Proteostasis describes the steady state of a cell, maintaining an appropriate balance of various forms of protein machinery in order to enable continued normal function. With advancing age, proteostasis becomes disrupted in numerous complicated ways. This is a downstream outcome of underlying molecular damage, the reactions to that damage, and immediate consequences of that damage. When a machine becomes worn and broken, it functions poorly. That is a simple thing to observe in a simple machine, but a cell is an enormously complex machine, and exhibits enormously complex dysfunctions as it departs from the proteostasis that is normal for youthful tissues.
The progressive decline in the buffering capacity of the proteostasis network represents one of the molecular hallmarks of aging. However, the biological reasons why the proteostasis network deteriorates during aging are complex and not well understood. A progressive decrease in the activity and efficacy of the protein quality control systems, as well as in the mechanisms mediating the functional cooperation between them, could be the cause of these dysfunctions.
A growing body of evidence indicates a complex and bidirectional association between protein quality control systems and inflammation. For example, Th1 or Th2 cytokines stimulated or inhibited autophagy, respectively. Also, TNF-α modulated proteasome and autophagy function in human skeletal muscle cells. LPS-induced neuroinflammation produced ER-stress and altered proteasome and autophagy activity. Also, unfolded protein response (UPR) activation has been found to increase the production of inflammatory cytokines. UPR components can activate the transcription factor NFκ-B, which has a pivotal role in the onset of inflammation.
Because aging is associated with a low grade of chronic inflammation, the modulation exerted by inflammation on cellular proteostasis might be particularly relevant in aged cells. For example, the immunoproteasome, which is not expressed in cells from young animals, is expressed in rat and human aged cells from several tissues. Moreover, proteasome turnover is regulated by neuroinflammation. Most of the age-related alterations observed in cellular proteostasis are often reproduced in young animals following LPS injection. For example, LPS induced the expression of the immunoproteasome and decreased proteasomal activity leading to the accumulation of polyubiquitinated proteins in pyramidal neurons.
This data collectively indicates that inflammation and proteostasis alteration should be considered as synergistic negative factors that might increase cell vulnerability in aging. This is especially relevant in the context of some age-related pathologies such as obesity, hypertension, diabetes, and neurodegenerative disorders, all of them characterized by oxidative stress and inflammation. However, having in mind the complexity in the reciprocal influences between inflammation and the different protein quality control systems, as well as the cell specificity of these interactions, further studies in the context of aging will be necessary to better understand the synergistic negative effects of these two processes.