In this episode, Matt and Nick delve into Bryan Johnson's recent decision to stop his off-label use of rapamycin, exploring the reasoning behind it and the broader implications. They discuss the potential benefits and risks of rapamycin, including dosage and lifelong use, while analyzing the pre-print data Bryan referenced. The conversation touches on the validity of epigenetic clock tests and the public's mixed reactions, including debates sparked on social media. Matt and Nick also review Bryan’s supplement routine and share their thoughts on impactful strategies for optimizing health. The episode concludes with reflective insights on the future of healthspan research.

Check out the links below for further information and reading about some of the topics we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings but present them as supplementary material to deepen your understanding of the subject. This list is in no way exhaustive but offers a good starting point.

DNAm aging biomarkers are responsive: Insights from 51 longevity interventional studies in humans | bioRxiv

This is the pre-print that Bryan referenced in his twitter post as one of the pieces of evidence that informed his recent decision to remove rapamycin from his longevity stack. This study harmonized databases of 51 public and private longitudinal interventional studies and calculated 16 different epigenetic biological age scores for each study to determine whether they are responsive to a variety of gerotherapeutic interventions. This study included first generation clocks (e.g. Horvath) that are trained on mortality, second generation clocks (e.g. PhenoAge) that are trained on morbidity and mortality, and explainable clocks (e.g. OmicsAge) that focus on epigenetic marks associated with sets of genes with known mechanisms of action. The interventions evaluated include lifestyle, supplements, drugs, and even medical procedures like gastric bypass. Different DNA clocks were found to be sensitive to different interventions and there was substantial variability in epigenetic age scores in response to the same intervention. Pharmaceutical interventions such as TNF-alpha inhibitors and metformin had strong, consistent effects across multiple studies while rapamycin showed no effect on epigenetic age. Counterintuitively, well validated lifestyle interventions like exercise and caloric restriction had no effect on epigenetic age either. Further studies are needed to make sense of what aspects of biology are reflected by different epigenetic clocks, how that may influence their responsiveness to interventions, and the value different epigenetic clocks may provide for evaluating health change. At a minimum, more studies are needed pairing epigenetic clocks with clinically validated endpoints of health and disease status (e.g.  metabolic blood panel, physical and cognitive functional assessments, and disease outcomes)

Evaluation of off-label rapamycin use to promote healthspan in 333 adults - PubMed

This registry trial collected data from 333 adults using rapamycin off-label for longevity.  Individuals reported taking rapamycin for anywhere between a month to several years and reported less adverse health outcomes during the length of the study including abdominal pain, muscle cramps, depression, and anxiety than the group not taking rapamycin. Further, individuals taking rapamycin were significantly less likely to have experienced moderate or severe COVID-19 symptoms compared to non-users. Finally, individuals taking rapamycin were 3x more likely to report improvements in general health, happiness, brain function, and several other aspects of quality of life. Notably, there was a lack of apparent side effects associated with rapamycin compared to the group of individuals not taking it.

Targeting ageing with rapamycin and its derivatives in humans: a systematic review - The Lancet Healthy Longevity

This review summarizes the safety and effectiveness of rapamycin in 19 different studies including both healthy and disease cohorts. The authors found that rapamycin and its derivatives improved physiological parameters associated with aging of the skin, immune and cardiovascular system of healthy individuals or individuals with age-related diseases. Notably, no serious adverse events were attributed to rapamycin within the studies in healthy cohorts; however, there were increased numbers of infections and increases in total cholesterol, LDL cholesterol, and triglycerides in individuals with age-related diseases taking rapamycin at higher doses and more frequent administration than the typical weekly dose administered for healthy longevity.

How do biological age tests work and are they accurate or helpful? : Shots - Health News : NPR

In this NPR blog post, author Allison Aubrey interviews key opinion leaders in the geroscience field (Luigi Ferruci, Matt Kaeberlein, Steve Horvath, and others) about their perspective on the value and accuracy of biological age clocks for predicting disease risk and informing the effectiveness of healthy aging interventions. Most of the experts agreed that in their present state, results from biological age tests are best viewed as a curiosity rather than a rigorous measure of health status. Steve Horvath, one of the leaders that established the first epigenetic age clock, says he developed it as a way for scientists to study aging, not necessarily for consumers to fret over their own epigenetic age. Several experts concluded that epigenetic age data should be collected alongside clinically validated measurements of health status (e.g. blood pressure and cognitive function) and this could provide a more complete picture of health and wellness. 

A single-center, double-blind, randomized, placebo-controlled, two-arm study to evaluate the safety and efficacy of once-weekly sirolimus (rapamycin) on muscle strength and endurance in older adults following a 13-week exercise program - PMC

Matt and Nick mention Brad Stanfield’s clinical trial evaluating the safety and efficacy of 6 mg, once-weekly rapamycin administration on muscle strength and endurance in older adults engaged in a 13-week exercise program. This paper goes over the study design of Brad’s randomized, double-blind, placebo-controlled trial in 40 participants aged 65-85. The rationale is that alternating rapamycin and resistance training will help achieve healthy mTOR balance. The primary outcome measure is change in muscle strength and endurance, assessed by the 30-second-chair-stand test. Secondary outcome measures include adverse events, change in muscle strength and endurance as measured by 6-min walk test, handgrip strength, and self-reported quality of life outcomes. Further, blood samples will be collected for assessing metabolic health, inflammation, organ function, and epigenetic age.