Time-restricted eating as a possible way to support a healthy lifespan: a review of current evidence

TRE restricts the daily eating window to the period when the circadian rhythm is active, reconstructing the phase synchronization between peripheral organs and the central clock of the suprachiasmatic nucleus (SCN), thereby correcting the phase dysregulation caused by modern lifestyles (). Specifically, the mechanism of this process lies in the fact that TRE directly acts on peripheral organs through regular feeding signals (such as the periodic fluctuations of insulin and free fatty acids), activating silent information regulator-1 (Sirtuin-1 and Sirt1) (), and then enhancing the rhythmic expression of core clock genes such as BMAL1 and PER2, effectively correcting the phase delay of the peripheral biological clock relative to the SCN. At the same time, by coordinating the feeding–fasting cycle with the biological clock signals, TRE can reverse the genes involved in glucose imbalance in the liver (such as GLUT2, pyruvate kinase, glucokinase, and glycogen synthase) and the genes involved in lipid imbalance (such as acetyl-CoA carboxylase, diacylglycerol O-acyltransferase, and medium-chain acyl-CoA dehydrogenase) (,). Generally speaking, TRE achieves the global coordination of the metabolic functions between the peripheral and central biological clock systems, restoring the temporal precision of the expression of metabolic genes. ^{9 10 11 12}

TRE triggers a switch of metabolic fuels by extending the fasting period, enabling the body to shift from relying on glucose to fatty acid oxidation and ketone body production (). After the fasting time reaches 12–16 h, the liver glycogen reserves are depleted, forcing the body to mobilize fat and activate the β-oxidation pathway, generating acetyl-CoA and synthesizing ketone bodies. Similarly, this process activates the AMPK and mTOR signaling pathways, thereby promoting fatty acid β-oxidation and the autophagy process (). The increased ketone bodies not only serve as an alternative energy source but also regulate gene expression, DNA repair, and genomic stability by inhibiting histone deacetylase (HDAC). Simultaneously, the reduction in the ATP/ADP ratio activates the AMPK/mTORC1 pathway, enhancing autophagy activity and promoting catabolism (). This optimizes mitochondrial function and accelerates the clearance of metabolic waste products, such as damaged proteins and abnormal mitochondria (,). The enhancement of mitochondrial function is achieved through the biosynthesis mediated by Forkhead Box Protein O, Peroxisome Proliferator-Activated Receptor-γ Coactivator 1-α (PGC-1α), and Nuclear Factor Erythroid 2-Related Factor 2 (NRF2). This process increases the oxygen consumption of individual mitochondria by approximately 40%, significantly improving the efficiency of energy metabolism. In conclusion, by enhancing mitochondrial function and metabolic flexibility, TRE further optimizes energy metabolism, enabling the body to switch fuel sources more efficiently under different energy demands, thereby achieving the benefits of metabolic regulation. ^{13 14 13 15 16}

TRE significantly improves oxidative stress and inflammatory responses through a multi-dimensional regulatory mechanism. At the level of antioxidant defense, TRE forms a dual protective barrier by activating the AMPK signaling pathway (). On the one hand, it inhibits the excessive production of mitochondrial reactive oxygen species (ROS), and on the other hand, it upregulates the expression of key antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (). It is worth noting that the autophagy process induced by fasting plays a synergistic role in this process. By removing dysfunctional organelles, it effectively blocks the continuous accumulation of ROS, thereby reducing the level of oxidative stress. In addition, studies have shown that TRE can also reduce the expression of inflammatory mediators such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in adipose tissue, and significantly inhibit the activity of NF-κB, blocking the cascade amplification of inflammatory signals from the source (). More importantly, the increase in adiponectin levels induced by TRE activates the PI3K/Akt signaling pathway, reducing the release of vascular endothelial cell adhesion molecules (such as VCAM-1, ELAM-1, and ICAM-1), thereby inhibiting local and systemic inflammatory responses (). ^{17 18 19 20}

TRE restores the chronobiological characteristics of the microbial community through regular feeding times (), mainly manifested in improving the structure of gut microbiota (increasing the number of beneficial bacteria while reducing the number of harmful bacteria), thus improving age-related gut barrier dysfunction. Specifically, the TRE intervention involving a 16-h daily fast resulted in reduced abundance of potentially pro-inflammatory bacteria such asand, while significantly increasing the abundance of, which possesses mucosal protective functions (). At the same time, the proportions of bacteria closely related to energy metabolism, such asandspp., increased (). Additionally, TRE significantly increases the abundance of probiotics such asand, promoting the proliferation of specific metabolically active genera within the phylum Firmicutes, notably short-chain fatty acid (SCFA)-producing bacteria likeand. These metabolically active bacteria generate short-chain fatty acids (SCFAs) such as acetic acid, propionic acid, and butyric acid by fermenting dietary fiber, exerting anti-inflammatory effects, enhancing gut barrier function, and reducing gut permeability (). It is noteworthy that TRE plays a particularly crucial role in promoting butyrate-producing bacteria, such as certainspecies,, and. At present, the function of these bacteria is closely related to the improvement of cognitive function, the delay of aging, and anti-inflammatory effects (). ^{21 22 23 24 25} Ruminococcaceae Alistipes Akkermansia muciniphila Ruminococcus Coprococcus Bifidobacteria Lactobacillus Clostridium butyricum Roseburia Clostridium Blautia Eubacterium

The weight trajectory can serve as a marker of the long-term energy balance status at different stages of the life cycle. During the aging process, as individuals advance in age (with middle age being a critical turning point), metabolic capacity often declines, leading to an increased risk of obesity. Preclinical studies have confirmed that implementing time-restricted feeding (TRF) may partially reverse abnormal circadian rhythmic oscillations of clock genes and their target genes, as well as the dysregulation in expression or activity of metabolic regulatory proteins such as AMPK, mTOR, and CREB that frequently accompany these changes (). Therefore, TRE can be considered a potential intervention strategy for regulating energy metabolism (). We summarize the trial designs, intervention protocols, and principal research outcomes of TRE trials involving healthy participants without a history of chronic or major diseases (). ^{27 28} Table 1

Clinical research on TRE in some healthy populations suggests that it exerts certain positive effects on weight and glycolipid metabolism-related indicators. However, its metabolic benefits are influenced by multiple factors, including calorie restriction, fasting duration, eating time windows, participant gender, exercise regimens, and others. First, we observed that the reduction in calorie intake may be an important reason why TRE plays a role. For example, a 10-week clinical trial showed that both TRE-4 and TRE-6 protocols spontaneously reduced calorie intake while achieving mild weight loss (~3%), accompanied by a decrease in insulin resistance and oxidative stress. In addition, there was no significant change in the dietary quality (such as sugar and alcohol intake) during the period (). It should be noted that some long-term studies have also not observed significant advantages in weight loss and body composition improvement (e.g., body fat reduction) compared with CR. Specifically, two 12-month RCTs showed that the TRE-8 protocols (with either ~25% calorie restriction oreating) did not produce a more significant weight loss effect than the daily calorie restriction (DCR) diets, suggesting calorie restriction may be the primary mechanism underlying TRE's benefits (,). Similarly, compared with conventional meal timing (CMT), a 12-week TRE-8 (12:00–20:00) intervention did not reduce calorie intake, and there was no significant difference in weight loss, fasting plasma glucose (FPG), glycated hemoglobin (HbA1C), lipid profiles, or blood pressure (). Another TRE-4 or TRE-8 (self-selected eating window) also confirmed this point. Despite no difference in caloric intake before and after intervention, TRE showed no significant weight change or positive metabolic benefits related to blood glucose and lipids. Instead, it raised low-density lipoprotein cholesterol (LDL-C) levels (). These studies suggest that the metabolic benefits of TRE may mainly come from “calorie restriction.” Additionally, research indicates that under caloric reduction, different eating time windows can vary in metabolic effects. Specifically, an RCT study confirmed that compared with mTRF-8 (12:00–20:00), eTRF-8 (06:00–15:00) has a more significant effect on improving insulin resistance in non-obese individuals, accompanied by increased diversity of gut microbiota and enhanced clock gene rhythms. These changes cannot be explained solely by weight loss (). ^{29 30 31 32 33 34} ad libitum

Subsequently, we observed that some current clinical intervention trials have excluded the “calorie restriction” factor. Significant changes in some clinical indicators were still observed when TRE-8 did not cause changes in calorie intake. For example, an 8-week RCT showed that TRE-8 can still improve body composition without reducing calorie intake. No significant changes were observed in the TRE-10/12 pattern with shorter fasting durations, which suggests that TRE-8 is a more effective TRE intervention pattern (). Moreover, some studies have confirmed that the TRE-8 intervention can exert certain positive effects on aging-related factors. Specifically, after 30 days of TRE-8 intervention, sustained weight loss of 2%−4% was observed even without caloric restriction. Peripheral blood showed reduced proportions of CD4+ senescent T cells, alongside significant upregulation of serum metabolites with anti-inflammatory and anti-aging effects [e.g., sphingosine 1-phosphate (S1P) and prostaglandin-1]. Concurrently, the abundance of longevity-associated gut microbiota (such asand) also increased (). This is consistent with existing research evidence. TRE may exert metabolic benefits independent of caloric restriction by regulating gut microbial composition through improving the circadian rhythms of gut microbes (). At the same time, studies on other patterns of TRE further suggest that “differences in fasting duration may explain variations in TRE efficacy.” For example, in the study of TRE with the commercial weight loss program (Jenny CraigRapid Results™), both the TRE-10 and TRE-12 groups carried out calorie restriction and macronutrient adjustment. The results showed that the TRE-10 group significantly lost weight (). Overall, these findings indicate that the health benefits of TRE depend not only on the reduction of calories but also on directly regulating the metabolic rhythm through restricted eating windows (such as optimizing lipid metabolism). The widely studied TRE-8 pattern may have relative advantages in metabolic regulation, indicating that appropriately extending fasting durations could enhance intervention efficacy. ^{35 36 37 38} Akkermansia Rikenellaceae ®

After analyzing multiple TRE-8-related studies in healthy populations, we noticed that the metabolic benefits of TRE may tend to be gender-different. We observed that although there was no obvious spontaneous decrease in calorie intake in TRE, the research results showed that some index results still had a statistically significant improvement. Specifically, in physically active male university-aged subjects, a 4-week TRE-8 intervention (self-selected eating window) achieved reductions in fat mass (FM), increases in high-density lipoprotein cholesterol (HDL-C), and decreases in blood pressure, under isocaloric conditions (). In an 8-week RCT study of middle-aged women, it was also found that, under identical calorie restriction conditions, TRE-8 significantly reduced body weight, body mass index (BMI), and diastolic blood pressure (DBP) more effectively than the non-TRE approach. It is worth noting that this method may increase FPG and worsen insulin resistance (). However, some trials did not exclude the “calorie restriction” factor. For example, a 3-month non-RCT showed that the weight, waist circumference (WC), and body fat percentage (BFP) of obese women decreased significantly after TRE-8 intervention, while there was no change in the indicators related to glycolipid metabolism (FPG, fasting insulin, and lipid profile). In addition, the 30-year risk of cardiovascular disease (CVDRisk30y) was reduced by 12%, with a positive correlation with BFP and a negative correlation with muscle percentage (). Similar to this research finding, an RCT reported that compared with the extended eating window group (EXE), female participants also achieved significant weight loss through the TRE-8 intervention (). At the same time, a 6-week TRE-8 intervention RCT showed a significant decrease in the weight of both elderly men and women by 1.8 and 1.3 kg, respectively. Notably, elderly men exhibited significant reductions in visceral fat mass and WC, whereas these measures showed no significant change in elderly women (). Therefore, there may be relatively few studies on male subjects, but overall, the available evidence still shows many benefits, such as reducing weight, body fat, and improving lipid metabolism indicators. Although women in some studies have also reduced their weight and WC, the improvement of sugar-lipid metabolism-related indicators is still limited. ^{39 40 41 42 43}

In addition, in the absence of other interventions (such as physical exercise), TRE tends to produce slight improvements in blood lipid levels of healthy individuals. We noticed that in a TRE-8 combined resistance training trial, the blood lipid spectrum (LDL-C and HDL-C) was significantly improved after 12 months of intervention. The study included healthy adults with at least 5 years of resistance training experience. The TRE group and the normal diet (ND) group were compared, with both groups combined with resistance training. Results showed reduced weight, fat mass, insulin-like growth factor 1, and testosterone levels in the TRE group. Additionally, the group's inflammatory markers [interleukin-6 (IL-6) and interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α)] and insulin sensitivity (glucose, insulin, and HOMA-IR) were significantly improved, with no impact on muscle performance. Notably, this long-term TRE trial reduced daily caloric intake by approximately 10%, with the reduction primarily derived from carbohydrates and fats while protein intake remained unchanged (). Similarly, a study of TRE combined with high-intensity intermittent training (HIIT) showed that TRE+HIIT offers metabolic advantages for overweight/obese women, primarily reflected in improved body composition (fat mass) and long-term blood glucose control (HbA1c) (). In short, in combination with some exercise interventions, TRE may have better metabolic benefits. However, it is necessary to pay attention to adaptive changes in body composition. Although this strategy does not impose strict calorie restriction, spontaneous calorie reduction is often associated with lean mass loss, potentially linked to protein conversion imbalance and water changes. While no severe adverse effects from lean mass reduction have been reported, existing researches recommend combining TRE with resistance training and adequate protein supplementation to ensure sustained weight and fat loss. ^{44 45}

With increasing age, pancreatic β-cell function undergoes progressive decline, leading to an imbalance in blood glucose regulation—a core pathological basis for the high prevalence of diabetes. Meanwhile, long-term irregular eating patterns and continuous 24-h eating behavior trigger circadian rhythm disruption, which in turn interferes with the rhythmic secretion of insulin and directly contributes to insulin resistance (). This metabolic imbalance further disrupts the rhythmic dynamic balance between hepatic glucose output and peripheral tissue glucose uptake. Additionally, disturbances in glucose metabolism, such as elevated blood glucose and persistent insulin resistance, act as key mediators driving aging and the progression of other chronic diseases by inducing mitochondrial dysfunction and oxidative stress. Current research suggests that TRE may exert a corrective effect on circadian dysregulation of glucose metabolism by synchronizing the eating window with the circadian rhythm (). Its potential mechanisms of action may involve multiple pathways, including activation of the AMPK signaling pathway and regulation of GLUT4 translocation. This suggests that TRE may influence insulin resistance reduction and blood glucose regulation, so we have summarized the trial designs, intervention protocols, and principal research outcomes of TRE trials involving prediabetes/diabetes participants (). Multiple clinical data show that TRE has differences in improving core indicators (weight, HbA1c, etc.) for prediabetic/diabetic patients due to differences in calorie intake, study population, program design, and other factors. ^{46 47} Table 2

After analyzing some research results, we found that the metabolic benefits of TRE may be directly related to “calorie restriction.” For example, a 6-month RCT involving patients with type 2 diabetes (T2D) showed that, with reduced calorie intake, the TRE-9 regimen decreased indicators such as body weight, body fat, and insulin resistance index. Furthermore, it achieved a reduction in HbA1c that was comparable to that of the individualized diabetes nutrition guidelines (DIET) group, while demonstrating higher adherence. These findings suggest TRE may serve as an alternative dietary strategy to DIET for improving glycemic control in T2D patients (). Similarly, several trials demonstrated that “significant calorie reduction” amplifies TRE's metabolic benefits. For instance, a 6-month TRE-8 study showed the TRE-8 group achieved a greater daily calorie reduction (313 kcal) than the DCR group (197 kcal), resulting in superior weight loss (−3.6%) compared to DCR (−1.8%). However, both groups exhibited similar reductions in glycated hemoglobin (HbA1c) levels (−0.91 and −0.94%, respectively), which may be related to both groups receiving individualized diabetes nutrition counseling that has been proven to improve HbA1c levels in patients with T2D. Furthermore, TRE groups demonstrated higher adherence compared to DCR groups (,). Another 14-week RCT also showed that compared with ND, TRE-10 reduced the spontaneous calorie intake of participants, which significantly improved the weight and glycolipid-related indicators of overweight T2D patients (). Interestingly, a study showed that a 3-month TRE-10 intervention did not affect calorie intake, and no improvements related to weight loss and glycolipid metabolism were observed (). Therefore, we speculate that the effects of TRE are likely to be related to the degree of realization of “caloric restriction.” Notably, research confirmed TRE may confer metabolic benefits independent of weight loss. Specifically, an RCT involving impaired fasting glucose (IFG) patients demonstrated that adhering to the TRE-9 protocol, with reduced calorie intake, significantly improved FPG, HbA1c, fasting insulin, HOMA-IR, triglycerides (TG), and DBP levels, even without weight loss (). Furthermore, there are also feasibility studies of TRE interventions targeting adolescents with T2D, which adopted an lTRE (12:00–20:00) protocol. However, compared with the control group, no significant metabolic benefits were observed, which may be due to the small sample size or impaired pancreatic islet function in adolescents (). In summary, TRE research findings indicate that the effects on the aforementioned trial principal research outcomes exhibit a certain degree of synchrony with differences in caloric intake. This suggests that the improvement effect of TRE on relevant metabolic indicators may be more significantly related to “calorie restriction.” ^{48 49 50 51 52 53 54}

Of course, there are also research results suggesting that TRE may bring metabolic benefits independent of “calorie restriction.” Whether TRE interventions can yield comparable metabolic benefits under isocaloric conditions has drawn attention. For instance, a 5-week randomized crossover trial of eTRE-6 (early eating window) in men with prediabetes minimized confounding effects from food intake or meal frequency variations by strictly requiring participants to consume only researcher-provided meals. Results showed that even without caloric reduction or weight loss, TRE still significantly improved participants' insulin levels, insulin sensitivity, β-cell responsiveness, blood pressure, and oxidative stress levels, suggesting it may function in addition to caloric restriction or weight loss. However, there were no significant improvements in blood glucose levels, arterial stiffness, lipid profiles, and inflammatory markers of the participants (). Therefore, short-term TRE can improve the impaired state of pancreatic islet function, but the study needs to be further verified due to the small sample size and single gender (all men). ⁵⁵

In the context of the accelerating global aging process, metabolic disorders can be regarded as a core threat to public health. Significantly, the complex manifestations are collectively represented by MetS, which encompasses components such as central obesity, impaired glucose tolerance, dyslipidemia, and hypertension. At present, NAFLD is generally considered to be the pathological outcome of MetS at the liver level (). Specifically, the relationship between the two depends on the common pathological mechanism, covering insulin resistance, lipotoxic lipid release, increased liver fat production, and systemic inflammation activation (,). Preclinical studies suggested that TRF has the potential to improve the pathological status of MetS and NAFLD (). Under isocaloric conditions, TRF intervention resulted in reduced hepatic inflammation without significant weight loss. These benefits may be mediated through mechanisms such as reducing lobular hepatic inflammation and reducing endoplasmic reticulum stress levels (). Therefore, TRE is considered likely to delay the development of MetS and NAFLD. We summarize the trial designs, intervention protocols, and principal research outcomes of TRE trials for MetS and NAFLD participants (). ^{56 57 58 59 60} Table 3

In clinical trials involving individuals with MetS, some studies indicate that despite spontaneous reductions in total caloric intake during TRE intervention, potential improvements in MetS-related markers are observed. However, further analysis suggests that these metabolic benefits show no significant correlation with caloric reduction or weight loss. For example, a small sample single-arm study of 19 MetS patients showed that TRE could still further reduce the relevant glycolipid indicators under the premise of combined drug use. Further analysis indicated these improvements were independent of weight changes. Specifically, the 12-week TRE-10 intervention significantly improved the patient's weight and WC, while reducing LDL-C, TC, and blood pressure levels, and the HbA1c of patients with elevated fasting blood glucose was also significantly reduced. The above results also provide a preliminary basis for the possible health benefits of TRE independent of weight loss, but given that this study is designed as a small sample single-arm study, this conclusion still needs to be verified by more high-quality research (). Similarly, another 3-month RCT demonstrated that compared to the standard of care (SOC)-only group, the TRE combined with standard of care (SOC) nutrition counseling group not only significantly improved metabolic syndrome components, but also achieved superior weight management (average weight loss of 2.98 kg, with 75% fat loss and only 9% lean mass loss), and reduced calorie intake primarily from carbohydrates and fats, with no impact on protein intake. Notably, personalized TRE protocols shortened the eating window to 8–10 h (≥4 h shorter than baseline and ≥3 h before habitual sleep). Further analysis indicated that TRE's improvement in HbA1c among individuals with metabolic syndrome shows extremely weak correlations with calorie changes (= 0.02) and weight loss (= 0.07), further suggesting that calorie reduction is not the sole driving factor (). In addition, trial results without measured caloric intake also demonstrated TRE's potential in reducing metabolic disease risk. Whether combined with a low-carb diet (LCD) or not, the 3-month TRE-8 intervention reduced the patients' body weight, HOMA-IR, TG, and uric acid (UA) indicators compared with the baseline. It is worth noting that the exploratory analysis of the TRE group showed that compared with lTRE-8, patients in the eTRE-8 (8:00–16:00) group could significantly reduce VFA. This suggests that the difference in the eating window period also causes differences, and e-TRE may be a more advantageous solution (). ^{61 62 63} R R 2 2

Among NAFLD populations, some trials have demonstrated that TRE improves body weight, body fat, inflammatory markers (such as hs-CRP and TNF-α), and liver-related assessments (including hepatic steatosis, liver fibrosis, and liver enzyme levels). Furthermore, long-term adherence to TRE-8 itself yields benefits by improving certain indicators, with these advantages potentially more closely linked to “calorie restriction.” For instance, a 12-month TRE-8 intervention reduced caloric intake compared to baseline while decreasing hepatic fat content (IHTG), improving liver fibrosis (LS, Liver Stiffness), liver enzyme levels, body weight, body fat, blood pressure, and indicators related to glycolipid metabolism. However, compared to DCR, TRE-8 did not yield particularly significant benefits without calorie reduction. Therefore, calorie control may be the primary mechanism at work when managing NAFLD through TRE protocols (). The advantages of TRE over strict DCR are not significant, but studies suggest that TRE has benefits compared to combined interventions of SOC and exercise requirements (aerobic and resistance training). Specifically, one RCT demonstrated that compared to the SOC plus exercise group, TRE-8 significantly reduced hepatic steatosis (CAP, Controlled Attenuation Parameter), body weight, and waist circumference in NAFLD patients without reducing caloric intake. This suggests that altering meal timing or frequency alone may be a mechanism for improving visceral fat and hepatic steatosis (). This finding aligns with previous research (), concluding that “spreading meals across more frequent intervals while maintaining the same caloric intake increases hepatic fat.” Additionally, the combination of TRE-8 with specific dietary strategies demonstrated more pronounced effects. A 12-week isocaloric RCT was conducted to compare this combination (TRE-8 plus a low-sugar diet) with conventional dietary allocation. Results showed that the TRE-8 combined with a low-sugar diet intervention not only significantly improved hepatic steatosis score/CAP and liver enzyme levels (ALT, AST, and GGT) but also reduced anthropometric measurements, body composition parameters (W, WC, and FM), glycolipid-related indicators, and the inflammatory marker hs-CRP (). Similarly, a 12-week TRE-8 combined with lacto-ovo vegetarian (LOV) intervention improved hepatic steatosis (FLI, Fatty Liver Index), body weight, waist circumference, glycolipid-related indicators (insulin levels, TG, and HDL-C), liver enzyme levels (ALT and GGT), and inflammatory status (TNF-α). However, no significant changes in liver fibrosis were observed (). ^{64 65 66 67 68}

In summary, standalone TRE interventions may yield limited effects in individuals with impaired metabolism. When combined with macronutrient guidance, disease-specific standard of care (SOC), or various dietary approaches (such as low-sugar diets or LOV), TRE may enhance efficacy through nutritional optimization, including sugar control and increased plant protein intake. Patients following eTRE-8 (8:00–16:00) may observe a reduction in visceral fat, or it may suggest that an earlier eating window combined with the TRE-8 protocol can achieve optimal effects.

In an aging society, the threat of cancer is particularly prominent. With the increase in age, the decline in DNA repair ability, the weakening of immune surveillance, and the accumulation of epigenetic abnormalities make the risk of cancer in people over 60 is more than 10 times higher than that in young people. Preclinical studies have confirmed that TRE can delay the onset, progression, and metastasis of obesity-related breast, kidney, and lung cancers (–). The primary mechanisms likely involve restoring circadian rhythms of gene expression in tumors, synchronizing biological rhythms, or improving clock gene function. A large prospective cohort study of early-stage breast cancer patients showed that, after controlling for the confounding effect of “calorie restriction,” nighttime fasting duration < 13 h remained associated with a 36% increased risk of breast cancer recurrence. Moreover, longer nighttime fasting duration was closely linked to reduced HbA1c levels (). However, the metabolic benefits of TRE for cancer survivors remain controversial. We summarized the intervention protocols of three single-arm TRE trials, and the effects of quality of life, fatigue, and psychological measures in cancer survivors (). ^{69 71 72} Table 4

In clinical trials among cancer survivors, TRE emerges as a potential supportive therapeutic strategy. TRE not only reduces recurrence risk through its positive effects on body composition and cardiovascular risk factors but also mitigates acute and long-term side effects of cancer treatments, including cancer-related fatigue and quality of life aspects. For example, a 14-day TRE-10 dietary intervention yielded clinically meaningful improvements in body weight and fatigue symptoms (FACIT-F, Functional Assessment of Chronic Illness Therapy—Fatigue; BFI, Brief Fatigue Inventory) among cancer survivors without affecting caloric intake (). Similarly, an 8-week TRE-8 (weekdays) study in obese/overweight breast cancer survivors who completed anthracycline chemotherapy 3 ± 1 years prior demonstrated spontaneous caloric intake reduction post-intervention, accompanied by concurrent decreases in body weight, total body fat mass, visceral adipose tissue, and 10-year Framingham cardiovascular disease risk. However, no significant changes were observed in the modifiable Framingham risk components (TC, HDL-C, and SBP), which indicates that there are individual differences in these indicators and the reduction in risk (). In addition, a study of 40 breast cancer survivors showed that after a 12-week TRE-11 intervention program, the subjects' BMI, anxiety, and depression (HADS, Hospital Anxiety and Depression Scale) and fatigue symptoms (FACIT-F) were significantly improved (). It should be noted that the role of TRE needs to be carefully evaluated in combination with the patient's nutritional status. In patients with advanced cancer malignancy, excessive restriction of the eating window may aggravate muscle breakdown, and it is necessary to weigh its dual impact on immune function improvement and nutritional support. ^{73 74 75}

At present, the multi-dimensional evaluation of healthy lifespan needs to take into account two aspects. It should not only pay attention to the core indicators related to the onset of chronic diseases and the risk of progression, such as weight management and glycolipid metabolism, but also include the assessment of cognitive, psychological, and other intrinsic abilities. In order to assess the health status of individuals in the aging process more comprehensively, we should not focus only on a single disease or a general quality of life (). Preclinical studies showed that TRF may protect cognitive function and slow down cognitive decline by optimizing metabolic rhythms, reducing neuron loss, and the accumulation of Aβ plaques (,). At the same time, some observational or interventional studies suggest that TRE may have a certain impact on the maintenance of memory function and the improvement of depressive symptoms. Its potential mechanisms are speculated to be related to insulin metabolism regulation, autophagy level regulation, neuroinflammatory response inhibition, and brain-derived neurotrophic factor (BDNF) expression regulation (–). These mechanisms may be involved in the regulation of neurogenesis and neuroplasticity. ^{76 77 78 79 81}

In the cognitive field, some evidence shows that TRE has the potential to improve the decline of cognitive ability related to aging, but there are relatively few clinical studies in this regard. Specifically, a cross-sectional study analyzed the relationship between TRE and cognitive status in 883 Italian adults. The results showed that, even with no difference in calorie intake, individuals who followed the TRE-10 protocol were less likely to have cognitive impairment than those who did not practice TRE. This effect was particularly pronounced when food intake restriction aligned with circadian rhythms by starting earlier in the day (e-TRE or m-TRE) (). Similarly, the 4-week eTRE-6 also improved the cognitive flexibility of college students without calorie reduction, which was manifested in the significant shortening of response times on the Trail Making Test-B (TMT-B). At the same time, this cognitive improvement was related to the ketone body in plasma (β-hydroxybutyrate) was negatively correlated, suggesting that ketones may play a role in it (). ^{82 83}

Current clinical evidence regarding the impact of TRE on human emotions and quality of life remains limited, but existing studies have shown a positive trend, and the effect of TRE may be independent of weight loss. Specifically, a 5-day isocaloric TRE-8 protocol improved participants' subjective happiness and optimized dietary patterns without weight loss. These benefits were not related to “calorie restriction” or weight loss (). Meanwhile, although some studies did not report changes in calorie intake, they also reached similar conclusions. After the implementation of the 12-week TRE-8 protocol in the overweight population, the participants lost weight by approximately 3.7%. The SF-36 questionnaire revealed significant improvements in both the “emotional wellbeing” and “perceived health change” dimensions. Further analysis confirmed that improvement in quality of life was independent of weight loss (). Another study similarly demonstrated that TRE's significant enhancement of health-related quality of life and sleep quality was not solely dependent on weight loss (). In addition, a study conducted a 4-week TRE-8 intervention on 10 elderly people who were overweight, at risk of, or had mobility impairments (slow gait, < 1.0 m/s). The results showed participants experienced approximately 2.68% weight loss, along with clinically meaningful improvements in walking speed and quality of life. This suggests that TRE-8 is safe and feasible for this population, but the long-term effect still needs to be further verified (). ^{84 85 86 87}

Based on the results of a number of clinical studies, TRE showed high overall adherence in different populations, as well as good feasibility and safety, and no serious adverse reactions related to intervention were reported in all studies. Most clinical studies show that TRE is more adherent than other diet patterns (such as CR and LCD). The key is easy operation and high flexibility of the scheme. Specifically, compared with CR, the TRE protocol can retain the original dietary preferences of individuals without controlling calorie intake. At the same time, unlike LCD, ketogenic diets, and MD, TRE does not require forced changes to dietary structure, but only limits the eating time to reduce the difficulty of diet adjustment. In summary, participants avoid complex calorie counting, food selection, or dietary restrictions. They can also independently choose eating windows based on work schedules and sleep patterns, making it easier to integrate into daily routines and minimizing disruption to lifestyle habits. The TRE dietary pattern demonstrates significant adherence advantages in clinical interventions and may serve as an adjunct or alternative therapeutic approach for weight management and age-related NCDs such as T2D, MetS, NAFLD, cancer, and others.

Regarding safety, TRE has demonstrated good short-term safety. Only a small number of participants experienced minor and transient symptoms such as hunger, headaches, and fatigue during the initial phase of the intervention (particularly during the first few weeks of adaptation), and no intervention-related serious adverse events were reported in any study. However, attention should be paid to its long-term potential risks, such as possible lean body mass reduction and micronutrient deficiencies, and long-term adherence may decrease due to social factors.