By MedicalXpress | Source

Restricting calories has long been recognized as a powerful way to live longer, with periods of intermittent fasting proving more effective than a steady diet. However, the mechanism behind this phenomenon has been unclear. Research led by UT Southwestern Medical Center scientists and published in Nature Communications suggests it’s not the fast itself that extends life, but how the body metabolically pivots during refeeding after fasting. Although the findings were made in Caenorhabditis elegans, a roundworm often used as a lab model, they could eventually lead to new ways to boost health in humans.

Refocusing attention on refeeding

“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.

When organisms undergo fasting, their cells quickly burn through meager glucose reserves and shift to breaking down stored lipids, a potent source of energy. This process, called catabolism, is mediated by a protein known as NHR-49, which activates when glucose runs low and prompts cells to digest lipids.

Refeeding causes NHR-49 to shut down, preventing cells from breaking down lipids and allowing them to rebuild their reserves.

NHR-49’s double duty in metabolism

In 2022, Dr. Douglas and his colleagues published a study showing that NHR-49 also serves as a sensor for intracellular lipid stores, activating a mechanism that prevents cellular starvation when lipid supplies deplete.

Dr. Douglas and colleagues suspected that NHR-49’s activity could be key to fasting’s life-extending benefits. To test this idea, the team used genetic engineering to delete NHR-49 in C. elegans, then fasted the worms for 24 hours.

Surprisingly, this did not diminish life extension. Fasting still boosted the altered worms’ average lifespan by about 41% and made older worms behave more youthfully, reflected in more movement, much like fasting did in C. elegans with intact NHR-49.

On a hunch, the researchers decided to examine the flip side of NHR-49 activation: What happened when the worms were refed after fasting and NHR-49 shut off?

To do this, they needed to better understand how NHR-49 naturally becomes inactivated.

The enzyme switch that turns NHR-49 off

Experiments led by Vincent Tagliabracci, Ph.D., Associate Professor of Molecular Biology at UTSW and a Howard Hughes Medical Institute Investigator, and Victor Lopez, Ph.D., a postdoctoral researcher in the Tagliabracci Lab, revealed that this occurs when an enzyme known as protein kinase CK1 alpha 1 (KIN-19) chemically modifies NHR-49 through a process called phosphorylation.

When Dr. Douglas and his colleagues tampered with this system to keep NHR-49 turned on—which maintained lipid breakdown even when C. elegans was refed—it eliminated any life extension from fasting.

What this could mean for human aging

Together, Dr. Douglas said, these results suggest that being able to efficiently deactivate NHR-49 after fasting is a key factor in caloric restriction’s ability to lengthen lifespan. Finding ways to manipulate this system could eventually help people live longer without the need to fast.

“Our findings bridge a gap between lipid metabolism and aging research,” Dr. Douglas said. “By targeting aging, the single greatest risk factor for human disease, we move beyond treating isolated conditions toward a preventive model of medicine that enhances quality of life for all individuals.”