A Reversal in Mice

Restoring a single fat molecule inside muscle cells reversed muscle wasting in mice and prevented their premature deaths, according to a new study in Nature Aging. The molecule, cardiolipin, declines with age in both mice and humans.

The research was led by the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen, with the University of Southern Denmark and more than 20 other institutions, ScienceDaily reported. Restoring cardiolipin to about two-thirds of normal levels began reversing muscle wasting in affected mice.

"Even a partial recovery of cardiolipin was enough to bring the muscle back," said senior author Zachary Gerhart-Hines, an associate professor at the center.

The reversal experiments were done only in mice. In humans, the study shows only that cardiolipin levels in muscle decline with age and disease. It does not show that cardiolipin causes muscle loss in people or that restoring it would help.

A Molecule That Keeps Mitochondria Folded

Cardiolipin is a specialized fat found almost exclusively in the inner membrane of mitochondria, the structures that produce most of a cell's energy. It helps maintain the membrane's tightly folded shape, which is essential for energy production.

When cardiolipin runs low, mitochondria struggle. Muscle is especially vulnerable because it burns large amounts of energy and is packed with mitochondria, so even modest disruptions can affect strength and endurance. Mitochondria low in cardiolipin produce less energy and become worse at generating the signals and building materials cells need.

Age-related muscle loss, called sarcopenia, affects nearly everyone eventually — the question is how fast and how much. It contributes to weakness, falls and loss of independence in older adults. As muscles age, they also shift toward slow-twitch fibers, which resist fatigue but produce less power than fast-twitch fibers.

The researchers found that lowering cardiolipin in young mice triggered that same shift, closely mirroring natural aging. In both humans and mice, cardiolipin in muscle mitochondria fell with age and disease, accompanied by structural abnormalities.

Antioxidants That Backfired

The most surprising result challenges popular thinking about antioxidant supplements. When cardiolipin fell, damaged mitochondria produced much more reactive oxygen species, or ROS. These molecules are often blamed for cellular damage, and antioxidants are marketed to neutralize them.

In this case, ROS acted as a signal. They helped trigger the shift toward slow-twitch fibers. When the researchers gave mice antioxidants, their muscles got worse, not better. The team concluded that the fiber shift is a protective response rather than simply a sign of decline.

"The fiber switch is not the muscle failing," said first author Fabian Finger, an assistant professor at the University of Copenhagen. He described it as muscle trading power for protection.

The mice offered another clue. Animals low in cardiolipin absorbed more glucose, but tracer experiments showed their muscle cells used much of that sugar to make their own antioxidants rather than energy. The muscle, in effect, was managing its own defenses.

A protein called ERRγ coordinates the reorganization behind the fiber shift. Blocking it in lab-grown muscle cells stopped the transition entirely, pointing to a possible drug target.

ERRγ is a nuclear receptor, a type of protein that switches genes on and off in response to signals. Nuclear receptors are already the targets of roughly 10% to 15% of FDA-approved small-molecule drugs, according to the researchers. That makes ERRγ a more practical target than many newly discovered molecules, though no ERRγ drug has been tested for muscle aging.

The study was large and collaborative, drawing on more than 20 institutions and funding from groups including the Novo Nordisk Foundation, the European Research Council and the U.S. National Institutes of Health.

Evidence Check: What Applies to People Today

Readers should weigh several limits. The mechanism and the reversal were shown in mice and in cultured cells. Human data come from muscle samples showing an age-related decline in cardiolipin, which is an association, not proof of cause.

The antioxidant finding also applies to the specific conditions tested — mice with experimentally lowered cardiolipin, not healthy older adults. It does not show that antioxidant supplements harm healthy people, and it does not test common products such as vitamin C or vitamin E pills. It does suggest that blocking ROS indiscriminately may interfere with useful signals, a theme other research on exercise and antioxidants has also raised.

There are possible treatment paths, though none has been tested for ordinary aging. Elamipretide, a drug that stabilizes cardiolipin, recently received accelerated approval from the U.S. Food and Drug Administration for Barth syndrome, a rare inherited disorder. Its effect on age-related muscle loss is unknown. ERRγ belongs to a family of proteins already targeted by many approved drugs, and compounds that activate it are being studied in early research.

For now, the proven tools against age-related muscle loss remain the familiar ones. Resistance training, regular physical activity, and adequate protein intake have strong evidence behind them. Separate research has found that endurance exercise can increase cardiolipin in aged muscle, according to a 2025 review of cardiolipin and muscle function. Older adults should talk with a doctor before starting or stopping supplements, especially if they take other medications.

The bottom line is that a disappearing molecule appears to drive a protective muscle shift in aging mice, and restoring it reversed muscle wasting in those animals. Human trials would be needed before anyone can say whether the same strategy helps people.

What Readers Want to Know

What is cardiolipin? A fat molecule found almost exclusively in the inner membrane of mitochondria, where it helps maintain the structure needed for energy production.

What did the study find? Low cardiolipin drove an aging-like shift in muscle fibers in mice, and restoring it to about two-thirds of normal reversed muscle wasting in those animals.

Does this apply to humans? Not yet. Human data show only that cardiolipin declines with age. The reversal was shown only in mice.

Why did antioxidants make things worse? Reactive oxygen species acted as signals that triggered a protective fiber shift. Blocking them interfered with that response in mice.

Should I stop taking antioxidant supplements? The study did not test common supplements in people. Talk with a doctor before changing supplements.

What helps prevent muscle loss now? Resistance training, regular physical activity, and adequate protein have the strongest evidence.