Aging Brings Loss of Protein Homeostasis

Proteostasis is the process by which proteins are regulated and maintained via complex pathways. Positive processes of translation (protein synthesis), chaperoning, protein degradation and trafficking maintain protein homeostasis. Proteins unfolding is common in stress-related conditions like high temperatures; hence the need for maintenance of normal temperature, pH, and bodily fluid composition. Elimination of abnormal proteins through the ubiquitin-proteasome pathway is also essential for the continuity of protein stability. A stable proteome needs a proper regulation of protein synthesis, folding, structural flexibility, and conformation as well as protein degradation. Loss of proteostasis is not only a hallmark of aging but also a proximate cause of some neurodegenerative disorders.

Random errors of protein synthesis during transcription, translation, RNA splicing, and mRNA maturation can result in the accumulation of abnormal proteins Interactions of those proteins with others can lead to characteristics of aging, degenerative / neurodegenerative disorders, and protein aggression toxicity. The protein network (PN) and proteome damage responses form a mechanism that human cells use to keep the proteome intact. The PN is composed of protein biosynthesis machinery, the unfolded protein response of the endoplasmic reticulum, the intra and extracellular molecular chaperones, proteases for the ubiquitin-mediated pathway which detoxifies cells from aberrant proteins and dividing cells that facilitates mitosis.

Protein folding machinery function deteriorates with aging. Age linked changes affect the mitochondrial activity of chaperones; hence less ATP is needed for chaperoning and ATP unavailability inhibits the protein folding process, giving rise to incorrect folding.

Chaperone concentration decreases with an increase in age. In vivo studies done on the hepatic microsome of rats showed that large aggregation of chaperones was found in younger animals.

The protein degradation mechanism also declines with age; as a result, misfolded and abnormal proteins accumulate hence the susceptibility of the elderly to neurodegenerative disorders. The autophagic mechanism also declines with age. A mass of misfolded protein is a hallmark of protein conformational disorders.

Loss of function of protein quality control mechanism as a result of aging leads to the pathogenesis of protein misfolding diseases such as cystic fibrosis, Parkinson's disease, Creutzfeldt–Jakob disease, Gaucher's disease, cardiac disorders, cancer, and many other neurodegenerative and degenerative diseases.

Loss of function of molecular chaperones such as heat shock protein 90 might lead to cancer. Heat shock protein 90 (Hsp 90) regulates cellular processes like cell survival, biosignal pathways, and cell cycle control. Dysregulation of such mechanisms may lead to the uncontrolled proliferation of cells.

Aberrant proteins in the heart cause cardiac disorders. Cardiomyopathy is a common disease among the elderly as a result of the loss of proteostasis. Atherosclerosis, a cardiac defect is also brought about by toxic protein aggregation. In vivo studies done on animal models showed that a mass of protein aggregation in the heart causes congestive heart failure.

Biochemical abnormalities among the elderly as a result of uncontrolled protein homeostasis partially explains why aging is linked to neurodegenerative disorders like Alzheimer's. Abnormal protein conformation of neuronal proteins triggers Presenile dementia pathogenesis.

Muscle atrophy is another effect of impaired protein homeostasis in old age. In vivo studies in mice have shown that depletion of spinal motor neuron protein may result in spinal muscular atrophy. The decline of survival motor neuron protein among the elderly causes loss of muscle mass; hence, vulnerability to skeletal disorders is linked with loss of proteostasis.

The deficit in protein homeostasis in the nervous system gives rise to Parkison’s disease. Loss of proteostasis as a result of aging degenerates dopaminergic neurons; the decline of these neurons inhibits dopamine biosynthesis thus impairing movement.

Visual impairment is common in old age. The human proteome in the eye needs stability and a quality control system to function appropriately. Accumulation of misfolded protein and degeneration of retinal proteins such as rhodopsin as a result of the loss of proteostasis may trigger the pathogenesis of eye disorders like Retinitis pigmentosa. Retinitis pigmentosa is common among the elderly and the susceptibility of being diagnosed with retinitis pigmentosa increases with age, although this condition can arise at any point in life and the average age at initial retinitis pigmentosa diagnosis is mid 30s.

Loss of protein homeostasis as a result of aging is also linked with hearing loss. Cochlear development depends on the ear’s proteome stability. Impaired proteostasis degenerates elongator complex proteins, therefore, hindering spiral ganglion differentiation as well downregulating polarity complex protein activity consequently resulting deafness.

There is no straightforward way to reverse protein homeostasis but it might be possible to manage altered proteostasis. Chaperone therapies, DNA repair, gene therapy, biologics, and replacement treatments have been used in the control of loss of proteostasis.