A single mitochondrial lipid turned out to be the switch behind muscle aging, and restoring it rescued mice from premature death

A single mitochondrial lipid turned out to be the switch behind muscle aging, and restoring it rescued mice from premature death

Scientists at the University of Copenhagen demonstrated in a paper in Nature Aging published on September 29, 2026, that the decline in cardiolipin, a lipid of the inner mitochondrial membrane, causally drives one of the central paradoxes of muscle aging. Reproducing the deficit in young mice produced hallmarks of aging, while restoring it in adult mice eliminated premature death.

Mitochondria in skeletal muscle deteriorate with age. Yet the composition of the muscle shifts toward the very fibers that depend most on mitochondria: slow, endurance-type fibers rather than fast, powerful ones. Why the muscle doubles down on these fibers while the mitochondria themselves are failing had remained unexplained for decades.

The answer, found by the team of Fabian Finger and Zachary Gerhart-Hines, is cardiolipin: a lipid found almost exclusively in the inner mitochondrial membrane, where it maintains the folded cristae structure required for energy production. Its levels fall with age in both mice and humans. In the study, five older individuals had less cardiolipin in their muscles than four younger ones.

Previous methods of disrupting cardiolipin synthesis either killed the mouse or affected other lipid pathways. The team therefore generated mice carrying a Crls1 gene, which synthesizes cardiolipin, that can be switched off selectively in muscle. In young animals this reproduced the hallmarks of aging: muscles stopped growing, mitochondria became deformed, and fast fibers converted to slow fibers, mirroring the fiber-type shift seen in human aging.

The signal from damaged mitochondria to the cell nucleus is relayed by ERRγ, a protein related to the estrogen receptor but insensitive to estrogen itself. Blocking ERRγ prevented the fiber-type switch. Without cardiolipin, mitochondria release more reactive oxygen species that damage the cell, and the remodeled fibers absorb several-fold more glucose from the blood, diverting it from energy production toward antioxidant synthesis. The antioxidant N-acetylcysteine, which should have helped, instead worsened muscle wasting: it removed the very reactive oxygen species the muscle was using to defend itself.

"The fiber-type switch is not a breakdown of the muscle but a trade-off: the muscle sacrifices power for protection. That is why interfering with the process can backfire. When we gave the mice antioxidants to clear reactive oxygen species, their muscles suffered more, not less," says Fabian Finger, first author of the study.

The decisive result came from the reverse experiment: when the deleted gene was reactivated in adult mice, cardiolipin recovered to only about two-thirds of normal levels, yet that was enough to reverse atrophy and eliminate premature death, which without restoration killed more than half of the animals.

"What encourages me most is that even partial restoration of cardiolipin was sufficient to return the muscle to normal. The question now is whether we can raise cardiolipin levels in aging muscle or target ERRγ to trigger a healthy adaptation," says senior author Zachary Gerhart-Hines.

Cardiolipin is already the target of the FDA-approved drug elamipretide, currently indicated for Barth syndrome, a different genetic disorder. Receptors of the ERRγ class are the target of 10–15% of all approved small-molecule drugs.

The rescue shown here was in mice with an artificially deleted gene. The next step, as the authors describe it, is to raise cardiolipin levels in mice that have aged naturally and to test whether the finding holds against ordinary aging.