While aging is an inevitable process, scientists across the globe are working either to find the mechanisms to control or slow down the process of aging. Several proteins wax and wane in our bodies as we age.
Proteins are major players in regulating many cellular functions in the body. They provide structure and support for cells, act as enzymes catalyzing different biochemical reactions, facilitate the transport of solutes, provide immunity (in the form of antibodies), regulate pH, etc. The accuracy of processes responsible for the synthesis, processing, and degradation of proteins plays an important role in cellular well-being. In other words, a proper balance of proteins or proteostasis is required.
To maintain this cellular homeostasis, the human body utilizes protein degradation machinery like ubiquitin-proteasome system (UPS) and lysosomal mediated digestion. This system enables the removal of defective proteins from the cell. Protein degradation via UPS involves tagging of proteins to be removed by transfer of ubiquitin group onto them. Such proteins are said to be ubiquitinated proteins. The ubiquitinated proteins are then identified, unfolded, and degraded by the proteasome (an organelle for intracellular digestion) followed by their degradation and removal from the cell. Lysosomal mediated degradation encompasses the action of various hydrolytic enzymes present in the lysosome on the proteins that are to be degraded or removed from the cell.
Scientific studies have shown a mechanistic relationship between aging and the accumulation of damaged proteins in cells. Such damaged and misfolded proteins interfere with normal metabolic functions resulting in a number of age-related conditions such as Alzheimer’s, Parkinson’s, Huntington’s disease, and amyotrophic lateral sclerosis. In all these diseases, the rate of accumulation of toxic proteins is higher than their rate of cellular clearance causing perturbed neuronal functions resulting in neurodegeneration. While Alzheimer’s disease is characterized by accumulation of beta-amyloid and tau protein, patients with Parkinson’s disease show accumulation of Lewy bodies (complex of different proteins), and Huntington’s disease is marked by the accumulation of Huntingtin gene product. Additionally, with aging the activity of proteasome has also been reported to reduce. Thus, timely degradation of proteins plays a critical role in determining the health and life span of an organism.
While the accumulation of unnecessary proteins and reduced activity of proteasome is associated with aging, sustained proteasomal activity is correlated with an increased life span. Cells derived from healthy centenarians show a more similar proteasomal activity to fibroblast cultures derived from younger donors in comparison to cultures from older donors. This relationship between protein degradation and aging suggests a possibility of extending life span by modulating protein degrading mechanisms. A recent report published in Nature showed that the level of certain proteasomal targets increases with age. This increase in level could be accounted to age-related deubiquitination. Since ubiquitination of target proteins is important for them to be recognized by the proteasomal machinery, such deubiquitinated proteins are subsequently less susceptible to proteasomal degradation resulting in their increased quantity. Thus, by reestablishing appropriate proteome ubiquitination and augmenting the function of the proteasome in an aged cell, we might be able to control the process of aging.