Eating, exercise, and "thrifty" genotypes: connecting the dots toward an evolutionary understanding of modern chronic diseases.

Survival of Homo sapiens during evolution was dependent on the procurement of food, which in turn was dependent on physical activity. However, food supply was never consistent. Thus it is contended that the ancient hunter-gatherer had cycles of feast and famine, punctuated with obligate periods of physical activity and rest. Hence, gene selection in the Late-Paleolithic era was probably influenced by physical activity and rest. To ensure survival during periods of famine, certain genes evolved to regulate efficient intake and utilization of fuel stores. Such genes were termed "thrifty genes" in 1962. Furthermore, convincing evidence shows that this ancient genome has remained essentially unchanged over the past 10,000 years and certainly not changed in the past 40-100 years. Although the absolute caloric intake of modern-day humans is likely lower compared with our hunter-gatherer ancestors, it is nevertheless in positive caloric balance in the majority of the US adult population mainly due to the increased sedentary lifestyle in present society. We contend that the combination of continuous food abundance and physical inactivity eliminates the evolutionarily programmed biochemical cycles emanating from feast-famine and physical activity-rest cycles, which in turn abrogates the cycling of certain metabolic processes, ultimately resulting in metabolic derangements such as obesity and Type 2 diabetes. In this context, we postulate that perhaps a crucial mechanism to break the stall of the metabolic processes would be via exercise through the regulation of "physical activity genes," some of which may also be potential candidates for the "thrifty genes" of our hunter-gatherer ancestors. Therefore, the identification of such "thrifty gene" candidates would help provide insight into the pathogenetic processes of the numerous physical inactivity-mediated disorders.