Life Extension - Pathology

Mitochondrial Theory of Aging - updated: 16 December 2008

The mitochondrial free radical theory of ageing--where do we stand?

Front Biosci. 2008 May 1;13:6554-79.

Gruber J, Schaffer S, Halliwell B.

Understanding the molecular mechanisms underlying the ageing process may provide the best strategy for addressing the challenges posed by ageing populations worldwide. One theory proposing such molecular mechanisms was formulated 50 years ago. Harman et al. suggested that ageing might be mediated by macromolecular damage through reactions involving reactive oxygen species (ROS). Today, a version of the free radical theory of ageing, focusing on mitochondria as source as well as target of ROS, is one of the most popular theories of ageing. Here we critically review the status of key principles and concepts on which this theory is based. We find that the evidence to date shows that many of the original assumptions are questionable, while on some critical issues further refinements in techniques are required. Even so, it is becoming evident that mitochondria and mtDNA integrity may indeed be crucial determinants of organismal ageing. Implications for the prospect of successful interventions as well as evidence for and against efficacy of current therapeutic approaches are discussed.

Publication Types:

• Review

Oxidative damage and mutation to mitochondrial DNA and age-dependent decline of mitochondrial respiratory function

Ann N Y Acad Sci. 1998 Nov 20;854:155-70

Wei YH, Lu CY, Lee HC, Pang CY, Ma YS.

Mitochondrial respiration and oxidative phosphorylation are gradually uncoupled, and the activities of the respiratory enzymes are concomitantly decreased in various human tissues upon aging. An immediate consequence of such gradual impairment of the respiratory function is the increase in the production of the reactive oxygen species (ROS) and free radicals in the mitochondria through the increased electron leak of the electron transport chain. Moreover, the intracellular levels of antioxidants and free radical scavenging enzymes are gradually altered. These two compounding factors lead to an age-dependent increase in the fraction of the ROS and free radical that may escape the defense mechanism and cause oxidative damage to various biomolecules in tissue cells. A growing body of evidence has established that the levels of ROS and oxidative damage to lipids, proteins, and nucleic acids are significantly increased with age in animal and human tissues. The mitochondrial DNA (mtDNA), although not protected by histones or DNA-binding proteins, is susceptible to oxidative damage by the ever-increasing levels of ROS and free radicals in the mitochondrial matrix. In the past few years, oxidative modification (formation of 8-hydroxy-2'-deoxyguanosine) and large-scale deletion and point mutation of mtDNA have been found to increase exponentially with age in various human tissues. The respiratory enzymes containing the mutant mtDNA-encoded defective protein subunits inevitably exhibit impaired respiratory function and thereby increase electron leak and ROS production, which in turn elevates the oxidative stress and oxidative damage of the mitochondria. This vicious cycle operates in different tissue cells at different rates and thereby leads to the differential accumulation of mutation and oxidative damage to mtDNA in human aging. This may also play some role in the pathogenesis of degenerative diseases and the age-dependent progression of the clinical course of mitochondrial diseases.

Publication Types:

• Review

The role of mitochondrial DNA mutations in aging and sarcopenia: implications for the mitochondrial vicious cycle theory of aging.

Exp Gerontol. 2008 Jan;43(1):24-33. Epub 2007 Oct 4

Hiona A, Leeuwenburgh C.

Aging is associated with a progressive loss of skeletal muscle mass and strength and the mechanisms mediating these effects likely involve mitochondrial DNA (mtDNA) mutations, mitochondrial dysfunction and the activation of mitochondrial-mediated apoptosis. Because the mitochondrial genome is densely packed and close to the main generator of reactive oxygen species (ROS) in the cell, the electron transport chain (ETC), an important role for mtDNA mutations in aging has been proposed. Point mutations and deletions in mtDNA accumulate with age in a wide variety of tissues in mammals, including humans, and often coincide with significant tissue dysfunction. Here, we examine the evidence supporting a causative role for mtDNA mutations in aging and sarcopenia. We review experimental outcomes showing that mtDNA mutations, leading to mitochondrial dysfunction and possibly apoptosis, are causal to the process of sarcopenia. Moreover, we critically discuss and dispute an important part of the mitochondrial 'vicious cycle' theory of aging which proposes that accumulation of mtDNA mutations may lead to an enhanced mitochondrial ROS production and ever increasing oxidative stress which ultimately leads to tissue deterioration and aging. Potential mechanism(s) by which mtDNA mutations may mediate their pathological consequences in skeletal muscle are also discussed.

Publication Types:

• Review

Mutations of mitochondrial DNA - cause or consequence of the ageing process?

Z Gerontol Geriatr. 2007 Oct;40(5):325-33

Meissner C.

Ageing is a stochastic process which leads to a gradual decline in cellular, tissue and even organ function, especially in energy dependent postmitotic tissues like skeletal muscle, brain and heart. The mitochondrial theory of ageing is based on the assumption that reactive oxygen species (ROS) and free radicals generated in the immediate vicinity of the electron transport chain during the lifespan of an organism damage proteins, lipids and mitochondrial DNA (mtDNA). Whereas it was generally believed that mitochondria are among the important players regarding the ageing process, two recent important approaches shed new light on the complex interactions. It has been shown by single cell experiments and computer simulation models that mitochondrial mutations are generated stochastically in childhood or early adolescence and accumulate clonally in a cell or muscle fibre, leading to a local age related impairment of cellular energy supply. Other important observations come from mitochondrial mutator mice, harbouring mitochondrial mutations due to a deficient repair enzyme (POLG). These mice reveal a premature senescence but do not exhibit a vicious cycle of increased oxidative damage or ROS production as has been postulated by the mitochondrial theory of ageing. At the moment it is hard to decide, if mitochondrial mutations are the cause or consequence of human ageing, but it is suggested that mitochondrial point mutations are just the consequence, while deletions seem to play a causal role.

Publication Types:

• Review

Program-like aging and mitochondria: instead of random damage by free radicals

J Cell Biochem. 2007 Dec 15;102(6):1389-99.

Blagosklonny MV.

As recently suggested, the target of rapamycin (TOR) pathway, rather than molecular damage by free radicals, drives aging and diseases of aging. But may mitochondria nevertheless contribute to aging? Here, I discuss aimless program-like aging (versus altruistic program), conflict between the cell and mitochondria, cell murder (versus cell suicide) and the role of mitochondria in aging. In particular, life-long selection among mitochondria may yield "selfish" (malignant) mitochondria resistant to autophagy. And TOR may create an intra-cellular environment that is permissive for such selfish mitochondria. In theory, pharmacologic inhibitors of the TOR pathway may reverse accumulation of defective mitochondria, while also inhibiting the aging process.

Publication Types:

• Review

The mitochondrial theory of aging

Biol Signals Recept. 2001 May-Aug;10(3-4):162-75

Kowald A.

Mitochondria are not only the main source of energy for most eukaryotic cells, but also the main source of free radicals. These reactive molecules can damage all components of a cell such as membranes, proteins and DNA. Therefore they have long been suspected to be involved in the biological aging process. The fact that mitochondria posses their own genetic material (mtDNA) and that they only have a limited arsenal of DNA repair processes makes them one of the prime targets for reactive oxygen species. The idea that genetically damaged mitochondria accumulate with time and are causally responsible for the aging phenotype via a disturbed energy budget is at the core of the so called mitochondrial theory of aging. In recent years this idea has gained impetus from the discovery of mitochondrial diseases and mtDNA deletions in old organisms. However, there are still many open questions regarding the mechanism of the accumulation of these deletions and their physiological relevance. This review is therefore intended to give an overview of the current state of the mitochondrial theory of aging and to discuss some recent experimental findings.

Publication Types:

• Review

The ageing mitochondrial genome

Nucleic Acids Res. 2007;35(22):7399-405.

Krishnan KJ, Greaves LC, Reeve AK, Turnbull D.

The population of elderly individuals has increased significantly over the past century and is predicted to rise even more rapidly in the future. Ageing is a major risk factor for many diseases such as neurodegenerative disease, diabetes and cancer. This highlights the importance of understanding the mechanisms involved in the ageing process. One plausible mechanism for ageing is accumulation of mutations in the mitochondrial genome. In this review, we discuss some of the most convincing data surrounding age-related mtDNA mutations and the evidence that these mutations contribute to the ageing process.

Publication Types:

• Review

Mitochondrial DNA and ageing

Biochim Biophys Acta. 2006 May-Jun;1757(5-6):611-7

Trifunovic A.

The accumulation of mitochondrial DNA mutations has been proposed as a potential mechanism in the physiological processes of ageing and age-related disease. Although mitochondria have long been anticipated as a perpetrator of ageing, there was little experimental evidence to link these changes directly with the cellular pathology of ageing. Recently, considerable progress in understanding basic mitochondrial genetics and in identifying acquired mtDNA mutations in ageing has been made. Furthermore, the creation of mtDNA-mutator mice has provided the first direct evidence that accelerating the mtDNA mutation rate can result in premature ageing, consistent with the view that loss of mitochondrial function is a major causal factor in ageing. This review will, therefore, focus on recent developments in ageing research related to the role played by mtDNA.

Publication Types:

• Review

Publication Types:

• Review