Life Extension - Pathology

Free Radicals - updated: 08 December 2008

An integrated view of oxidative stress in aging: basic mechanisms, functional effects, and pathological considerations

Am J Physiol Regul Integr Comp Physiol 292: R18-R36, 2007

Kevin C. Kregel and Hannah J. Zhang

Aging is an inherently complex process that is manifested within an organism at genetic, molecular, cellular, organ, and system levels. Although the fundamental mechanisms are still poorly understood, a growing body of evidence points toward reactive oxygen species (ROS) as one of the primary determinants of aging. The "oxidative stress theory" holds that a progressive and irreversible accumulation of oxidative damage caused by ROS impacts on critical aspects of the aging process and contributes to impaired physiological function, increased incidence of disease, and a reduction in life span. While compelling correlative data have been generated to support the oxidative stress theory, a direct cause-and-effect relationship between the accumulation of oxidatively mediated damage and aging has not been strongly established. The goal of this minireview is to broadly describe mechanisms of in vivo ROS generation, examine the potential impact of ROS and oxidative damage on cellular function, and evaluate how these responses change with aging in physiologically relevant situations. In addition, the mounting genetic evidence that links oxidative stress to aging is discussed, as well as the potential challenges and benefits associated with the development of antiaging interventions and therapies

Publication Types:

• Review

The free radical theory of aging matures

Physiol Rev. 1998 Apr;78(2):547-81

Beckman KB, Ames BN.

The free radical theory of aging, conceived in 1956, has turned 40 and is rapidly attracting the interest of the mainstream of biological research. From its origins in radiation biology, through a decade or so of dormancy and two decades of steady phenomenological research, it has attracted an increasing number of scientists from an expanding circle of fields. During the past decade, several lines of evidence have convinced a number of scientists that oxidants play an important role in aging. (For the sake of simplicity, we use the term oxidant to refer to all "reactive oxygen species," including O2-., H2O2, and .OH, even though the former often acts as a reductant and produces oxidants indirectly.) The pace and scope of research in the last few years have been particularly impressive and diverse. The only disadvantage of the current intellectual ferment is the difficulty in digesting the literature. Therefore, we have systematically reviewed the status of the free radical theory, by categorizing the literature in terms of the various types of experiments that have been performed. These include phenomenological measurements of age-associated oxidative stress, interspecies comparisons, dietary restriction, the manipulation of metabolic activity and oxygen tension, treatment with dietary and pharmacological antioxidants, in vitro senescence, classical and population genetics, molecular genetics, transgenic organisms, the study of human diseases of aging, epidemiological studies, and the ongoing elucidation of the role of active oxygen in biology.

Publication Types:

• Review

Oxidative Stress, Mitochondrial DNA Mutation, and Impairment of Antioxidant Enzymes in Aging

Experimental Biology and Medicine 227:671-682 (2002)

Yau-Huei Wei and Hsin-Chen Lee

Mitochondria do not only produce less ATP, but they also increase the production of reactive oxygen species (ROS) as by-products of aerobic metabolism in the aging tissues of the human and animals. It is now generally accepted that aging-associated respiratory function decline can result in enhanced production of ROS in mitochondria. Moreover, the activities of free radical-scavenging enzymes are altered in the aging process. The concurrent age-related changes of these two systems result in the elevation of oxidative stress in aging tissues. Within a certain concentration range, ROS may induce stress response of the cells by altering expression of respiratory genes to uphold the energy metabolism to rescue the cell. However, beyond the threshold, ROS may cause a wide spectrum of oxidative damage to various cellular components to result in cell death or elicit apoptosis by induction of mitochondrial membrane permeability transition and release of apoptogenic factors such as cytochrome c. Moreover, oxidative damage and large-scale deletion and duplication of mitochondrial DNA (mtDNA) have been found to increase with age in various tissues of the human. Mitochondria act like a biosensor of oxidative stress and they enable cell to undergo changes in aging and age-related diseases. On the other hand, it has recently been demonstrated that impairment in mitochondrial respiration and oxidative phosphorylation elicits an increase in oxidative stress and causes a host of mtDNA rearrangements and deletions. Here, we review work done in the past few years to support our view that oxidative stress and oxidative damage are a result of concurrent accumulation of mtDNA mutations and defective antioxidant enzymes in human aging.

Publication Types:

• Review

The oxidative hypothesis of senescence

J Postgrad Med. 2007 Jul-Sep;53(3):207-13

Gilca M, Stoian I, Atanasiu V, Virgolici B.

The oxidative hypothesis of senescence, since its origin in 1956, has garnered significant evidence and growing support among scientists for the notion that free radicals play an important role in ageing, either as "damaging" molecules or as signaling molecules. Age-increasing oxidative injuries induced by free radicals, higher susceptibility to oxidative stress in short-lived organisms, genetic manipulations that alter both oxidative resistance and longevity and the anti-ageing effect of caloric restriction and intermittent fasting are a few examples of accepted scientific facts that support the oxidative theory of senescence. Though not completely understood due to the complex "network" of redox regulatory systems, the implication of oxidative stress in the ageing process is now well documented. Moreover, it is compatible with other current ageing theories (e.g, those implicating the mitochondrial damage/mitochondrial-lysosomal axis, stress-induced premature senescence, biological "garbage" accumulation, etc). This review is intended to summarize and critically discuss the redox mechanisms involved during the ageing process: sources of oxidant agents in ageing (mitochondrial -electron transport chain, nitric oxide synthase reaction- and non-mitochondrial- Fenton reaction, microsomal cytochrome P450 enzymes, peroxisomal beta -oxidation and respiratory burst of phagocytic cells), antioxidant changes in ageing (enzymatic- superoxide dismutase, glutathione-reductase, glutathion peroxidase, catalase- and non-enzymatic glutathione, ascorbate, urate, bilirubine, melatonin, tocopherols, carotenoids, ubiquinol), alteration of oxidative damage repairing mechanisms and the role of free radicals as signaling molecules in ageing.

Publication Types:

• Review

Free radical theory of aging

Curr Opin Clin Nutr Metab Care. 2002 Jan;5(1):5-10

Biesalski HK.

The free radical theory of the aging process is based on the hypothesis that with increasing age, mutations of the mitochondrial DNA will accumulate and will at least lead to a loss of function with subsequent acceleration of cell death. Even if this theory is widely accepted, the reactive-oxygen-species-induced mutations of mitochondrial DNA, the accumulation of mitochondrial DNA and the role of antioxidants are not fully understood. Based on this theory, supplements with unproven mixtures of antioxidants or hormones, such as melatonin with antioxidant properties, are widely recommended and cover a big market. However, we are far away from understanding their specific role and we have to consider that, based on the free radical theory of aging, the balance of antioxidants and prooxidants in both directions is of importance in maintaining the physiological function of both reactive oxygen species and antioxidants.

Publication Types:

• Review

New insights into structure and function of mitochondria and their role in aging and disease

Antioxid Redox Signal. 2006 Mar-Apr;8(3-4):417-37

Lenaz G, Baracca A, Fato R, Genova ML, Solaini G.

This review covers some novel findings on mitochondrial biochemistry and discusses diseases due to mitochondrial DNA mutations as a model of the changes occurring during physiological aging. The random collision model of organization of the mitochondrial respiratory chain has been recently challenged on the basis of findings of supramolecular organization of respiratory chain complexes. The source of superoxide in Complex I is discussed on the basis of laboratory experiments using a series of specific inhibitors and is presumably iron sulfur center N2. Maternally inherited diseases due to mutations of structural genes in mitochondrial DNA are surveyed as a model of alterations mimicking those occurring during normal aging. The molecular defects in senescence are surveyed on the basis of the "Mitochondrial Theory of Aging", establishing mitochondrial DNA somatic mutations, caused by accumulation of oxygen radical damage, to be at the basis of cellular senescence. Mitochondrial production of reactive oxygen species increases with aging and mitochondrial DNA mutations and deletions accumulate and may be responsible for oxidative phosphorylation defects. Evidence is presented favoring the mitochondrial theory, with primary mitochondrial alterations, although the problem is made more complex by changes in the cross-talk between nuclear and mitochondrial DNA.

Publication Types:

• Review

Oxidative stress and mitochondrial DNA mutations in human aging

Proc Soc Exp Biol Med. 1998 Jan;217(1):53-63

Wei YH.

The mitochondrial respiratory system is the major intracellular source of the reactive oxygen species (ROS) and free radicals, which are generated as byproducts during the transfer of electrons from NADH or FADH2 to molecular oxygen under normal physiological conditions. An age-dependent increase in the fraction of these toxic byproducts that may escape the defense mechanism of human and animal cells can induce a broad spectrum of oxidative damage to the biomolecules in the mitochondria and the cell as a whole. Abundant evidence has been gathered to suggest that an elevation of oxidative stress and associated oxidative damages gradually occur in the mitochondria of tissue cells during aging. The mitochondrial DNA (mtDNA), while not protected by histones or DNA-binding proteins, is continually exposed to a high steady-state level of ROS and free radicals in the matrix of the mitochondria. Thus, oxidative modification and mutation of mtDNA occur with great ease, and the extent of such alterations of mtDNA increases exponentially with age. The concurrent enhancement of lipid peroxidation and oxidative modification of proteins in mitochondria elicited by the ever-increasing amount of the ROS further aggravate the mutation and oxidative damage to mtDNA in the aging process. The respiratory enzymes containing the defective mtDNA-encoded protein subunits exhibit impaired electron transport function and thereby increase the electron leak and ROS production, which in turn elevate the oxidative stress and oxidative damage to mitochondria. This vicious cycle operates in various tissue cells at different rate and leads to differential accumulation of oxidatively modified and mutant mtDNAs. This may explain the difference in functional decline and structural deterioration of different organs and tissues in human aging. The central role that alterations of the mitochondria and mtDNA may play in aging and age-related degenerative diseases is discussed in relation to the "Mitochondrial theory of aging."

Publication Types:

• Review

The mitochondrial theory of aging and its relationship to reactive oxygen species damage and somatic mtDNA mutations

Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):18769-70

Loeb LA, Wallace DC, Martin GM.

Mitochondria are cellular energy factories that generate ATP via the reaction of hydrocarbons with oxygen. Every human cell contains hundreds of mitochondria, and each mitochondrion contains multiple copies of mitochondrial DNA (mtDNA). The ancestry of the mitochondrial genome can be traced to early eubacteria, and it is therefore unexpected that this organelle may have a major role in governing the pace of human aging. Three recent papers (1–3) plus a work published in a recent issue of PNAS (4) have demonstrated that accelerating the mtDNA mutation rate can result in some features suggestive of premature aging, consistent with the view that loss of mitochondrial function is a major causal factor in aging.

Publication Types:

• Review

Mutation and oxidative damage of mitochondrial DNA and defective turnover of mitochondria in human aging

J Formos Med Assoc. 1997 Oct;96(10):770-8

Lee HC, Wei YH.

Accumulation of somatic mutations in the mitochondrial DNA (mtDNA) is a major contributor to human aging and degenerative diseases. Rapid progress has been made in unraveling the molecular changes associated with aging. MtDNA mutations are likely early molecular events associated with human aging that may be responsible for the age-dependent decline in mitochondrial respiratory functions. Many types of mutations of the mitochondrial genome impair the function of the respiratory and oxidative phosphorylation systems. This not only results in the age-dependent decline in cellular functions, but also increases the generation of reactive oxygen species (ROS) through the respiratory chain. ROS may cause oxidative damage to mtDNA, further impairing cellular functions and thereby increasing the rate of aging. How aging is elicited by the relatively low amount (< 5%) of aging-associated mutated mtDNA in human tissues is poorly understood. Protein degradation may be a key mechanism in the formation of lipofuscin and possibly in cellular aging. The thiol proteases, critical for protein turnover and degradation, are particularly susceptible to free radical damage at their active sites. If the degradative pathway in mitochondria is defective, the mitochondrion-derived degradation intermediates accumulate within secondary lysosomes, leading to the formation of residual bodies. These degradation products may become another "stressor" to tissue cells. We therefore propose that defective mitochondrial turnover is a cause of accumulation of defective mitochondrial constituents and an important contributory factor to human aging.

Publication Types:

• Review

Publication Types:

• Review