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Calorie restriction, SIRT1 and metabolism: understanding longevity

Nature Reviews Molecular Cell Biology volume 6, pages 298–305 (2005)Cite this article

Key Points

  • Calorie restriction (CR) is a dietary regimen, which has been shown to extend lifespan in a multitude of organisms. In addition, CR has been shown to reduce the incidence of age-related disorders (such as diabetes, cancer and cardiovascular disorders).

  • CR induces metabolic changes, improves insulin sensitivity and alters neuroendocrine functions in animals.

  • CR is a highly regulated process, which requires regulatory proteins that can sense food scarcity and mount an appropriate physiological response. The NAD-dependent deacetylase SIRT1 might link the energetics of cells to their lifespan.

  • CR has been shown to produce changes in the levels of hormones that are produced in the fat tissue (such as adiponectin, leptin, TNFα and resistin) that could mediate the beneficial effects of this regimen.

  • SIRT1 renders cells stress resistant by inhibiting the pro-apoptotic transcription factors p53 and forkhead. And, in white adipose tissue, SIRT1 has been shown to mobilize fat by repressing peroxisome proliferator-activated receptor (PPAR)γ.

  • CR has beneficial effects on glucose metabolism, and CR mice have lower glucose and insulin levels.

  • CR can protect against neurodegeneration in animal models of Huntington's disease, Alzheimer's disease, Parkinson's disease and stroke.

  • The levels of uncoupling proteins increase under CR and this might ameliorate the generation of oxidative damage by reducing reactive oxygen species and, thereby, slowing ageing.

Abstract

Calorie restriction (CR) is the only experimental manipulation that is known to extend the lifespan of a number of organisms including yeast, worms, flies, rodents and perhaps non-human primates. In addition, CR has been shown to reduce the incidence of age-related disorders (for example, diabetes, cancer and cardiovascular disorders) in mammals. The mechanisms through which this occurs have been unclear. CR induces metabolic changes, improves insulin sensitivity and alters neuroendocrine function in animals. In this review, we summarize recent findings that are beginning to clarify the mechanisms by which CR results in longevity and robust health, which might open new avenues of therapy for diseases of ageing.

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Figure 1: Models of calorie restriction in yeast.
Figure 2: Calorie restriction, SIRT1 and WAT.
Figure 3: Calorie restriction and metabolic changes.
Figure 4: SIRT1 and neuroprotection.
Figure 5: UCPs, calorie restriction and oxidative damage.

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Acknowledgements

We thank members of the Guarente laboratory for editorial comments and apologize to those whose work was not cited due to space limitations. The work in the Guarente laboratory was supported by grants from the National Institutes of Health.

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  1. Department of Biology, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Laura Bordone & Leonard Guarente

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  1. Laura Bordone
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  2. Leonard Guarente
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Correspondence to Leonard Guarente.

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Leonard Guarente is founder, stockholder and consultant for Elixin Pharmaceuticals.

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DATABASES

Entrez

aP2

C/EBPα

C/EBPβ

Saccharomyces genome database

PNC1

SIR2

Swiss-Prot

Adiponectin

leptin

p53

PPARγ

PGC1α

resistin

SIRT1

TNFα

UCP1

UCP2

UCP3

UCP4

UCP5

Glossary

REACTIVE OXYGEN SPECIES

(ROS). A reactive intermediate oxygen species that usually contains an unpaired electron in its outermost shell of electrons. Examples include: superoxide anion (O2•−), hydroxyl radical (OH•), hydroxyl ion (OH−), hydrogen peroxide (H2O2) and hypochlorite ion (OCl−).

ELECTRON-TRANSPORT CHAIN

The electron-transport chain comprises complexes I–IV and an ATPase, which couples the transfer of an electron from NADH or FADH to molecular oxygen (O2). This process pumps protons (H+) across the mitochondrial membrane, which generates a proton gradient, the energy of which drives ATP synthesis by the ATPase.

HISTONE DEACETYLASE

An enzyme and chromatin-remodelling factor that deacetylates histone proteins. Because deacetylation is energetically favoured, the class-I and -II deacetylases do not require any cofactors, such as ATP or NAD. However, the Sir2 class-III histone deacetylase uses NAD as a co-substrate.

NICOTINAMIDE

One of the cleavage products of nicotinamide adenine dinucleotide (NAD) that is produced in each deacetylation cycle (along with acetyl-ADP-ribose). It is also a non-competitive inhibitor of Sir2 deacetylases.

SIRTUIN

A protein that has sequence homology to the conserved enzymatic domain of yeast Sir2. In mammals, there are seven sirtuins, SIRT1–7.

FORKHEAD TRANSCRIPTION FACTOR

A member of a conserved family of transcription factors. Forkhead transcription factors belong to the winged-helix class of DNA-binding proteins. They function as key regulators of stress resistance and metabolism in mammals and of lifespan in C. elegans.

WHITE ADIPOSE TISSUE

(WAT). A depot of specialized cells that function as the main storage site for fat in the form of triglycerides. WAT has different functions, such as a heat insulator, a mechanical cushion and, most importantly, a source of energy. Also, WAT has been found to produce hormones, the levels of which are regulated by the amount of stored fat.

HYPERINSULINAEMIA

A state of abnormally high levels of insulin in the blood. One cause of hyper-insulinaemia is high insulin production by pancreatic β-cells to compensate for insulin resistance in peripheral tissues.

HYPERGLYCAEMIA

A state of high levels of glucose in the blood. Hyperglycaemia is usually an early sign of insulin resistance, which can lead to diabetes mellitus.

WALLERIAN STRAIN OF MICE

A strain of mice that carries a spontaneous dominant mutation in the Wld locus that stabilizes the axons of peripheral neurons from degeneration after neuronal damage. The Wld locus is at a translocation that fuses the gene encoding ubiquitin fusion degradation protein 2a (UFD2a), a ubiquitin-chain-assembly factor, to the complete sequence of the nicotinamide mononucleotide adenyl-transferase-1 (Nmnat1) gene. The resulting increase in NMNAT1 expression causes the phenotype.

UNCOUPLING PROTEINS

(UCPs). A family of mitochondrial-inner-membrane proteins. They allow the leakage of protons down the electrochemical gradient that is generated by respiration, thereby uncoupling oxygen consumption and ATP synthesis from the production of chemical energy.

BROWN ADIPOSE TISSUE

A depot of fat cells that is used for thermogenesis in rodents, brown adipose tissue derives its colour from rich vascularization and densely packed mitochondria; these properties reflect its high metabolism of fat in response to cold exposure.

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Bordone, L., Guarente, L. Calorie restriction, SIRT1 and metabolism: understanding longevity. Nat Rev Mol Cell Biol 6, 298–305 (2005). https://doi.org/10.1038/nrm1616

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