Free Radical Hypothesis Of Aging Research Articles

Evidence of Oxidative Stress in Alzheimer's Disease Brain and Antioxidant Therapy

Alzheimer's disease (AD) is the most common form of neurodegenerative disease associated with dementia in the elderly. Although the initiating events are still unknown, it is clear that AD, at least in its sporadic form, results from the combination of genetic risk factors with different epigenetic events. Among them, a growing body of evidence suggests that an imbalance between free radical formation and destruction is involved in AD pathogenesis. This concept originally derived from the free radical hypothesis of aging, which states that the age-related accumulation of free radicals results in damaged cell components. The fact that age is a key risk factor in AD provides support for this hypothesis. There is a long list of surrogate markers, which includes lipid, DNA, and protein oxidation, of oxidant stress-mediated injury that have been reported as elevated in the AD brain. Moreover, epidemiologic studies show that dietary intake of natural or synthetic products with a putative antioxidant effect, such as (but not only) vitamin E, reduces the risk of AD. On the other hand, antioxidative intervention studies in animal models of AD-like amyloidosis show a significant reduction in amyloid beta deposition and behavioral improvements. However, a randomized clinical trial of vitamin E supplementation in AD patients shows only a marginal positive effect. Another study reports no effect of vitamin E on the rate of progression of AD in subjects with mild cognitive impairment. This article will review both promises and caveats of the available data and propose future directions to be taken for addressing them.

Regulation of replicative senescence by NADP +-dependent isocitrate dehydrogenase

The free radical hypothesis of aging postulates that senescence is due to an accumulation of cellular oxidative damage, caused largely by reactive oxygen species that are produced as by-products of normal metabolic processes. Recently, we demonstrated that the control of cytosolic and mitochondrial redox balance and the cellular defense against oxidative damage is one of the primary functions of cytosolic (IDPc) and mitochondrial NADP +-dependent isocitrate dehydrogenase (IDPm) by supplying NADPH for antioxidant systems. In this paper, we demonstrate that modulation of IDPc or IDPm activity in IMR-90 cells regulates cellular redox status and replicative senescence. When we examined the regulatory role of IDPc and IDPm against the aging process with IMR-90 cells transfected with cDNA for IDPc or IDPm in sense and antisense orientations, a clear inverse relationship was observed between the amount of IDPc or IDPm expressed in target cells and their susceptibility to senescence, which was reflected by changes in replicative potential, cell cycle, senescence-associated β-galactosidase activity, expression of p21 and p53, and morphology of cells. Furthermore, lipid peroxidation, oxidative DNA damage, and intracellular peroxide generation were higher and cellular redox status shifted to a prooxidant condition in the cell lines expressing the lower level of IDPc or IDPm. The results suggest that IDPc and IDPm play an important regulatory role in cellular defense against oxidative stress and in the senescence of IMR-90 cells.

S15. The Free Radical Hypothesis of Aging

S15. The Free Radical Hypothesis of Aging

The free-radical hypothesis of aging goes prokaryotic.

With respect to oxidative damage and its targets, growth-arrested bacterial cells show some of the same signs of senescence as aging insects, worms and mammals. In addition, the fact that the life span of growth-arrested Escherichia coli cells is greatly extended by limiting oxygen availability suggests that free radicals may be one causal factor behind bacterial senescence. Recent analysis reveals a novel culprit in this oxidation, namely the production of aberrant proteins, which are especially susceptible to oxidative attack. This route of oxidation appears to elude the classical oxidative defense proteins. In addition, the failure of growth-arrested cells to fully combat oxidative damage may be linked to a trade-off between proliferation activities and stress management. Even during stasis, E. coli cells maintain a basal transcription of reproduction-related genes, and resources are thus partly diverted from maintenance and stress defences to activities relating to proliferation. Thus, some aspects of bacterial senescence may lend support to contemporary theories of aging, including the free radical, antagonistic pleiotropy, and disposable soma theories.

Expression Profile of Aging and Oxidative Stress Response in Drosophila melanogaster.

INTRODUCTION. The free radical hypothesis of aging suggests that reactive oxygen species accumulated with age cause oxidative damages to molecules, such as nucleic acids, proteins and lipids, and are causally linked to aging and death(1). The regulation of gene expression in aging and its correlation with that in response to oxidative stress, however, is poorly understood. We have used the microarray technique to study the genome-wide expression patterns of aging and oxidative stress response in Drosophila melanogaster.

Reducing equivalents in the aging process.

Reducing equivalents may play a major role in the aging process. These metabolites are responsible for the endogenous redox potential in the living cell which is kept under tight regulation. Among their various roles is the ability to donate electrons to reactive oxygen species and by doing so to scavenge them. Most of the reducing equivalents in the cell are molecules with low molecular weights, such as glutathione and NADH which are synthesized by the cell. Other members of this group, such as uric acid are produced as waste products, while others, such as ascorbic acid and tocopherol, are derived from the diet. We studied the role of these equivalents in the aging process in various rat tissues. We demonstrated that the reducing power of a tissue may reflect its antioxidant activity. We used cyclic voltammeter methodology in order to evaluate the overall reducing power of tissue homogenates and other biological fluids. It was found that reducing power changes during the aging process in a bell-shaped manner in liver, lungs and kidneys, but not in heart and brain. We also showed that skin possesses strong reducing power which decreases dramatically with age. A non-invasive procedure to evaluate the oxidation status and the antioxidant activity of skin was developed. Using this method we demonstrated that there is an accumulation of organic peroxide in old skin compared to young skin, supporting the free radical hypothesis of aging.

Chronic antioxidant treatment improves the cognitive performance of aged rats

Free radicals and oxidative damage have been implicated in brain aging and several neurodegenerative diseases. The purpose of the present study was to determine whether antioxidants could alleviate age-associated cognitive and motor changes. Aged 24-month-old male Sprague-Dawley rats were treated for 4–5 months with daily i.p. injections of the spin-trapping compound phenyl-α- tert-butylnitrone (PBN; 32 mg/kg) and α-tocopherol (200 mg/kg) or with vehicles. Antioxidant-treated animals also received ascorbate in their drinking water. In Morris water maze testing after two months, antioxidant-treated rats had a greater rate of acquisition (learning), although overall acquisition was not affected. Moreover, antioxidant-treated rats exhibited significantly greater memory retention than vehicle-treated rats in water maze testing. Subsequent tests for passive avoidance behavior and motor activity/skill revealed no effect of antioxidant treatment. In a separate group of aged 33-month-old rats that received the same combination of antioxidants for only 14 days, antioxidant treatment did not affect basal levels of brain lipid peroxidation (as indexed by TBAR formation) compared to controls. The results of this study provide initial evidence that chronic antioxidant treatment can improve cognitive function during aging, thus supporting the ‘free radical hypothesis of aging’ related to brain function.

Extension of Life-Span by Overexpression of Superoxide Dismutase and Catalase in Drosophila melanogaster

The hypothesis that oxygen free radicals are causally involved in the aging process was tested by a study of the effects of simultaneous overexpression of copper-zinc superoxide dismutase and catalase. As compared to diploid controls, transgenic flies carrying three copies of each of these genes exhibited as much as a one-third extension of life-span, a longer mortality rate doubling time, a lower amount of protein oxidative damage, and a delayed loss in physical performance. Results provide direct support for the free radical hypothesis of aging.

Relationship between mitochondrial superoxide and hydrogen peroxide production and longevity of mammalian species

The objective of this study was to examine the possible involvement of oxygen free radicals in the aging process. Rates of mitochondrial O 2 .− and H 2O 2 production and oxygen consumption in the kidney and the heart were compared among seven different mammalian species namely, mouse, hamster, rat, guinea pig, rabbit, pig, and cow, whose maximum life span potential (MLSP) varies from 3.5 to 30 years. The rates of mitochondrial O 2 .− and H 2O 2 generation were inversely correlated to MLSP, and directly related to specific metabolic rate and state 4 mitochondrial respiration. Results of this study indicate that under identical conditions, mitochondria from shoter-lived species produce relatively higher amounts of reactive oxygen species than those from the longer-lived species, and, thus, support the free radical hypothesis of aging.

Comparison of mitochondrial pro-oxidant generation and anti-oxidant defenses between rat and pigeon: possible basis of variation in longevity and metabolic potential

Non-passerine birds and mammals of similar body weight have a roughly comparable metabolic rate, but the life span and the metabolic potential, i.e. the total amount of energy consumed per unit of body mass during life, is several times higher in the birds. The objective of this study was to explore the possible basis of this characteristic in the context of the predictions of the free radical hypothesis of aging. Accordingly, pigeon and rat, which have a similar body weight, were compared by examining the mitochondrial rates of O 2 - and H 2O 2 generation and activities of superoxide dismutase, catalase and glutathione peroxidase and concentration of glutathione in the brain, heart and kidney. Compared with the rat, the rate of mitochondrial O 2 - generation in the pigeon ranged between 50 and 67%, and H 2O 2 production between 31 and 77%. Activity of superoxide dismutase was uniformly higher and catalase activity consistently lower in the tissues of the pigeon compared with the rat. Glutathione peroxidase activity and glutathione concentration were higher in the pigeon in two out of the three organs studied, and comparable in the third organ. The magnitude of the differences between the two species was greater in the rates of O 2 - and H 2O 2 generation than in anti-oxidant defenses. Results indicate that the relatively greater longevity and metabolic potential of the pigeon may be related to significantly lower rates of O 2 - and H 2O 2 generation and higher overall level of anti-oxidant defense.

Biochemical Correlates of Longevity in Two Closely Related Rodent Species

The objective of this study was to explore the basis of variations in the life span and metabolic potential, i.e., total amount of energy consumed during life, between different species, in context of the free radical hypothesis of aging. A comparison was made between the house mouse ( Mus musculus) and the white-footed mouse ( Peromyscus leucopus): the latter has >2-fold greater life span and metabolic potential than the former. Longer life span and higher metabolic potential of Peromyscus were associated with low rates of mitochondrial O .− 2 and H 2O 2 generation, higher activities of catalase and glutathione peroxidase and low levels of protein oxidative damage as well as low susceptibility to oxidative damage in response to experimental oxidative stress. Results support the role of oxidative stress in aging.

The free radical hypothesis of aging: An appraisal of the current status

The objective of this review article is to assess the current status of the predictions of the free radical hypothesis of aging, highlighting some of the controversies surrounding the previous assumptions. Topics for discussion include: metabolic rate and aging, oxidative stress and molecular damage during aging, antioxidants and aging, antioxidant defenses and life spans of different species, and pro-oxidant generation and aging. On the basis of currently available evidence, it is concluded that the free radical hypothesis has neither been proven nor disproven. Some of the earlier assumptions such as that antioxidant intake increases life span, or antioxidant defenses decline with age, or antioxidant defenses are positively correlated with life spans of different species, or that longer life spans are associated with lower autoxidizability, are not clearly supportable. Similarly, the assumption that oxygen free radicals govern the rate of aging via the infliction of molecular damage lacks compelling support. Enough information to lift the free radical hypothesis above the level of speculation has not yet been amassed. Clearly, further studies, some of which specifically focus on disproving this hypothesis, are needed to confirm its veracity.

Relationship between antioxidant defenses and longevity in different mammalian species

The general objective of this investigation was to examine the relationship between oxygen free radicals and the aging process. Comparisons of antioxidant defenses were made in six diferent mammalian species, namely, mouse, rat, guinea pig, rabbit, pig and cow, which range from 3.5 to 30 years in their maximum life span potential (MLSP). Activities of superoxide dismutase (SOD), catalase, and glutathione peroxidase, and concentration of glutathione were measured in the liver, the heart, and the brain. SOD and catalase activities were positively correlated whereas glutathione concentration was negatively correlated with MLSP. Glutathione peroxidase activity exhibited a variable pattern: being positively correlated with MLSP in the brain and negatively correlated in the liver and the heart. In each organ, MLSP was correlated with relatively high levels of one or two of the above antioxidants and low levels of the other antioxidants, indicating the possibility of a compensatory balance among various components of the antioxidant system. No obvious pattern of a relationship was detectable between the overall level of antioxidant defenses and MLSP among the mammalian species examined. The implications of this finding concerning the role of oxidative stress in the aging process and the free radical hypothesis of aging are discussed.