Fasting may be key to improving health, UTSW-led research suggests.Cutting calorie intake has long been linked to longer life, and intermittent fasting often appears to work better than maintaining a constant diet. Even so, scientists have struggled to explain exactly why this happens.
New research from UT Southwestern Medical Center, published in Nature Communications, suggests that the key factor is not the fasting period itself, but how the body adjusts its metabolism when food is reintroduced.
The experiments were carried out in Caenorhabditis elegans, a type of roundworm commonly used in laboratory studies, and the findings could eventually inform approaches to improving human health.
“Our discoveries shift the focus toward a neglected side of the metabolic coin – the refeeding phase. Our data suggest that the health-promoting effects of intermittent fasting are not merely a product of the fast itself, but are dependent on how the metabolic machinery recalibrates during the subsequent transition back to a fed state,” said study leader Peter Douglas, Ph.D., Associate Professor of Molecular Biology and a member of the Hamon Center for Regenerative Science and Medicine at UT Southwestern. Dr. Douglas co-led the study with Lexus Tatge, Ph.D., a former member of the Douglas Lab.
Metabolic switch drives fasting benefits
During fasting, cells quickly use up limited glucose supplies and then switch to breaking down stored lipids for energy. This shift, known as catabolism, is controlled by a protein called NHR-49. When glucose levels drop, NHR-49 activates and triggers lipid breakdown. Once food is available again, NHR-49 turns off, allowing cells to stop breaking down fats and begin restoring their energy reserves. Earlier work published in 2022 by Dr. Douglas and colleagues showed that NHR-49 also monitors lipid levels inside cells and helps prevent starvation when those reserves run low.
To explore whether NHR-49 is responsible for the lifespan benefits of fasting, Dr. Douglas and colleagues removed the gene for this protein in C. elegans and then subjected the worms to a 24-hour fast. The outcome was unexpected. The absence of NHR-49 did not reduce the lifespan benefit. The fasted worms still lived about 41 percent longer on average and showed more youthful behavior, including increased movement, similar to worms with normal NHR-49 function.
