Old Proteins in Man: A Field in its Infancy

Abstract

It has only recently been appreciated that the human body contains many long-lived proteins (LLPs). Their gradual degradation over time contributes to human aging and probably also to a range of age-related disorders. Indeed, the role of progressive damage of proteins in aging may be indicated by the fact that many neurological diseases do not appear until after middle age. A major factor responsible for the deterioration of old proteins is the spontaneous breakdown of susceptible amino acid residues resulting in racemization, truncation, deamidation, and crosslinking. When proteins decompose in this way, their structures and functions may be altered and novel epitopes can be formed that can induce an autoimmune response.

Keywords: age-related disease.; post-translational modification; protein aging; racemization.

Figure 1

Long-lived proteins are present throughout the body. Their inevitable degeneration over time is associated with the age-related decline of human organs and tissues and may also be implicated in the diseases that accompany old age. This figure was created using BodyParts3D/Anatomography.

Figure 2

Important structures within cells, and extracellularly, are composed of long-lived proteins. A Neuron is illustrated because the proteins of myelin (derived from oligodendrocytes) are long-lived. Synapsin 1 is a client protein for protein isoaspartate methyl transferase (PIMT) and has been suggested to be long-lived [80].

Figure 3

Long-lived proteins (LLPs) decompose in the body. A common site of deterioration is at asparagine and aspartic acid which can undergo racemization via succinimide intermediates. These are spontaneous events that occur primarily in unstructured regions of the protein, leading to four possible Asp isomers: L-Asp, D-Asp, L-isoAsp, and D-isoAsp. Asp residues converted to isoAsp appear to be stable and undergo little interconversion. In most cells protein isoaspartate methyl transferase (PIMT) can ameliorate Asp racemization by methylating L-isoAsp and D-Asp, enabling the conversion back to L-Asp. Currently this is the only known repair enzyme for the repair of racemised Asp in LLPs.