Portrait of two scientists posing outdoors with trees and a building in the background.
Paula Desplats (right) and postdoctoral researcher Daniel Whittaker (left) study how time-restricted eating resets the biological clock in Alzheimer’s disease.
Paula Desplats

The rhythm of life is hardwired into our DNA. More than forty percent of the human genes that code for proteins sync transcription to a twenty-four-hour cycle.1 A small hub of neurons deep inside the brain acts as a timekeeper, translating visual light cues into biomolecular signals that coordinate time on a cellular level.2 The metabolic response to food also regulates biological time. “The feeding-fasting cycle is one of the strongest signals you can send the body to entrain the circadian clock,” said Paula Desplats, an associate professor of neuroscience and pathology at the University of California, San Diego. 

The sleep-wake cycle is among the most well-known circadian rhythms in the body and is severely affected in Alzheimer’s disease (AD). “Eighty percent of patients with AD suffer dysregulation or disruption of circadian rhythms, and the obvious clinical manifestations are the sleep-wake reversals,” Desplats said. “These patients are very sleepy during the day, agitated during the night, more confused, and sometimes aggressive.”

The feeding-fasting cycle is one of the strongest signals you can send the body to entrain the circadian clock.
-Paula Desplats, University of California, San Diego

In a recent study published in Cell Metabolism, Desplats’s team used mice that are genetically engineered to develop AD to test whether intermittent fasting improves circadian rhythm abnormalities.3 Rather than restricting calories or making dietary changes, they simply limited food access to a defined six-hour daily window. They found that time-restricted eating improved sleep, metabolism, memory, and cognition, and reduced brain amyloid deposits and neuroinflammatory gene expression. “Many of the genes that are affected in AD are rhythmically expressed in the brain, meaning that they are in direct relation with the circadian clock and are involved in functions that are fundamental to AD pathology,” Desplats said. Intermittent fasting restored the rhythmic activity of these genes, but the real surprise was the extent to which it mitigated brain amyloid deposits and improved cognition and sleep-wake behaviors. “I didn’t expect that it will have such a dramatic impact on pathology,” Desplats said.

See Also “The Fight Against Time: Stem Cells and Healthy Aging”

Fluorescence microscopy image of blue amyloid plaques and green microglia in a mouse brain tissue.
Amyloid plaques form in the brain of a genetically engineered mouse model of Alzheimer’s disease. Microglial cells (green) surround the amyloid plaques (blue) in an attempt to remove them from the brain.
Paula Desplats

Restoration of rhythmic gene activity is among the mechanisms that help explain such improvements. “When you eat influences the circadian clock,” said Valter Longo, a professor of gerontology and biological sciences at the University of Southern California and the director of the USC Longevity Institute. Time-restricted eating has other metabolic benefits. “There are probably different ways to get to the same reset,” Longo said. Intermittent fasting decreases overall inflammation in the body, triggers autophagy—the maintenance process that clears cellular junk, including amyloid deposits—and shifts energy metabolism from glucose to ketones, which are a better energy source for the brain. 

“This work is very promising,” Longo said. These findings provide important proof of principle for future clinical trials of intermittent fasting as a simple and cost-effective lifestyle intervention to stall AD progression. “The brain is the most fascinating organ. Even beyond the biological processes, there are those that shape our individuality, our essence, our thoughts, our cognitive abilities, who we are,” Desplats said. As researchers continue to discover how environmental timekeepers synchronize gene activity and influence the brain, who we are may have more to do with how we spend the minutes, hours, days, and seasons of our life than we realize.

References:

  1. Zhang R, et al. A circadian gene expression atlas in mammals: implications for biology and medicine. PNAS. 2014;111(45):16219-16224.
  2. Hastings MH, et al. Generation of circadian rhythms in the suprachiasmatic nucleus. Nat Rev Neurosci. 2018;19(8):453-469.
  3. Whittaker DS, et al. Circadian modulation by time-restricted feeding rescues brain pathology and improves memory in mouse models of Alzheimer's disease. Cell Metab. 2023;35(10):1704-1721.e6.