Aging Brings Loss of Protein Homeostasis

Proteostasis is the process by which an organism maintains the appropriate level of various proteins needed to ensure well functioning tissue. The biochemical pathways involved in proteostasis tend to be complex. Protein homeostasis processes include translation (protein synthesis), chaperoning, protein degradation and moving protein within the cell and organism. In stress-related conditions like high temperatures proteins unfold and become ineffective; 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. A stable proteome needs a proper regulation of protein synthesis, folding, structural flexibility, and conformation as well as protein degradation. When the organism loses the ability to maintain protein homeostasis, it loses functions. Loss of proteostasis is not only a hallmark of aging but also a proximate cause of some neurodegenerative disorders.

The production, or synthesis, of proteins involves transcription, translation, RNA splicing, and mRNA maturation. Mistakes in these biochemical processes can result in the accumulation of abnormal proteins. Interactions of those abnormal proteins with normal proteins can lead to the phenotypical characteristics of aging and of degenerative and neurodegenerative disorders. The proteostasis 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. This affects 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.

When the protein quality control mechanism declines as a result of aging, the person is more likely to get 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.

Heat shock protein 90 (Hsp 90) is a molecular chaperone that regulates cellular processes like cell survival, biosignal pathways, and cell cycle control. Dysregulation of such mechanisms may lead to the uncontrolled proliferation of cells and cancer.

Aberrant proteins in the heart cause cardiac disorders. Cardiomyopathy can arise as a result of the loss of proteostasis and indeed cardiomyopathy is a common disease among the elderly. Atherosclerosis 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 development of presenile dementia.

Muscle atrophy is another effect of impaired protein homeostasis in old age. Less protein in the body means higher probability of muscular atrophy. When levels of survival motor neuron protein decline, the elderly experience 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 its prevalence 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. When proteostasis is impaired, elongator complex protein production declines, hindering spiral ganglion differentiation as well downregulating polarity complex protein activity. This cascade can result in deafness. Some also speculate that sarcopenia can be attributed to biological and environmental factors cooperating in a positive feedback cycle.

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 proposed to control the loss of proteostasis.