Loss of Proteostasis

The proteostasis network has three layers of defense. Molecular chaperones (HSP70, HSP90, small HSPs) recognize hydrophobic patches on unfolded proteins and shepherd them to correct folding. When chaperone capacity is exceeded, misfolded proteins are tagged with ubiquitin chains and delivered to the 26S proteasome for degradation. When both fail, selective autophagy (aggrephagy) captures protein aggregates in autophagosomes and degrades them in lysosomes.

With age, all three fail simultaneously. Chaperone expression declines because HSF1 — the master transcription factor for the heat shock response — becomes increasingly suppressed by SIRT1 loss (which itself results from NAD+ decline). Proteasome activity drops ~30% between ages 30 and 70. Autophagy becomes impaired as mTOR is chronically overactivated and AMPK underactivated.

The consequence is protein aggregate accumulation: amyloid-β and tau in neurons (Alzheimer’s), α-synuclein in dopaminergic neurons (Parkinson’s), TDP-43 in motor neurons (ALS), and Lewy bodies across multiple cell types. These aggregates are not merely passive markers of disease — they actively inhibit proteasome function, spread via prion-like mechanisms, and drive neuroinflammation.

Outside the brain, proteostasis failure drives: cataracts (crystallin aggregation), atherosclerosis (oxidized LDL accumulation), and muscle wasting (impaired myosin/actin turnover). Maintaining proteostasis is the upstream intervention for cognitive longevity — and it starts with the redox environment that determines how many proteins oxidize in the first place.