Urolithin A boosts heart health and mitochondrial function

The scientific paper by Liu et al., titled Urolithin A Provides Cardioprotection and Mitochondrial Quality Enhancement Preclinically and Improves Human Cardiovascular Health Biomarkers, explores how Urolithin A (UA), a gut-derived compound from ellagitannin-rich foods like pomegranates and walnuts, can support heart health during aging. Published in iScience in 2025, the study investigates the role of UA in improving mitochondrial function—a key factor in age-related cardiovascular decline—through a combination of preclinical animal models and a randomized clinical trial in older adults. The research highlights UA’s ability to enhance mitophagy, restore mitochondrial structure, and reduce blood ceramides linked to heart disease, offering a promising nutritional strategy for improving cardiovascular health.

Heart disease is the number one cause of death worldwide. It’s especially common in older adults. The heart undergoes several changes as we age, making it harder to work well. These changes include thicker and stiffer heart walls, more fibrous tissue, and problems with how the heart handles energy.

The heart is one of the body’s most energy-demanding organs. It relies heavily on tiny “power plants” inside our cells called mitochondria. These mitochondria create energy for the heart to beat—over 100,000 times per day! However, as we age, mitochondria can become damaged and become less efficient. Mitophagy is the process that helps clean out and replace faulty mitochondria, which also become weaker with age.

The study explains, “Mitochondrial dysfunction is a key driver of functional decline in the aging heart by negatively impacting cardiomyocyte bioenergetics.” In other words, poor mitochondrial health can lead to a tired, weak heart.

That’s where Urolithin A (UA) comes in. It’s a compound your gut makes when you eat foods rich in ellagitannins, like pomegranates, walnuts, and berries. UA has already been shown to boost mitophagy and help muscles work better. This study explored whether it could do the same for the heart.

To determine if Urolithin A could support heart health, the researchers used several types of tests in animals and humans.

• Heart Failure Model in Rats: Rats had a heart attack induced by surgery to create a model of heart failure with reduced ejection fraction (HFrEF). They were then given UA by mouth for 2 months.
• Aging Model in Mice: Older mice (24 months old) were compared with young mice. Some of the older mice were given UA in their food for 8 weeks.
• The scientists measured heart performance with echocardiograms and checked the shape and function of mitochondria using transmission electron microscopy (TEM). They also looked at gene expression and mitophagy markers in the heart tissues.

• Healthy older adults were enrolled in a randomized, placebo-controlled clinical trial.
• Participants took either a placebo or 1 gram of UA every day for 4 months.
• Blood tests were used to check levels of ceramides, which are fats in the blood that are known to predict the risk of heart disease.

One of the first findings of the study was that aging and diseased hearts have a lot in common. Both show a loss of important mitochondrial functions. The researchers analyzed human heart tissue data and found that key genes involved in mitochondrial respiration and mitophagy were downregulated.

They wrote, “We observed significant downregulation of several mitophagy genes, including PINK1 and OPTN1, as well as mitochondrial dynamics and cristae regulators, such as OPA1.” These genes help manage energy and keep mitochondria in good shape. Their decline means the heart can’t make or recycle energy efficiently.

In rats that had suffered heart attacks, UA made a clear difference:

• After 2 months of treatment, rats given UA had better ejection fraction (how much blood the heart pumps out with each beat) and fractional shortening (how well the heart contracts).
• The researchers noted, “The decline of EF and fractional shortening was reduced by 35% and 39%, respectively, by comparing UA to vehicle groups.”
• UA also helped lower the telesystolic volume, meaning the heart could empty itself better after each beat.

Importantly, when scientists checked the heart tissue, they saw that UA increased a key marker of mitophagy called phospho-ubiquitin, showing that damaged mitochondria were being cleared out properly again.

The results in older, non-diseased mice were just as promising:

• UA improved how well the heart relaxed between beats—what’s known as diastolic function.
• Under high workload conditions, like the heart experiences during exercise, UA-treated mice performed better than untreated mice.
• The study showed that “UA significantly preserved the age-related decline in diastolic function.”

Under the microscope, aged mice showed clear signs of damaged mitochondria: cristae were less organized and more circular (a sign of stress). But UA helped restore the healthy, folded cristae structure and improved overall mitochondrial shape.

A big bonus was that UA helped aged mice maintain their muscle strength, an essential part of staying active as we age.

• Unlike untreated aged mice, mice treated with UA didn’t lose muscle force over 8 weeks.
• Mitochondrial shape and size were closer to what was seen in young mice.
• The study reported that UA “rescued the age-dependent decline in cristae volume density,” helping mitochondria become more efficient energy producers again.

UA also seemed to repair stalled mitophagy processes by improving lysosomal function, which is the part of the cell that helps break down damaged mitochondria.

In the human trial, the researchers focused on ceramides—fats in the blood that can predict future heart problems.

• After 4 months, people taking UA had lower levels of C16:0, C18:0, and C24:1 ceramides.
• These ceramides are part of a clinical score called CERT1, which doctors use to estimate heart disease risk.
• The study highlighted that “UA significantly reduced clinically validated ceramide species associated with risk of CVD found in the plasma.”

This is exciting because these changes happened in healthy older adults, suggesting that UA may help even before symptoms of heart disease begin.

The study presents a powerful idea: protecting our mitochondria may be the key to keeping our hearts healthy as we age. By improving how cells clean and renew their energy systems, UA helped hearts pump better, recover from damage, and resist aging-related decline.

Unlike many heart supplements that only reduce cholesterol, UA works deep inside heart cells. It helps clean out and replace faulty parts of mitochondria. This makes it a unique and targeted way to fight heart aging.

The study authors wrote, “UA improves both diastolic and systolic function in the models investigated,” adding that this dual effect distinguishes UA from other compounds like spermidine or NAD+ boosters, which may help with only one type of heart function.

This scientific study shows that Urolithin A may be a safe and effective nutritional strategy for supporting heart health during aging. By helping the heart’s mitochondria work better, UA improves heart performance and key biomarkers linked to disease risk.

It’s one of the few nutritional compounds shown to work inside heart cells, improving their structure and energy production. With promising results from animal models and human trials, UA may offer a new way to protect the heart as we age.

Future studies will help us learn more about long-term effects, but for now, this research opens the door to a natural, science-backed approach to heart health and aging.