Is caloric restriction enough to increase longevity? Fasting and circadian alignment

Abstract

Effects of caloric restriction, fasting and circadian alignment on longevity in mice and potential risks and benefits of extrapolation to humans.

The modification of diet for longevity has long been of interest, research generally having been conducted in animal experiments. Caloric restriction (CR) is known to contribute to a prolongation of lifespan, even in highly evolved animals; it was first reported by Colman et al. ¹ in 2009 that caloric restriction delays disease onset and mortality in rhesus monkeys. Recently, caloric restriction, fasting, and fasting intervals, and the time of eating with consideration to species‐appropriate circadian alignment has been investigated. While caloric restriction itself has been found in numerous species to result in a significant prolongation of lifespan, it has also been shown that fasting regimens can independently promote longevity as well as improve deteriorated metabolic functions.

In an article published in Science, Acosta‐Rodriguez et al. ² report that circadian alignment in addition to fasting promotes longevity independently of caloric restriction in male mice. Although whether these findings in nocturnal rodents can be extrapolated to diurnally active humans must be established, the findings are highly suggestive. The study compares the contribution of adjusted feeding times in addition to fasting in five caloric restriction groups on behavioral, metabolic, and molecular outcomes using automated feeders. Diet energy was restricted by 30% in all caloric restriction groups of mice fed under five caloric restriction protocols: two of the groups were fed during the active (night) or non‐active (day) period for 2 h; two groups were fed regularly every 90 min during half (12 h) of the active or non‐active period; and one group was fed every 160 min throughout the 24 h day (Figure 1). The results are intriguing. Caloric restriction itself extended the lifespan by 10%; when the fasting time was added, the lifespan was increased to 20%; and when the feeding time was aligned to the active period, the lifespan was further extended to 35%, demonstrating that when food intake is restricted to an appropriate time of the day there is an additional benefit to caloric restriction and fasting on lifespan. Thus, circadian alignment, also called time‐restricted feeding (TRF) in experimental animals and time‐restricted eating (TRE) in humans, had a significantly greater effect on prolongation of lifespan, establishing that eating at regular mealtimes is critical in chrono‐nutrition. There was no difference in 12 h and 22 h fasting, indicating that longer fasts are not helpful in this regard.

Figure 1.

Effects of caloric restriction, fasting, and circadian alignment on longevity in mice (right panel) and potential risks and benefits of extrapolation to humans (left panel). In mice, caloric restriction and fasting with misaligned feeding times results in extended lifespan that is extended further by the addition of circadian‐adjusted feeding, suggesting that standard mealtimes may be critical for health. However, while eccentric eating habits may well be a factor in metabolic and cardiovascular disease, when extrapolating these findings clinically, potential adverse effects of muscle and bone mass loss must be carefully considered, especially in older individuals.

The authors also investigated the changes in gene expression profiles, and performed gene ontology analysis to clarify the mechanisms of lifespan extension by caloric restriction, fasting, and circadian alignment. Ad libitum feeding resulted in up‐regulation of 2031 of 13,997 genes (14%) related to inflammation and immune function and down‐regulation of 568 genes (4%) related to metabolic pathways; caloric restriction alone improved age‐related changes of these up‐regulated and down‐regulated genes by 44% and 60%, respectively. Fasting promoted an increased expression in about 10% of genes involved in thermogenesis, while circadian alignment by time‐restricted feeding also improved the expression of 68 genes related to immune function and age‐related inflammation, which may well underlie the additional 15% improvement of longevity observed in the time‐restricted feeding group.

Neoplasms were found to be the major cause of death in the study, suggesting that the dietary regimens extended the lifespan by delaying their onset. In humans, inappropriate dietary habits and lack of exercise are known to lead to obesity, hyperglycemia, and various comorbidities such as arteriosclerosis, renal dysfunction, and cancer that result in a shortened lifespan. As caloric restriction and circadian alignment in mice was found to suppress age‐associated increases in inflammation‐related factors and metabolism‐related genes, such interventions may well serve as effective preventative measures. However, nocturnal animals and diurnal animals have differing circadian rhythms and different expression patterns of various genes including clock genes, making extrapolation problematic.

The importance of gastric emptying has been recognized in humans and it is well known that caloric restriction, fasting, and nutrition are important for health, especially in the treatment of metabolic diseases ³ . There are inconsistent findings on comparable effects of caloric restriction, fasting, and time‐restricted eating in humans, mainly on metabolism, and it is considered that variables including carbohydrate and protein composition, and the degree and duration of fasting contribute to the varied results. Indeed, some investigative methods obliquely involve caloric restriction and time‐restricted eating; these include alternate‐day fasting and intermittent caloric restriction which is also referred to as the “5:2” diet (2 days fasting per week) as well as time‐restricted fasting. The findings also vary by differences in protocol and participant health status, sex, genotype, and age at intervention.

The potential adverse effects of caloric restriction and fasting must be carefully considered before a fasting regimen is considered. Older adults have increased dietary protein requirements and missed meals can be detrimental. Moreover, analysis of data from the National Health and Nutrition Examination Survey III in which the mean age of subjects was 53.2 years, shows that skipping breakfast impacts both cardiovascular and all‐cause mortality ⁴ . In addition, whether time‐restricted eating without caloric restriction extends lifespan remains a question. Because fasting and time‐restricted eating naturally lead to a certain amount of reduction in calorie intake, it will be difficult to establish that time‐restricted eating itself can significantly extend lifespan.

The value of good health with longevity is paramount. As circadian alignment/time‐restricted eating has the potential to promote both good health and longevity, the study by Acosta‐Rodriguez et al. shines welcome new light on chrono‐nutrition.

DISCLOSURE

The authors declare no conflict of interest.

Approval of the research protocol: N/A.

Informed consent: N/A.

Registry and the registration no. of the study/trial: N/A.

Animal studies: N/A.