Investigating fasting for metabolic health and longevity.

Humans have evolved adaptive mechanisms that enable survival even with zero calories for periods of months or longer. Intermittent 'low-dose' exposure to the metabolic stress of fasting may also activate pathways that promote metabolic health and longevity, although such benefits have not been proven in humans. Here we present our perspective of the current rationale and evidence base to support fasting for gain in metabolic health. In the absence of individual level risk factors for potential harm, such as frailty, osteoporosis or osteopenia, or a current/historical eating disorder, a trial of intermittent fasting or time-restricted eating to promote weight loss and metabolic health is reasonable for the motivated patient who is overweight or obese. We conclude, however, that the current state of evidence is limited and not sufficient to justify widespread adoption of fasting practices, nor is it sufficient to exclude the possibility that fasting holds a key to a longer life. We provide a template for the types of studies that will be required to optimize fasting protocols and establish therapeutic proof of concept. In our opinion, incorporation of mechanistic and multi-omics endpoints will be critical to understand potential mechanisms of benefit in humans; pathways that could ultimately be targeted with a fasting mimetic drug to obviate the need for long-term adherence to onerous dietary restriction.