Catalase is an important antioxidant enzyme, defending cells against oxidative stress. Aging brings with it mitochondrial dysfunction and other sources of excess oxidative molecules, and some animal studies have shown improved health to result from upregulation of catalase expression. Regardless of whether or not more of a given molecule in cells is beneficial, it is often the case that removing it is harmful, and thus it is usually hard to draw conclusions based on gene knockout studies as to whether a given molecule is a potential target for upregulation.
Lysosomes are a central hub for cellular metabolism and are involved in the regulation of cell homeostasis through the degradation or recycling of unwanted or dysfunctional organelles through the autophagy pathway. Catalase, a peroxisomal enzyme, plays an important role in cellular antioxidant defense by decomposing hydrogen peroxide into water and oxygen.Both impaired lysosomes and catalase have been linked to many age-related pathologies with a decline in lifespan.
Aging is characterized by progressive accumulation of macromolecular damage and the production of high levels of reactive oxygen species. Although lysosomes degrade the most long-lived proteins and organelles via the autophagic pathway, the role of lysosomes and their effect on catalase during aging is not known. The present study investigated the role of catalase and lysosomal function in catalase-knockout (KO) mice.
We performed experiments on wild-type (WT) and catalase KO younger (9 weeks) and mature adult (53 weeks) male mice and mouse embryonic fibroblasts isolated from WT and KO mice from E13.5 embryos as in vivo and in ex vivo respectively. We found that at the age of 53 weeks (mature adult), catalase-KO mice exhibited an aging phenotype faster than WT mice. We also found that mature adult catalase-KO mice induced leaky lysosome by progressive accumulation of lysosomal content, such as cathespin D, into the cytosol. Leaky lysosomes inhibited autophagosome formation and triggered impaired autophagy. The dysregulation of autophagy triggered mTORC1 activation. However, the antioxidant N-acetyl-L-cysteine and mTORC1 inhibitor rapamycin rescued leaky lysosomes and aging phenotypes in catalase-deficient mature adult mice.