Effect of inactivation of the USP19 deubiquitinase gene in mice on important phenotypes of aging.

Aging is associated with many chronic conditions that increase morbidity and mortality. These include obesity, diabetes, sarcopenia, osteoporosis, and neurodegeneration. The deubiquitinase USP19 is involved in many of these disorders suggesting that it may modulate common mechanism(s) that impact the aging process. Inactivation of USP19 is protective against muscle atrophy, obesity, and diabetes in young adult mice. Whether such protection persists in older adult mice remains unknown. In addition, the potential role of USP19 in osteoporosis remains unexplored. Here, we demonstrate that loss of USP19 is protective against loss of muscle mass and obesity in mice aged 22-24 months. Glucose tolerance was also improved in these older adult USP19 KO mice, but only in females. Bone mineral content was decreased in the USP19 KO bone, more evidently in cortical bone than in trabecular bone and only in males. This was associated with a reduced work-to-failure in the KO femurs. Osteoblasts derived from USP19 KO bone marrow cells demonstrated decreased ex-vivo mineralization compared to WT cells and the KO marrow cells showed enhanced differentiation into TRAP-positive multinucleated osteoclasts. These findings identify important potential benefits as well as risks of therapeutic targeting of USP19 for the prevention or treatment of key aging related disorders.