New findings from the Texas A&M College of Veterinary Medicine and Biomedical Sciences (VMBS) point to one possible answer. Researchers found that certain compounds in coffee may activate NR4A1, a receptor that is becoming increasingly important in studies of aging, stress responses and disease.

The research, recently published in Nutrients, offers one of the first direct links between coffee compounds and NR4A1. That connection may help explain some of the broad health effects associated with drinking coffee.

“Coffee has well-known health-promoting properties,” said Dr. Stephen Safe, distinguished professor and Sid Kyle Endowed Chair in Veterinary Toxicology in VMBS’ Department of Veterinary Physiology and Pharmacology. “What we’ve shown is that some of those effects may be linked to how coffee compounds interact with this receptor, which is involved in protecting the body from stress-induced damage.”

How NR4A1 Helps Protect the Body

NR4A1 is part of a group of nuclear receptors that help control gene activity when the body is exposed to stress or tissue damage.

In earlier research, Safe and his collaborators described NR4A1 as a “nutrient sensor,” meaning that it can respond to dietary compounds and contribute to the body’s ability to remain healthy with age.

“If you damage almost any tissue, NR4A1 responds to bring that damage down,” Safe said. “If you take that receptor away, the damage is worse.”

Studies have connected NR4A1 with inflammation, metabolism and tissue repair. Each of these processes is closely involved in age-related conditions, including cancer, neurodegenerative disease and metabolic disorders.

A Possible Mechanism Behind Coffee’s Benefits

Large observational studies have linked coffee consumption with a reduced risk of Alzheimer’s disease, Parkinson’s disease and metabolic disease. However, those studies have generally shown associations rather than explaining exactly how coffee might produce protective effects.

Safe and his team proposed that NR4A1 could be one part of that explanation.

The project involved researchers from across Texas A&M, including Dr. Robert Chapkin, Dr. Roger Norton, Dr. James Cai and Dr. Shoshana Eitan. Their work helped show coffee’s protective effects in neurological models.

The researchers found that several compounds in coffee can bind to NR4A1 and alter its activity. The most active included polyhydroxy and polyphenolic compounds such as caffeic acid.

“What we’re saying is that at least part of coffee’s health benefits may come through binding and activating this receptor,” Safe said.

In laboratory models, these compounds also changed cell behavior in ways associated with disease protection. They reduced cellular damage and slowed the growth of cancer cells.

When the researchers removed NR4A1 from the cells, those protective effects disappeared. That result provided additional evidence that the receptor helps mediate at least some of coffee’s biological effects.

Coffee’s Benefits May Extend Beyond Caffeine

Caffeine is the largest individual component in coffee, but the study indicates that it may not be the main source of the beverage’s protective effects.

Instead, naturally occurring compounds that are also present in many fruits and vegetables appeared to have a stronger influence on NR4A1.

“Caffeine binds the receptor, but it doesn’t do much in our models,” Safe said. “The polyhydroxy and polyphenolic compounds are much more active.”

This finding may help explain why large population studies have linked both caffeinated and decaffeinated coffee with similar health benefits.

One Pathway Among Many

Safe cautioned that coffee is chemically complex and probably affects the body through multiple biological routes.

“There are many receptors and many mechanisms involved,” he said. “What we’re showing is that this could be one of the important pathways.”

The study was designed to investigate biological mechanisms. It does not establish direct cause and effect in people or prove that drinking coffee prevents disease.

“There’s still a lot of work to be done,” Safe said. “We’ve made the connection, but we need to better understand how important that connection is.”

The results support a growing body of research showing that diet, especially plant-based compounds, can influence biological pathways involved in aging and disease.

Because NR4A1 plays a role in several medical conditions, the findings may also contribute to future drug development. Safe’s team is studying synthetic compounds that target the receptor more effectively than natural dietary substances, with the aim of developing possible treatments for cancer and other diseases.

The work also highlights the potential importance of routine dietary choices.

“Coffee is a very complex mixture of compounds,” Safe said. “It’s a very potent combination.”

What the Findings Mean for Coffee Drinkers

The research does not change current recommendations for coffee consumption. People can also respond differently depending on their health, sensitivity to caffeine and other individual factors.

Still, the findings provide scientists with something that has been difficult to identify: a possible biological explanation for coffee’s long-standing association with better health and longevity.

“I think it helps explain why coffee has the effects that it does,” Safe said. “It’s not just an observation — there’s a mechanism behind it.”

Researchers found that fluvoxamine (sold under the brand name Luvox), an inexpensive medication already commonly used to treat depression and other conditions, reduced fatigue and improved quality of life in adults with long COVID. The randomized, placebo-controlled trial was published in the Annals of Internal Medicine.

A Potential Treatment for Long COVID Fatigue

Fatigue is among the most frequent and disabling symptoms reported by people with long COVID. For some, the exhaustion is severe enough to interfere with employment, family responsibilities, and everyday activities. Despite the scale of the problem, there are still few treatments supported by strong clinical evidence.

“This is an important step forward for patients who have been desperate for evidence-based options,” says Edward Mills, senior author, professor in McMaster’s Department of Health Research Methods, Evidence, and Impact, and co-principal investigator of the trial. “Fluvoxamine showed consistent and meaningful benefits, and because it’s already widely used and well understood, it has clear potential for clinical use.”

Researchers from Canada, Brazil, and the United States jointly led the study. Clinical sites were located in Belo Horizonte and throughout Minas Gerais, Brazil.

The REVIVE-TOGETHER trial brought together investigators from McMaster University, the University of British Columbia, Stanford University, the University of Pittsburgh, Duke University, Georgetown University, and several Brazilian institutions.

Testing Fluvoxamine and Metformin

The trial included 399 adults in Brazil who had experienced ongoing fatigue for at least 90 days after a confirmed SARS-CoV-2 infection. Participants were randomly placed into one of three groups and received fluvoxamine (sold under the brand name Luvox), metformin (a common diabetes medication), or a placebo for 60 days.

“We wanted to test whether two existing, widely available, and affordable medications could help. Both had biological reasons to think they might work against long COVID fatigue, but neither had been rigorously tested for this purpose in a proper clinical trial,” says Mills.

Fluvoxamine performed better than the placebo in reducing fatigue. The statistical analysis indicated a 99 percent probability that the medication was more effective than the placebo. Participants who received fluvoxamine also reported gains in overall quality of life across several measures.

Metformin did not produce the same results. Earlier research found that taking metformin during the initial stage of a COVID infection could lower the risk of later developing long COVID. In this trial, however, the drug provided no meaningful improvement for people who already had established long COVID fatigue.

An Adaptive Clinical Trial Design

Researchers used a Bayesian adaptive trial design, which allowed them to end individual treatment groups early once the evidence became sufficiently clear. This approach can produce reliable conclusions more quickly than a conventional trial while maintaining scientific rigor.

“The trial used a sophisticated adaptive design that allowed it to reach conclusions more efficiently than traditional trials, stopping early when the evidence was clear enough – a design innovation as important as the findings themselves,” says Gilmar Reis, lead author, researcher with Cardresearch, a Brazilian clinical research center based in Belo Horizonte. Reis is also a part-time associate professor at McMaster.

More Research Is Still Needed

Long COVID continues to pose a major global health challenge and is estimated to affect about 65 million people worldwide. Because proven therapies remain scarce, most medical recommendations focus on supportive strategies, including activity pacing and management of individual symptoms.

The researchers caution that fluvoxamine is not a complete solution for long COVID. The condition can involve many different symptoms and biological processes, and the medication appears specifically promising for fatigue management.

Additional studies will be needed to determine which patients are most likely to benefit, understand why the drug works, and explore whether it could be used alongside other developing treatments.

“This trial gives clinicians their first strong evidence for a medication that helps reduce long COVID fatigue. Patients want something they can try today – and this finding brings us closer to that reality,” says Jamie Forrest, corresponding author and postdoctoral research fellow at the University of British Columbia.

The research was funded by The Latona Foundation.

The study followed nearly 13,000 adults and examined seven sweeteners that contain little or no calories. People who consumed the largest total amounts showed a more rapid decline in cognitive abilities than those who consumed the smallest amounts. The association was especially strong among people with diabetes.

The results do not show that sweeteners directly cause cognitive decline. They reveal an association, meaning other factors could help explain the pattern.

Seven Common Sweeteners Examined

Researchers studied aspartame, saccharin, acesulfame K, erythritol, xylitol, sorbitol and tagatose.

These ingredients are frequently added to ultra processed products, including flavored water, soft drinks, energy drinks, yogurt and desserts marketed as low in calories. Several are also sold separately for use in coffee, tea, cooking or baking.

“Low- and no-calorie sweeteners are often seen as a healthy alternative to sugar, however our findings suggest certain sweeteners may have negative effects on brain health over time,” said study author Claudia Kimie Suemoto, MD, PhD, of the University of São Paulo in Brazil.

Tracking Brain Health for Eight Years

The research included 12,772 adults living across Brazil. Participants were 52 years old on average and were monitored for approximately eight years.

At the beginning of the study, participants completed detailed food questionnaires describing what they had eaten and drunk during the previous year. Researchers then placed them into three groups according to their total sweetener intake.

People in the lowest consumption group averaged 20 milligrams per day (mg/day), while those in the highest group averaged 191 mg/day. In the case of aspartame, the amount consumed by the highest group was roughly equal to the aspartame in one can of diet soda.

Sorbitol was consumed in the largest quantity of any individual sweetener, with an average daily intake of 64 mg/day.

Participants completed cognitive assessments at the beginning, midpoint and end of the study. The tests measured several aspects of brain function, including verbal fluency, working memory, word recall and processing speed.

Verbal fluency refers to the ability to quickly retrieve and produce words. Working memory is the brain’s short term system for holding and using information, while processing speed reflects how quickly a person can understand and respond to information.

Higher Intake Linked to Faster Cognitive Decline

After accounting for age, sex, high blood pressure, cardiovascular disease and other relevant factors, the researchers found a clear difference between the intake groups.

People who consumed the greatest amounts of sweeteners experienced a 62% faster decline in overall thinking and memory abilities than those who consumed the least. Researchers estimated that this difference was comparable to about 1.6 additional years of aging.

Participants in the middle consumption group experienced a decline that was 35% faster than the decline observed in the lowest group. That difference was comparable to approximately 1.3 years of aging.

Stronger Association in Adults Under 60

Age appeared to influence the results. Among participants younger than 60, those who consumed the most sweeteners experienced faster declines in verbal fluency and overall cognitive performance than those who consumed the least.

Researchers did not find the same association among participants older than 60.

The connection between sweetener intake and faster cognitive decline was also stronger among people with diabetes than among those without the condition. People with diabetes may use sugar substitutes more frequently because they are often advised to limit products that rapidly raise blood sugar.

Six Sweeteners Linked to Memory Changes

When the researchers examined the sweeteners separately, six were associated with faster declines in overall cognition, particularly memory.

Those sweeteners were aspartame, saccharin, acesulfame K, erythritol, sorbitol and xylitol.

Tagatose was the only sweetener in the study that was not linked to cognitive decline.

“While we found links to cognitive decline for middle-aged people both with and without diabetes, people with diabetes are more likely to use artificial sweeteners as sugar substitutes,” Suemoto said. “More research is needed to confirm our findings and to investigate if other refined sugar alternatives, such as applesauce, honey, maple syrup or coconut sugar, may be effective alternatives.”

Important Limits of the Research

The study did not include every artificial sweetener currently used in food and beverages, so the findings cannot be applied to all sugar substitutes.

The dietary information was also provided by the participants themselves. Because people may forget foods or misjudge how much they consumed, self reported diet data can be imperfect.

Most importantly, the study was observational. It identified a relationship between higher sweetener consumption and faster cognitive decline, but it could not establish that the sweeteners caused those changes.

Key Findings

• The study followed 12,772 adults with an average age of 52.
• Researchers examined seven sweeteners commonly found in flavored water, soda, energy drinks, yogurt, low calorie desserts and other ultra processed foods.
• Participants who consumed the largest total amounts experienced faster declines in overall thinking and memory skills than those who consumed the smallest amounts.
• The difference was comparable to approximately 1.6 additional years of aging.
• The association appeared in adults younger than 60 but was not detected in those older than 60.
• The findings show a link, but they do not prove that sugar substitutes cause cognitive decline.

The research was supported by the Brazilian Ministry of Health, the Ministry of Science, Technology, and Innovation, and the National Council for Scientific and Technological Development.

Published in Clinical Nutrition, the study followed 99 adults who were overweight or obese. Half of the participants were women. Researchers found that limiting daily food intake to an eight hour period helped participants preserve more of their weight loss than maintaining an eating window of 12 hours or longer.

Intermittent Fasting Benefits Persisted for a Year

The researchers examined the popular 16:8 approach to intermittent fasting. Under this method, people fast for 16 hours each day and eat during the remaining eight hours.

The lasting benefits did not depend on whether participants ate earlier or later in the day. An early schedule allowed eating between 9 a.m. and 5 p.m., while a later schedule used a window between 1 p.m. and 9 p.m.

One year after the intervention ended, both the early and late fasting groups had maintained significantly more weight loss than participants who continued eating across 12 hours or more each day. Those assigned to the early schedule also preserved a larger reduction in fat mass.

The findings suggest that time restricted eating may be practical in the short term while also producing effects that continue well beyond the initial program.

Tracking Weight and Body Composition

The study appeared in Clinical Nutrition, the official journal of the European Society for Clinical Nutrition and Metabolism. Scientists from the University of Granada (UGR), the Granada Institute for Biomedical Research (ibs.GRANADA), the Public University of Navarra, and the Biomedical Research Networking Center (CIBER) participated in the research.

During the first 12 weeks, all 99 participants received education about following a Mediterranean diet. They were then placed into four groups.

The control group continued using its usual daily eating window of 12 hours or longer. The early fasting group followed an eight hour window beginning before 10:00 a.m. The late fasting group used an eight hour window beginning after 1:00 p.m. Participants in the self selected group chose their own eight hour schedule.

Researchers measured body weight, fat mass, and fat free mass before and after the intervention. They assessed the same measurements again one year after the program had concluded.

The work was part of a broader research project whose primary findings were published in Nature Medicine. Those results showed that participants practicing TRE lost an average of 3-4 kilos more than people who received nutritional guidance alone, regardless of when their eating window occurred.

Weight Changes Remained After the Program

Dr. Alba Camacho Cardeñosa, a researcher at the University Joint Institute for Sport and Health (iMUDS) at the University of Granada (UGR) and a postdoctoral fellow at ibs.GRANADA in the Endocrinology and Nutrition Department at San Cecilio University Clinical Hospital, is the first author of the study.

She explains that “to date, although we knew that intermittent fasting promotes modest weight loss in the short term, it was unclear whether its effects were sustained over time. By evaluating the participants 12 months after the intervention ended, we demonstrated that the changes in body weight persist.”

The researchers also point to evidence that the routine may be manageable outside a controlled study. They highlight that “a very positive finding is that one in three people decided to continue practicing intermittent fasting on their own during that year of follow-up, suggesting that it is a relatively easy habit to integrate into daily life.”

A Flexible Approach to Weight Management

Researchers from the PROFITH CTS-977 research group at the University of Granada (UGR) led the study through ibs.GRANADA. Professor Jonatan Ruiz Ruiz heads the group.

The project also included collaborators from San Cecilio University Clinical Hospital, Virgen de las Nieves University Hospital in Granada, the Public University of Navarra, the CIBER on Obesity (CIBEROBN), and the CIBER on Frailty and Healthy Aging (CIBERFES).

According to the research team, even a 12 week period of intermittent fasting could provide an effective medium term option for weight management among adults who are overweight or obese.

Because both early and late eating windows produced lasting benefits, patients may be able to choose the schedule that fits their routines most comfortably. That flexibility could make the approach easier to follow and potentially improve its usefulness in obesity treatment.

Research Into Metabolic and Cardiovascular Health

The MP20 group, Biomarkers of Metabolic and Bone Diseases at ibs.GRANADA, studies biological markers and potential treatment targets related to metabolic, bone, and cardiovascular conditions.

The group combines bioinformatics with clinical research to create diagnostic tools and assess possible therapies. Its work includes investigating intermittent fasting as a treatment for obesity and associated health problems, along with studying whether bone markers can help predict cardiovascular risk.

Through its multidisciplinary and collaborative approach, the group aims to produce research with practical clinical applications.