
2 Dr Monika Gladka received her PhD in Molecular Cardiology from the Maastricht University in
3 The Netherlands, where she learned the basics of molecular cardiology and developed an
4 interest in transcriptional and post-transcriptional gene regulation during heart failure. She is
5 currently an Assistant Professor at University Medical Center in Amsterdam, and her current

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6 research focuses on understanding the molecular mechanisms that regulate cardiac repair,

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7 intending to identify new players to develop novel, improved gene therapies. She uses several
8 state-of-the-art techniques such as single-cell sequencing, enabling an in-depth mechanistic

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9 understanding of the biological processes in injured cardiomyocytes. In 2016 and 2020, she
10 received two prestigious Dr. E. Dekker personal grants from the Dutch Heart Foundation for
11 heart repair research. She is also a board member of Young@Heart from the Netherlands Heart

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12 Institute and a nucleus member of the Scientists of Tomorrow from the European Society of
13 Cardiology.

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1 Professor David Le Couteur is a clinical pharmacologist and geriatrician at the University of Sydney. He is
2 also a director of the Centre for education and research on ageing (CERA) and director of the
3 Biogerontology Laboratory of the ANZAC Research Institute at the Concord Repatriation General
4 Hospital in Sydney. His research interest focuses on effects of nutrition on aging.
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 1 Prof. Stephen Simpson is Academic Director of the Charles Perkins Centre at the University of
2 Sydney, Australia, and Executive Director of Obesity Australia. After graduating as a biologist
3 from the University of Queensland, he undertook his PhD at the University of London, then
4 spent 22 years at Oxford before returning to Australia in 2005 as an Australian Research Council
5 Federation Fellow, then ARC Laureate Fellow. He was involved in developing an integrative

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6 modelling framework for nutrition (the Geometric Framework), which was devised and tested

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7 using insects and has since been applied to a wide range of organisms, from slime moulds to
8 humans, and problems, from aquaculture and conservation biology to the dietary causes of
9 human obesity and ageing. He has also pioneered understanding of swarming in locusts, with

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10 research spanning neurochemical events within the brains of individual locusts to continental-
11 scale mass migration. He co-authored hundreds of peer-reviewed papers and two books: The

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12 Nature of Nutrition (Simpson & Raubenheimer, 2012, Princeton University Press) and Eat Like
13 the Animals (Raubenheimer & Simpson, 2022, HarperCollins).
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