Aubrey de Grey recently shared what he expects will be one of the final lifespan updates for the RMR1 study. This research explores the effects of various interventions on the lifespan and healthspan of mice, with a focus on distinguishing between male and female responses.
As the study nears its conclusion, with only four male mice surviving into 2025, de Grey has started analyzing survival trends and intervention effectiveness. His latest update offers valuable insights into what works, what doesn’t, and how future studies might refine these approaches.
Female Mice: Rapamycin Steals the Spotlight
The data for female mice provides some clear takeaways, though not all of them are encouraging. Rapamycin, a drug known for its potential to extend lifespan, has consistently outperformed other interventions in this study. As de Grey noted, “Most of the signal seems to be from the one non-damage-repair intervention, rapamycin.” The survival curve for female mice receiving rapamycin alone was nearly identical to that of mice receiving all four interventions combined, suggesting rapamycin’s dominant role in driving longevity.
But the study design allows for a deeper comparison: the survival curve of mice receiving all but rapamycin (the “all-but-rapa” group) versus the no-treatment group. This revealed an intriguing trend. The all-but-rapa group reached the 50% survival mark only one week younger than the all-four group, indicating early benefits. However, their survival rates then dropped steeply, aligning closely with the no-treatment group. This suggests the damage repair interventions in this group were effective initially but their benefits diminished after about a year.
“This screams that the damage repair interventions WERE working, but that their benefits waned after a year,” de Grey explained. He proposes repeating such interventions every 6-9 months in future studies to maintain their effectiveness. Unlike damage repair interventions, rapamycin was continuously present in the mice’s chow throughout the study, potentially explaining its sustained impact. Interestingly, even short-term rapamycin supplementation has been reported to extend lifespans, though that remains a separate area of investigation.
Male Mice: A More Complex Story
In male mice, the results were less straightforward, reflecting more variability and potential statistical anomalies. Initially, the all-four intervention group appeared to have the strongest performance. However, the last six mice in this group died within a short period, contrary to expectations. "I am pretty sure [this] is a pure case of statistical scatter, with no actual meaning,” de Grey clarified. He emphasized the importance of larger sample sizes to smooth out such anomalies, noting, “That’s why we use 50 mice per group, and honestly we’d be happier if we could use 500.”
The survival trends for the all-but-rapa group in males diverged sharply from those in females. This group performed worse than the no-treatment controls during the early stages of the study. But in a surprising twist, its performance improved dramatically later on, with five mice showing remarkable resilience. As of the update, one mouse in this group was still alive, significantly outperforming expectations. De Grey acknowledged this might also be a statistical anomaly but plans to investigate further with rigorous analyses.
Meanwhile, the rapamycin-only males followed a different trajectory. Despite three of these mice outliving the entire all-four group, the rapa-only group generally underperformed relative to the all-four group for most of the study. This contrast between male and female outcomes highlights the importance of sex-specific analyses in aging research.
Gal-Nav and mTERT: Unexpected Underperformance
Two specific interventions, Gal-Nav and mTERT, raised red flags in male mice. Both performed worse than the no-treatment controls, a result de Grey found concerning. “Their underperformance relative to no-treatment controls was enough that I can’t put it down to statistical noise,” he stated. Interestingly, this poor performance was not observed in female mice, suggesting a potential sex-specific response or an issue with the delivery mechanism.
To explore this further, de Grey plans to examine mock versus naive controls across multiple groups. This comprehensive analysis aims to uncover whether the delivery vehicle might explain these unexpected results. He emphasized the importance of slicing through the data from several perspectives to extract meaningful insights.
Lessons and Next Steps
As the RMR1 study approaches its final stages, de Grey has begun outlining key lessons and potential directions for future research. One clear takeaway is the need to refine the timing and repetition of damage repair interventions. The dramatic decline in the all-but-rapa group after initial success underscores the importance of maintaining intervention efficacy over time.
Another lesson is the necessity of large sample sizes to minimize the impact of statistical anomalies. While intriguing outliers, such as the long-lived male in the all-but-rapa group, can provide valuable clues, they also highlight the variability inherent in such studies.
Finally, the contrasting results between male and female mice underscore the importance of sex-specific analyses in understanding the mechanisms of aging. Differences in response to interventions like rapamycin and the underperformance of Gal-Nav and mTERT in males point to the complexity of designing effective lifespan and healthspan studies.
Looking Ahead: Statistical Analysis and Healthspan Reports
De Grey’s next updates will focus on in-depth statistical analyses of the survival curves and comprehensive reports on healthspan data. These insights will not only clarify some of the anomalies observed in this study but also help design better interventions for future research.
