Forms of fasting and calorie restriction all function to produce sweeping, favorable alterations to metabolism. In short-lived animals, these changes significantly extend healthy life span. In long-lived animals, the effects on life span are more muted. The challenge in understanding the interaction between reduced calorie intake and pace of aging is that near everything changes in response to diet. There is no firm understanding at the detail level to link the copious observations into a coherent explanation of how aging is slowed. While evidence points to upregulation of autophagy as the primary mechanism connecting reduced calorie intake to slowed aging, it seems clear that researchers will still be writing papers like this one for decades yet.
Dietary restriction (DR) has multiple beneficial effects on health and longevity and can also improve the efficacy of certain therapies. Diets used to instigate DR are diverse and the corresponding response is not uniformly measured. We compared the systemic and liver-specific transcriptional response to intermittent fasting (IF) and commercially available fasting-mimicking diet (FMD) after short- and long-term use in C57BL/6 J mice.
We show that neither DR regimen causes observable adverse effects in mice. The weight loss was limited to 20% and was quickly compensated during refeeding days. The slightly higher weight loss upon FMD versus IF correlated with stronger fasting response assessed by lower glucose levels and higher ketone body, free fatty acids, and especially FGF21 concentrations in blood. RNA sequencing demonstrated similar transcriptional programs in the liver after both regimens, with PPARα signalling as top enriched pathway, while on individual gene level FMD more potently increased gluconeogenesis-related, and PPARα and p53 target gene expression compared to IF. Repeated IF induced similar transcriptional responses as acute IF. However, repeated cycles of FMD resulted in blunted expression of genes involved in ketogenesis and fatty acid oxidation.
Link: https://doi.org/10.1...915-024-02061-2
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