Time-Restricted Feeding Studies and Possible Human Benefit

Abstract

Metabolic syndrome consists of a constellation of clinical factors associated with an increased risk of cardiovascular disease, type 2 diabetes, and cancer. Preclinical studies demonstrate that restricting the time during a 24-hour period when an obese animal eats (time-restricted feeding) leads to metabolic benefits. These benefits, which may or may not be associated with weight loss, often lead to improvements in glucose tolerance and insulin sensitivity. Studies seeking to determine whether similar benefits result when humans restrict daily eating time (time-restricted eating) are less mature and less consistent in their findings. In this commentary, we outline some of the exciting preclinical findings, the challenges that preliminary studies in humans present, and efforts of the US National Institutes of Health and specifically the National Cancer Institute to address the role of time-restricted eating in cancer.

Although some individuals with obesity are metabolically fit, with a metabolic profile like nonobese individuals (1), obesity is an important risk factor for the development of metabolic syndrome (2). Clinical manifestations of metabolic syndrome include a waistline that measures 35 or more inches (women) or 40 or more inches (men), elevated triglycerides, decreased HDL cholesterol, blood pressure at or above 130/85 mm Hg, and elevated fasting blood sugar.

Time-restricted feeding ([TRF] in animals) or time-restricted eating ([TRE] in humans) is a type of intermittent fasting (IF) that can potentially improve metabolic health. IF involves restricting caloric intake to specific hours of the day or to specific days of the week or month. In humans, the TRE window generally lasts for 3-12 h/d and allows ad libitum intake during eating windows (3). Although TRF or TRE does not overtly attempt to reduce caloric intake, preliminary evidence from small studies suggests that TRF or TRE may lead to a concomitant reduction in total caloric intake (4,5) as well as improvements in metabolic health and weight loss. Unique features of TRF or TRE, including the fact that one does not have to restrict calories but only when calories are consumed, may facilitate adherence and long-term weight loss maintenance (6). There are at least 2 reasons why TRE has gained popularity in recent years. First, TRE restricts the time of eating each day, but not the calories consumed during the eating window. This is unique among dietary strategies, which generally restrict calories, macronutrients, or food types. As such, TRE may be appealing to people who want to improve their health but do not want to reduce their caloric consumption or restrict their dietary content. Second, studies have shown that many of the health benefits of IF in general, and TRE specifically, are not simply the result of reduced free radical production or weight loss. Instead, these health benefits are due to evolutionarily conserved, adaptive cellular responses that are integrated between and within organs in a manner that improves glucose regulation, increases stress resistance, and suppresses inflammation (7). Preclinical studies consistently show the robust disease modifying effect of TRF or other forms of IF on a wide range of chronic disorders, including obesity (8), cardiovascular disease (8), cancer (9), and neurodegenerative diseases (10).

A key component of why TRE promotes health and improves metabolic functioning is that it facilitates metabolic switching (11,12). Metabolic switching occurs when fasting and/or exercise result in the periodic depletion of glycogen stores and the associated shift from lipid synthesis and fat storage to mobilization of fat in the form of free fatty acids and fatty acid–derived ketones. Metabolic switching has potential utility for the treatment of obesity and related metabolic conditions, including metabolic syndrome and type 2 diabetes (13). Metabolic switching rarely occurs in individuals who eat over a period longer than 12 h/d (12). Metabolic switching not only provides ketones during fasting but also elicits responses that bolster physiologic performance and disease resistance (7).

Metabolic syndrome has been associated with an increased risk of cardiovascular disease, type 2 diabetes, and cancer (2). A population study involving 16 677 individuals found statistically significantly increased risks for pancreatic cancer in males and colorectal cancer in females who had metabolic syndrome vs those who did not (14). A systematic review and meta-analysis of studies evaluating metabolic syndrome spanning 43 articles with 38 940 cases of cancer found that in men, metabolic syndrome was statistically significantly associated with liver, colorectal, and bladder cancer, and in women it was statistically significantly associated with endometrial, pancreatic, postmenopausal breast, and colorectal cancers (2). Weight loss decreases the risk of developing metabolic syndrome and its components: central obesity, hypertension, prediabetes, and dyslipidemia (15).

Reasons Why TRE May Lead to Human Benefit

Do People on TRE Eat Less Than They Did Before?

Indeed, participants practicing TRE on average reduce caloric consumption by approximately 20% despite the ability to consume food and drink ad libitum during the eating window each day (16). This caloric reduction is similar to diets with intentional daily caloric restriction (CR), suggesting that TRE may be a more sustainable strategy for weight loss than standard diets (16). Short-term adherence (<6 months) to TRE in a recent report is generally good, exceeding 80% in 8 of 10 assessed studies (16). We are not aware of a report that assessed long-term (>6 months) adherence for participants enrolled on a TRE study that lasted longer than 12 months. Nineteen participants who completed a 12-week TRE study were contacted approximately 16 months after study completion to determine their elective continuation of TRE (5). Almost two-thirds (63.2%) were engaged in some form of TRE. Long-term adherence assessment is important to determine if a diet will be successful in the real world. Observational studies of religious fasting among Seventh Day Adventists (3) and the Women’s Healthy Eating and Living study, an epidemiological study that evaluated breast cancer survivors (17), suggest that some individuals are able to adhere to TRE for years. In the Women’s Healthy Eating and Living study, after a mean 7.3 years of participation involving 2413 participants, there was a 36% higher risk of breast cancer among those who fasted less than 13 hours daily compared with those who fasted 13 hours or longer (P = .02). Although the risk of breast cancer mortality and overall mortality were also higher (21% and 22%, respectively), these differences were not statistically significant (17).

TRE and Adherence

Several key features of TRE promote adherence relative to CR. Within eating windows, TRE allows continuation of one’s usual diet without restriction, which may require less cognitive effort and facilitate dietary satisfaction. Additionally, TRE alternates periods of ad libitum intake with periods of fasting, which may reduce conflict with the homeostatic drive to eat and prevent dietary lapses resulting from prolonged negative energy balance (3). However, reported TRE studies have lasted for days to weeks, and long-term adherence investigations are needed. On the other hand, TRE is not for everyone. Some individuals find the long periods between eating windows undesirable. Adhering to a TRE diet is likely not wise for type 1 diabetics, because metabolic switching, which can occur with TRE, may lead to diabetic ketoacidosis (18). Finally, many people initiate a diet with the primary goal to lose weight, with metabolic improvement as a secondary benefit. TRE does not lead to weight loss among all individuals, especially if the individual is able to consume as many or more calories than they did prior to initiating a TRE diet. For individuals whose primary purpose is weight loss, they may not adhere to TRE in the long term.

TRE and Metabolic Benefits

Many studies suggest that TRE provides beneficial metabolic effects, regardless of the degree of CR (16). For example, a randomized isocaloric study evaluating TRE showed a decrease in the average blood sugar level and reduced insulin resistance (19). Likewise, a crossover randomized trial (20) demonstrated that short-term TRE improved nocturnal glycemic control. An isocaloric trial of TRE (21) showed an improvement in glucose tolerance and a major decrease in systolic and diastolic blood pressure (11 ± 4 mm Hg, P = .03 and 10 ± 4 mm Hg, P = .03, respectively).

The metabolic improvement observed with TRF and TRE in some studies despite no loss of weight has led to speculation that triggering the fasting response daily or at specific times is in itself beneficial. This would explain why dietary dilution, a form of CR in which mice eat all day to compensate for the low density of energy in their diet, does not result in lifespan extension. Hence, chronic CR may improve health, at least in part, through an extended period of fasting (22).

Does When One Eats During the Day Matter?

Most preclinical studies suggest that when an animal eats influences the metabolic effects. Investigators have pointed to an animal’s 24-hour circadian clock, which is based on a feedback circuit composed of many transcription factors and accessory proteins (23). A recent report in Drosophila demonstrated that every other day TRF extended lifespan and delayed the onset of aging markers (24) among flies that were fasted at night, leading to autophagy, but not those that were fasted during the day, suggesting a misalignment of the eating window with the flies’ circadian clock. On the other hand, it was found that TRF prevented obesity and metabolic syndrome in mice lacking a circadian clock (25). Some studies in humans support an influence of when one eats on metabolic impact and suggest that eating at night is harmful because it makes a person prone to obesity (26). Women with metabolic syndrome who consumed 3 daily meals whose primary meal was at breakfast showed greater weight loss and waist circumference reduction and more reduction in fasting glucose, insulin, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) (27) than those whose primary meal was at dinner. There was also a larger decrease in mean triglyceride levels, glucose, ghrelin, and insulin levels and higher rates of satiety in the breakfast group. Women eating after 10 pm were found to have a higher risk of breast cancer than those who did not (28). Individuals adhering to a dietary pattern involving eating one’s last meal earlier with a longer interval between that meal and sleep had a lower risk of breast and prostate cancer (29). Men with prediabetes have also shown health benefits (eg, improved insulin sensitivity, blood pressure, and oxidative stress) from eating earlier in the day over a 6-hour window compared with a control group who consumed a similar number of calories over a 12-hour window (20).

Not all human studies support the idea that eating earlier during the day is metabolically superior to eating later in the day. For example, it appears that evening protein ingestion might be beneficial, leading to increased whole body and muscle protein synthesis (30). This is thought to be due to the fact that casein is a slow release protein and eating before sleep might prolong the anabolic milieu. Perhaps the largest evidence for late eating being metabolically beneficial compared with an unrestricted eating time is Ramadan, the ninth month in the Islamic calendar, which is observed worldwide by Muslims with daily daylight fasting, prayer, and community. During Ramadan, fasting is generally 8-20 hours, with the period of eating on average being about 10 hours (15), similar to what is otherwise practiced with TRE. A study that compared TRE with Ramadan fasting found that the 2 fasting strategies had similar characteristics and positive health effects (31).

Are There Negative Effects of TRE?

TRE does not require CR but often leads to fewer calories being eaten than a control diet that does not restrict when one can eat (5). CR has demonstrated many health benefits, but also potential downsides, at least in animal studies. Chronic moderate (30%) CR in gray mouse lemur primates increased lifespan by 50% and reduced aging-associated diseases, but accelerated the loss of gray matter in the cerebrum without obviously affecting cognitive performance (32).

Diet composition plays an important role in human health throughout the lifespan, and the optimal composition of dietary protein, especially animal protein, appears to change with age. A diet high in animal protein was found to increase overall mortality and risk of death from cancer among individuals aged 40-65 years, whereas the opposite was true for those older than 65 years.³³ This influence on cancer among younger individuals is thought to be due to the increase in circulating growth hormone receptor and insulin like growth factor-1 with animal protein consumption, because both increase the risk of cancer and other age-related diseases (33). On the other hand, the development of frailty in elderly individuals because of the loss of muscle mass negatively influences overall mortality. Frailty has been linked both to low daily protein consumption and to protein consumption at only 1 meal (34). Thus, any diet in the elderly that restricts overall daily protein or when protein can be consumed (such as TRE) could be harmful, whereas a diet higher in protein that is consumed during at least 3 daily meals should at least partially mitigate muscle mass loss (34).

There are also potentially negative social consequences associated with TRE in humans (35). Social support plays a critical role in how successful a CR dietary intervention is for an individual (36), and social support with TRE should be no different. As such, the ability to maintain a consistent eating window to adhere to TRE may depend on similar dietary approaches being shared by important others in one’s social circles. In the absence of such support, withstanding social pressures or forgoing situations that may result in eating outside of one’s preferred eating window (eg, going to dinner with friends, family, or colleagues) may result in feelings of awkwardness or social isolation and ultimately decrease TRE adherence. Conversely, being able to share the benefits of TRE with close others can strengthen relationships and resulting social support to increase TRE adherence.

Limitations of Currently Published TRE Studies

Most of what we know about the benefits from TRF and TRE comes from animal studies (37). Thus far, human studies have generally been of small size and short duration, even those published in the last 3 years (Table 1). These studies were limited both in participant number (10-60), length (days or weeks, all <6 months), and eating window duration (4-12 hours). When assessed, participants generally lost weight, resulting in a lower body mass index. Assessments of metabolic function, including blood pressure, changes in lipids, glucose level, fasting insulin, and insulin resistance were not consistently noted to improve on a TRE diet. Overall, adherence to the TRE intervention was high across these short-term studies (Table 2).

Table 1.

Sample of TRE studies published 2019-2021^a

Reference	Participants			Baseline BMI, kg/m2	TRE time, h	C	On study	Blood pressure, lipid, glucose, insulin effects
	All	Tx	C					BMI	Wt	CI	SBP	DBP	TC, nmol/L	HDL	LDL	TG	Glucose	Hb1A	FI	IR
Cienfuegos et al. (38)	58	39	19	30-50	4 vs 6	8 wk	8 wk	dec	dec	dec	NC	NC	NC	—	—	—	—	—	dec	dec
Phillips et al. (15)	54	28	26	>20	12	6 mo	6 mo	NA	NC	NA	NC	NC	—	NC	—	NC	—	dec	NA	NA
Crose et al. (39)	20	11	9	>25	8	12 wk	12 wk	—	—	—	—	—	—	—	—	—	—	—
Wilkinson et al. (5)	19	19		MS	10	12 wk	12 wk	dec	dec	NA	dec	dec	dec	NC	dec	NC	NC	NC	NC	NC
Anton et al. (13)	10	10	0	>25	8	4 wk	4 wk	dec	dec	NA	NC	NC	NA	NA	NA	NC	NA	NA	NA	NA
Jamshed et al. (19)	11	11	11	>25	6	4 d	4 d	NA	NA	NA	NA	NA	inc	inc	inc	NC	dec	NA	NA	dec in am, inc in pm
Peeke et al. (40)	60	30	30	>30	10	8 wk	8 wk	dec	dec	NA	NA	NA	NA	NA	NA	NA	dec	NA	NA	NA
Jones et al. (41)	16	8	8	Nl wt	8	2 wk	2 wk	dec	dec	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	dec

^aThis is not meant to be an exhaustive list. BMI = body mass index; C = control; CI = caloric intake; DBP = diastolic blood pressure; dec = decrease; FI = fasting insulin; HDL = high density lipoproteins; inc = increase; IR = insulin resistance; LDL = low density lipoproteins; dec: decreased; inc: increased; MS = all with metabolic syndrome; NA = not analyzed; NC = no statistically change; Nl = normal; NR = no time restrictions on eating; SBP = systolic blood pressure; TC = total cholesterol; TG = triglycerides; TRE = time-restricted eating; Tx = treatment; wt = body weight; — = data not provided.

Table 2.

Adherence in a sample of TRE studies published 2019-2021

Reference	Mean adherence rate	Drop-out rate	Adherence measurement	Adherence definition	Other notes
Cienfuegos et al. (38)	In 4 h TRE group: 6.2 ± 0.2 d/wk In 6 h TRE group: 6.2 ± 0.1 d/wk Overall rate: 88.6%	n  = 4 in Tx group; n = 5 in C group	Daily logs recorded start and stop time of eating	Days were adherent if all food was consumed within 4-h or 6-h eating window	None
Phillips et al. (15)	Mean decrease in eating duration of 3.0 h ± 1.6 from baseline	n = 2 in Tx group; n = 3 in C group	myCircadianClock smartphone app was used to log all food intake	Statistically significant decrease in eating duration during intervention	Used term “compliance”
Chow et al. (42)	56% ± 22% of d adherent ± 15 m 60% ± 23% d adherent ± 30 m 66.3% ± 20.7% of d adherent ± 60 m	n = 2 in Tx group; none in C group	myCircadianClock smartphone app was used to log all food intake	Adherence reported ±15, ±30, and ±60 min buffers of 8-h eating window duration	None
Wilkinson et al. (5)	7.12% ±7.55% of all d nonadherent 95% eating window decreased from 15.13 h ± 1.13 to 10.78 h ± 1.18	n = 22 lost to follow-up	myCircadianClock smartphone app was used to log all food intake	All intake within 15 min buffer of 10-h eating window on valid days	At ∼16 ± 4 mo postintervention, majority (N = 17/19) reported following TRE to some extent after intervention ended
Anton et al. (13)	6/7 d of week (84% adherence) Mean fasting duration: 15.8 h	n = 1 dropped out	Food diaries used to record time of first and final intake each day	Fasting 14–18 h/d during intervention	In exit interviews, most participants were willing to continue a modified TRE dietary pattern
Jamshed et al. (19)	100% compliance	n = 7 dropped out	— a	— a	4-d randomized crossover trial with high compliance
Peeke et al. (40)	a	n = 4 lost to follow-up; n = 14 dropped out	Daily journal to log time of first and last meal	14-h fast beginning 5-8 pm (with “fasting snack” 12 h after starting fast)	None
Jones et al. (41)	Adherence was high; only 1 eating event occurred outside of prescribed window	Full retention	Food diaries were used to track eating	Daily energy intake restricted to 8 am-4 pm	None

^aNot explicitly defined or measured. Tx = treatment; C = control; TRE = time-restricted eating.

National Institutes of Health (NIH)–Supported Research on TRF and TRE

Interest in understanding the metabolic effects of TRF and TRE has increased among the lay public and in the scientific community. NIH funding can be used as a barometer with which to assess the growing interest in TRE and to determine future research directions. As such, a search performed on August 17, 2021, using the search terms “time restricted feeding” and “time restricted eating” of all grants submitted to NIH from FY2010 to FY2022 on the topic of TRE identified 324 submissions. The National Institute of Diabetes and Digestive and Kidney Diseases received the largest number (128, 40%), and 60 (19%) were submitted to the National Cancer Institute (NCI). Interest in the topic has grown, with 177 (55%) proposals submitted in FY2020-2022.

The first NCI proposal on TRF or TRE was submitted in FY2014. Of the TRF or TRE proposals submitted to NCI prior to FY2021, only 1 (5R01CA196853) was awarded. This R01 focused entirely on preclinical studies. Increased interest in the possible beneficial effects of IF and TRF or TRE on cancer led the NCI to address the topic as a 2020 provocative question (PQ) (PQ2: How does intermittent fasting affect cancer incidence, treatment response, or outcome? RFA-CA-20–004 and RFA-CA-20–005: https://provocativequestions.cancer.gov/current-rfas-and-pqs). Although the PQ2 required human studies, supportive preclinical studies were allowed.

In describing the intent of PQ2, successful applications could investigate 1) the relationship between IF and cancer risk factor modification (eg, weight loss, dietary patterns), 2) the approach to IF (eg, duration or timing, combination therapy with a nonpharmacologic intervention such as exercise) leading to optimal cancer outcomes, and/or 3) factors related to an individual’s adherence to IF. It is notable that 4 of the 5 submitted PQ2 grants that received fundable scores addressed TRF or TRE rather than other forms of IF (Table 3).

Table 3.

A sample of funded NIH grants on TRE and IF^a

Grant No. (funding period)	Project title	Rationale or preliminary data	Aims	Study design
2020 PQs funded
1R21CA258139-01A1 (9/10/21–8/31/23)	The effects of TRE on AGE-RAGE signaling in women at high risk for breast cancer	Advanced AGEs accumulate in tissues as we grow older and contribute to insulin resistance, diabetes, and breast tumor growth. sRAGE is thought to sequester AGE in the circulation by acting as a decoy receptor. TRE-mediated decreases in dietary AGE-induced tumor growth led to statistically significant increase in sRAGE. The investigators hypothesize that increases in sRAGE due to TRE represent cancer risk modification by reducing AGE-RAGE toxicity in patients with prediabetes.	The aims were to 1) assess the impact of TRE on AGE-RAGE toxicity in women at increased risk of breast cancer and 2) explore the mechanistic implications of TRF-induced sRAGE in dietary-AGE mouse tumor models.	A pilot RCT to examine the effect of TRF on AGE-RAGE toxicity among postmenopausal women with prediabetes, and a mechanistic in vivo model.
1R01CA257807-01A1 (9/10/21–8/31/26)	Effects of TRE vs daily continuous calorie restriction on body weight and colorectal cancer risk markers among adults with obesity	Adults with obesity are at 30% greater risk than normal-weight adults of developing CRC. The authors point out the adherence challenges that exist with daily fasting, indicating a need for innovation.	The aims were to compare the effects of TRE, daily CR, or control (no dietary restrictions) on 1) body weight, body composition, and intervention adherence; 2) circulating metabolic, inflammation, and oxidative stress–related biomarkers; 3) colonic mucosal gene expression profiles and mucosal inflammation, DNA damage, and cellular growth; and 4) maintenance of benefits on body weight or composition and systemic or mucosal CRC risk markers.	A controlled, parallel arm trial among adults with obesity randomized to 1) TRE, 2) daily CR, or 3) control, with no dietary restrictions.
1R01CA258179-01A1 (9/22/21–8/31/26)	Effects of intermittent energy restriction on intraabdominal fat and the gut microbiome: A randomized trial	It has been suggested that IER may be advantageous over DER for sustained weight loss and cancer risk reduction. More evidence is needed regarding the relative advantages of IER over DER.	The aims were to 1) compare IER+MED vs MED/DER for reduction in MRI-measured visceral and liver fat and dexa-measured total adiposity; 2) assess each intervention’s effects on cancer-related biomarkers and fecal markers of microbial metabolite production; and 3) attempt to identify behavioral predictors of adherence to the prescribed IER, including psychosocial measures of self-efficacy and outcome expectancies, and dietary patterns based on timing and frequency of eating episodes.	A 24-week randomized trial among adults with VAT greater than the population median. IER (70% energy restriction on 2 consecutive days) + a euenergetic MED diet the other 5 d of the week will be compared with a MED diet with 20% daily energy restriction.
1R01CA258221-01A1 (9/1/21–8/31/26)	Impact of TRE in reducing cancer risk through optimizing mitochondria function	This project will provide critical mechanistic insight into how 1 form of IF can help prevent cancer onset and improve treatment outcomes. The investigators hypothesize that TRE optimizes mitochondrial function through both cell-autonomous and systemic mechanisms, thereby reducing cancer risk.	The aims were to 1) determine the impact of TRF on mitochondrial function in aged mice, 2) use metabolomics and mitochondria respiration assays to determine the impact of TRF on mitochondria function in normal and cancer cells, and 3) test the effect of TRE on mitochondrial function and cancer risk in humans using plasma collected from a recently concluded human TRE intervention study.	A comparative analysis of TRE in humans and mice. Animal models and human samples will be used to test the effect of daily fasting on mitochondrial function and cancer risk reduction.
1R01CA258222-01 (6/15/21–5/31/26)	TRE and cancer: clinical outcomes, mechanisms, and moderators	The investigators propose to focus on the effect of TRE on rectal cancer because it is possible to assess tumor size and characteristics before and after treatment.	The aims were to 1) assess how TRE affects treatment-related adverse effects (toxicity index based on CTCAE v.5), patient-reported outcomes (PRO-CTCAE), quality of life (EORTC QLQ-C30), and cCRs and pCRs; 2) test whether TRE acts through the insulin-like growth factor (IGF)-1 pathway to increase stress resistance in healthy cells (DNA damage and antioxidant defenses) and enhance tumor cell death; 3) compare longitudinal changes in mood, social functioning, sleep, diet, and daily physical activity and explore how these changes interact with intervention arms to predict clinical outcomes.	The investigators will enroll adult patients with newly diagnosed localized rectal cancer (stage II to III) of normal or elevated BMI. Participants will be randomized to 1) control: >12-h daily eating period or 2) TRE: 8-h daily eating period. Participants will be counseled to maintain their weight. All endpoints will be measured at least 3 times: at diagnosis prior to the onset of chemoradiation (baseline), after chemoradiation treatment, and at tumor resection (postintervention).
NIA Planning Grants funded
1U01AG073204-01 (9/5/21–8/31/24)	A planning project to pilot test and optimize dietary approaches to slow aging and design a long-term trial	The investigators propose to determine the feasibility and preliminary efficacy of CR and TRE interventions to modulate healthspan and biomarkers of aging in young (25-45 y) individuals without obesity (BMI 22-29.9 kg/m2).	The aims were to 1) evaluate intervention feasibility and refine the interventions, 2) establish novel methods to measure healthspan, biological age, and hallmarks of aging, 3) collect preliminary data to select endpoints and statistically power a 5-y trial, and 4) plan and design the future 5 y trial.	A 5-arm, 24-wk pilot and feasibility trial. The study arms include 1) traditional CR (25%), 2) TRE (8-h window), 3) adaptive CR (25%), 4) adaptive TRE (8-h window), and 5) control.
1U01AG073240-01 (8/15/21–7/31/24)	Health Aging and Later-Life Outcomes Planning (HALLO-P)	HALLO-P investigators have led 17 trials of CR, which showed benefits for physiological mechanisms associated with disease risk. TRE may be an alternative to CR if it is able to produce similar benefits or better long term adherence. Rigorous multi-site RCTs are needed to examine TRE in relation to CR.	The aims were to 1) establish a scientific advisory board and other structures for the design of a full-scale RCT; 2) refine the mHealth behavior change and adherence tracking platform (the HALLO-P Companion App) to optimize delivery of the interventions; 3) conduct focus groups and a 12-mo pilot RCT; 4) model aging biomarker changes for differing CR doses using repositories and the pilot; and 5) integrate new data, the scientific literature, and expert advice to prepare for the larger trial.	The 12-mo pilot study will enroll 120 older adults (≥60 y) with obesity (BMI = 30 to <35 kg/m2) or overweight (BMI = 27 to <30 kg/m2) and an indication for weight loss (eg, hypertension, hyperlipidemia, knee osteoarthritis) randomized to 1 of 3 groups: 1) 20% CR delivered in-person; 2) 20% CR delivered remotely via video conferencing; 3) TRE: (8 to 10 h) with ad libitum caloric intake.
Other grants funded
5R01CA196853 (4/1/16–3/31/22)	TRF and breast cancer	Obesity is a risk factor for breast cancer among postmenopausal women, and this may be attributed to hormonal changes that contribute to inflammation and increases in insulin levels. Investigators previously found that a high-fat diet restricted in time improves insulin resistance in the context of obesity.	This study aimed to test whether a TRF dietary intervention can protect against breast cancer growth in mice and physiological changes linked to tumor growth.	This study will test a TRF intervention with a high-fat diet on mammary cancer outcomes in mice.

^aAGE = glycation end product; BMI = body mass index; cCR = clinical complete response rate; CR = caloric restriction; CRC = colorectal cancer; DER = daily energy restriction; IER = intermittent energy restriction; IF = intermittent fasting; MED = Mediterranean; NIH = National Institutes of Health; pCR = pathological complete response rate; PQ = provocative question; RCT = randomized control trial; sRAGE = soluble RAGE; TRE = time-restricted eating; TRF = time-restricted feeding; VAT = visceral adipose tissue.

In addition to PQ2, the National Institute of Aging (NIA) issued a request for applications (RFA-AG-21–016) for investigators to propose “Planning Projects for Clinical Trials on Effects of Sustained Reductions in Caloric Intake and Related Dietary Practices in Younger and Older Persons (U01 Clinical Trial Optional).” Two of the submitted proposals were funded, both investigating TRE: 1 in younger persons, the second in older persons (Table 3).

Summary

There is excitement in the health-care community about the potential of TRE to improve metabolic dysfunction in those with metabolic syndrome and to assist with weight loss among individuals with overweight or obesity. This potential benefit, combined with the ability to maintain usual dietary preferences during the daily eating window, has led many lay individuals to practice TRE as well. There is reason to believe this approach will produce greater adherence than standard CR diets; however, future studies focusing on long-term adherence are needed.

Preclinical studies demonstrate convincing evidence of weight loss in obese animals and improvement in metabolic parameters in those with metabolic dysfunction. Studies in humans are not as consistent in their findings, though this may be due to their mostly being of small sample size and short duration. Thus, it is still not certain if TRE is beneficial in humans. If it is, many questions regarding who is most likely to benefit remain, such as the following: 1) Are the metabolic benefits more likely among individuals with overweight and obesity than among normal-weight individuals? 2) A corollary to question #1: Are the metabolic benefits entirely due to weight loss, or do they accrue in its absence? 3) Does when one fasts each day influence TRE benefit? 4) What are the mechanism(s) involved in TRE’s effects? and 5) Are there circumstances in which TRE may be harmful?

To help answer these questions, the NCI issued a PQ in 2020 on IF, which includes TRE. Five proposals have been funded, 4 R01s and 1 R21. Each addresses how TRE influences cancer, some with an entirely human focus, others combining human and animal studies to delve in the mechanism(s) by which TRE may work. The NIA has issued a request for information to evaluate if sustained reductions in caloric intake and related dietary practices influence health span and longevity, funding 2 planning projects: 1 in younger and a second in older individuals. Because there is a lack of prospective studies evaluating long-term adherence to TRE, the NIA funded study that evaluates TRE in older individuals for a year should provide important information in this regard. An important limitation of this report relates to the fact that there are relatively few human TRE studies, especially those that have been conducted for 1 year or longer. Our understanding of whether and how TRE works will continue to expand in the coming years. The promise of TRE is great, especially given its good short-term adherence profile, preliminary evidence from observational and epidemiologic studies that long-term adherence is feasible, as well as the possibility that metabolic benefit can be achieved even in the absence of weight loss.

Funding

No funding was used for this commentary.

Notes

Role of the funder: Not applicable.

Disclosures: The authors have no disclosures.

Author contributions: PB: methodology, data curation, writing-review and editing. SGO: methodology, data curation, writing-review and editing. BMH-S: conceptualization, writing-review and editing. ERS: conceptualization, methodology, data curation, writing-original draft, writing-review and editing.

Disclaimers: Opinions expressed by the authors are their own and this material should not be interpreted as representing the official viewpoint of the US Department of Health and Human Services, the National Institutes of Health, or the National Cancer Institute.

Prior presentations: March 11, 2020: “Intermittent Fasting and Time Restricted Eating: Implications for Biomarkers, Body Composition and Cancer Outcomes.” NIH Obesity and Cancer Working Group webinar, virtual only.

Data Availability

No new data were analyzed in the preparation of this manuscript.