The ups and downs of caloric restriction and fasting: from molecular effects to clinical application

Abstract

Age-associated diseases are rising to pandemic proportions, exposing the need for efficient and low-cost methods to tackle these maladies at symptomatic, behavioral, metabolic, and physiological levels. While nutrition and health are closely intertwined, our limited understanding of how diet precisely influences disease often precludes the medical use of specific dietary interventions. Caloric restriction (CR) has approached clinical application as a powerful, yet simple, dietary modulation that extends both life-and healthspan in model organisms and ameliorates various diseases. However, due to psychological and social-behavioral limitations, CR may be challenging to implement into real life. Thus, CRmimicking interventions have been developed, including intermittent fasting, time-restricted eating, and macronutrient modulation. Nonetheless, possible side effects of CR and alternatives thereof must be carefully considered. We summarize key concepts and differences in these dietary interventions in humans, discuss their molecular effects, and shed light on advantages and disadvantages.

Adult neural stem cells and neurogenesis are resilient to intermittent fasting

“…We first set out to establish a fasting protocol to study adult neurogenesis. IF is a popular form of fasting that encompasses a group of dietary interventions that rely on alternating fasting and feeding periods (Hofer et al, 2022). One of the most widely used IF interventions -and the one we chose for this study- is every-other-day-fasting (also known as alternate-day-fasting), which consists of cycles of 24h of food deprivation followed by 24h of free access to food, where food is removed or added always at the same time of the day.…”

Healthy Aging and Dietary Patterns

“…The benefit of CR in lean people already following a healthy diet and lifestyle is uncertain. Moreover, there are important adverse effects of CR including infertility, chronic lack of energy perception, mental stress, and sexual dysfunction that may result in depression and loss of appetite with increased risk of anorexia [165].…”

Dietary change without caloric restriction maintains a youthful profile in ageing yeast

“…Dietary restriction can improve ageing health in eukaryotes ranging from budding yeast to primates and even humans, but remains an unrealistic approach for improving ageing health in human populations as this sacrifice requires substantial commitment (Didier et al, 2016;Fontana and Klein, 2007;Fontana et al, 2010;Green et al, 2022;Hofer et al, 2022). However, the beneficial effects of dietary restriction are not simply due to a reduction in calories as equivalent effects can be achieved through limiting or even tailoring amino acid intake, indicating that improved ageing health results from altered metabolic state rather than minimal energy intake (Jiang et al, 2000;Mair et al, 2005;Trautman et al, 2022).…”

“…Therefore, the link between mitochondrial dysfunction and senescence is supported across studies, but nucleolar changes are more variable across experimental systems and the importance and timing of rDNA instability remains to be clarified. A major contributor to these differences may be variation in rDNA copy number between strains, which changes during routine yeast transformation and influences both lifespan and rDNA recombination rate (Hotz et al, 2022;Kwan et al, 2016).…”