193 Chaperones accompany and safeguard proteins through each of their conformational changes including de novo folding, assembly and disassembly, transport through membranes, and targeting for degradation. Once targeting for degradation takes place, chaperones may decide which proteolytic pathway the misfolded protein will follow: through the proteasome -a multi-subunit protease accountable for the degradation of proteins often tagged with ubiquitin, or through autophagy in the lysosomes. Certain age-related cellular alterations can influence chaperoning activities. The loss of chaperone function and a decline in their availability further worsen the difficulties with protein quality control. Improper age-related modifications in the substrate protein can also obstruct the chaperones capability to recognize its target. Thus, accumulation of advanced glycation end-products via nonenzymatic alterations on long-lived proteins upon aging disturbs the normal chaperone activity (Table ). Proteasome activity and autophagy have also been reported to decline with aging. Stimulating proteasome or autophagy activity by overexpressing proteasome subunits or essential autophagy genes enhances lifespan and imparts resistance to stress in S. cerevisiae, C. elegans, and D. melanogaster. Evidence of such interventions in mammals is also emerging. Examples exist showing that genetic manipulations can improve proteostasis and delay aging in mammals. 199