Sublethal mitochondrial stress with an attendant stoichiometric augmentation of reactive oxygen species may precipitate many of the beneficial alterations in cellular physiology produced by caloric restriction, intermittent fasting, exercise and dietary phytonutrients: "Mitohormesis" for health and vitality

Med Hypotheses. 2006;66(4):832-43. doi: 10.1016/j.mehy.2005.09.009. Epub 2005 Oct 18.


The precise mechanistic sequence producing the beneficial effects on health and lifespan seen with interventions as diverse as caloric restriction, intermittent fasting, exercise, and consumption of dietary phytonutrients is still under active characterization, with large swaths of the research community kept in relative isolation from one another. Among the explanatory models capable of assisting in the identification of precipitating elements responsible for beneficial influences on physiology seen in these states, the hormesis perspective on biological systems under stress has yielded considerable insight into likely evolutionarily consistent organizing principles functioning in all four conditions. Recent experimental findings provide the tantalizing initial lodestones for an entirely new research front examining molecular substrates of stress resistance. In this novel body of research, a surprising new twist has emerged: Reactive oxygen species, derived from the mitochondrial electron transport system, may be necessary triggering elements for a sequence of events that result in benefits ranging from the transiently cytoprotective to organismal-level longevity. With the recent appreciation that reactive oxygen species and reactive nitrogen species function as signaling elements in a interconnected matrix of signal transduction, the entire basis of many widely accepted theories of aging that predominated in the past may need to be reconsidered to facilitate the formulation of an new perspective more correctly informed by the most contemporaneous experimental findings. This perspective, the mitohormesis theory, can be used in many disparate domains of inquiry to potentially explain previous findings, as well as point to new targets of research. The utility of this perspective for research on aging is significant, but beyond that this perspective emphasizes the pressing need to rigorously characterize the specific contribution of the stoichiometry of reactive oxygen species and reactive nitrogen species in the various compartments of the cell to cytoprotection and vitality. Previous findings regarding the influences of free radical chemistry on cellular physiology may have represented assessments examining the consequences of isolated elevation of signaling elements within a larger signal transductive apparatus, rather than definitive characterizations of the only modality of reactive oxygen species (and reactive nitrogen species) influence. In applying this perspective, it may be necessary for the research community, as well as the practicing clinician, to engender a more sanguine perspective on organelle level physiology, as it is now plausible that such entities have an evolutionarily orchestrated capacity to self-regulate that may be pathologically disturbed by overzealous use of antioxidants, particularly in the healthy.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Caloric Restriction
  • Cell Physiological Phenomena
  • DNA, Mitochondrial / metabolism
  • Diet
  • Exercise
  • Fasting
  • Health*
  • Humans
  • Mitochondria / metabolism*
  • Oxidative Stress*
  • Reactive Oxygen Species / metabolism*


  • DNA, Mitochondrial
  • Reactive Oxygen Species