Toward a unified theory of caloric restriction and longevity regulation

Mech Ageing Dev. 2005 Sep;126(9):987-1002. doi: 10.1016/j.mad.2005.03.019.


The diet known as calorie restriction (CR) is the most reproducible way to extend the lifespan of mammals. Many of the early hypotheses to explain this effect were based on it being a passive alteration in metabolism. Yet, recent data from yeast, worms, flies, and mammals support the idea that CR is not simply a passive effect but an active, highly conserved stress response that evolved early in life's history to increase an organism's chance of surviving adversity. This perspective updates the evidence for and against the various hypotheses of CR, and concludes that many of them can be synthesized into a single, unifying hypothesis. This has important implications for how we might develop novel medicines that can harness these newly discovered innate mechanisms of disease resistance and survival.

Publication types

  • Review

MeSH terms

  • Aging
  • Animals
  • Caloric Restriction*
  • Cell Survival
  • Cytokines / metabolism
  • Gene Expression Regulation
  • Glucocorticoids / metabolism
  • Histone Deacetylases / metabolism
  • Humans
  • Immunity, Innate
  • Longevity*
  • Models, Biological
  • Models, Chemical
  • Niacinamide / metabolism
  • Nicotinamide Phosphoribosyltransferase
  • Reactive Oxygen Species
  • Resveratrol
  • Saccharomyces cerevisiae / metabolism
  • Sirtuins / metabolism
  • Stilbenes / pharmacology


  • Cytokines
  • Glucocorticoids
  • Reactive Oxygen Species
  • Stilbenes
  • Niacinamide
  • Nicotinamide Phosphoribosyltransferase
  • nicotinamide phosphoribosyltransferase, human
  • Sirtuins
  • Histone Deacetylases
  • Resveratrol