The role of thrifty genes in the origin of alcoholism: A narrative review and hypothesis

Alcohol Clin Exp Res. 2021 Jun 12. doi: 10.1111/acer.14655. Online ahead of print.ABSTRACTIn this narrative review, we present the hypothesis that key mutations in two genes, occurring 15 and 10 million years ago, were individually and then collectively adaptive for ancestral humans during periods of starvation, but are maladaptive in modern civilization (i.e., "thrifty genes"), with the consequence that these genes not only increase our risk today for obesity, but also for alcoholism. Both mutations occurred when ancestral apes were experiencing loss of fruit availability during periods of profound climate change or environmental upheaval. The silencing of uricase (urate oxidase) activity 15 million years ago enhanced survival by increasing the ability for fructose present in dwindling fruit to be stored as fat, which was a consequence of enhanced uric acid production during fructose metabolism that stimulated lipogenesis and blocked fatty acid oxidation. Likewise, a mutation in class IV alcohol dehydrogenase (ADH4) ~10 million years ago resulted in a remarkable 40-fold increase in the capacity to oxidize ethanol, which allowed our ancestors to ingest fallen, fermenting fruit. In turn, the ethanol ingested could activate aldose reductase that stimulates the conversion of glucose to fructose, while uric acid produced during ethanol metabolism could further enhance fructose production and metabolism. By aiding survival, these mutations would have allowed our ancestors to gener...
Source: Alcoholism, Clinical and Experimental Research - Category: Addiction Authors: Source Type: research