Intermittent fasting, particularly in the form of fasting mimicking diets that enhance autophagy and last long enough to trigger significant reduction and replacement of immune cells, is growing in popularity as a way to activate the range of cellular stress responses known to modestly improve health. It isn't the only way to alter behavior and the environment to upregulate beneficial cellular stress responses such as autophagy, however. Thus the authors of this open access paper propose that a broader program of periodic challenges should be introduced as a best practice for human health, and be as strongly recommended as regular exercise. The health benefits may be in the same ballpark. They choose to call this "intermittent living." A great deal of gathering and analysis of data lies between here and the realization of their vision, of course.

The number of people with chronic diseases such as cardiovascular diseases (CVD), diabetes, respiratory diseases, mental disorders, autoimmune diseases and cancer has increased dramatically over the last three decades. The increasing rates of these chronic systemic illnesses suggest that inflammation, caused by excessive and inappropriate innate immune system activity, is unable to respond appropriately to danger signals that are new from the perspective of evolution.

These, mostly environment-driven, risk factors seem inevitable in current Western societies and their shares and intensities are most likely destined to further increase in the future. Importantly, many of these risk factors exhibit interaction, while contemporary humans are likely to suffer from these challenges in concert. This contrasts with the stress factors experienced by traditionally living populations who still live in the environment of our ancestors. In that environment, they had to cope with short-term mono-metabolic danger factors (e.g. hunger, thirst, cold, heat), whereas modern humans are exposed to multi-metabolic risk factors that stimulate an energy conflict between organs and major systems. The ensuing conflict between current experience and to what our genes and stress systems are adapted is the basis of the so-called 'mismatch hypothesis' of 'typically Western' diseases.

Mono-metabolic stress factors have shaped adaptive mechanisms for survival and reproduction, such as short-lasting inflammation, insulin resistance, activation of the sympathetic nervous system and others. Mild triggers might at least in part reset physiologic and metabolic dysfunctioning in patients with 'typically Western' diseases. In other words they may provide low-cost opportunities for secondary prevention. Conversely, the chronic absence of mild stress factors may have rendered modern 21st century humans less resistant to major toxic insults and susceptible to the development of many, 'typically Western', chronic diseases of affluence, including metabolic disorders.

Several of our studies showed that the combination of certain intermittent stress factors produce a hormetic early stress response with a compensatory improvement of multiple metabolic and immunological indices, and wellbeing. The employed hormetic triggers included: intermittent fasting, intermittent heat, intermittent cold, intermittent hypoxia, intermittent drinking, and the consumption of a great number of nutrients with hormetic effects. The use of intermittent challenges, combined in a homework-protocol, could serve as a vaccine against the deleterious effects of modern life. We named this concept "intermittent living", defined as the daily intermittent use of known ancient triggers for a period of seven days per month. We propose to use this concept as a basis for interventions for individuals with chronic disease and/or its prevention. Intermittent living is no more than the reintroduction of mild environmentally-based short lasting stress (including cold, heat, hunger, thirst).