Ageing is a natural biological process, determined by both genetic and environmental/stochastic factors. It is characterized by a gradual decline of physiological function and the eventual failure of organismal homeostasis. The phenomenon is represented in vitro by replicative senescence. The proteasome is one of the major cellular proteolytic systems. It is responsible for the degradation of normal proteins as well as of damaged proteins (abnormal, misfolded and otherwise modified proteins) that tend to accumulate during ageing. Impaired proteasome function has been tightly correlated with ageing both in vivo and in vitro. We have shown that proteasome is down-regulated during replicative senescence of human fibroblasts. Its partial inhibition triggers a premature senescence phenotype that is p53-dependent. By contrast, its genetic activation through overexpression of proteasome subunits confers lifespan extension and maintenance of youthful morphological features for longer. We have also identified natural compounds that activate the transcription factor Nrf2, a key molecule involved in cellular protection against chemically-induced oxidative stress thus promoting proteasome activation. Proteasome induction results in lifespan extension and delayed establishment of senescence morphology, consistent with the effects of proteasomal genetic activation. More recently, we have revealed the results of proteasome activation on the lifespan of the Caenorhabditis elegans model. Our initial results confirm the beneficial effects of the proteasome genetic activation on the lifespan of the nematode. We also provide evidence that proteasome activation might be a potential strategy to minimize protein homeostasis deficiencies underlying aggregation-related diseases such as Alzheimer’s or Huntington’s. We are currently screening for compounds with proteasome activating properties that could be used in preventive or therapeutic approaches against Alzheimer’s disease. In conclusion, our results show that there is a dynamic interconnection between the proteasome, the proteostatic mechanisms and the progression of ageing and age-related diseases.