Time-restricted eating and cancer: lessons learned and considerations for a path forward

Abstract

Time-restricted eating is a type of intermittent fasting. Food can be consumed as desired during the eating period but not during the remainder of the day. Studies suggest that many of the health benefits of fasting may not simply be the result of weight loss but also due to the body’s responses to the fasting that leads to improved metabolic functioning. Whereas animal studies are convincing regarding the benefits of time-restricted feeding, human time-restricted eating studies are less consistent and generally short term (<1 year). In 2020, the National Cancer Institute funded 5 intermittent fasting studies, 4 of which focused on time-restricted eating, which addressed the question: How does intermittent fasting affect cancer incidence, treatment response, or outcome? The National Cancer Institute sponsored a webinar in 2023 featuring investigators of the funded studies in which they discussed challenges as well as their thoughts regarding the most important time-restricted eating topics that should be addressed going forward; 6 areas were identified, which are discussed below as well as in a recently published NOT-CA-24-073: Factors Impacting How Time-Restricted Eating (TRE) Influences Cancer-Related Outcomes. Moving the science forward will allow the scientific community to better understand time-restricted eating’s potential. This potential includes the development of targeted time-restricted eating interventions to optimize long-term adherence to the intervention, which is required to better understand its potential benefits in cancer risk and increased response to cancer treatment, as well as improved quality and quantity of life among cancer survivors.

Introduction

Time-restricted eating, a type of intermittent fasting, is a dietary strategy that has recently become increasingly popular. There is preclinical evidence that time-restricted eating may help prevent or treat metabolic syndrome, a group of clinical factors that increase several chronic diseases, including cardiovascular disease, type 2 diabetes, and cancer.^1-4 Studies report metabolic syndrome is associated with increased risk for liver, colorectal, and bladder cancers in males and endometrial, pancreatic, postmenopausal breast, and colorectal cancers in females.^5-7 Although such improvements may be attributed to weight loss, these benefits persisted in studies that controlled for body weight. Preclinical studies consistently show the robust disease-modifying effect of time-restricted eating on a wide range of chronic disorders, including obesity,⁸ cardiovascular disease,⁸ cancer,^4,9 and neurodegenerative brain diseases.¹⁰

In humans, restricting the eating window to a set time period each day, referred to as time-restricted eating, is a dietary strategy whose perceived mechanism of health benefit is in metabolic improvement, whether or not weight is lost in the process. Time-restricted eating involves an ad libitum eating window of 3-12 hours per day.¹¹ A unique feature of time-restricted eating is that it allows the continuation of one’s usual diet without restriction; though it does not overtly attempt to reduce caloric intake, those who transition to time-restricted eating may inadvertently reduce caloric intake with a smaller eating window.^12,13 Additionally, by alternating periods of ad libitum intake with periods of fasting, as opposed to a daily caloric restriction diet, time-restricted eating may reduce conflict with the homeostatic drive to eat and prevent dietary lapses resulting from prolonged negative energy balance.³

Studies suggest that many of the health benefits of fasting may not simply be the result of weight loss but also due to the body’s responses to the fasting that lead to improved glucose regulation, increased stress resistance, and inflammation downregulation.¹⁴ Indeed, some studies suggest that time-restricted eating provides beneficial metabolic effects, regardless of the degree of caloric restriction.¹⁵ In addition to improved HbA1c, prolonged nightly fasting was associated with a statistically significant lower risk of disease recurrence in a cohort of breast cancer survivors.¹⁶ Additional studies are needed to further examine the potential beneficial effects of time-restricted eating.

It is important to better understand the potential benefits of time-restricted eating, given that it may be an easier dietary strategy to adhere to compared with other, more involved approaches or dietary changes. Not only can time-restricted eating allow for the continuation of dietary pattern preferences and thereby facilitate dietary satisfaction, it may also require less cognitive effort and have greater compliance over the long term because of its flexibility.¹⁷ However, human time-restricted eating studies thus far are less mature and consistent in their findings than animal studies, and the long-term impact of time-restricted eating on health is not well known. A recent systematic review highlighted that short-term (<6 month) adherence to time-restricted eating exceeded 80% in 8 of 10 small clinical studies that measured adherence.¹⁵ For practical, real-world considerations, there is an important gap in addressing adherence to time-restricted eating for more than 12 months as part of the initial study design, though a few studies suggest long-term adherence to time-restricted eating is feasible. In one small study where 19 participants were contacted approximately 16 months after they completed a time-restricted eating intervention, 63% reported an elective continuation of time-restricted eating.¹³ Findings from observational studies of fasting among Seventh Day Adventists¹¹ and a secondary analysis within the Women’s Healthy Eating and Living study, a randomized controlled trial among breast cancer survivors,¹⁶ also suggest that some individuals may benefit from long-term time-restricted eating adherence.

Furthermore, like many dietary changes, it is important to consider that time-restricted eating may not be the best dietary strategy for everyone. It is important to consider different needs among subpopulations by age (eg, considering the potential impact on protein consumption and unintended negative consequences in those at risk of frailty¹⁸) and healthy vs clinical populations (eg, considering if time-restricted eating may contribute to optimal care during or after treatment among cancer survivors). As such, a personalized approach that tailors individuals’ diets to their health status and needs should be advocated.

In 2020, the National Cancer Institute (NCI) challenged scientists to determine if intermittent fasting, including time-restricted eating, improved metabolic health with Provocative Question (PQ) 2: How does intermittent fasting affect cancer incidence, treatment response, or outcome? As stated then, the intent of the PQ was to “better understand the effects of intermittent fasting in humans on cancer risk factors, cancer incidence, treatment response, or cancer-related outcomes (such as disease recurrence or survival)”. Indeed, the more explicit focus of this PQ further refined the call for research related to timing of meals and circadian rhythms initially highlighted in the 2018 PQ11: Through what mechanisms do diet and nutritional intervention affect the response to cancer treatment? NCI held a webinar May 19, 2023, with the PQ2 principal investigators to discuss their progress and challenges and explore their thoughts regarding the most important time-restricted eating topics that should be addressed going forward. Based on the input received during the webinar, as well as unmet challenges in the area, 6 areas were identified that highlight the needs for further investigation to help elucidate the potential benefits (or lack thereof) of time-restricted eating.

Areas to address

Is long-term adherence (>1 year) to time-restricted eating more sustainable than long-term adherence to a caloric restriction diet or other dietary strategy?

There are potentially negative social consequences associated with time-restricted eating in humans.¹⁹

Barriers of time-restricted eating include feelings of hunger and sluggishness, skipping eating routines or inadequate diet quality during the eating window, conflict between time-restricted eating and an individual’s 24-hour activity behaviors, difficulties with self-monitoring, social situations that discourage time-restricted eating, and irregular schedules.²⁰ Facilitators of adherence vary between individuals and therefore need to be tailored to the individual.²⁰ Evidence suggests that social support plays a critical role in how successful a caloric restriction dietary intervention is for an individual,²¹ and as such, the ability to consistently maintain a time-restricted eating window may also depend on similar dietary approaches being shared by important others in one’s social circles, such as family and friends.

There is speculation, as previously highlighted, that long-term adherence to time-restricted eating is more sustainable than a caloric restriction–based diet, because an individual only alters when but not what calories are consumed. The sustainability of time-restricted eating and the factors that impact adherence are important to study. We await long-term time-restricted eating studies to gain a better understanding of this important consideration.

Is metabolic dysfunction improved with time-restricted eating in the absence of weight loss?

Many of the health benefits of time-restricted eating may not simply be the result of weight loss but, as discussed above, may also be due to the biological and physiological changes occurring during fasting that improve glucose regulation, increase stress resistance, and suppress inflammation.¹⁴ Given most evidence comes from animal studies, there is a need to better understand the metabolic impact of time-restricted eating in humans.

To better address this question, isocaloric time-restricted eating studies would be most helpful. Because some individuals lose weight when they practice time-restricted eating, measuring caloric intake in the time-restricted eating and control groups, ideally with an objective measure such as doubly labeled water²² rather than or in addition to 24-hour recalls or food records, should be considered.

Does the timing or length of the eating window matter regarding benefit? Is there objective metabolic evidence that allowing an individual to choose their own time of day and length of eating window is better than prescribing a specific time and length each day that one eats?

(1) Does the timing of when one eats matter?

Most preclinical studies in rodents suggest that when during the day an animal eats influences the metabolic effects. Investigators have pointed to an animal’s 24-hour endogenous daily rhythms, more often known as their circadian clock, which is based on a feedback circuit composed of many transcription factors and accessory proteins.²³ Though the circadian clock influences many physiologic processes, including when the animal eats and when it sleeps, a previous study found that time-restricted eating prevented obesity and metabolic syndrome in mice lacking a circadian clock.²⁴ Research is needed to better understand if there are differential effects of timing (eating early vs late in the day) in humans. Some human studies support an influence of when one eats on metabolic impact and suggest that eating at night is harmful as it makes a person prone to obesity.²⁵ In one study, participants adhering to a dietary pattern involving eating one’s last meal earlier in the day with a longer interval between that meal and sleep had a lower risk of breast and prostate cancer.²⁶ Conversely, evening protein ingestion might also be beneficial, leading to increased whole body and muscle protein synthesis.²⁷ Most of the current evidence on the metabolic benefits of later eating windows comes from studies conducted during Ramadan, where fasting occurs during daylight hours, and the period of eating—similar to time-restricted eating—is on average 10 hours.²⁸ It has been estimated that 1.6-2 billion Muslims observe Ramadan each year.²⁹ A scoping review of 25 publications (15 original papers and 10 reviews) found that Ramadan fasting is a form of time-restricted eating. The authors concluded that Ramadan fasting and other time-restricted eating approaches have demonstrated positive health effects.³⁰ However, whether a meal timing early vs late in the day is better in humans remains an open question.

(2) Does the length of time that one eats each day matter?

The length of time one eats may also impact the efficacy of time-restricted eating. Previous short-term (8-12 weeks) studies in humans have shown that time-restricted eating windows ranging from 4 to 10 hours led to improved metabolic outcomes and lipid profiles.^13,31,32 In one study, men with prediabetes randomly assigned to a 6-hour time-restricted eating regimen had greater improvements in insulin sensitivity, blood pressure, oxidative stress, and appetite compared with the control group (12-hour time-restricted eating), independent of weight loss.³² Insulin resistance and oxidative stress are associated with an increased risk of cancer.⁵

It is also unclear if there is metabolic evidence of a difference between allowing one to choose the timing and length of the eating window vs following a prescribed eating window. Research is needed to better understand differences in effect between self-chosen vs prescribed eating windows if time-restricted eating is to be followed long term in real-world settings to promote health.

Do certain subpopulations benefit from time-restricted eating more or less than others (eg, differences by sex, race and ethnicity, age, healthy vs clinical populations)?

Studies are needed to examine if there are differences by sex, race and ethnicity, age, and healthy vs unhealthy clinical populations (including if time-restricted eating may contribute to positive outcomes and optimal care for cancer survivorship populations during and/or after treatment).

Are there concerns about time-restricted eating in certain populations?

Further research is needed to better understand which subpopulations may most benefit from following time-restricted eating. Of particular interest is how time-restricted eating may improve cancer treatment response and outcomes (especially for cancer types, such as head and neck,³³ gastric,³⁴ and esophageal cancer,³⁵ whose treatment has been associated with weight loss and muscle wasting) and/or improve other obesity and cancer-related outcomes, including among long-term cancer survivors. Additionally, limitations and potential negative consequences in certain populations must be better understood. For example, the use of time-restricted eating should be considered with caution in adults aged 65 years and older. Any dietary strategy that restricts overall daily protein intake or the timing of protein intake—including time-restricted eating—may contribute to loss of muscle mass and increase risk of frailty.¹⁸ Human populations that come to mind for additional study are individuals such as those aged 65 years and older, pregnant women, and children, who are most likely to benefit from or require caloric intake, including protein, over a greater time period daily than time-restricted eating encourages.

Is sleep health improved by following time-restricted eating?

Anecdotal evidence indicates that patients who follow time-restricted eating sleep better, not only compared with individuals on a caloric restriction diet but perhaps even before starting any diet. However, a review of 9 small, short-term time-restricted eating trials totaling 388 individuals with overweight or obesity that addressed sleep parameters found that sleep quality, as measured by the Pittsburgh Sleep Quality Index, was unchanged after vs before starting time-restricted eating.³⁶ Further research is warranted using validated tools to capture diet and sleep to better understand how time-restricted eating may benefit participants experiencing sleep disturbances.

What granularity of data is needed to best capture adherence and understand the impact of time-restricted eating on health outcomes?

Studies are needed to clarify how best to define and assess adherence to time-restricted eating and the intersection between time-restricted eating adherence and dietary assessment as well as how best to capture both. Only assessing adherence to eating windows without diet quality and energy intake would limit the understanding and interpretability of study findings (eg, are observed effects due to time-restricted eating, changes in diet quality and/or total energy intake). There is currently wide variability in how trials capture time-restricted eating adherence and diet assessment. Additionally, feasible and appropriate assessment tools and metrics need to be developed and validated to capture meal timing and time-restricted eating in community settings and for epidemiological studies.

Moving forward

On July 9, 2024, the NCI issued a Notice of Special Interest (NOT-CA-24-073) that asked investigators to research one or more of the topics outlined above. Understanding which factors most impact the efficacy of time-restricted eating, either favorably or unfavorably, and the effects of time-restricted eating on health outcomes, including cancer risk, treatment response, and prognosis, is important, given the increasing, widespread use of the dietary strategy in research and among the general public. Moving the science forward will allow us to better understand the potential of time-restricted eating. This potential includes a targeted time-restricted eating intervention and better adherence short and long term to the intervention, which is required to fully achieve its benefits in cancer. Full achievement of the potential of time-restricted eating would lead to decreased metabolic dysfunction, with a reduction in cancer risk and increased response to cancer treatment, as well as improved quality and quantity of life among cancer survivors.

Author contributions

Marissa Shams-White, PhD, MSTOM, MPH (Conceptualization; Writing—review & editing), Audrey Goldbaum, PhD, MPH (Writing—review & editing), Tanya Agurs-Collins, PhD, RDN (Investigation; Writing—review & editing), Susan Czajkowski, PhD (Conceptualization; Writing—review & editing), Kirsten Herrick, PhD, MSc (Writing—review & editing), Linda Nebeling, PhD, MPH, RDN (Writing—review & editing), Jill Reedy, PhD, MPH, RDN (Writing—review & editing), Gabriela Riscuta, MD (Writing—review & editing), Sharon Ross, PhD, MPH (Writing—review & editing), and Edward Sauter, MD, PhD (Conceptualization; Formal analysis; Writing—original draft; Writing—review & editing).

Funding

No funding was used for this manuscript.

Conflicts of interest

No conflicts of interest exist.

Data availability

No relevant data generated for this manuscript.