calorie restriction; dietary restriction; food restriction

Introduction

Restriction of dietary caloric intake.

Biochemistry

• eNoSC complex may play a role
  • in mammals, calorie restriction activates Sirt1 & Sirt3
  • expressed Sirt1 protein inhibits PPAR-gamma; the effect is lipolysis
  • SIRT1 appears to be a component of the eNoSC complex that mediates silencing of rDNA in response to intracellular energy status
  • calorie restriction may inhibit Alzheimer's disease amyloid pathology via activation of SIRT1, inhibition of ROCK1 & activation of alpha-secretase
• nutrient/energy sensing function of mTOR & associated complexes TORC1 & TORC2 may play role
  • increased AMP kinase (AMPK) activity in hepatocytes during calorie restriction
  • AMPK may sense energy status as a downstream target of the mTOR pathway
  • ULK1 & ULK1 interact with mTOR & AMPK as part of regulatory feedback loop in autophagy
    • under nutrient sufficiency, ULK1 is phosphorylated by mTOR, disrupting the interaction with AMPK & preventing activation of ULK1 (putative)
    • in response to nutrient limitation, ULK1 is phosphorylated & activated by AMPK, leading to autophagy activation
    • in response to nutrient sufficiency ULK1 is phosphorylated by mTOR, disrupting the interaction with AMPK & preventing activation of ULK1
    • ULK2 acts both as a downstream effector & negative regulator of mTORC1 via interaction with RPTOR
    • ULK2 is activated via phosphorylation by AMPK
    • ULK2 also acts as a regulator of AMPK by mediating phosphorylation of AMPK subunits PRKAA1, PRKAB2 & PRKAG1, negatively regulating AMPK activity
  • metformin increases the activity of AMPK & extends life span of female mice
• SIRT2 deacetylates FOXO3a in response to calorie restriction
• in C elegans, the longevity of calorie restriction is linked to PHA-4.; orthologous genes in humans encode the Foxa family of transcription factors Foxa1, Foxa2 & Foxa3

Benefit/risk

• postulated benefits in humans
  • diminished non-enzymatic protein glycation (see Laboratory: below)
  • beneficial changes in WBC cell immunologic responses
  • epigenetic stability
    • reduced phenotypic drift from
      • altered DNA-protein interactions
      • DNA methylation
      • histone acetylation

Laboratory

Biomarkers associated calorie restriction include:

• diminished body temperature
• diminished mean plasma insulin
  • diminished mean plasma glucose
    • diminished non-enzymatic protein glycation
• decreased DNA damage*

* DNA damage measured by comet tail moment

Inconsistent or negative effects of calorie restriction

• increased plasma dehydroepiandrosterone sulfate (DHEA-sulfate), no change
• protein carbonyls
• fasting serum glucose
  • diminished average serum glucose likely results in changes in protein glycation

Clinical trials

[10]

• short-term study of 3 months:
• 30% calorie restriction improved memory in elderly women
• there are no long-term controlled studies in humans (also see weight reduction)

[13]

• a randomized controlled trial of calorie restriction as a treatment for cancer has been approved by the institutional review board at Duke University

Comparative biology

• calorie restriction slows the rate of aging in rodents & delays onset of diseases of old age, including malignancies
• disparate findings in longevity studies examining effect of calorie restriction (CR) in rhesus monkeys
  • NIA study found no increase in survival with CR
  • Wisconsin study found an increase in survival with CR

Notes

• according to, results in loss of muscle mass in obese elderly thus is less preferable to exercise alone for weight reduction
  • outcomes not considered

More general terms

• nutritional therapy

Additional terms

• very low-calorie diet (VLCD)
• weight reduction; intentional weight loss; excess weight reduction