Two New Sarcopenia Mechanisms, Both Still Short of Human Proof

Sarcopenia has no approved drug. A review published in Nature Reviews Drug Discovery in September says so plainly, and it lists the strategies under study: mitochondrial support, autophagy, anabolic signaling, androgen receptor modulators and more. Two papers from the past few months add mechanisms to that list. One argues that old muscles weaken because the junction where nerve meets muscle fails to fire. The other argues that the liver stops clearing lactate and acidifies muscle. Both are interesting and both are early, and the gap between a mechanism and a medicine is the point of this article.

Paper one: the junction that stops firing

The Journal of Clinical Investigation paper, led by W. David Arnold and published in July, starts from a long held assumption that the neuromuscular junction (NMJ) stays reliable with age. The team tested it directly. They recruited 10 older adults who reported physical limitations (mean age 85.9, range 83 to 96, 40% women) and 8 younger and middle aged adults (mean age 29.5). Using single fiber electromyography, they measured jitter, the variability in when a muscle fiber's signal arrives, and blocking, the complete failure of a nerve signal to trigger a muscle fiber.

Nine of the ten older adults had clinically meaningful leg extensor weakness. Transmission failure correlated with how weak they were relative to their muscle volume, and up to 35% of synapses failed in an individual older adult. Old rats showed a similar pattern, with blocking in about 30% of synapses on average. The researchers then found that the muscle specific sodium channel NaV1.4 was reduced at the junction in aged mice and rats. In surgical biopsies of hand muscle, with three samples per group, the rim of NaV1.4 around the junction was markedly narrower in older people, even though the junctions looked structurally intact. Blocking NaV1.4 with a toxin in adult rats reproduced the same electrical failures. Finally, small molecule inhibitors of a chloride channel, ClC-1, restored contractile function in old rodents, during both stimulated and voluntary contractions.

Many of the authors are affiliated with NMD Pharma A/S in Aarhus, a company working on ClC-1 inhibitors, and the compounds tested carry its initials. That does not undermine the data, which also come from several academic groups, but it explains why the paper ends on a drug target.

Paper two: the liver and lactate

The Science Advances paper, with Eguchi as first author, comes from a different direction. In aged mice, systemic lactate tolerance fell because the liver processed lactate less well, and lactate accumulated in muscle, acidifying it. The authors link the acidification to lower NAD+ levels and to weaker mitochondrial function. In 18 month old mice, roxadustat, a drug already marketed for anemia in kidney disease that activates the hypoxia inducible factor (HIF) pathway, improved lactate tolerance, softened the age related drop in muscle force, and raised treadmill endurance. A virus that switched on HIF1α only in the liver produced similar benefits. The authors also report that genes tied to human sarcopenia in a reanalyzed dataset resemble the signature of lactic acidosis. Groups had roughly 10 mice each, and the work did not test people.

What people can do now

The unglamorous options still have the human evidence. A 2026 open access review of creatine monohydrate in the journal Longevity says systematic reviews and meta analyses show benefits for lean mass, strength and function in older adults, especially when combined with resistance exercise. It also says the effect in people actually diagnosed with sarcopenia is relatively unknown and frames creatine as one tool alongside adequate protein, vitamin D when deficient, and structured resistance training. That is a review of evidence, not a trial, and it suggests where the real uncertainty sits. We covered one version of the exercise and diet question in our piece on the IMPACT trial.

The JCI paper adds a context worth remembering. The authors note that therapies built on increasing muscle mass, such as myostatin inhibitors, have shown only modest gains in function. Our review of myostatin antibodies and GLP-1 drugs found the same gap between volume and strength. Recent consensus, the paper says, treats weakness rather than mass loss as the core of sarcopenia, and a junction defect fits that framing better than a story about missing tissue.

I would read these papers as a map, not a path. The junction paper has the stronger design because it measured the failure in living older people and tied it to strength, but 10 volunteers with an average age near 86 is a small window. The liver paper is a clean mouse story with a drug that already exists, which makes it tempting and makes the missing human trial more conspicuous. Both would need a randomized trial of strength and walking in older adults, with safety data in that group, before either becomes advice. Until then the headline claims, such as reversing sarcopenia, are accurate only for rodents.