The role of ubiquitin-proteasome system in ageing.

Maintenance of cellular homeostasis influences ageing and it is determined by several factors, including efficient proteolysis of damaged proteins. The ubiquitin-proteasome system is the major protein degradation pathway in the cell. Specifically, the proteasome is responsible for clearance of abnormal, denatured or in general damaged proteins as well as for the regulated degradation of short-lived proteins. In this review the involvement of the ubiquitin-proteasome pathway in protein degradation at different levels of cellular life is discussed in relation with ageing. Though the exact underlying mechanism is unclear, an age-related decrease in proteasome activity weakens cellular capacity to remove oxidatively modified proteins and favours the development of diseases. Up-regulation of proteasome activity is characteristic of muscle wasting conditions, but may not be rate limiting. Meanwhile, enhanced presence of immunoproteasomes in ageing brain and muscle tissue could reflect a persistent inflammatory defence and anti-stress mechanism. Insulin/IGF-1 signalling regulates ageing in worms, flies and mammals. The insulin/IGF-1 receptor inhibits the forkhead transcription factor, FoxO through activating a cascade of conserved kinases. Longevity increases when FoxO becomes activated in response to reduced insulin/IGF-1 signalling. The ubiquitin-proteasome system plays a major role in signal transduction associated with stress and ageing. The understanding of specific proteolytic targeting paves the way for a new generation of active molecules that may control particular steps of normal and pathological ageing.