Protein Posttranslational Modifications: Roles in Aging and Age-Related Disease

Abstract

Aging is characterized by the progressive decline of biochemical and physiological function in an individual. Consequently, aging is a major risk factor for diseases like cancer, obesity, and type 2 diabetes. The cellular and molecular mechanisms of aging are not well understood, nor is the relationship between aging and the onset of diseases. One of the hallmarks of aging is a decrease in cellular proteome homeostasis, allowing abnormal proteins to accumulate. This phenomenon is observed in both eukaryotes and prokaryotes, suggesting that the underlying molecular processes are evolutionarily conserved. Similar protein aggregation occurs in the pathogenesis of diseases like Alzheimer's and Parkinson's. Further, protein posttranslational modifications (PTMs), either spontaneous or physiological/pathological, are emerging as important markers of aging and aging-related diseases, though clear causality has not yet been firmly established. This review presents an overview of the interplay of PTMs in aging-associated molecular processes in eukaryotic aging models. Understanding PTM roles in aging could facilitate targeted therapies or interventions for age-related diseases. In addition, the study of PTMs in prokaryotes is highlighted, revealing the potential of simple prokaryotic models to uncover complex aging-associated molecular processes in the emerging field of microbiogerontology.

Scheme 1

Two categories of posttranslational modifications of proteins: (1) covalent modification of a nucleophilic amino acid side chain by an electrophilic fragment of a cosubstrate and (2) cleavage of a protein backbone at a specific peptide bond. Reproduced with permission from Walsh et al. [20].

Scheme 2

Five major types of covalent additions to protein side chains: phosphorylation, acylation, alkylation, glycosylation, and oxidation. Reproduced with permission from Walsh et al. [20].

Figure 1

Accumulation of protein aggregates and inclusion bodies in E. coli. Reproduced with permission from Lindner et al. [180].

Figure 2

Schematic relationship between survival and protein carbonylation for different species (A, B, and C) as a function of radiation dose or age. Blue lines depict survival. Red lines depict protein carbonyl levels. Reproduced with permission from Radman [127].

Figure 3

Aggregate distribution and associated fluorescence levels along the cell axis in E. coli throughout successive divisions. Reproduced with permission from Lindner et al. [180].

Figure 4

Aging correlation with the presence of protein aggregation. The aging effect was calculated from the relative growth rate difference between old-pole and new-pole offspring of newborn mother cells where inclusion bodies are inherited by the old pole cell (population 1) or the new pole cell (population 2). Reproduced with permission from Lindner et al. [180].

Figure 5

Possible strategies for spatial and temporal regulation of polar localization. (a) Asymmetric polar patterns can be naturally produced by a cell division event. Left: bipolar to old-pole localization; right: propagation of an old pole accumulation. Misfolded proteins produced in the progeny accumulate onto the existing polar aggregate. Eventually, de novo polar accretions can appear in progeny that did not acquire a polar focus (top cell), for example, after new protein synthesis. (b) The ability of some proteins to self-assemble and thereby to localize at the poles could be influenced by modifications such as phosphorylation upon a specific signal. The question mark indicates a hypothetical step. (c) The concentration of a self-assembling protein or oligomer and, thereby, its propensity to multimerize can be modified locally through protein-protein interaction with a partner whose subcellular distribution is asymmetric. In step 1, the protein (blue) has an asymmetric distribution inherent to a cell cycle event. The concentration of the diffusing protein oligomer (red) increases locally owing to interaction with the asymmetric protein. In step 2, the self-assembly of a protein or oligomer leads to the formation of a large structure at the pole. This provides spatial and temporal regulation to a multimerization-dependent polar localization. Reproduced with permission from Laloux and Jacobs-Wagner [169].