Mouse Models of Oxidative Stress Indicate a Role for Modulating Healthy Aging

Abstract

Aging is a complex process that affects every major system at the molecular, cellular and organ levels. Although the exact cause of aging is unknown, there is significant evidence that oxidative stress plays a major role in the aging process. The basis of the oxidative stress hypothesis is that aging occurs as a result of an imbalance between oxidants and antioxidants, which leads to the accrual of damaged proteins, lipids and DNA macromolecules with age. Age-dependent increases in protein oxidation and aggregates, lipofuscin, and DNA mutations contribute to age-related pathologies. Many transgenic/knockout mouse models over expressing or deficient in key antioxidant enzymes have been generated to examine the effect of oxidative stress on aging and age-related diseases. Based on currently reported lifespan studies using mice with altered antioxidant defense, there is little evidence that oxidative stress plays a role in determining lifespan. However, mice deficient in antioxidant enzymes are often more susceptible to age-related disease while mice overexpressing antioxidant enzymes often have an increase in the amount of time spent without disease, i.e., healthspan. Thus, by understanding the mechanisms that affect healthy aging, we may discover potential therapeutic targets to extend human healthspan.

Deficiency of metallothionein-1 and -2 genes shortens the lifespan of the 129/Sv mouse strain

“…MT deficiency may weaken overall ability to reduce ROS toxicity in cells and tissues. Gene defects of several antioxidant proteins also have an effect on the lifespan in knockout mouse models (reviewed by Hamilton et al, 2012); for instance, knockout mice of manganese-superoxide dismutase (Mn-SOD, also known as SOD2), phospholipid hydroperoxide glutathione peroxidase (PHGPx), thioredoxin, and thioredoxin reductase show lethal phenotypes. Copper and zinc-SOD (Cu, Zn-SOD, also known as SOD1) and peroxiredoxin knockout mice had lifespans reduced by 30% and 15%, respectively, compared with the WT, whereas the lifespan was not shortened by glutathione peroxidase 1 (GPx1) knockout.…”

A genetic reduction in antioxidant function causes elevated aggression in mice

“…There are a range of different mouse models with genetically impaired antioxidant defence and varying degrees of associated pathophysiology (Pérez et al, 2009); examination of sexual signalling and aggression in these mice may reveal the general sensitivity of these reproductive traits to perturbations in redox status. Conditional knockouts of antioxidant defence, where the expression of a particular gene in that defence process can be manipulated over a specific period of an animal's life cycle, may be particularly helpful in determining the impact of oxidative stress on these traits during a specific period of adulthood (Hamilton et al, 2012). Ultimately, however, direct links between oxidative stress and aggression need to be tested for in organisms other than biomedical models, as these model animals show alterations in their behaviour and life history as a result of selective breeding in laboratory conditions.…”

Progress in understanding the molecular oxygen paradox – function of mitochondrial reactive oxygen species in cell signaling

“…The importance of antioxidant systems in preventing cellular damage is underscored by the consequences of genetically disabling different ROS eliminating enzymes in mitochondria. The genetic knockout of SOD2 or thioredoxin-2 (TRX2), which plays a vital role in PRX3 reactivation, is embryonically lethal (Hamilton et al, 2012). Loss of glutathione peroxidase-1 (GPX1) accelerates oxidative stress and damage and removing GPX4, which preferentially detoxifies lipid hydroperoxides, is also embryonically lethal (Ardanaz et al, 2010;Yoo et al, 2012).…”