A number of studies reported a relation between longevity, oxidative stress and age-related diseases. Every aerobic organism is inevitably exposed to a permanent flux of free radicals and oxidants. Due to the limited activity of antioxidant and repair mechanisms, levels of reactive oxygen species can increase during aging. Protein damage caused by elevated levels of free radicals or oxidants has an important influence on cellular viability and leads to malfunction of proteins in aged cells. In addition, modified and impaired proteins can cross-link and form the bases of many senescence-associated alterations and also of neurodegenerative diseases. To ensure the maintenance of normal cellular functions, eukaryotic cells exert proteolysis through two systems: the proteasomal system and the lysosomal system, which is degrading cellular components after autophagy. During cellular differentiation and aging, both systems are subject to extensive changes that significantly affect their proteolytic activity. It has been suggested that highly modified proteins and undegradable protein aggregates also affect the intracellular proteolytic systems. Therefore, it is essential to understand the relationship between protein oxidation, intracellular proteolytic systems and cellular defence mechanisms.