Metabolic and Molecular Effects of Prolonged Fasting

Luigi Fontana, M.D., Ph.D.

Progress Report:

My current research is directed to finding interventions that promote metabolic and molecular health and extend healthy longevity. We have been studying the effects of calorie restriction in humans for several years and, more recently, the effects of intermittent fasting (IF), protein restriction and other of diet modifications that impact gut microbiome metabolism. Our first study of a potential CR mimetic is the ongoing study of protein restriction in patients with localized prostate cancer. This study has been completed and we are now finishing to analyze the tissue and blood samples. We found that protein restriction (without CR) in humans lowers body weight and body fat, significantly reduces fasting glucose, LDL-cholesterol, C-reactive protein, but does not modify serum insulin, IGF-1, IGFBP-1 and IGFBP-3 concentrations. However, we found that protein restriction powerfully increases serum levels of FGF-21, a factor that has been shown to increase maximal lifespan in mice. We are now conducting proteomics studies on the prostate samples to elucidate the molecular effects of protein restriction on several aging and cancer pathways.


Our second study of a potential CR mimetic is the ongoing study of long-term IF in overweight and mildy obese men and women. In this study, middle-aged participants are fasting for two or three days per week. The rationale for this study is that in laboratory rodents, IF mimics the effects of CR on slowing aging and protecting against cancer. This study has also been completed and we are now finishing the analysis of tissue and blood samples. We found that IF, in humans, results in some of the same metabolic adaptation as chronic CR.


A third study is the ongoing study of the effects of combining a change in diet quality (Mediterranean diet) with IF in overweight men and women. The last participant graduated in June 2017, and we are now starting to perform the measurement in plasma, urine, immune cells and colon mucosa samples.


Finally, we are currently conducting a fourth study to determine the effects of prolonged fasting (up to two weeks of supervised water-only fasting) on molecular and cellular adaptations that promote cell rejuvenation, such as (I) removal of damaged proteins, organelles and cells, (II) improved stem cell function, and (III) enhanced DNA repair capacity with removal of DNA adducts and DNA double strand breaks. The latter is an important clinical study because it may lead to the discovery of new and exciting potential pharmacological and non-pharmacological targets for the removal of molecular and cellular damage, which is linked with the development of multiple age-associated chronic diseases, disability and accelerated aging.