"I Made Myself Older By Mistake" - Dr Brad Reacts

Brad explains that to validate a biological age test, you need a long-term study showing that people with lower biological age have lower rates of cancer, heart disease, or death. No such study exists. Therefore, interpreting a change in epigenetic clock as 'accelerated aging' is speculative. He also notes that people who take rapamycin are a self-selected group that may engage in other risky behaviors, confounding any observational associations. He urges focusing on hard outcomes like actual mortality and disease incidence.

Brad details the side effects Brian experienced: mouth ulcers, impaired wound healing, elevated cholesterol and glucose, increased resting heart rate. He notes that these are consistent with known rapamycin toxicity at high doses. He also points out that isolating rapamycin's effects is difficult when doing many interventions simultaneously. He emphasizes that the doses used in transplant patients are much higher and combined with other immunosuppressants, but even lower intermittent doses in healthy people lack long-term safety data. He advises waiting for RCT results.

Brad describes the evidence pyramid: case reports at the bottom, then case-control, cohort, RCTs, systematic reviews. He explains that medicine uses this hierarchy to grade evidence and make recommendations. He expresses concern that Brian's high-production-value video might lead people to believe his personal experience outweighs RCTs. He states that as a doctor, he would never base patient advice on a case report.

Brad argues that the ultimate goal is to reduce death and disease, not to change a number on a test. He notes that no trial has shown that lowering biological age via an intervention leads to fewer hard events. Therefore, using epigenetic clocks as a primary endpoint is premature. He advocates for trials with clinical endpoints like the 30-second chair stand test (a functional measure) or, ideally, mortality and morbidity.

Brad explains that rapamycin (sirolimus) has a 'dirty name' in medicine due to its use as an immunosuppressant in organ transplant patients at high doses. This has made it difficult to get trials approved in otherwise healthy people. His trial uses everolimus (Certican), a rapamycin analog that is more selective for mTORC1, potentially reducing side effects. The dose is 6 mg once weekly, much lower than transplant doses. Both groups exercise, so the trial isolates the drug's effect on muscle strength retention. The primary outcome is the 30-second chair stand test, a functional measure of lower body strength. Brad notes that results are imminent, which will provide a higher level of evidence than case reports.

Brad explains that if a 60-year-old gets a biological age result of 50 or 70, we don't know if that translates to different risks of disease or death. To validate these tests, a long-term observational trial of about 5 years would be needed, and none exist. Therefore, interpreting changes in epigenetic clocks as 'accelerated aging' is premature. He also notes that people who take rapamycin are self-selected and may engage in other risky behaviors, confounding any observational associations. He emphasizes that hard outcomes like actual death rates, cancer incidence, and cardiovascular events are what matter, not surrogate biomarkers.

Brad outlines the evidence pyramid: case series/case reports at the bottom, then case-control studies, cohort studies, randomized clinical trials, and systematic reviews at the top. He places Brian's self-experimentation at the bottom. He expresses concern that some viewers might think Brian's results supersede RCTs, which is dangerous. He emphasizes that just because something worked or didn't work for one person doesn't mean it applies to others. The only way to establish causality at a population level is through RCTs. He states that he would never make recommendations to patients based on a case report, and no doctor should.

Brad notes that rapamycin (sirolimus) has poor bioavailability and a short half-life, so pharmaceutical companies developed analogs. Everolimus (Certican) is more selective for mTORC1, while temsirolimus targets both mTORC1 and mTORC2. Because mTORC2 inhibition is linked to metabolic side effects (insulin resistance, lipid abnormalities), using a more selective agent might reduce those risks. In his trial, he chose everolimus for this reason. He speculates that Brian may have used a less selective form or high doses, contributing to his side effects. He also mentions that the triangle-shaped pill Brian showed is likely everolimus, as it's made by Pfizer.

Brad acknowledges that Brian is free to spend his money and publish his results, but he worries that viewers might imitate him. He stresses that if you experiment with interventions lacking human RCT evidence, you could be doing yourself harm. He points to the known side effects of rapamycin at high doses: mouth ulcers, impaired wound healing, elevated cholesterol and glucose, increased resting heart rate, and potential immunosuppression. He also notes that isolating cause and effect is nearly impossible when doing many interventions simultaneously. He advocates sticking to the 'foundations of health' that medicine recommends, which provide far more benefit than unproven biohacks.