This very readable review paper walks through what is known of modifications to proteins that occur after their creation, and the role these modifications play in aging. If you are familiar with the SENS view of aging as an accumulation of damage, you'll recall that this damage includes the buildup of numerous forms of metabolic waste, and many of these items are modified proteins. Equally, the vast majority of other age-related changes in modified proteins are downstream consequences of the damage of aging or reactions to the damage of aging, not root causes - the details matter on a case by case, per-protein and per-modification basis.
From a biodemographic point of view, aging is defined as an exponential increase in mortality with time, sometimes accompanied by a deceleration or plateau at later ages. Although the changes that underlie aging are complex, it is characterized by the gradual accumulation of a wide variety of molecular and cellular damage throughout the lifespan. The nine proposed hallmarks of aging in mammals are genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. However, the connections between these hallmarks, their contributions to aging, and their links with frailty and disease remain incompletely understood. In fact, uncovering the biological basis of aging is one of the greatest contemporary challenges in science.
Interestingly, epigenetics plays a crucial role in aging. While there are several different types of epigenetic mechanisms, protein posttranslational modifications (PTM) are intriguing contributors in regulating aging. Proteins are the basis of cellular and physiological functioning in living organisms, and the physical and chemical properties of proteins dictate their activities and functions. The primary sequence of a protein is a main determinant of protein folding and final conformation as well as biochemical activity, stability, and half-life. However, at any given moment in the life of an individual, its proteome is up to two or three orders of magnitude more complex than the encoding genomes would predict. One of the main routes of proteome expansion is through posttranslational modifications (PTM) of proteins.
Protein PTM results from enzymatic or nonenzymatic attachment of specific chemical groups to amino acid side chains. Such modifications occur either following protein translation or concomitant with translation. PTM influences both protein structure and physiological and cellular functions. Examples of enzymatic PTMs include phosphorylation, glycosylation, acetylation, methylation, sumoylation, palmitoylation, biotinylation, ubiquitination, nitration, chlorination, and oxidation/reduction. Nonenzymatic PTMs include glycation, nitrosylation, oxidation/reduction, acetylation, and succination. Some rare and unconventional PTMs, such as glypiation, neddylation, siderophorylation, AMPylation, and cholesteroylation, are also known to influence protein structure and function.
Generally, protein PTMs occur as a result of either modifying enzymes related to posttranslational processing (such as glycosylation) or signaling pathway activation (such as phosphorylation). Moreover, PTM patterns are known to be affected by disease conditions. Similarly, the dysregulation of PTM is associated with the aging process. In this context, both enzymatic and nonenzymatic PTMs can undergo age-related alterations. Alteration in the pattern of nonenzymatic PTMs depends mainly on the nature of the modifying substances, such as metabolites and free radicals. For instance, reactive oxygen species can lead to oxidation of amino acid side chains (oxidation of thiols to different forms, oxidation of methionine, formation of carbonyl groups, etc.), modification by-products of glycoxidation and lipoxidation, and formation of protein-protein cross-links as well as oxidation of the protein backbone, resulting in protein fragmentation. In contrast, changes in the nature of enzymatic PTMs rely primarily on the activities of modifying enzymes.
As awareness of the role of PTMs in aging and aging-related diseases grows, there is an urgent need for the development of methods to detect protein PTMs more rapidly and accurately. Furthermore, the recent finding of rare and unconventional modifications in age-related pathologies calls for the development of more specific and sensitive methods to detect such modifications. The recent rapid progress in large-scale genomics and proteomics technologies is likely to be a catalyzing factor for such studies. Drugs that target PTMs, such as phosphorylation, acetylation, methylation, and ubiquitination, will serve as useful tools in exploring the basic mechanism of PTM modulation and provide a pharmacological platform to combat the detrimental effects of aging.