Is there more to aging than mitochondrial DNA and reactive oxygen species?

Abstract

With the aging of the population, we are seeing a global increase in the prevalence of age-related disorders, especially in developed countries. Chronic diseases disproportionately affect the older segment of the population, contributing to disability, a diminished quality of life and an increase in healthcare costs. Increased life expectancy reflects the success of contemporary medicine, which must now respond to the challenges created by this achievement, including the growing burden of chronic illnesses, injuries and disabilities. A well-developed theoretical framework is required to understand the molecular basis of aging. Such a framework is a prerequisite for the development of clinical interventions that will constitute an efficient response to the challenge of age-related health issues. This review critically analyzes the experimental evidence that supports and refutes the Free Radical/Mitochondrial Theory of Aging, which has dominated the field of aging research for almost half a century.

Fig. 1

A major pathway for the detoxification of ROS in the mitochondrial matrix. O₂^.− is formed by the reduction of the O₂ with electrons leaked from the ETC. O₂^.− is efficiently converted to H₂O₂ by mitochondrial superoxide dismutase (Sod2). H₂O₂ is then detoxified to H₂O either by mitochondrial glutathione peroxidase (GPx1) with concomitant oxidation of glutathione (GSH), or by peroxiredoxins III and V (PrxIII and PrxV).

Fig. 2

Potential interactions between mtDNA repair and degradation pathways. ROS induce in mtDNA both single- and double strand breaks, as well as abasic (AP) sites and base damage. Both base damage and AP sites are converted to single-strand breaks, which in turn are either repaired by BER, or converted to double-strand breaks. Formation of double-strand breaks is a commitment step leading to degradation. Glycosylase I and Glycosylase II, mono- and bifunctional DNA glycosylases. A bifunctional DNA glycosylase also posseses an AP-lyase activity (makes an incision at an abasic site). AP site, abasic site; APE, apurinic/apyrimidinic endonuclease APE/Ref1; SSB and DSB, single- and double strand breaks, respectively.