Proteolysis dysfunction in the process of aging and age-related diseases

Abstract

In this review, we discuss in detail the most relevant proteolytic systems that together with chaperones contribute to creating the proteostasis network that is kept in dynamic balance to maintain overall functionality of cellular proteomes. Data accumulated over decades demonstrate that the effectiveness of elements of the proteostasis network declines with age. In this scenario, failure to degrade misfolded or faulty proteins increases the risk of protein aggregation, chronic inflammation, and the development of age-related diseases. This is especially important in the context of aging-related modification of functions of the immune system.

Global Proteomic Profile of Aluminum-Induced Hippocampal Impairments in Rats: Are Low Doses of Aluminum Really Safe?

“…In the last years, we have shown that xenobiotics such as mercury, lead, and fluoride, have an interesting ability to modulate the proteostasis system [ 52 , 53 , 66 , 67 ]. One complex involved in proteostasis is the ubiquitin-proteasome, which regulates the degradation of proteins, along with the Heat Shock Proteins (HSP), which also work on the degradation process, but have special functions in preventing the misfolding of proteins that could lead to the formation of protein aggregates [ 68 , 69 ]. Our proteomic approach showed the up-regulation of HSP-70 kDa (P0DMW0, P0DMW1, and P14659) and HSP-90 KDa subunits (P34058 and P82995).…”

To aggregate or not to aggregate – Is it a matter of the ribosome?

“…Because cellular compensation mechanisms decline with aging. [4,5] Decompensation of cellular homeostasis occurs late in life because of an aging-associated decline in homeostasis mechanisms, either of synthesis, maintenance, or degradation (Figure 1). Here, I would like to propose a two-hit hypothesis of neurodegeneration that could explain the late onset of neurodegenerative diseases of the aging brain.…”

“…The other compartments of proteostasis-maintenance involving the chaperone system and mitochondria and finally degradation by the ubiquitin/proteasome system or micro/macroautophagy/lysosomal system-are also subject to functional decline during aging. [4,5,65] Thereby, all three compartments of proteostasis are affected by cellular aging, synthesis, maintenance and degradation. Maintenance and degradation constitute the "buffering" capacity of cells, that is, the ability to cope with proteotoxic stress.…”

“…[ 4 ] Even degradation mechanisms could lose functionality. [ 5 ] These assumptions about singular mechanisms leading to cellular demise and disease are insufficient because they cannot explain why healthy aging is possible and does not mandatorily end in dementia when it is only long enough. Accordingly, these assumptions fail to elucidate the fact that most neurodegenerative diseases are of late onset.…”

Polo-Like Kinase 2 Plays an Essential Role in Cytoprotection against MG132-Induced Proteasome Inhibition via Phosphorylation of Serine 19 in HSPB5

“…It has been reported that proteasome dysfunction induces ER stress through decreased degradation of denatured proteins. Diabetes, neurodegenerative diseases, metabolic diseases, cancer, and hypertension are closely related to ER stress associated with aging and genetic factors [ 1 ]. Recently, in skeletal muscle tissue, increased ER stress has been reported in myopathies, such as muscular dystrophy and inclusion body inflammation [ 2 ].…”