Fight Aging!

Every cell contains hundreds of mitochondria, the descendants of ancient symbiotic bacteria now integrated into the cell. Mitochondria generate oxidative molecules as a consequence of the processes that generate the chemical energy store molecule adenosine triphosphate (ATP), used to power the cell. Those oxidative molecules cause damage, near all rapidly repaired. They also serve as signals, such as in the beneficial response to exercise. With aging, however, mitochondrial function becomes impaired and the degree of oxidative stress generated by the operation of mitochondria becomes harmful.

Researchers have in the past produced modestly extended life in short-lived model organisms by overexpression of natural mitochondrial antioxidants such as catalase or via use of engineered antioxidant molecules targeted to mitochondria like SkQ1. This approach of dampening excessive mitochondrial generation of oxidative molecules seems generally beneficial, but the effects on life span in mice are small in more recent, more rigorously conducted studies. Today's open access paper provides a further data point, in that the scientists involved demonstrate that catalase upregulation fails to reduce the burden of cellular senescence in old mice. As they point out, this somewhat complicates present thinking on the interactions between age-related mitochondrial dysfunction and burden of cellular senescence.

Mitochondria-Targeted Catalase Does Not Suppress Development of Cellular Senescence during Aging

The loss of mitochondrial function is a potentially important driver of aging and can limit the life and health span of mammals. One aspect of this loss is an increase in mitochondrial reactive oxygen species (ROS) as these organelles are a major site for ROS generation. Murine knockouts of antioxidant enzymes such as superoxide dismutases 1 and 2 (SOD1 and SOD2) and catalase (CAT) are short-lived, indicating that cellular antioxidant defenses are required for normal life and health spans. Furthermore, increasing antioxidant proteins or treatment with antioxidants can extend the life span of invertebrate models. Despite these data, the overexpression of most antioxidant enzymes does not extend the life span of mice, suggesting that antioxidant defenses in these animals are already sufficient for geroprotection under unstressed conditions.

A notable exception to this occurs in the case of a mitochondrially targeted catalase (mCAT) transgene. In this model, catalase-which converts hydrogen peroxide into O2 and water-specifically targets mitochondria, providing these organelles with an added layer of protection from a common source of ROS-mediated damage. These mice live 10-20% longer than wild-type (WT) mice and are protected from the age-related loss of mitochondrial function, but it remains unclear if mCAT can attenuate the development of other aspects of aging, such as cellular senescence.

Cellular senescence is a stress or damage response characterized by a proliferative growth arrest accompanied by the release of various cytokines, chemokines, growth factors, proteases, oxylipins, and other signaling molecules collectively known as the senescence-associated secretory phenotype (SASP). Senescent cells have been linked to a number of age-related diseases and can limit both life and health spans, as the elimination of these cells protects against the development of several age-related pathologies. Importantly, mitochondrial dysfunction and ROS can drive cellular senescence in culture, as well as in the skin and adipose tissue of mice.

We previously demonstrated that mitochondrial dysfunction can result in a senescent phenotype that lacks multiple proinflammatory features found in the SASP. This mitochondrial-dysfunction-associated senescence (MiDAS) occurs in response to alterations in the cytosolic NAD+/NADH ratio, regardless of ROS status, indicating that mitochondrial dysfunction may drive senescence independent of ROS production; however, other models suggest that mitochondrial ROS may drive nuclear DNA damage or downstream signaling events that result in senescence and the SASP. It is therefore unclear if reducing mitochondrial ROS is effective in reducing the burden of senescent cells or the SASP during natural aging.

Here, we show that transgenic mCAT has no effect on senescent phenotypes in cultured human fibroblasts. Furthermore, gonadal adipose tissue from aged WT and mCAT mice shows increases in many markers of senescence both at 17 and after 25 months, but mCAT has no discernable effect on these markers. Together, these data support a model in which mitochondrial ROS are not universally required for senescence or the SASP during natural aging.