Waging war on physical inactivity: using modern molecular ammunition against an ancient enemy

A hypothesis is presented based on a coalescence of anthropological estimations of Homo sapiens' phenotypes in the Late Paleolithic era 10,000 years ago, with Darwinian natural selection synergized with Neel's idea of the so-called thrifty gene. It is proposed that humans inherited genes that were evolved to support a physically active lifestyle. It is further postulated that physical inactivity in sedentary societies directly contributes to multiple chronic health disorders. Therefore, it is imperative to identify the underlying genetic and cellular/biochemical bases of why sedentary living produces chronic health conditions. This will allow society to improve its ability to effect beneficial lifestyle changes and hence improve the overall quality of living. To win the war against physical inactivity and the myriad of chronic health conditions produced because of physical inactivity, a multifactorial approach is needed, which includes successful preventive medicine, drug development, optimal target selection, and efficacious clinical therapy. All of these approaches require a thorough understanding of fundamental biology and how the dysregulated molecular circuitry caused by physical inactivity produces clinically overt disease. The purpose of this review is to summarize the vast armamentarium at our disposal in the form of the extensive scientific basis underlying how physical inactivity affects at least 20 of the most deadly chronic disorders. We hope that this information will provide readers with a starting point for developing additional strategies of their own in the ongoing war against inactivity-induced chronic health conditions.