The Free Radical Theory of Aging

Harman, Denham

doi:10.1089/152308603770310202

Cited by 740 publications

(416 citation statements)

References 43 publications

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“…The free radical theory of aging proposes that, in biologic systems, ROS attack and degrade molecules, causing functional decline (2). This theory predicts that increasing antioxidant defenses would enhance longevity and protect functionality.…”

Section: •ϫmentioning

confidence: 99%

Reactive oxygen species detoxification by catalase is a major determinant of fecundity in the mosquito Anopheles gambiae

DeJong

Miller²,

Molina-Cruz³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

119

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The mosquito Anopheles gambiae is a primary vector of Plasmodium parasites in Africa. The effect of aging on reproductive output in A. gambiae females from three strains that differ in their ability to melanize Plasmodium and in their systemic levels of hydrogen peroxide (H2O2), a reactive oxygen species (ROS), was analyzed. The number of eggs oviposited after the first blood meal decreases with age in all strains; however, this decline was much more pronounced in the G3 (unselected) and R (refractory to Plasmodium infection) strains than in the S (highly susceptible to Plasmodium) strain. Reduction of ROS levels in G3 and R females by administration of antioxidants reversed this age-related decline in fecundity. The S and G3 strains were fixed for two functionally different catalase alleles that differ at the second amino acid position (Ser2Trp). Biochemical analysis of recombinant proteins revealed that the Trp isoform has lower specific activity and higher Km than the Ser isoform, indicating that the former is a less efficient enzyme. The Trp-for-Ser substitution appears to destabilize the functional tetrameric form of the enzyme. Both alleles are present in the R strain, and Ser/Ser females had significantly higher fecundity than Trp/Trp females. Finally, a systemic reduction in catalase activity by dsRNA-mediated knockdown significantly reduced the reproductive output of mosquito females, indicating that catalase plays a central role in protecting the oocyte and early embryo from ROS damage.insect ͉ malaria ͉ Plasmodium ͉ reproduction ͉ single-nucleotide polymorphism

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Section: •ϫmentioning

confidence: 99%

Reactive oxygen species detoxification by catalase is a major determinant of fecundity in the mosquito Anopheles gambiae

DeJong

Miller²,

Molina-Cruz³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

119

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“…A ging is a complex process involving progressive and deleterious changes in cell functions that are believed to result, in part, from the production of reactive oxygen species resulting in cell senescence, dysfunction, and/or death (1)(2)(3)(4)(5). The oxidative and metabolic alterations that occur during aging increase the vulnerability of cells and organ systems to various diseases including cancers, cardiovascular disease, and neurodegenerative disorders (6)(7)(8).…”

mentioning

confidence: 99%

Calorie restriction up-regulates the plasma membrane redox system in brain cells and suppresses oxidative stress during aging

Hyun

Emerson

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

249

160

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The plasma membrane (PM) contains redox enzymes that provide electrons for energy metabolism and recycling of antioxidants such as coenzyme Q and ␣-tocopherol. Brain aging and neurodegenerative disorders involve impaired energy metabolism and oxidative damage, but the involvement of the PM redox system (PMRS) in these processes is unknown. Caloric restriction (CR), a manipulation that protects the brain against aging and disease, increased activities of PMRS enzymes (NADH-ascorbate free radical reductase, NADH-quinone oxidoreductase 1, NADH-ferrocyanide reductase, NADH-coenzyme Q10 reductase, and NADH-cytochrome c reductase) and antioxidant levels (␣-tocopherol and coenzyme Q10) in brain PM during aging. Age-related increases in PM lipid peroxidation, protein carbonyls, and nitrotyrosine were attenuated by CR, levels of PMRS enzyme activities were higher, and markers of oxidative stress were lower in cultured neuronal cells treated with CR serum compared with those treated with ad libitum serum. These findings suggest important roles for the PMRS in protecting brain cells against age-related increases in oxidative and metabolic stress.Alzheimer's disease ͉ reactive oxygen species ͉ coenzyme Q10 ͉ oxidoreductase

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“…Many studies have indicated that increased free radical levels contribute significantly to aging (Harman, 2003). In particular, mitochondria are a major source of free radicals including ROS, and it is accepted that mitochondrial dysfunction contributes considerably to the aging process (Bratic & Larsson, 2013; Murphy, 2009).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Nmnat3 efficiently increases NAD and NGD levels and ameliorates age‐associated insulin resistance

et al. 2018

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SummaryNicotinamide adenine dinucleotide (NAD) is an important cofactor that regulates various biological processes, including metabolism and gene expression. As a coenzyme, NAD controls mitochondrial respiration through enzymes of the tricarboxylic acid (TCA) cycle, β‐oxidation, and oxidative phosphorylation and also serves as a substrate for posttranslational protein modifications, such as deacetylation and ADP‐ribosylation by sirtuins and poly(ADP‐ribose) polymerase (PARP), respectively. Many studies have demonstrated that NAD levels decrease with aging and that these declines cause various aging‐associated diseases. In contrast, activation of NAD metabolism prevents declines in NAD levels during aging. In particular, dietary supplementation with NAD precursors has been associated with protection against age‐associated insulin resistance. However, it remains unclear which NAD synthesis pathway is important and/or efficient at increasing NAD levels in vivo. In this study, Nmnat3 overexpression in mice efficiently increased NAD levels in various tissues and prevented aging‐related declines in NAD levels. We also demonstrated that Nmnat3‐overexpressing (Nmnat3 Tg) mice were protected against diet‐induced and aging‐associated insulin resistance. Moreover, in skeletal muscles of Nmnat3 Tg mice, TCA cycle activity was significantly enhanced, and the energy source for oxidative phosphorylation was shifted toward fatty acid oxidation. Furthermore, reactive oxygen species (ROS) generation was significantly suppressed in aged Nmnat3 Tg mice. Interestingly, we also found that concentrations of the NAD analog nicotinamide guanine dinucleotide (NGD) were dramatically increased in Nmnat3 Tg mice. These results suggest that Nmnat3 overexpression improves metabolic health and that Nmnat3 is an attractive therapeutic target for metabolic disorders that are caused by aging.

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The Free Radical Theory of Aging

Cited by 740 publications

References 43 publications

Reactive oxygen species detoxification by catalase is a major determinant of fecundity in the mosquito Anopheles gambiae

Reactive oxygen species detoxification by catalase is a major determinant of fecundity in the mosquito Anopheles gambiae

Calorie restriction up-regulates the plasma membrane redox system in brain cells and suppresses oxidative stress during aging

Overexpression of Nmnat3 efficiently increases NAD and NGD levels and ameliorates age‐associated insulin resistance

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