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Proteostasis is the name given to successful maintenance of youthful levels of proteins and minimal protein damage in cells. With age, the molecular damage of aging leads to changes in expression of proteins and dysfunction in cellular maintenance processes. The result is ever more damaged proteins and altered cellular behavior. Some of those behavioral changes are compensatory, some cause further disruption to cell and tissue function. Loss of proteostasis is a hallmark of aging, but it isn’t a root cause of aging. It is a downstream consequence of forms of damage that change cell behavior and impede the operation of cellular maintenance via autophagy or the ubiquitin-proteasome system.
In higher organisms, cells age and die by natural processes. What are the molecular mechanisms that drive it? It has been difficult to disentangle causes from effects because aging impacts most cellular biomolecules. Oxidative damage is known to play a key role. Much of what is known about cellular aging comes from “bottom-up” experiments, by perturbing a few genes at a time – by knockouts, knock-ins, or point mutations, or by gene-to-gene comparisons using sequence databases. Our interest here is in the “top-down” question of the aging mechanism, which we take to be a more system-wide failure in the cell. Any single gene cannot reverse aging or abolish life span limits. Oxidative damage is indiscriminate and nonspecific in which class of biomolecule it hits or its spatial location in the cell. We take the mechanism of aging and longevity to be more about a general and stochastic destruction than a pinpoint action.
One view is that aging results from declining protein quality-control systems involved in protein synthesis, degradation, and chaperoning that normally protect the proteins in the cell’s proteome. Central to proteostasis, the decline in protein quality control is implicated in more than 50 diseases of abnormal protein deposition (proteinopathies), for which the principal risk factor is advancing age, probably because cell regulation and protein production and disposal becomes increasingly compromised with age. Proteostasis is a natural culprit in aging because it is a front line of response to stress and because proteins are the primary repairers of the cell and sustainers of the genome.
Here, we model how proteostasis – i.e., the folding, chaperoning, and maintenance of protein function -ncollapses with age from slowed translation and cumulative oxidative damage. Irreparably damaged proteins accumulate with age, increasingly distracting the chaperones from folding the healthy proteins the cell needs. The tipping point to death occurs when replenishing good proteins no longer keeps up with depletion from misfolding, aggregation, and damage. The model agrees with experiments in the worm Caenorhabditis elegans that show the following: Life span shortens nonlinearly with increased temperature or added oxidant concentration, and life span increases in mutants having more chaperones or proteasomes. It predicts observed increases in cellular oxidative damage with age and provides a mechanism for the Gompertz-like rise in mortality observed in humans and other organisms. Overall, the model shows how the instability of proteins sets the rate at which damage accumulates with age and upends a cell’s normal proteostasis balance.