image: Figure 4. Acute effects of OT+A5i on de novo systemic proteomes of males and females. (A) Schematics of the experimental approach. (B) Uniform Manifold Approximation and Projection (UMAP) plots of the profiles of de-novo synthesized systemically present proteins of young control, old control, and old OT+A5i mice, males and females. AHA and ANL data are merged. (C) Sex-annotated comparison of the mean SDs of the Levene’s test passed proteins (p < 0.05) with lower noise in young control vehicle mice compared to old control vehicle mice and in old mice administered with OT+A5i vs. vehicle control. In the shown line graphs, SDs of all groups are normalized by the SDs of the old vehicle control and presented on a log scale. (D) cirFunMap visualization of KEGG enriched pathways of de-novo synthesized systemic proteomes after OT+A5i treatment. (E) cirFunMap visualization of KEGG enriched pathways of the de-novo synthesized proteins that are noisier in the old as compared to young mice and become youthfully normalized by OT+A5i in old males and females. n = 4 each young and old MetRSL274G vehicle control, n = 4 each young and old C57.B6 vehicle control, n = 4 old OT+A5i C57.B6.
Credit: Copyright: © 2025 Kato et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
“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.”
BUFFALO, NY — October 1, 2025 — A new research paper featured as the cover of Volume 17, Issue 9 of Aging-US was published on August 21, 2025, titled “Sex-specific longitudinal reversal of aging in old frail mice.”
The study, led by first author Cameron Kato and corresponding author and Aging-US Editorial Board Member Irina M. Conboy from the University of California, Berkeley, reports that a combination of oxytocin and an Alk5 inhibitor (OT+A5i) significantly extended both lifespan and healthspan in frail, elderly, male mice. These rejuvenating effects were not seen in female mice, highlighting key biological differences between the sexes in their response to aging therapies.
The researchers tested a dual-drug approach targeting two biological pathways that change with age. Oxytocin, a hormone that declines with aging and supports tissue repair, was combined with an Alk5 inhibitor that blocks the TGF-beta pathway. TGF-beta becomes overactive with age and contributes to chronic inflammation and tissue damage. In this study, frail mice at 25 months of age—roughly equivalent to 75 human years—were treated regularly with the OT+A5i combination.
Male mice receiving the therapy lived over 70% longer than untreated controls and showed significant improvements in physical endurance, agility, and memory. According to hazard ratio analysis, the treated males were nearly three times less likely to die at any given time than untreated males.
“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.”
The therapy also reduced “biological noise” in circulating blood proteins—an established marker of aging—bringing those levels back to a more youthful state. Short-term benefits, were seen in both sexes, however, after four months of continuous treatment, only the male mice showed sustained improvement in systemic protein balance. Female mice did not experience significant gains in lifespan or healthspan, though middle-aged females did show improved fertility after treatment.
These results underscore the importance of understanding sex-specific biology when developing treatments for aging. While the reasons for these differences remain unclear, the findings provide a new model for studying and designing longevity therapies.
Oxytocin is already FDA-approved, and Alk5 inhibitors are currently in clinical trials, suggesting that this approach could be translated to humans. With strong results in aged and frail male animals, OT+A5i appears to be a promising candidate for improving late-life health and survival.
DOI: https://doi.org/10.18632/aging.206304
Corresponding authors: Irina M. Conboy — irina@generationlab.co
Abstract video: https://www.youtube.com/watch?v=bpWxDd7hHhM
Keywords: aging, lifespan, healthspan, Alk5 inhibitor, oxytocin, sex-specific differences
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Journal
Aging-US
Method of Research
News article
Subject of Research
Animals
Article Title
Sex-specific longitudinal reversal of aging in old frail mice
Article Publication Date
21-Aug-2025
COI Statement
The authors declare no conflicts of interest related to this study.