Metabolic Effects of Caloric Restriction

Abstract

Caloric restriction (CR) improves health and increases longevity in organisms from yeast to mammals. Studies in rodent models show that CR suppresses a wide range of diseases that contribute to human morbidity and mortality such as cancer, cardiovascular disease and diabetes. Although the metabolic and physiological changes induced by CR have been investigated for over 70 years, the precise mechanism by which it is able to slow the progression of age‐related degeneration remains a subject of much debate. This article summarizes our current understanding, including recent findings that implicate specific enzymes and signalling pathways in the process. Further study of CR may provide insight into the nature of aging and reveal new opportunities to improve the quality and quantity of human life. Key concepts Reducing energy intake in the absence of malnutrition (caloric restriction) improves health and extends longevity. Caloric restriction causes widespread changes in physiology and metabolism, many of which are distinct from fasting responses. Manipulation of specific genetic pathways can block or mimic some responses to caloric restriction. Insulin/IGF‐1 signalling is consistently implicated in the mechanism of caloric restriction. Neither aging nor its retardation by caloric restriction is understood, however much of the available data is compatible with the Free Radical Hypothesis.

Resveratrol, sirtuins, and the promise of a DR mimetic

“…By way of comparison, single-gene mutations were first shown to extend lifespan in worms in 1988 (Friedman and Johnson, 1988), and in rodents in 1996 (Brown-Borg et al, 1996). Whereas most genetic manipulations in rodents have been tested only once, with limited phenotypic assessment, the effects of DR have been tested in hundreds of labs, and its effects on nearly every age-related change have been documented (Baur, 2009; Masoro, 2005; Weindruch and Walford, 1988). The overwhelming conclusion is that DR affects something very fundamental to the aging process, as determined by its effects on disparate age-related diseases, as well as detailed analyses of mortality rates (Yen et al, 2008).…”

Rapamycin has a biphasic effect on insulin sensitivity in C2C12 myotubes due to sequential disruption of mTORC1 and mTORC2

“…However, very little is known about the changes in physiology or intracellular signaling that accompany this effect. Interestingly, rapamycin was tested for effects on lifespan in part because it is proposed to mimic some of the signaling events triggered by caloric restriction (CR), which extends life in most species that have been tested ( Weindruch and Walford, 1988 ; Baur, 2009 ; Cox and Mattison, 2009 ). Two hallmarks of CR in rodents are improved insulin sensitivity ( McKee Alderman et al, 2010 ) and increased mitochondrial biogenesis ( Nisoli et al, 2005 ).…”

Elixir of immortality? Wine, resveratrol and sirtuins: an overview

“…In essence, these preliminary studies suggested that DR could extend lifespan in rodents, and adumbrated more modern approaches. A wide variety of studies have shown this effect on lifespan, and also the beneficial effects of DR with regard to heart disease, cancer, neuroprotection and more (Baur, 2009;Masoro, 2005;Weindruch & Walford, 1988).…”