Mitochondria-targeted catalase does not suppress development of cellular senescence during aging

Authors: MOGCK, BRONWYN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; JEZAK, SAMANTHA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; WILEY, CHRISTOPHER - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Biomedicines
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/8/2024
Publication Date: 2/10/2024
Citation: Mogck, B., Jezak, S., Wiley, C. 2024. Mitochondria-targeted catalase does not suppress development of cellular senescence during aging. Biomedicines. https://doi.org/10.3390/biomedicines12020414.
DOI: https://doi.org/10.3390/biomedicines12020414

Interpretive Summary: Mitochondria, the power houses of the cell, are necessary for proper energy generation in the body, but can undergo changes as we age that compromise their integrity and could drive age-related diseases. One of these changes is the release of reactive oxygen species (ROS), toxic byproducts of metabolism that can damage our cells. A potential consequence of this damage is a form of cellular aging known as cellular senescence. We tested the idea that mitochondrial ROS might drive cellular senescence in both cultured cells and aged mice by targeting an antioxidant gene (catalase - CAT) to the mitochondria to deplete mitochondrial ROS (model name: mCAT). Surprisingly, despite mCAT mice living longer than controls, no changes in any aspect of senescence were observed in either cultured cells or aged mice. Our data indicate that mitochondrial ROS may not be a major driver of cellular senescence in culture or during natural aging.

Technical Abstract: Cellular senescence is a complex stress response marked by stable proliferative arrest and the secretion of biologically active molecules collectively known as the senescence-associated secretory phenotype (SASP). Mitochondria-derived reactive oxygen species (ROS) have been implicated in aging and age-related processes, including senescence. Stressors that increase ROS levels promote both senescence and the SASP, while reducing mitochondrial ROS or mitochondria themselves can prevent senescence or the SASP. Mitochondrially targeted catalase (mCAT), a transgene that reduces mitochondrial levels of ROS, has been shown to extend the lifespan of murine models and protect against the age-related loss of mitochondrial function. However, it remains unclear whether mCAT can prevent senescence or the SASP. In this study, we investigated the impact of mCAT on senescence in cultured cells and aged mice in order to discover if the lifespan-extending activity of mCAT might be due to the reduction in senescent cells or the SASP. Contrary to expectations, we observed that mCAT does not reduce markers of senescence or the SASP in cultured cells. Moreover, mCAT does not prevent the accumulation of senescent cells or the development of the SASP in adipose tissue from aged mice. These results suggest that mitochondrial ROS may not always play a causal role in the development of senescence during natural aging and underscore the need for a nuanced understanding of the intricate relationship between mitochondrial ROS and cellular senescence.