She was 52, healthy, and she brought a three-ring binder. Tabbed sections. Color-coded. The first tab was labeled "mTOR Inhibition" and contained six PubMed abstracts, two podcast transcripts, and a handwritten comparison of rapamycin dosing protocols from a longevity forum. She wanted to know if I would prescribe rapamycin for anti-aging.
I trained in surgery, not gerontology. My clinical world is preoperative risk, tissue healing, and functional recovery. Longevity medicine was not part of my residency, not part of my board prep, and for a long time, not part of my intellectual life. I put it in the same mental category as IV vitamin drips and infrared saunas: things patients asked about that I could comfortably ignore.
I get some version of the binder conversation at least twice a month now. The patients are smart. They have done real reading. What they usually lack is the clinical training to distinguish a promising mouse study from something I can responsibly act on. But here is what I have had to admit to myself over the past two years: what I sometimes lack is the humility to recognize when a patient's reading has outpaced my own.
The trial that ended my default dismissal
For years, rapamycin was the longevity community's most-discussed drug based almost entirely on animal data. Harrison et al. demonstrated a 9-14% lifespan extension in mice in their landmark 2009 Nature paper, and the community extrapolated aggressively from there. Conferences built entire sessions around it. Forums debated dosing protocols with the intensity of religious doctrine. And physicians like me would say some version of "interesting, but we only have mouse data" and move on.
That changed in April 2025. The PEARL trial, published in Aging, delivered the first large randomized controlled trial of rapamycin in healthy humans: 110 participants, 48 weeks, double-blind, placebo-controlled. The result was more interesting than either camp expected.
No significant safety differences versus placebo. Reassuring. But the broad anti-aging signal the community had been banking on? Not there. Women on the 10mg weekly dose showed increased lean mass (+0.8 kg, P=0.03) and reduced pain scores, but men showed nothing meaningful, and no biomarker of aging shifted consistently across the cohort.
I tell patients about PEARL directly now. It replaced the conversation I used to have. Instead of "we only have mouse data," I can say: we ran the human trial, and the answer was more complicated than the podcasts predicted. The study was well-designed. The signal was not there for most people. That is not failure. That is how science works when you actually run it in humans instead of extrapolating from C57BL/6 mice.
The finding that made me uncomfortable
I used to dismiss longevity medicine more categorically than I do now. I had a comfortable position: the evidence is not there, the supplements are unregulated, the clinics are selling hope. Clean. Simple. And partly wrong.
In July 2025, a randomized controlled trial showed that semaglutide reversed multiple epigenetic aging clocks. PCGrimAge dropped 3.1 years (P=0.007). PhenoAge dropped 4.9 years (P=0.004). DunedinPACE improved by 0.09 units (P=0.01). Single trial. 40 participants. Needs replication. Epigenetic clocks are surrogate endpoints, not hard outcomes like mortality. I know all the caveats.
But here is why this result genuinely shifted my thinking, and why I am writing about it rather than waiting: semaglutide already has a decade of safety data, existing prescribing infrastructure, and insurance coverage for approved indications. If the epigenetic findings hold, the path to clinical validation is years, not decades. Compare that to the TAME trial (Targeting Aging with Metformin), which Nir Barzilai spent over ten years trying to launch before it was effectively absorbed into ARPA-H's FAST initiative. As Barzilai himself noted in a 2024 Nature Medicine interview, Eli Lilly may beat academic longevity research to a clinically meaningful answer simply because commercial molecules move through regulatory pipelines faster than NIH-funded geroscience.
I had been waiting for longevity medicine to produce evidence on the academic timeline. The market was not waiting for me.
The five-drug stack and the missed colonoscopy
Last fall, a 58-year-old patient came in taking metformin (off-label, no diabetes), low-dose rapamycin (sourced from an online clinic I later identified as AgelessRx), NMN at 500mg daily, resveratrol, and BPC-157. Five compounds. Monthly cost: roughly $900. He could recite the mechanism of action for each one with more fluency than most medical students.
He was also two years overdue for a colonoscopy. His last lipid panel was from 2022. No DEXA scan. No VO2 max test.
This is the pattern that concerns me most. The psychological appeal of optimization, the sense of proactive control, can paradoxically distract from the preventive care that actually has mortality data behind it. I have seen this three times in the past year alone: patients who can explain rapamycin's effect on mTORC1 versus mTORC2, who have never had a cardiac calcium score. One patient brought handwritten notes from a Peter Attia podcast episode that were more detailed than any medication history I have ever received from a referring physician, and had not seen his primary care doctor in three years.
But I have also started wondering whether the dismissive response, "just get your colonoscopy and stop wasting money on supplements," is part of the problem. That 58-year-old came to me because his primary care doctor had rolled her eyes at his binder. He did not stop taking the supplements. He stopped seeing the doctor. The eye-roll did not protect him. It removed him from medical oversight entirely.
What a patient taught me about NAD+
I will admit something uncomfortable. Last year, a patient brought in a paper I had not read. Igarashi et al., a 2024 RCT published in GeroScience, tested NMN (250mg/day) in 60 older adults over 12 weeks. The NMN group maintained walking speed (6-minute walk test, P=0.04), showed improved grip strength, and reported better sleep quality on the Pittsburgh Sleep Quality Index versus placebo.
I had been telling patients that NAD+ precursor data was "mostly animal studies." That was no longer fully accurate, and I had not updated my position. The patient had. She was polite about it, but the correction was clear.
A 2025 head-to-head comparison in Nature Metabolism (Dellinger et al.) confirmed that both NMN and NR raise blood NAD+ levels after 14 days of supplementation, while plain nicotinamide does not. These are real findings. Small trials, short durations, preliminary. But real. Dismissing them as "just supplements" is intellectually lazy. I was being intellectually lazy.
That said, and I told this patient directly: small positive trials for NAD+ precursors do not justify a $300-per-month supplement protocol as a substitute for a colonoscopy. The supplements might have modest benefits. The colonoscopy might save your life. Those are not equivalent claims and I refuse to pretend they are.
Where I draw hard lines
I will not prescribe BPC-157. In September 2023, the FDA placed it on its Category 2 bulk drug substances list, effectively banning it from 503A and 503B compounding pharmacies. In February 2026, under the new FDA leadership, that decision was partially reversed. Banned, then partially unbanned, within 28 months. Whatever your politics, that regulatory trajectory is not the foundation for a therapeutic decision. The human safety data remains essentially nonexistent: most cited studies are rodent models or in vitro work by a single research group (Sikiric et al., University of Zagreb), and no Phase I human trial has been published.
I will not prescribe off-label rapamycin for general anti-aging after PEARL. The trial was well-designed and the broad signal was not there. I tell patients this directly: "If someone is prescribing this to you without discussing PEARL, ask them why." I will revisit this if future sex-stratified studies or different dosing protocols change the picture. That is not stubbornness. That is how evidence-based medicine is supposed to work.
I will not order unregulated IV NAD+ infusions. The FDA issued a Class I recall (the most serious category, indicating "reasonable probability of serious adverse health consequences") against GenoGenix NAD+ injections for endotoxin contamination. When patients tell me they are getting IV NAD+ at a wellness clinic, I ask what they know about the sourcing, the sterility testing, and the compounding pharmacy. Usually the answer is nothing.
The position that satisfies nobody
A 2025 Swiss framework published in Aging and Health Research (Bischof et al.) attempted to define clinical standards for responsible longevity medicine practice. The fact that such a framework was needed tells you where the field is: growing faster than its evidence base, with enough legitimate science to be taken seriously and enough unregulated commerce to be dangerous.
Here is where I have landed. It satisfies nobody fully, which I have come to believe is the correct sign.
The interventions with the strongest human evidence for longevity remain stubbornly unsexy: 150 to 300 minutes per week of moderate aerobic activity (Ekelund et al., BMJ 2019, n=44,370, showing a dose-response mortality reduction), resistance training, adequate sleep, a Mediterranean-pattern diet, social connection, and not smoking. Decades of data. Nearly free. Routinely ignored by patients who would rather optimize a supplement stack. Those basics come first. Always. I will not discuss rapamycin dosing with someone who does not exercise.
After the basics? Stay curious. Read the trials, the actual trials, not the podcast summaries. The computational tools accelerating aging biomarker discovery are real, but the clinical validation pipeline remains slow by design. That slowness is a feature, not a bug.
The woman with the binder left my office without a rapamycin prescription. She left with a referral for a DEXA scan, an updated lipid panel order, and a printed summary of the PEARL trial results. She emailed me two weeks later: "I read the full paper. Thank you for not rolling your eyes at me."
That is the conversation I want to have. Not the one where I am right and the patient is naive. The one where we are both looking at the same evidence and being honest about what it does and does not show. The willingness to say "I do not know" out loud, to patients, is the beginning of taking this seriously.
Frequently Asked Questions
What did the 2025 PEARL trial show about rapamycin for anti-aging?
The PEARL trial (110 participants, 48 weeks, double-blind, placebo-controlled, published in Aging April 2025) found no significant safety concerns versus placebo but no clear broad anti-aging signal. Women on 10mg weekly showed increased lean mass (+0.8 kg) and reduced pain, but no consistent biomarker improvement across the full cohort. The data does not support prescribing rapamycin as a general anti-aging intervention.
Can semaglutide reverse biological aging?
A July 2025 RCT (n=40) showed semaglutide reversed several epigenetic aging markers: PCGrimAge by 3.1 years (P=0.007), PhenoAge by 4.9 years (P=0.004), and DunedinPACE by 0.09 units (P=0.01). This was the first randomized trial showing a licensed drug reversing epigenetic age, but epigenetic clocks are surrogate endpoints, not hard outcomes. Replication is needed before recommending semaglutide specifically for longevity.
Are NAD+ supplements worth taking?
The evidence is early but real. Igarashi et al. (2024, GeroScience, n=60) showed NMN improved grip strength, walking speed, and sleep quality over 12 weeks versus placebo. Dellinger et al. (2025, Nature Metabolism) confirmed NMN and NR raise blood NAD+ levels while plain nicotinamide does not. These are small, short trials. Injectable NAD+ carries additional safety risks (FDA Class I recall of GenoGenix for contamination). Standard preventive care should come first.
What does Dr. Sina Bari recommend for longevity?
The foundation is evidence-based preventive care: 150-300 minutes of weekly moderate exercise, resistance training, sleep optimization, Mediterranean-pattern diet, social connection, and not smoking. Beyond that, I stay current on emerging trial data and discuss specific findings with patients rather than offering blanket dismissals. Every recommendation is anchored in the individual's risk profile, labs, and whether they have completed standard screening first.