A simple change in when people eat may offer a promising new approach for Huntington's disease, according to research led by Oregon Health & Science University.
In a 12-week pilot study, researchers found that people with early-stage Huntington's disease were able to safely follow a form of intermittent fasting known as time-restricted eating, limiting food consumption to a six-to-eight-hour window each day. Participants avoided unintended weight loss and showed improvements in measures of disease severity; in a blood biomarker linked to nerve cell damage; and in cellular energy production.
The findings, published today in Nature Metabolism, represent the first clinical study to test time-restricted eating in people with Huntington's disease.
"This is the first time this approach has been formally studied in people with Huntington's disease," said Russell Wells, a fourth-year OHSU medical student and lead author of the study. "We found that participants were able to follow the eating schedule, maintain their weight and show encouraging improvements in clinical and biological measures that are important in Huntington's disease. These results suggest time-restricted eating deserves further study in a larger clinical trial."
Huntington's disease is a rare, inherited neurological disease that gradually damages nerve cells responsible for movement, cognitive and emotional regulation. Wells said it can be compared to having Parkinson's disease, Alzheimer's disease and ALS at the same time.
The condition affects about 41,000 Americans, while more than 200,000 others are at risk because they have a family history of the disease, according to the Huntington's Disease Society of America. Each child of a parent with Huntington's disease has a 50% chance of inheriting the gene mutation that causes the disorder. Symptoms typically begin between ages 30 and 50 and worsen over 10 to 25 years.
Although researchers have known the genetic cause of the disease for decades, no treatments have been approved that slow or stop its progression.
Intermittent fasting
The idea for the study grew out of earlier research in animal models showing that intermittent fasting can activate cellular pathways that help protect brain cells. Yet researchers were unsure whether the approach would be safe for people with Huntington's disease because unintended weight loss is already a concern.
Those concerns initially gave senior author Amie Hiller, M.D., pause. Hiller is professor of neurology in the OHSU School of Medicine and director of the Portland Veteran's Administration Northwest Parkinson's Disease Research, Education and Clinical Center.
"When Russell first brought me the idea, I was skeptical," Hiller said. "Weight loss is a major challenge for many people with Huntington's disease, so asking them to eat within a limited time window seemed counterintuitive.
"What was exciting about this study is that participants were able to maintain their weight while showing signs that the intervention may be positively affecting the disease itself."
The study enrolled 20 adults with early-stage Huntington's disease. Participants selected an eating window that fit their daily routine, typically between late morning and early evening, and followed it for 12 weeks. Researchers encouraged participants to maintain their normal calorie intake and monitored weight and safety throughout the study.
The approach appeared well-tolerated. Participants followed the eating schedule on average more than five days per week; reported few side effects; and maintained both body weight and lean muscle mass. Most adapted to the schedule within the first one to two weeks.
For study participant Anna White of Portland, adapting to the eating schedule turned out to be easier than expected.
"When Russell called me a few years ago and asked if I would be interested in this trial, I jumped at the chance," White said. "I had been interested in intermittent fasting for a while because it is a much friendlier way to initiate autophagy by restricting the time of eating, rather than what you eat."
White, who had previously followed a ketogenic diet in hopes of slowing Huntington's disease progression, said she initially wondered whether the fasting schedule would be difficult to maintain.
"I was worried that I would struggle with the fasting part, but it became pretty easy and sort of matches my own hunger window," she said. "I am never hungry for breakfast anyway, so I could start my eating at 11 a.m. and finish by 5 to 7 p.m. easily."
Participants used a smartphone app to document their first meal of the day with a photo and timestamp. White said she appreciated being able to eat foods she enjoyed while monitoring her weight throughout the study.
"I could eat whatever I liked and, because I was weighing myself several times a week, I felt confident that my weight was staying very stable," she said.
Signs of progress
Researchers found encouraging signals that the dietary intervention could influence disease progression.
Participants experienced an average improvement of 0.5 points on a widely used Huntington's disease severity scale known as the composite Unified Huntington's Disease Rating Scale, or cUHDRS. The score typically declines by about one point annually in people with early-stage disease.
In addition, blood levels of neurofilament light, a biomarker released when nerve cells are damaged, fell by an average of 13%. In Huntington's disease, those levels usually increase over time as the disease progresses.
"We saw a reversal of the trend we would normally expect," Wells said. "Neurofilament light typically rises as neurodegeneration continues, but after three months we observed a significant decrease. For a pilot study, that was a remarkable finding."
White has continued practicing time-restricted eating since the study ended and believes it has helped her maintain cognitive function.
"Many people have told me that for a 52-year-old woman with as much movement as I have, I am still self-aware and sharp," White said. "I try to finish The New York Times crossword puzzle every day, and I think the time-restricted eating has helped."
The research team also examined mitochondrial function in participants' blood cells. Mitochondria generate energy for cells, and impaired energy production is a hallmark of Huntington's disease.
Researchers found improvements in several measures of mitochondrial activity after the intervention.
"One theory is that fasting acts as a mild stressor that prompts cells to become more efficient," Wells said. "If cells, including brain cells, become better at producing energy and handling stress, they may be more resilient to the disease process."
Because the study was small and did not include a comparison group, researchers caution that the findings should not be considered proof that time-restricted eating slows Huntington's disease. Larger, randomized controlled trials will be needed to determine whether the benefits are real and sustained over time.
Still, researchers say the results are especially promising because the intervention is relatively simple and could be accessible to many people.
"We do not currently have any disease-modifying treatments for Huntington's disease," Hiller said. "If future studies confirm these findings, this could become an approach available to people regardless of where they live or their financial resources. That makes it particularly exciting."
The team is currently pursuing funding for a larger, randomized clinical trial that would compare time-restricted eating with standard dietary habits.
For Wells, the study represents an important step toward finding practical strategies that could help people before symptoms become severe and debilitating.
"One of the unique aspects of Huntington's disease is that some people know years in advance that they carry the genetic mutation," Wells said. "That creates a window of opportunity to explore interventions that might delay onset or slow progression. Lifestyle approaches such as time-restricted eating could someday become an important part of that strategy."
In addition to Wells and Hiller, OHSU co-authors on the study include Andrew McHill, Ph.D., Nora Gray, Ph.D., and Joseph Quinn, M.D., as well as Lee Neilson, M.D., with the University of Iowa and VA Iowa City Healthcare System.
The researchers acknowledge the help of the OHSU Oregon Clinical and Translational Research Institute for input on the trial design and OHSU Biostatistics and Design Program for data analysis expertise.
This research was supported by an OHSU Parkinson Center of Oregon pilot award, Department of Veterans Affairs Clinical Science Research and Development Career Development Award-2 (CDA-2) grant CX00253, the Parkinson's Disease Research, Education, Clinical Center at the VA Portland Health Care System, and by the National Center for Advancing Translational Sciences, National Institutes of Health, through award numbers TL1TR002371 and UL1TR002369. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other funders.
