AGING THEORY: CAUSE 4: PROTEIN MISFOLDING
Protein folding is the physical process by which a protein chain acquires its native 3-dimensional structure, a conformation that is usually biologically functional, in an expeditious and reproducible manner. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from a random coil.[1] Each protein exists as an unfolded polypeptide or random coil when translated from a sequence of mRNA to a linear chain of amino acids. This polypeptide lacks any stable (long-lasting) three-dimensional structure (the left hand side of the first figure). As the polypeptide chain is being synthesized by a ribosome, the linear chain begins to fold into its three-dimensional structure. Folding begins to occur even during translation of the polypeptide chain. Amino acids interact with each other to produce a well-defined three-dimensional structure, the folded protein (the right hand side of the figure), known as the native state. The resulting three-dimensional structure is determined by the amino acid sequence or primary structure (Anfinsen’s dogma).[2]Protein misfolding (PM) has been identified as a major cause of decline as we age [14]. Many neurodegenerative disorders share common features including the accumulation of aggregated misfolded proteins, neuroinflammation and apoptotic neuronal death (ref). PM contributes to Alzheimer’s, Parkinson’s, and other age-associated diseases such as arthritis [15]. To reduce the amount of PM, specific nutrients have been identified with proven mechanisms of action.
I read, and cite below, specific nutrients that are likely to slow the rate of PM. These nutrients are Generally Recognized As Safe (GRAS) by the Food and Drug Administration, and can be incorporated into supplements which may slow the epidemic of Alzheimer’s and other age-related diseases that are related to PM.
EGCG (Epigallocatechin gallate) slows the transcription process so proteins can fold properly. Quercetin inhibits the enzyme which degrades EGCG. Thus, consuming the amount of quercetin in one serving of blueberries along with the EGCG content of a serving of green tea can provide an EGCG timespan in the body equivalent to the benefit of 6 cups of green tea. Quercetin blocks the action of the enzyme responsible for degrading EGCG, which is the active ingredient in green tea [16]. Servings of green tea consumed daily have been shown to be correlated with health. The health benefit has been shown to increase linearly from zero to 4 cups of green tea daily. [17]. This reduces protein misfolding and activates the beneficial processes similar to those of dietary restriction.
In addition, EGCG has antibiotic (Ab) effects, particularly enhancing Ab effectiveness against Ab-resistant bacteria. Researchers at the University of Surrey combined EGCG with many types of antibiotics, finding the combination was up to 31 per cent more effective at killing off harmful bacteria compared to the drug antibiotic alone [18].
Deficiency of the amino acids tyrosine and cysteine contributes to protein misfolding during transcription. Many diets are deficient in these 2 amino acids, and people in regions of the world where people live longest have higher levels of these 2 amino acids in their diets. These findings are based on work with Rolf Martin [19]. When the diet is deficient in these, phenylalanine and alanine are likely to be substituted in tRNAs, so when the protein is synthesized, it misfolds because the wrong side chains are present.
Bioflavonoids, including quercetin, have numerous health benefits. It was recently discovered that one bioflavonoid, apigenin [20], mimics the metabolic pathway effect of caloric restriction. It inhibits CD 38, also known as cyclic ADP ribose hydrolase, a glycoprotein found on the surface of many immune cells and the main reducer of NAD+ concentration during aging. So apigenin helps restore NAD+ toward more youthful levels. Parsley is a rich source of apigenin, but also has been praised as a dietary source of many other benefits. “[A] wide range of pharmacological activity including antioxidant, hepatoprotective, brain protective, anti-diabetic, analgesic, spasmolytic, immunosuppressant, anti-platelet, gastroprotective, cytoprotective, laxative, estrogenic, diuretic, hypotensive, antibacterial and antifungal activities have been exhibited for this plant in modern medicine” [21, 22].
