Decreased Proteasomal Activity Causes Age-Related Phenotypes and Promotes the Development of Metabolic Abnormalities

Abstract

The proteasome is a multicatalytic enzyme complex responsible for the degradation of both normal and damaged proteins. An age-related decline in proteasomal activity has been implicated in various age-related pathologies. The relevance of decreased proteasomal activity to aging and age-related diseases remains unclear, however, because suitable animal models are not available. In the present study, we established a transgenic (Tg) mouse model with decreased proteasomal chymotrypsin-like activity. Tg mice exhibited a shortened life span and developed age-related phenotypes. In Tg mice, polyubiquitinated and oxidized proteins accumulated, and the expression levels of cellular proteins such as Bcl-xL and RNase L were altered. When Tg mice were fed a high-fat diet, they developed more pronounced obesity and hepatic steatosis than did wild-type mice. Consistent with its role in lipid droplet formation, the expression of adipose differentiation-related protein (ADRP) was elevated in the livers of Tg mice. Of note, obesity and hepatic steatosis induced by a high-fat diet were more pronounced in aged than in young wild-type mice, and aged wild-type mice had elevated levels of ADRP, suggesting that the metabolic abnormalities present in Tg mice mimic those in aged mice. Our results provide the first in vivo evidence that decreased proteasomal chymotrypsin-like activity affects longevity and aggravates age-related metabolic disorders, such as obesity and hepatic steatosis.

RNase L controls terminal adipocyte differentiation, lipids storage and insulin sensitivity via CHOP10 mRNA regulation

“…Interestingly, Tomaru et al 33 recently produced a transgenic mouse with decreased proteasomal chymotrypsin-like activity. These mice overexpressed RNase L and presented a loss of adipose tissue.…”

Age‐associated microRNA expression in human peripheral blood is associated with all‐cause mortality and age‐related traits

“…Human aging is a complex process that has been linked to dysregulation of numerous cellular and molecular processes, including shortened telomere length (Harley et al ., 1990), altered DNA damage response (Moskalev et al ., 2013), loss of protein homeostasis (Tomaru et al ., 2012), cellular senescence (Childs et al ., 2015), and mitochondrial dysfunction (Green et al ., 2011). Those cellular and molecular processes can lead to a variety of diseases including cancer, cardiovascular disease, and neurological disease, as well as an increased risk of mortality (Fontana et al ., 2010; López‐Otín et al ., 2013).…”

The role of protein clearance mechanisms in organismal ageing and age-related diseases

“…Knockdown of 19S and 20S subunits during adulthood shortens lifespan in Caenohabditis elegans 53,54 . Strikingly, a transgenic mouse with reduced chymotrypsin-like activity by replacement of the b5 subunit with b5t exhibits a shortened lifespan, premature agerelated phenotypes and aggravation of age-related metabolic disorders 55 . Similarly, PA28g deficiency promotes premature ageing in mice 56 .…”