A combination of oxytocin and an Alk5 inhibitor significantly extended remaining lifespan and improved health in very old, frail male mice, according to research from the University of California, Berkeley. The treatment increased their remaining life by about 73% but did not lengthen lifespan in females, underscoring key sex differences in aging biology and in responses to longevity therapies.
A study published in the journal Aging-US reports a notable advance in longevity research using a simple two-drug combination in very old mice.
Led by first author Cameron Kato and corresponding author Irina M. Conboy at the University of California, Berkeley, the work focused on frail C57BL/6J mice aged 24–26 months (about 25 months on average), an age the authors say is roughly equivalent to about 75 human years.
The treatment paired oxytocin (OT) — a hormone that supports tissue repair and declines with age — with an Alk5 inhibitor (A5i) that blocks signaling through the transforming growth factor‑beta (TGF‑β) pathway. TGF‑β activity tends to rise in older tissues and is linked to fibrosis, inflammation and other age‑related damage.
Male mice receiving regular OT+A5i injections lived more than 70% longer, measured from the start of treatment, than untreated male controls. The study reports a 73% increase in additional life from the beginning of therapy and a 14% increase in overall median lifespan in treated males compared with controls. Treated males also showed improved physical performance, endurance and short‑term memory, and hazard‑ratio analysis indicated that untreated males were almost three times more likely to die at any given time.
As the authors wrote in Aging‑US: "Treatment of old frail male mice with OT+A5i resulted in a remarkable 73% life extension from that time, and a 14% increase in the overall median lifespan. Further, these animals had significantly increased healthspan, with improved physical performance, endurance, short term memory, and resilience to mortality."
The therapy also altered circulating blood proteins in ways that resembled a more youthful state. Using metabolic proteomics, the researchers found that a short, seven‑day course of OT+A5i reduced so‑called "protein noise" — chaotic variation in circulating proteins associated with aging — and youthfully reset systemic signaling in old mice of both sexes. However, after four months of intermittent treatment, only the old male mice maintained a youthful pattern in the systemic proteome; females no longer showed sustained normalization of blood‑protein profiles.
Despite the strong health and survival benefits in males, the study found no significant extension of lifespan in old female mice given the same OT+A5i regimen. The authors note that, in separate experiments, middle‑aged female mice did show improved fertility with the drug combination, hinting at complex, sex‑ and age‑specific responses. The paper concludes: "These findings establish the significant health-span extension capacity of OT+A5i and emphasize the differences in aging and in response to longevity therapeutics between the sexes."
Because oxytocin is already used clinically for certain indications in humans and Alk5‑pathway inhibitors are being explored in clinical development, commentators have suggested this strategy could, in principle, be adapted for testing in people. However, the current findings come from a small mouse study, and researchers stress that more work is needed before any conclusions can be drawn about safety or effectiveness in humans.
