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A groundbreaking new study from UC Berkeley reports that combining oxytocin (OT) with an Alk5 inhibitor (A5i) dramatically extended lifespan and healthspan in old frail male mice - showing the potential of a dual-pathway longevity therapy.
Key Points
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73% life extension in old frail male mice from the start of treatment.
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Improved healthspan: better physical performance, endurance, memory, and resilience to death.
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Short-term rejuvenation in both sexes: systemic protein signaling was restored to youthful patterns after just 7 days.
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Sex-specific response: long-term benefits were seen only in males, though middle-aged females showed improved fertility.
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Human relevance: oxytocin is already FDA-approved, and Alk5 inhibitors are in cancer clinical trials, suggesting a feasible path to translation.
Study Methods
Researchers worked with 25-month-old mice, equivalent to about 75-year-old humans. At this age, the animals were already frail, making the study unusually challenging.
The mice were divided into four groups:
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Male control (vehicle only)
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Male treated with OT+A5i
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Female control
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Female treated with OT+A5i
Treatment consisted of subcutaneous injections three times per week for two weeks, followed by a two-week rest, repeated in cycles until natural death.
Health was tracked through treadmill endurance, grip strength/balance (4-limb hanging test), memory (novel object recognition), and a 31-point frailty index.ย
The researchers used advanced proteomics to study how the systemic protein environment changed with treatment.
Dramatic Lifespan Extension in Old Male Mice
The standout result:
โTreatment 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 lifespanโ.
Treated males lived an average of 221 days longer than controls (127 days).ย
Even more striking, when measured as median additional life after treatment began, OT+A5i males lived 157% longer than controls.
โMeasuring median additional life, OT+A5i male mice lived 240.5 median days post-injection, 157.22% longer than the control male mice, which lived only 93.5 median days post-injection.โ
The likelihood of death (hazard ratio) was nearly three times higher in untreated males compared to treated ones.
This survival curve shows the proportion of each group of mice remaining alive throughout the study. Males treated with OT+A5i (blue line) lived substantially longer than their untreated counterparts (orange line). In contrast, the survival rates for treated (green line) and untreated (purple line) females were almost identical, indicating the treatment did not extend their lifespan.
Healthspan: More Energy, Better Memory, Greater Resilience
Beyond living longer, the treated male mice were healthier.
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Endurance: Mice ran longer on the treadmill before exhaustion.
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Strength & agility: Hanging time on the grip test improved.
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Memory: Novel object recognition scores were higher, showing better short-term memory.
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Resilience: Even after reaching frailty thresholds, treated males survived longer than controls.
โThese animals had significantly increased healthspan, with improved physical performance, endurance, short term memory, and resilience to mortalityโ.
Resetting the Aging Clock at the Molecular Level
Using advanced proteomics, the researchers found that the treatment triggered a systemic reset.ย
Within just seven days, the blood protein patterns of the old, treated mice closely resembled those of young, healthy mice.
โThe acute, 7-day, treatment of the old mice with OT+A5i youthfully restored systemic signaling determinants and reduced protein noise in old mice of both sexesโ.
In other words, within a week, the blood proteome of both males and females shifted toward a younger, healthier state.ย
Pathways linked to inflammation and aging, like TNF and JAK-STAT, were reset to more youthful patterns.
Critical Findings on Sex Differences
One of the most important findings was the difference in response between sexes.ย
The profound lifespan and healthspan benefits were primarily observed in male mice. While female mice showed initial molecular improvements, they became unresponsive to the treatment after four months.
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Males: still showed a rejuvenated systemic proteome, with reduced inflammatory proteins and normalized pathways such as JAK-STAT and MAPK.
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Females: lost responsiveness, showing no proteomic improvements, matching the lack of lifespan and healthspan benefit.
โOld female mice become unresponsiveโฆwhile old male mice continuedly have beneficial effects of this pharmacologyโ.
Fertility Benefits in Females
Intriguingly, middle-aged female mice did benefit in another way:
โOT+A5i treatment improved a key age-diminished metric of fertility, resulting in higher numbers of weaned pupsโ.
This suggests that starting therapy earlier in life might extend female healthspan too, especially around reproductive aging.
Why This Matters for Human Longevity
This study highlights a new principle in longevity science: combining two interventions that correct opposite age-related imbalances can produce stronger effects than either alone.
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Oxytocin declines with age and is essential for muscle, bone, and tissue maintenance.
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TGF-ฮฒ signaling increases with age, driving inflammation and fibrosis. Blocking its receptor (with A5i) helps restore tissue homeostasis.
By lowering what goes up with age (TGF-ฮฒ) and replenishing what goes down (oxytocin), the researchers achieved synergistic rejuvenation.
Even more exciting, both components already have paths to clinical use:
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Oxytocin is FDA-approved and widely used in medicine.
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Alk5 inhibitors like Vactosertib are already in human trials for cancer, with no major safety concerns reported.
โOT+A5i holds a promise of rapid medical translation and use as a health-expansion therapyโ.
Conclusion
This is one of the most powerful demonstrations yet that aging can be reversed, even in already frail, elderly animals, by carefully rebalancing systemic signaling pathways.
While sex-specific differences raise new questions, the results are extraordinary:
โOT+A5i demonstrates unique outcomes, such as significantly (over 70%) increased life expectancy from the start of this therapy in old and frail male mice, and a robust decrease in mortality riskโ.
For longevity enthusiasts, this points toward a future where safe, clinically feasible therapies might not just slow aging, but actively restore youthful health and resilience.
