The redox stress hypothesis of aging

Abstract

The main objective of this review is to examine the role of the endogenous reactive oxygen/nitrogen species (ROS) in the aging process. Until relatively recently, ROS were considered to be potentially toxic by-products of aerobic metabolism, which, if not eliminated, may inflict structural damage on various macromolecules. Accrual of such damage over time was postulated to be responsible for the physiological deterioration in the post-reproductive phase of life and eventually the death of the organism. This “structural damage-based oxidative stress” hypothesis has received support from the age-associated increases in the rates of ROS production and the steady-state amounts of oxidized macromolecules; however, there are increasing indications that structural damage alone is insufficient to satisfactorily explain the age-associated functional losses. The level of oxidative damage, accrued during aging, often does not match the magnitude of functional losses. Although experimental augmentations of antioxidant defenses tend to enhance resistance to induced oxidative stress, such manipulations are generally ineffective in the extension of life span of long-lived strains of animals. More recently, in a major conceptual shift, ROS have been found to be physiologically vital for signal transduction, gene regulation and redox regulation, among others, implying that their complete elimination would be harmful. An alternative notion, advocated here, termed “redox stress hypothesis”, proposes that aging-associated functional losses are primarily caused by a progressive pro-oxidizing shift in the redox state of the cells, which leads to the over-oxidation of redox-sensitive protein thiols and the consequent disruption of the redox-regulated signaling mechanisms.

Linkages between the life-history evolution of tropical and temperate birds and the resistance of their cells to oxidative and non-oxidative chemical injury

“…Over time, damage from these reactive oxygen species (ROS) is thought to be an important aspect of the aging process, encapsulated in the free-radical theory of aging (Huang and Manton, 2004;Fukagawa, 1999;Finkel and Holbrook, 2000;Golden et al, 2002;Dufour and Larsson, 2004). Some level of oxidants, particularly H 2 O 2 , is thought to be essential for cell survival because of their role in gene regulation, cell signaling and apoptosis (Sohal and Orr, 2012). However, cells also have a number of mechanisms to combat oxidative stress and scavenge free radicals, including antioxidants such as glutathione peroxidase, catalase and super oxide dismutase (Finkel and Holbrook, 2000;Sohal and Orr, 2012).…”

“…Some level of oxidants, particularly H 2 O 2 , is thought to be essential for cell survival because of their role in gene regulation, cell signaling and apoptosis (Sohal and Orr, 2012). However, cells also have a number of mechanisms to combat oxidative stress and scavenge free radicals, including antioxidants such as glutathione peroxidase, catalase and super oxide dismutase (Finkel and Holbrook, 2000;Sohal and Orr, 2012). It is thought that the production of potentially harmful ROS and the concentration of antioxidants exist in a balance, which is important in the aging process (Sohal and Orr, 2012).…”

Evidence that a mitochondrial death spiral underlies antagonistic pleiotropy

“…In Drosophila, hydrogen peroxide production significantly increases during aging (Cochemé et al ., 2011; Sohal & Orr, 2012; Orr et al ., 2013) and increased ROS release during aging was observed from rodent muscles, heart, liver, and brain (Sohal et al ., 1994; Bejma & Ji, 1999; Bejma et al ., 2000; Driver et al ., 2000; Vasilaki et al ., 2006; reviewed in Hekimi et al ., 2011). …”

Interplay between redox and protein homeostasis

“…Many data suggest that ROS may react to age-dependent damages as second messenger and aging is in general accompanied by changes of the whole redox circuit. (For reviews see 13,14 ). Although the induction and initial trigger of aging processes are still unclear, it is established that the subcellular redox levels change during the aging process.…”