Metabolic Effects of Caloric Restriction

Abstract

Caloric restriction (CR) is a dietary intervention that robustly extends lifespan in diverse species. In mammals CR extends the period in which the animal is fit and vigorous, and attenuates age‐related disease vulnerability. Benefits of CR include reduced incidence of cancer, improved cardiovascular health, increased insulin sensitivity, and resistance to neurodegenerative diseases. The fact that CR extends not only average lifespan but also maximum lifespan has led to the consensus that an optimised CR diet slows the aging process itself. Here we outline the effects of CR on physiology and metabolism and where these may fit with current theories of aging. The authors describe factors that are likely to mediate the physiological adaptations to CR, placing an emphasis on nutrient sensitive regulators of metabolism. A major incentive for research into the mechanisms of CR is the promise of novel treatments for age‐related diseases and disorders that are relevant to human aging.

Key Concepts:

  • CR has a system‐wide physiological impact.

  • Metabolic factors are responsive to CR.

  • Metabolism and aging are tightly linked.

  • Growth factor signalling impacts metabolism.

  • CR research is highly relevant for human aging.

Keywords: caloric restriction; metabolism; aging; longevity; sirtuins; AMPK; mTOR

Figure 1.

Simplified model of metabolic reprogramming by CR. Reduction in calorie intake extends lifespan suggesting an inverse relationship between energy and aging rate. This simple model predicts that a reduction in calorie intake induces differences in nutrient and energetic status (signals) that are detected by nutrient and energy sensitive factors (effectors) that regulate in the balance of energy use and energy sparing (outcomes). Regulation through systemic growth factors is superimposed on these cellular pathways, that together lead to changes in metabolism, growth, and energy sparing. How these changes translate to delayed aging and prevention of age‐related diseases is yet to be resolved.

Figure 2.

Diverse cellular functions regulated by sirtuins. The actions of the sirtuin family of posttranslational modification enzymes are coupled to metabolism due to their requirement for NAD as a cosubstrate. There are 7 mammalian sirtuins that populate distinct subcellular compartments, and mediate regulation of diverse metabolic processes including (1) metabolic enzymes – enzymes involved in multiple aspects of metabolism that are direct targets of sirtuin activity; (2) gene expression – regulation of transcription factors, coactivators, and regulatory factors; (3) structure – broad impact on the microtubule cytoskeleton and more specifically localised impact in chromatin; and (4) inflammation – direct regulation of NfκB inflammatory pathway.

Figure 3.

Integration of growth and nutrient signalling pathways through mTOR. Growth signalling and nutrient sensing are among the inputs that activate the mTOR signalling pathway. mTOR impinges on multiple key processes including protein synthesis, ribosome biogenesis, and autophagy, as part of the anabolic response. Crosstalk between the mTOR and the insulin signalling pathways is complex, with feedback inhibition of insulin signalling mediated in part by mTORC1‐dependent phosphorylation of insulin receptor interacting proteins.

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Lamming, Dudley W, and Anderson, Rozalyn M(Oct 2014) Metabolic Effects of Caloric Restriction. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021316.pub2]