Targeting Energy Intake and Circadian Biology to Engage Mechanisms of Aging in Older Adults With Obesity: Calorie Restriction and Time-Restricted Eating

Abstract

With the rise in obesity across age groups, it has been a hindrance to engaging in physical activity and mobility in older adults. Daily calorie restriction (CR) up to 25% has been the cornerstone of obesity management even though the safety in older adults remains incompletely understood. Although some adults can follow CR with clinically significant weight loss and improved health metrics, CR faces 2 obstacles—many fail to adopt CR and even among those who can adopt it short term, long-term compliance can be difficult. Furthermore, there is a continuing debate about the net benefits of CR-induced weight loss in older adults because of the concern that CR may worsen sarcopenia, osteopenia, and frailty. The science of circadian rhythm and its plasticity toward the timing of nutrition offer promise to alleviate some challenges of CR. The new concept of Time-Restricted Feeding/Eating (TRF for animal studies and TRE for human studies) can be an actionable approach to sustaining the circadian regulation of physiology, metabolism, and behavior. TRE can often (not always) lead to CR. Hence, the combined effect of TRE through circadian optimization and CR can potentially reduce weight and improve cardiometabolic and functional health while lessening the detrimental effects of CR. However, the science and efficacy of TRE as a sustainable lifestyle in humans are in its infancy, whereas animal studies have offered many desirable outcomes and underlying mechanisms. In this article, we will discuss the scope and opportunities to combine CR, exercise, and TRE to improve functional capacity among older adults with obesity.

The population of older adults (age ≥ 65 years) with obesity (body mass index [BMI] ≥ 30 kg/m²) is rapidly increasing. Through shared pathophysiologic mechanisms with aging (eg, inflammaging) (1), obesity exacerbates the age-related decline in physical function in older adults which leads to frailty and disability (2). Calorie restriction (CR)-induced weight loss in older adults delays functional decline and medical complications as well as improves the quality of life. However, CR-induced weight loss is accompanied by adverse effects of muscle and bone loss which can exacerbate sarcopenia and osteopenia. Moreover, long-term compliance with CR in older adults can be difficult. Therefore, there is a need to explore the potential of other approaches that may confer benefits similar to CR in older adults with obesity. Time-restricted eating (TRE) consists of restricting the window of time for eating in order to sustain circadian rhythms and improve metabolism by prolonging the daily fast, which, in turn, activates cellular pathways that are implicated in mediating the benefits of CR (3). TRE may be a sustainable lifestyle approach to accomplish CR and improve health among older adults with obesity without the detrimental effects of CR on muscle and bone mass. In this article, we will discuss the scope and opportunities to combine CR, exercise, and TRE to improve functional capacity among older adults who are obese.

The Public Health Challenge of Obesity in Older Adults

The number of older adults with obesity in the United States has markedly increased because of both an increase in the total number of older persons and in the percentage of the older population who are obese. The prevalence of obesity, which currently affects ~37% of older Americans, will likely continue to increase (4). The increasing prevalence of obesity and obesity-related complications with aging is expected to challenge our existing health care delivery and financing systems. In fact, obesity is already an escalating problem in nursing homes (NH), raising concerns about NH preparedness and access (eg, equipment, staffing, and social support necessary for safe nursing care) (5).

Obesity causes serious medical complications that lead to considerable morbidity and premature mortality. Although the relative risk associated with increasing BMI decreases with increasing age, the absolute mortality risk associated with increasing BMI increases with age. Coronary heart disease is still a major cause of death, and the prevalence and severity of cardiometabolic risk factors increase with age and BMI. Accordingly, the public health gains in reduced cardiovascular mortality in recent decades could be jeopardized by rising obesity rates.

Effect of Obesity on Age-Related Decline in Function and Frailty

Elevated BMI is associated with impairments in activities of daily living (ADLs), decreased physical performance, and increased risk for functional decline (2,6). Moreover, obesity is associated with increased NH admissions (5). Older adults are particularly susceptible to the adverse effects of excess body fat on physical function because of (a) decreased muscle mass and strength, and (b) a need to carry greater weight due to obesity. In 1 study, 96% of community-living older adults with BMI ≥ 30 kg/m² were frail as determined by low scores in a physical performance test, low peak oxygen consumption, and reduced ability to perform ADL (7). In another study, obesity was associated with an increased risk of frailty (OR = 3.5) as determined by weakness, slowness, weight loss, low physical activity, and exhaustion (8). In addition, both obesity and aging contribute to chronic inflammation, and obesity acts synergistically with sarcopenia to increase the risk of physical disability (9).

Effect of Obesity on Age-Related Loss of Muscle and Bone Mass

Aging is associated with a decline in lean body mass (LBM; primarily skeletal muscle) and function referred to as sarcopenia. Although obesity is associated with greater absolute LBM, there is disproportionately greater FM relative to LBM, resulting in relative muscle mass deficit. In a study evaluating the interrelationships among body composition and physical function, the obese older group had the poorest muscle quality (ratio of lower extremity muscle torque per kilogram of lower extremity lean mass) compared to the nonobese, nonfrail, and nonobese frail groups (7). Thus, compared to people who are lean, older adults with obesity have lower relative muscle mass and lower muscle strength per muscle area despite having a greater body weight. Although aging itself is associated with a decline in muscle quality, these findings indicate that obesity is also associated with lower muscle strength in older adults. The mechanism (s) responsible for aging- and obesity-related alterations in muscle quality include a reduction in type-II fibers, increased connective tissue content, fatty infiltration, impaired muscle energetics, and altered substrate metabolism.

Decreased bone mineral density (BMD) with age and osteoporosis increases the risk of hip fracture. That low body weight is a risk for osteoporosis and fractures is well established. It is believed that obesity is osteoprotective, possibly because of increased adipose tissue conversion of androstenedione to estrone and weight-induced mechanical stimulation of bone formation. Recent evidence, however, indicates that although the prevalence of fractures is reduced as BMI goes from underweight to normal, an increase in BMI to the obese range is associated with a higher prevalence of fractures when adjusted for BMD (10). This finding suggests a nonlinear relationship between bone and body weight and that fracture incidence increases at each end of the spectrum; thus, obesity may be a risk factor for fractures. Because of reduced physical mobility, older adults with obesity are at increased risk for fall during activities with little momentum. The absence of soft tissue in the ankle and legs together with the high impact of the fall makes these sites more vulnerable to fall injury.

Effect of Calorie Restriction on Muscle Mass and Physical Function in Older Adults

CR is a consistent pattern of reducing average daily energy intake without incurring malnutrition. A low-calorie balanced diet, which reduces energy intake by 500–750 kcal/d resulting in weight loss of ~8–10% by 6 months, is recommended for older adults who are obese and have functional or medical complications (2). However, weight loss results in a decrease in both fat mass (FM) and LBM. Thus, there has been some reluctance in prescribing CR in older adults because of the concern that it will exacerbate sarcopenia. Additionally, it is a general belief among geriatricians that some “reserve” of muscle mass is advantageous if the older adult becomes hospitalized. Indeed, a 1-year randomized controlled trial (RCT) in older adults with obesity showed that CR-induced weight loss of ~10 kg resulted in LBM loss of ~3 kg (assessed by dual-energy x-ray absorptiometry), which was not prevented but attenuated by exercise (11). A similar CR-induced reduction in thigh muscle volume was demonstrated by magnetic resonance imaging. However, despite lower muscle mass during CR, muscle strength was preserved indicating improvement in muscle quality. Importantly, CR alone (without exercise) improved physical function as assessed objectively by the Physical Performance Test and Peak Oxygen Consumption and subjectively by the Functional Status Questionnaire. The mechanisms by which CR improves physical function could include the reduction in relative sarcopenia (low muscle mass relative to body weight) (7) owing to the larger reduction in FM relative to LBM as well as the loss of excess total body mass which can interfere with range of motion, gait, etc. Moreover, CR likely improves muscle quality by reducing muscle lipid content and by reducing local and systemic inflammation, which can interfere with muscle fiber contractility (12). Indeed, various cytokines are secreted from adipose tissue, and excess fat induces a pro-inflammatory state which is associated with lower muscle strength and incident disability.

Effect of Calorie Restriction on Bone Mass and Metabolism in Older Adults

CR-induced weight loss decreases BMD at the hip associated with an increase in markers of bone formation and resorption (13). In an RCT of older adults with obesity, CR-induced weight loss of ~10% resulted in BMD loss of ~3% at the total hip and ~30% increase in serum C-terminal telopeptide and osteocalcin (11,14). The decrease in hip BMD was attenuated, although the increase in markers of bone turnover was prevented by the addition of exercise to CR. The precise mechanisms for bone loss during CR are unknown. Bone and muscle interact closely in both an anatomical and chemical fashion. Mechanical loading of muscle stimulates bone formation by inhibiting osteocyte secretion of sclerostin, which is an inhibitor of the Wnt/Lrp5 signaling pathway vital to osteoblast differentiation (15). CR-induced weight loss increased serum sclerostin, which was prevented by the addition of exercise (16). Moreover, changes in LBM and thigh muscle volume were strong predictors of the changes in hip BMD. Therefore, the unloading of the weight-bearing skeleton through muscle–bone interactions may be an important mechanism for the bone loss that occurs during CR. Another potential mechanism is through a decline in bone-active hormones secreted by adipocytes during CR. For example, leptin may act peripherally by increasing osteoprotegerin levels leading to the binding of RANKL and inhibition of osteoclastogenesis (17). Thus, the levels of leptin in individuals with obesity are osteoprotective, and the reduction of leptin during CR-induced weight loss could contribute to the increase in bone resorption. Additionally, there is a decrease in intestinal absorption of calcium during CR which may contribute to the negative alterations in calcium balance. On the other hand, obesity is a chronic state of inflammation and visceral adipose tissue (VAT) is particularly pro-inflammatory, which has been associated with lower trabecular bone volume, lower bone formation rate, and lower stiffness all suggesting decreased bone quality (13). It is not known whether the reduction of the pro-inflammatory state because of VAT loss during CR improves bone quality despite a reduction in BMD.

Effect of Calorie Restriction on Cardiometabolic Risk Factors and Cognitive Function in Older Adults

The marked increase in the prevalence of obesity in older adults is an important contributor to the increase in cardiometabolic risk factors, including the metabolic syndrome that occurs with aging. Excess fat accumulation causes adipose tissue dysfunction including adipocyte hypertrophy and hyperplasia, increased inflammation, impaired extracellular matrix remodeling, and fibrosis together with an altered secretion of adipocytokines (18). Aging exacerbates the chronic positive balance typical of obesity by redistributing lipids into VAT and other ectopic depots (eg, skeletal muscle, liver, heart) that are associated with insulin resistance, dyslipidemia, chronic inflammation, hypertension, and physical dysfunction (19). In addition, “inflammaging” is considered a prominent aging-associated alteration in intercellular communication that is involved in the pathogenesis of obesity and type 2 diabetes (1). In an RCT of older adults with obesity, CR-induced weight loss improved not only insulin sensitivity index (ISI), but also glucose and insulin areas under the curve, VAT, tumor necrosis factor, high-sensitivity C-reactive protein (hs-CRP), adiponectin, waist circumference, and systolic and diastolic blood pressure (20). These CR effects were associated with a 15% decrease in the prevalence of metabolic syndrome.

Obesity may also exacerbate the age-related decline in cognitive function. Obesity further predisposes to dementia in older adults because of convergent mechanisms such as insulin resistance and chronic inflammation (21). Insulin resistance is associated with a lower cerebral glucose metabolism rate whereas inflammation and oxidative stress are linked to increased vascular and metabolic insult that contributes to cognitive decline. In an RCT of older adults with obesity, CR-induced weight loss improved cognitive domains related to attention and executive function (22). Moreover, in the CR group, changes in ISI and hs-CRP were independent predictors of the changes in global cognition (assessed by the Modified Mini-Mental State Examination, 3MS) explaining 25% of the variance. A recent meta-analysis that included 7 RCTs concluded that intentional weight loss in obese people is associated with improvement in attention and memory, although most RCTs were conducted in middle-aged rather than older adults (23).

Exercise Interventions During Calorie Restriction in Older Adults

Given the positive effects of exercise on physical function, healthy aging in older adults with obesity would require an intervention that involves regular exercise. Accordingly, weight loss therapy that minimizes muscle and bone masses is recommended for older adults with obesity who have functional impairments or medical complications (2). Although exercise (combined aerobic and resistance training) compared to CR did not induce significant weight loss, exercise attenuated the CR-induced reduction of muscle and bone mass and additively improved the physical function in older adults with obesity (11). Moreover, 1 year of exercise added to CR further improved ISI and additively decreased the number of components and prevalence of the metabolic syndrome (40% decrease) (20). Exercise therapy also improved cognitive function, although the effect was not additive to that of CR (22). Not surprisingly, exercise plus CR additively improved the health-related quality of life. The independent and combined effects of CR and EX in older adults with obesity are summarized in Table 1.

Because the physiologic adaptations to aerobic and resistance training differ, their independent and combined effects during CR-induced weight loss in older adults have been directly examined (24). Despite negative energy balance during CR, aerobic training improved cardiovascular fitness and resistance training improved strength. The aerobic and resistance training resulted in additive effects that translated into substantial improvement in physical function and reduction of frailty. Resistance training alone and combined resistance and aerobic training attenuated the loss of LBM and muscle mass during aerobic training. Although only resistance training prevented the weight loss–induced reduction in hip BMD, combined aerobic and resistance training attenuated the loss of hip BMD associated with aerobic training alone. The underlying mechanisms for the attenuation of muscle and bone loss during CR by resistance training alone and by combined aerobic and resistance exercise training could include better preservation of muscle growth regulators, reduction of atrogen expression, improvement of muscle protein synthesis response to anabolic stimuli, and a lesser increase in bone turnover (25,26).

Feasibility of Long-term Calorie Restriction in Older Adults

A key challenge in CR is the long-term maintenance of CR-induced weight loss. Sustained CR is likely to produce the most meaningful change in health outcomes in older adults—for example, maintenance of functional independence and prevention of NH placement. Factors such as neurologic, hormonal, and behavioral adaptations can make it difficult to adhere to long-term CR in humans. Moreover, over 75% of weight recovered after CR-induced weight loss is fat rather than LBM, which could further exacerbate sarcopenia. Therefore, debate continues as to whether the benefits of long-term CR outweigh the risks in older adults. The challenge in addressing this question is the paucity of long-term follow-up studies (eg, >1 year). A reassuring finding is that increasing age seems to be a good predictor of adherence to lifestyle interventions. In 1 study, CR-induced weight loss (7%) was maintained at 30 months associated with improved physical function and metabolic profile; however, despite some weight regain, hip BMD further decreased (–4%) (27). In the Look AHEAD trial, the group randomized to intensi3ve lifestyle intervention had a 39% increase in the risk of frailty fractures after a median follow-up time of 11.3 years (28). This occurred despite improved fitness and physical activity and was attributed in part to loss of LBM during CR. Because older adults typically reduce the overall daily energy expenditure during structured exercise, an intervention to increase daily movement may better assist in the maintenance of CR-induced weight loss (29).

What Is Time-Restricted Feeding/Time-Restricted Eating?

TRF (preclinical studies) or TRE (humans) is a lifestyle intervention in which all daily calories are consumed within a consistent, window of 8–10 hours, followed by a >12-hour fasting window that overlaps with overnight sleep (3). The conceptual foundation of the health-promoting effects of TR is different from that of CR. CR is based on the premise that reduced calorie intake creates a negative energy balance, which triggers the loss of excess adiposity, and the loss of FM is considered causal to the health benefits of CR. Although TRE/TRF does not propose to reduce calories or improve nutritional quality, it intends to align daily energy consumption within a consistent window of 8–12 hours with the body’s circadian rhythm in nutrient-seeking behavior and nutrient absorption. The resulting daily eating–fasting cycle sustains circadian rhythms in cellular and organismal physiology leading to pleiotropic health benefits, sometimes without significant weight loss.

Circadian (or ~24 hours) rhythms are cell-autonomous, molecular rhythms driven by more than a dozen transcriptional regulators, coordinating rhythmic gene expression, and function in every cell. These rhythms benefit health because they temporally separate anabolic and catabolic pathways, synchronize the expression of genes involved in similar cellular processes, promote cellular repair processes in all cell types, and prepare both brain and peripheral organs in anticipation of predictable daily events such as feeding, fasting, sleep, and arousal. These cell-autonomous rhythms are organized in a hierarchical manner, with the hypothalamic suprachiasmatic nucleus (SCN) serving as the master circadian oscillator. The SCN clock produces a daily behavioral rhythm of sleep–wake and a dependent rhythm in rest–activity and fasting–feeding. With the change in seasons, the SCN clock is aligned to the changing day length through the light signal perceived through the eye. The SCN, in turn, uses multiple mechanisms to synchronize peripheral clocks in the rest of the body.

In addition to signals originating from the SCN, the peripheral clocks are also synchronized by other timing cues indirectly controlled by the SCN clock in natural conditions, including a daily rhythm in core body temperature and nutrient sensing or feeding. However, when presented with an opposite and conflicting timing cue, as in the case of daytime-restricted feeding in night-active (and night feeding) mice, the circadian clocks in peripheral tissues follow the timing cues from the feeding time and hence time of feeding is the dominant timing cue for the peripheral clocks (30). In other words, TRF is a novel behavioral approach to sustain robust circadian rhythms in peripheral organs and when it is aligned with the natural sleep–wake cycle of the animal (ie, night TRF in rodents and day TRF in humans), TRF/TRE synchronizes circadian rhythms in peripheral organs with that in the SCN (3) Such alignment of feeding–fasting with wake–sleep cycle improves circadian rhythms in all tissues (31) and consequently lead to the health-promoting benefits of circadian rhythms.

Conversely, circadian rhythms are disrupted when an individual has irregular and/or insufficient sleep and associated irregular light exposure, irregular daily eating pattern, or eating over an extended period within 24-hour days, which are common across ages in modern society. Furthermore, older adults suffer from age-related dampening of the clock oscillation and a desynchronization with the environment, including a disrupted sleep–wake cycle (32). In mice fed a high-fat diet ad libitum, the eating–fasting rhythm is dampened with a higher calorie intake during the day and a parallel reduction in calorie intake during the night. Such spreading of calorie intake over 24 hours is associated with a dampening of the circadian clock as well as desynchronization of clocks across tissues. In mice fed a high-fat diet, TRF, without changing the quality or quantity of diet, can restore robust circadian rhythm and prevents weight gain and metabolic diseases (33). This original observation triggered interest in TRF or TRE as a behavioral intervention to improve health. Given the relatively recent history of TRF/TRE compared to almost a century of research on CR, there are very few animal studies and even fewer human intervention studies with TR. Hence, we will discuss both animal and human TR studies in the following sections.

Animal TRF Studies and Their Relevance for Older Adults With Obesity

Animal TRF studies in Drosophila and mice using various diets, age and both sexes have shown many promises of TRE as an intervention for older adults with obesity. TRF attenuates or improves a number of age- and obesity- related health conditions. TRF of 8–12 hours reduces insulin resistance, adiposity, inflammation, hypertension, hypercholesterolemia, dyslipidemia, hepatic lipid accumulation, and improves cardiac performance, endurance capacity, motor coordination, and, in some cases, can increase muscle mass (3). Although most animal studies are done in relatively young mice, some experiments with older Drosophila and middle-aged mice have also shown the earlier health improvements (34,35). In young and middle-aged female mice fed a high-fat diet, TRF does not attenuate weight gain, yet it prevents hepatic fat deposit, improves glucose tolerance, reduces circulating TG and sustains muscle mass, and improves survival against LPS challenge (35). In mice fed a normal diet, TRF can increase muscle mass in male mice (36). Hence, some of the health benefits of TRF are independent of weight change. Many benefits of TRF in animal models overlap with that of CR. As CR in rodents inadvertently imposes TRF of reduced daily calories within a narrow window of 3–8 hours, careful studies dissecting the contribution of CR and TRF in rodents have revealed a significant portion of life-extension effects of CR in rodents can be due to TRF. In fact, rodents under CR intervention, if fed during the night, remain more active and live longer than rodents who receive their daily CR ration spread over 24 hours (37). Hence, rodent studies suggest a combination of CR and TRF can have synergistic health benefits (37).

Human TRE Studies

The approach to implementing TRE also necessitates the study of daily eating patterns in free-living conditions to identify individuals with a prolonged eating window who can benefit from TRE. As questionnaire-based approaches often fail to capture the timing of ingestion of every calorie-containing food and its day-to-day variation, an app-based approach to longitudinally record all ingestive behaviors over several days is a better approach to find the time window within which a person is more likely to eat. Such an approach has shown the median eating window among young to middle-aged adults is >14 hours, and less than 10% of adults eat consistently within ≤12-hour window (38). Although objective data on the eating pattern of the older population with obesity are not currently available, it is safe to assume that the vast majority of this population eats >12 hours and may benefit from 8 to 10 hours of TRE.

Sustainable human TRE studies often involve restricting daily calorie intake to a consistent window of 8–10 hours. Although short term (up to 4 months) of 4- and 6-hour TRE have shown health benefits, participants often show mild adverse events, and long-term compliance is not reported. Conversely, 12-hour TRE did not produce as many health benefits as seen in 8- to 10-hour TRE (3).

The majority of TRE clinical trials are conducted in young, healthy to obese people, and are frequently feasibility or pilot studies with a small number of participants. Nevertheless, these initial TRE studies show promising effects with body mass and fat loss, improved insulin sensitivity, and blood pressure (3). Although some TRE studies report no reduction in BMD, these studies are of short duration, and hence the effect of long-term TRE on BMD is an open question. Furthermore, older adults are vastly understudied, and the knowledge of TRE in the older population is limited (39). Nevertheless, a handful of studies specifically investigating the effects of TRE on older adults show promising results. TRE is feasible, and no adverse effects were observed.

In short-term TRE studies (<12 weeks), adherence in the older population is higher than 85% and can result in reducing hunger and improving gait speed with a modest or no decrease in body weight (40,41). Currently, 9 studies are registered on clinicaltrials.gov investigating the effects of TRE on people 50 or older. We can thus hope for further insights in the near future.

Time-Restricted Eating: Effects on the Function and Mass of the Musculoskeletal System

As mentioned earlier, muscle mass, function, and strength decline with age, contributing to sarcopenia, drastically reducing the quality of life and increasing mortality. Although aging, malnutrition, and inactivity are known risk factors for sarcopenia and obesity, more recent studies showed that circadian rhythm disruption, including shift work–like lifestyle, is also a risk factor (42,43). TRE could, therefore, be a powerful strategy to counteract obesity-associated sarcopenia in older adults.

Very few clinical studies focused specifically on older adults above the age of 60 years and the effect of TRE on FM and LBM. However, 2 (40,41) measured the body composition of older, overweight men or women before and after 6 weeks of TRE and found a significant decrease in FM whereas LBM was unchanged. Due to limited TRE studies in older adults, information on TRE’s effects on muscle function may be derived from studies with young adults or preclinical animal models.

One recent study focusing on skeletal muscle health performed long-term TRE (12 months) in healthy young men performing strength exercises and found no LBM difference before and after TRE or compared to the control group. Furthermore, even though the cross-sectional area was decreased in TRE compared to baseline or control, force output increased with resistance exercise and is similar to the gain observed in the control group, suggesting a more functional muscle (44). Analyzing blood samples for muscle health, inflammatory, and metabolic health markers, they found that almost all markers improved after 12 months of TRE, compared to pre-TRE values, suggesting that long-term TRE has no adverse effects on muscle health and strength in young males.

Sarcopenia is a multifactorial condition, resulting from age-related changes in skeletal muscle-specific as well as systemic biologic processes. Although it is difficult to investigate possible mechanisms in clinical trials, TRF improves age-related and obesity-induced abnormalities in myofibrillar organization and mitochondrial defects that contribute to skeletal muscle dysfunction in flies (45). Moreover, TRF improved autophagy and inflammation, both pathways altered in sarcopenia and obesity.

TRE as an Approach for CR and Improving Nutrition Quality

Although CR is associated with improvements in metabolic health, the potential for bone and muscle loss and difficulty in long-term adherence have been major concerns. TRE, as an alternative to CR, has some promise. CR as a sustainable lifestyle requires the participants to be able to keep track of their food intake throughout the day. In contrast, TRE requires a relatively low participant burden as the major explicit instruction is to limit energy intake within a consistent time window. However, unlike the controlled animal TRF studies, in most human TRE studies, participants inadvertently improve the food quality by reducing the intake of highly processed food and energy-dense snacks and also modestly reducing daily calorie intake leading to a modest weight loss of 2.5–4% in 3–4 months (3). The health benefits of TRE are not entirely explained by calorie reduction and the associated weight loss, because controlled TRE studies with weight-stable individuals have found improved insulin sensitivity and reduction in blood pressure (46), and TRE studies in patients with metabolic syndrome also found that the health benefits were disproportionately larger than what would have been expected from the observed weight loss (47).

Conclusion

Dietary intervention in older adults with obesity should carefully consider the quality, quantity, as well as timing of calorie intake. However, as intentional modification of all 3 aspects of diet may impart excessive participant burden, the process may start with TRE. Unlike animal CR studies, in human CR studies such as CALERIE II, the CR cohort did not significantly reduce their eating window. However, a small number of participants who had a shorter eating window and smaller day-to-day variance in breakfast timing achieved better adherence to CR (48). This raises the hope that TRE can be a primary approach to help individuals adopt the dietary intervention. As TRE of 8–10 hours often leads to modest CR, the next step can be to improve nutritional quality; that is, a modest increase in protein intake to lessen the potential for LBM loss. In addition, resistance exercise training can attenuate the potential loss of muscle and bone mass associated with CR. Furthermore, TRE improves circadian rhythm, and improved circadian rhythms correlate with reduced risk for age-related diseases including cardiometabolic diseases which are more prevalent among older adults. Hence, TRE, combined with improved nutrition quality and resistance training, holds promise in improving multiple aspects of the health of older adults.

It is also important to pay attention to the barriers to adopting TRE. Personal habits, interpersonal or community norms, and shift work or shift work–like lifestyle can be a significant barrier to adopting TRE. Identifying these barriers may help develop strategies for customizing TRE implementation for people of diverse lifestyles and occupations. For example, 5 days of TRE and 2 days of ad libitum eating outside the TRE window have also shown several health benefits. Similarly, animal studies have shown TRE can be a feasible approach to quickly adapt to changing shift schedules in some models of shift work. In summary, a judicious combination of TRE and CR offers promising opportunities to improve the health of older individuals with obesity by promoting adherence to dietary intervention and lessening the risk for significant loss of LBM and the quality of life.

Acknowledgments

The contents do not represent the views of the US Government or the US Department of Veterans Affairs. All authors contributed to the critical revision of the manuscript for intellectual content.

Funding

This work was supported by National Institutes of Health (RO1-AG031176, RO1-DK109950, CA236352, CA258221, RF1-AG068550, R01-AG065569) and US Department of Veterans Affairs (CX000906, CX002161).

This supplement is sponsored by the National Institute on Aging (NIA) at the National Institutes of Health (NIH).

Conflict of Interest

S.P. is the author of the books “The Circadian Code” and “The Circadian Diabetes Code” and is a consultant for Hooke London. Any opinions or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the views of the NIA, National Institutes of Health and Human Services, or the U.S. Department of Health and Human Services. The other authors declare no conflict.

References