Abstract

Proteostasis Breakdown: Cell ageing and death.

Author(s): Jerzy Romano

We show a result of slower translation and accumulated oxidative damage, proteostasis, or the folding, chaperoning, and preservation of protein function collapses with age. With time, irreversibly damaged proteins accumulate, distracting chaperones from folding the healthy proteins the cell need. When the rate of replacement of excellent proteins can no longer keep up with the rate of depletion caused by misfolding, aggregation, and damage, the organism dies. Life duration shortens nonlinearly with increased temperature or added oxidant concentration in the worm Caenorhabditis elegans, while life span increases in mutants with more chaperones or proteasomes, according to the model. It accounts for the Gompertz like rising in mortality seen in humans and other creatures by predicting increases in cellular oxidative damage with age. Overall, the model demonstrates how protein instability influences the rate at which damage accumulates with age, upsetting the cell's regular proteostasis equilibrium. Cells in higher organisms age and perish as a result of natural processes. The responsible molecular mechanism is most cellular macromolecules are affected by ageing, it's proven difficult to separate causes from consequences. The role of oxidative damage is well understood. Much of what we know about cellular ageing comes from "bottom-up" investigations, which include perturbing a few genes at a time with knockouts, knock-ins, or point mutations, or utilizing sequence databases to compare genes to genes.