How increased oxidative stress promotes longevity and metabolic health: The concept of mitochondrial hormesis (mitohormesis)

doi:10.1016/j.exger.2010.03.014

Experimental Gerontology

Volume 45, Issue 6, June 2010, Pages 410-418

https://doi.org/10.1016/j.exger.2010.03.014 Get rights and content

Abstract

Recent evidence suggests that calorie restriction and specifically reduced glucose metabolism induces mitochondrial metabolism to extend life span in various model organisms, including Saccharomyces cerevisiae, Drosophila melanogaster, Caenorhabditis elegans and possibly mice. In conflict with Harman’s free radical theory of aging (FRTA), these effects may be due to increased formation of reactive oxygen species (ROS) within the mitochondria causing an adaptive response that culminates in subsequently increased stress resistance assumed to ultimately cause a long-term reduction of oxidative stress. This type of retrograde response has been named mitochondrial hormesis or mitohormesis, and may in addition be applicable to the health-promoting effects of physical exercise in humans and, hypothetically, impaired insulin/IGF-1-signaling in model organisms. Consistently, abrogation of this mitochondrial ROS signal by antioxidants impairs the lifespan-extending and health-promoting capabilities of glucose restriction and physical exercise, respectively. In summary, the findings discussed in this review indicate that ROS are essential signaling molecules which are required to promote health and longevity. Hence, the concept of mitohormesis provides a common mechanistic denominator for the physiological effects of physical exercise, reduced calorie uptake, glucose restriction, and possibly beyond.

Section snippets

Calorie restriction

A limited reduction of nutritional calorie uptake, so-called calorie restriction (CR), has been shown to extend life span in multiple species and model organisms, as initially observed by McCay et al. (1935). It is beyond the scope of this review to summarize the multiple findings on CR, since excellent reviews on this topic have been published in the past (Weindruch and Walford, 1988, Masoro, 2000, Speakman et al., 2002, Heilbronn and Ravussin, 2003, Ingram et al., 2004, Anson et al., 2005,

Reduction of specific macronutrients

Nutritional, i.e. metabolizable calories are derived from carbohydrates, triacylglycerols (fat) and proteins. These contain a few different monosaccharides (including glucose), and significant numbers of fatty acids and amino acids, respectively. Limited evidence exists whether the generally accepted effects of calorie restriction can be attributed to specific macronutrients, i.e. whether restriction of a single macronutrient may exert the same effects than overall CR does. This topic has been

Glucose restriction

A specific restriction of nutritive glucose is, with the exception of yeast and D. melanogaster, difficult to achieve in eukaryotic model organisms. In Saccharomyces cerevisiae, it was shown that reduced glucose availability significantly extends chronological life span, and this extension depends on induction of respiration (Lin et al., 2002) as well as sirtuins (Lin et al., 2000). While the dependence on sirtuins is a matter of debate (Kaeberlein et al., 2004, Agarwal et al., 2005, Guarente,

Impaired insulin/IGF-1 signaling and glucose availability

Insulin and insulin-like growth factor 1 (IGF-1) are peptide hormones. Insulin is produced in and secreted from the pancreatic beta-cells, while IGF-1 is produced in the liver. IGF-1 production and release depends on a third hormone named somatotropin (STH) a.k.a. growth hormone (GH) which stems from the anterior pituitary gland. Insulin, GH and IGF-1 are hormones that bind to specific and, at least in mammals, distinct receptors. However, GH exerts some of its effects indirectly by regulating

Induction of mitochondrial metabolism by calorie/glucose restriction

While some papers suggest that the net uptake of calories is not reduced over life time in states of CR (Masoro et al., 1982, Mair et al., 2005), it is by definition agreed upon that during the actual CR intervention a relative depletion of available energy occurs.

Mitochondria convert nutritional energy more effectively into readily available energy, i.e. ATP, than non-oxidative metabolism of carbohydrates and some amino acids does. E.g., while glycolytic metabolism of one mol of glucose

Oxidative stress and mitochondrial hormesis (mitohormesis)

About five decades ago and as stated above, increased formation of ROS as a consequence of increased metabolic rate was proposed to be the major culprit for the ageing process and decreased life span (Harman, 1956). Mitochondria are the main source of ROS. For a long time, these were considered exclusively unwanted by-products of OxPhos. In support of this view, a significant number of studies in various model organisms suggests that amelioration of oxidative stress contributes to an increase

Physical exercise

As summarized above, CR and specifically glucose restriction induce mitochondrial respiration and ROS formation in various model organisms. The ROS signal appears to induce ROS defense mechanisms, culminating in extended lifespan, which reflects a typical adaptive response, consistent with the mitohormesis hypothesis. Antioxidants prevent this adaptive response, and extension of lifespan is abolished. It remains to be resolved, in which time-resolved order these processes occur, and

Acknowledgments

Studies in the authors’ laboratory have been or are supported by the German Research Association (DFG), the German Ministry of Education and Research (BMBF), the European Foundation for the Study of Diabetes (EFSD), the Leibniz Association (WGL), the Fritz-Thyssen-Stiftung and the Wilhelm-Sander-Stiftung. We apologize to those whose work relevant for the topic has not been cited solely due to limitations of space.

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ReviewHow increased oxidative stress promotes longevity and metabolic health: The concept of mitochondrial hormesis (mitohormesis)

Abstract

Section snippets

Calorie restriction

Reduction of specific macronutrients

Glucose restriction

Impaired insulin/IGF-1 signaling and glucose availability

Induction of mitochondrial metabolism by calorie/glucose restriction

Oxidative stress and mitochondrial hormesis (mitohormesis)

Physical exercise

Acknowledgments

Ageing Res. Rev.

Mayo Clin. Proc.

J. Biol. Chem.

Free Radic. Biol. Med.

Lancet

Cell Metab.

J. Biol. Chem.

Mol. Cell.

Toxicol. Appl. Pharmacol.

Free Radic. Biol. Med.

Cell

J. Biol. Chem.

Am. J. Clin. Nutr.

Biochem. Biophys. Res. Commun.

Mech. Ageing Dev.

Ageing Res. Rev.

Trends Neurosci.

Am. J. Clin. Nutr.

Curr. Biol.

Cell Metab.

Mol. Cell.

Mech. Ageing Dev.

Am. J. Clin. Nutr.

J. Nutr.

Exp. Gerontol.

Exp. Gerontol.

Mech. Ageing Dev.

Exp. Gerontol.

Cell Metab.

Clin. Nutr.

Free Radic. Biol. Med.

FEBS Lett.

Mech. Ageing Dev.

J. Nutr.

Effects of tocotrienols on life span and protein carbonylation in Caenorhabditis elegans

J. Gerontol. A Biol. Sci. Med. Sci.

Caloric restriction augments ROS defense in S. cerevisiae by a Sir2p independent mechanism

Free Radic. Res.

Alpha- Tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: effects of base-line characteristics and study compliance

J. Natl. Cancer. Inst.

Long-lived growth hormone receptor knockout mice. Interaction of reduced insulin-like growth factor i/insulin signaling and caloric restriction

Endocrinology

High oxidative damage levels in the longest-living rodent, the naked mole-rat

Aging Cell

The diet restriction paradigm: a brief review of the effects of every-other-day feeding

Age (Ohama)

The AMP-activated protein kinase aak-2 links energy levels and insulin-like signals to lifespan in C. elegans

Genes Dev.

A randomized trial of antioxidant vitamins to prevent second primary cancers in head and neck cancer patients

J. Natl. Cancer. Inst.

Oxygen radicals, a failure or a success of evolution?

Free Radic. Res. Commun.

Extending the lifespan of long-lived mice

Nature

From mice to men: insights into the insulin resistance syndromes

Annu. Rev. Physiol.

Genetic links between diet and lifespan: shared mechanisms from yeast to humans

Nat. Rev. Genet.

Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis

JAMA

Extended longevity in mice lacking the insulin receptor in adipose tissue

Science

Review
How increased oxidative stress promotes longevity and metabolic health: The concept of mitochondrial hormesis (mitohormesis)