Aging and the Unfolded Protein Response in the Endoplasmic Reticulum

The endoplasmic reticulum, like many structures in the cell, becomes dysfunctional in old tissues. Since it is involved in the later stages of the construction of properly formed proteins, this is one of the more problematic failures; degraded performance here has many secondary consequences. In this open access paper, researchers review what is known of how the endoplasmic reticulum fails to properly fold proteins in old tissues, and how it tries to respond to that failure with what is known as the unfolded protein response - a maintenance process that itself declines with age.

These disruptions of normal function are a downstream consequence of the fundamental forms of molecular damage that cause aging, those described in the SENS rejuvenation research outline, but the precise chain of cause and effect that lies between these two has yet to be well mapped. Much of the research community is more interested in trying to override consequences rather than repair root cause damage, in effect trying to to force a damaged machine to act as though it isn't damaged. In this case, that means spurring greater unfolded protein response activity. There are obviously limits to how well this approach can work, as the underlying damage remains to cause all of its other harms, but like many of these strategies it can be shown to produce some degree of benefit.

The cellular homeostasis maintains existence of life through integrative communication among various macromolecules working in unity through numerous biochemical pathways. The endoplasmic reticulum (ER) not only maintains Ca2+ homeostasis but also controls translation, folding, maturation, and trafficking of about one third of cellular proteins. Various environmental insults can disturb proper functioning of ER, leading to accumulation of unfolded/misfolded protein cargo in the ER that gives rise to a condition called ER stress. The cell responds through a highly conserved pathway known as the ER unfolded protein response (UPRER). UPRER first focuses on alleviation of the imposed stress by initiating steps of adaptive mechanisms in the secretory pathway for restoration of homeostasis but conditions of prolonged stress and damage provokes a cell into self-destruction through apoptosis.

Aging is notably a process during which the cell witnesses decline in its ability to respond to stress. Age related frailty perturbs the multifarious schematic of UPRER giving rise to a myriad of pathologies characterized by the presence of disease specific misfolded proteins playing havoc with cellular homeostasis. Further, the master transcriptional regulator of inflammation nuclear factor-κB (NF-κB) has been reported to be upregulated during ER stress. UPRER touches inflammatory signaling cascade directly/indirectly through NF-κB.

The process of aging causes decline in the proper functioning of cellular metabolic pathways. The changes in cells undergoing aging weaken UPRER, causing it to fail to recuperate ER stress. The various molecular chaperones in the ER undergo oxidative damage in the aging cell that diminishes the efficiency of these molecular chaperones to fold proteins; hence, presenting a mass of misfolded protein cargo. This causes protein toxicity, leading to derangement in proteostasis, which becomes an underlying cause of age related diseases.

Neurodegenerative diseases find their source of origin in the perturbations that alter proper functioning of ER. Age related frailty disarms the adaptive arm of UPRER and presents distressing conditions in the brain to promote accumulation of misfolded protein cargo in the ER that later on become inclusions of specific abnormal proteins. Most of the models of aging driven neurodegenerative disease have been marked with the presence of specific protein inclusions because of ER stress in the brain and central nervous system, which are toxic to the post-mitotic neurons.

Studies of model organisms have reinforced the importance of the activation of UPRER molecular markers in stimulating longevity. Age related dysfunction in UPRER promotes the accumulation of misfolded protein cargo, which eventually becomes toxic intracellular inclusions. As the prominent aging driven neurodegenerative diseases share a common pathology of toxic misfolded protein accumulations, this provides an opportunity for therapeutic interventions in the UPRER pathway that can stave off both aging and neuropathologies.



HSP70-5 is the heat shock protein responsible for proper protein folding in the ER of cells (Jurgen Radons, 2016 The HSP70 family of chaperones: Where do we stand ?). HSP70-5 activity declines with aging and stress factors, inflammation, etc., and results in Parkinson's Disease, AD, and other neurodegenerative disorders. Some drugs have been designed to activate the HSP70-5 to do its work (especially in providing ATPase) in properly folding or refolding proteins in the ER system of the cells, with limited success. Perhaps some of the problem occurs because the newly formed proteins have mutations already, because of diminishing DNA repair with aging. Then the unfolded proteins pile up causing neurodegeneration, PD, AD, etc.

Posted by: Biotechy at November 29th, 2017 8:21 AM

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