The oxidative stress theory of aging: embattled or invincible? Insights from non-traditional model organisms

Abstract

Reactive oxygen species (ROS), inevitable byproducts of aerobic metabolism, are known to cause oxidative damage to cells and molecules. This, in turn, is widely accepted as a pivotal determinant of both lifespan and health span. While studies in a wide range of species support the role of ROS in many age-related diseases, its role in aging per se is questioned. Comparative data from a wide range of endotherms offer equivocal support for this theory, with many exceptions and inconclusive findings as to whether or not oxidative stress is either a correlate or a determinant of maximum species lifespan. Available data do not support the premise that metabolic rate and in vivo ROS production are determinants of lifespan, or that superior antioxidant defense contributes to species longevity. Rather, published studies often show either a negative associate or lack of correlation with species longevity. Furthermore, many long-living species such as birds, bats and mole-rats exhibit high levels of oxidative damage even at young ages. Similarly genetic manipulations altering expression of key antioxidants do not necessarily show an impact on lifespan, even though oxidative damage levels may be affected. While it is possible that these multiple exceptions to straightforward predictions of the free radical theory of aging all reflect species-specific, "private" mechanisms of aging, the preponderance of contrary data nevertheless present a challenge to this august theory. Therefore, contrary to accepted dogma, the role of oxidative stress as a determinant of longevity is still open to question.

Fig. 1

A schematic representation of the oxidative stress theory of aging as outlined by Harman (1956). The theory predicts that, as an inevitable byproduct of metabolic activity, reactive oxygen species (ROS) are produced. If these are not completely neutralized, oxidative damage to proteins, DNA and lipids may occur. Oxidized lipids are themselves potent ROS, autocatalyzing this process. Unrepaired damage accumulates and results in the typical aging phenotype

Fig. 2

Rates of ROS production in 12 species of birds and mammals with disparate longevities. Although species ROS production significantly correlates with longevity, significant differences fail to appear between specific similar-sized mammals, e.g., rodents (inset; NS not significant) and bats, with divergent longevity. Data in modified figure are taken from Lambert et al. (2007). Copyright permission was kindly granted by Wiley-Blackwell Publishing, Oxford, UK

Fig. 3

Bat and rodent catalase (a) and protein carbonyl (b) levels do not correlate with maximum species lifespan (MLS). LM Laboratory mouse (Mus musculus; 4 years) or rat (Rattus norvegicus; 4 years), AGS arctic ground squirrel (Spermophilus parryii; 11 years), VB vampire bat (Desmodus rotundus; 29 years), GP guinea pig (Cavia porcellus; 12 years), DMR damara mole-rat (Fukomys damarensis; 18 years), NMR naked mole-rat (Heterocephalus glaber; >28.3 years), MFT Mexican free-tailed bat (Tadarida brasiliensis; 12 years), LBB little brown bat (Myotis lucifugus; 34 years). Data sources for catalase and protein carbonyl levels: Andziak et al. ; Ferreira-Cravo et al. ; Hermes-Lima et al. ; Wilhelm Filho et al. ; R. Buffenstein et al. unpublished data. Lifespan data are from Buffenstein and unpublished data for F. damarensis; http://genomics.senescence.info and http://www.blueplanetbiomes.org/arctic_ground_squirrel.htm