Brain ageing and neurodegenerative disease: The role of cellular waste management

Ageing is defined as a time-dependent functional decline that occurs in most of live organisms. Brain modification during the ageing process has been considered to predispose to neurodegenerative disorders. Despite intensive research, the exact mechanisms accounting for the switch from physiological brain ageing to neurodegeneration remain to be fully elucidated. At a cellular level, brain ageing is characterized by growing inflammation, oxidative stress, increased genomic instability, altered metabolism and the destruction of protein homeostasis, which causes the accumulation of cellular waste. In this respect, the ubiquitin proteasome system and autophagy represent the two main proteolytic systems accountable for misfolded proteins degradation in neurons. Not surprisingly, the impairment of these systems has been reported in ageing and neurodegenerative disorders characterized by inclusions of protein aggregates. Herein, we provide an overview of the molecular mechanisms that regulate ageing and neurodegenerative disorders, in particular those linked to an alteration of protein degradation. Moreover, the current therapeutic and nutritional interventions used to target protein degradation pathways are explored and discussed in the prospective of stalling or even reversing ageing and neurodegenerative processes.