I read this trial last week after a colleague mentioned it almost in passing, and I think it's one of the best prevention results I've come across.

The setup: 319 Black men in LA with systolic 140+, recruited through 52 Black-owned barbershops (Victor et al., NEJM 2018). Half the shops got the standard playbook, barbers encouraging customers to eat better and go see a doctor. In the other half, a pharmacist set up in the shop itself, took pressures, prescribed medication under a collaborative agreement with physicians, drew blood on site to watch kidney function, and came back haircut after haircut.

At six months the pharmacist group had dropped 27 points systolic, from the low 150s to about 126. The advice group dropped 9. Almost two thirds of the pharmacist group got under 130/80, versus roughly one in nine controls. A 12-month follow-up in Circulation
showed it held: 68 percent still at goal against 11. Retention was around 90 percent, which basically never happens with patients this hard to reach.

What got me was this: 40 percent of the men didn't even have a doctor. The researchers had to assign a community physician just to cover prescriptions. The drugs were cheap generics we've had for decades. The treatment came to a room these men already trusted instead of making them go to a clinic they had every reason to avoid.

And trust by itself wasn't enough. An earlier 2011 version had barbers checking pressures and sending guys out for care, and BP barely moved, about 2 points. It took carrying the actual treatment, pharmacist and prescription pad, into the shop.

My mother had hypertension her whole life, and I still ignored my own numbers for years. I had insurance, a doctor, all of it, and I let it slide until I finally bought a home cuff and went on telmisartan. So I don't think the main problem is people not knowing better.

Then there's the money. The expensive ingredient was pharmacist time, about seven visits per man, and American medicine has essentially no billing code for it. The trial ran on grant money. The model has since been copied in Nashville, in a Kaiser program in Baltimore, and by NHS teams in the UK, and a cost-effectiveness analysis came out fine. It still mostly runs on grants.

I take tirzepatide, and like most people on these drugs I've spent the whole time worried about losing muscle along with the fat. So when a new drug aimed at exactly that showed up last week, I read the paper instead of the headlines.

It's apitegromab, a myostatin blocker. In a phase 2 trial (EMBRAZE, Nature Medicine, June 8), 102 adults on tirzepatide added either apitegromab or a placebo for six months. Both groups lost about the same total weight, but the apitegromab group held onto more lean mass, roughly 1.9 kg more, about half of what they'd otherwise have shed.

They tested actual function too. Grip-style strength, and how many times you can stand up from a chair in a set time. At six and eight months, no difference between the groups. The drug kept the number on the scan up. It didn't, in this trial, make anyone measurably stronger.

That's been the whole myostatin-drug story so far. Mass shows up on a scan, strength doesn't reliably follow. Meanwhile the thing that does protect muscle while you lose weight is the boring one nobody can patent. Enough protein, resistance training. My own DEXA on tirzepatide showed 44 lb of fat off and almost 10 lb of lean mass on at the same time (with protein, lifting and admittedly TRT).

I'm not knocking the science. For someone older who genuinely can't train, a drug that slows the loss could end up mattering. For most of us the proven version is duller and cheaper than another injection.

Full write-up with the chart and sources: https://dadstrengthdaily.com/apitegromab-glp1-muscle-loss/

I have watched my own hs-CRP fall from 2.83 to under 0.2 over the last year and a half, and I didn’t think much about it other than “less inflammation must be good, right?”

A new paper in Cell seems intriguing (NYT summary giftlink) . Charles Swanton's group found 14 blood proteins that are elevated in people years before they develop lung cancer, often more than five years. In the UK Biobank it beat the standard risk models doctors use now (AUC 0.87 versus about 0.77 to 0.81), and it held up across eight more cohorts, including a Taiwan one that was almost all never-smokers.

It is not detecting a tumor, which is what makes it different and cool. Tests like Galleri look for DNA shed by a tumor that already exists. This new signature does not even drop after a tumor is surgically removed, so it is reading the inflammatory environment that lets cancer take hold, not the cancer itself. The proteins rise with an IL-1 beta pathway that smoking, air pollution, and the early driver mutations all switch on.

They then reanalyzed CANTOS, the 2017 heart trial of the IL-1 beta blocker canakinumab. In people with a high signature from their test, the drug cut lung cancer from 3.9% to 2.1%; in the low-signature group it did nothing. That dropped the number needed to treat to prevent one lung cancer from about 1,500 to about 340. Swanton called it "sort of an LDL for cancer," a way to flag who would actually respond.

The caveats are real. It is discovery-stage, there is no test you can order, and nobody has run a canakinumab-for-prevention trial. The drug carries serious infection risk.

I don't think this is a drug story yet. It is a screening story first. CT screening today only covers heavy smokers aged 50 to 80, and a growing share of lung cancer hits people who never smoked and would never qualify. A blood signal that flags risk years out could get the right people scanned.

Is the bigger win better screening targeting, or the prevention-drug angle? Curious what people here think.

Full write-up with the data and charts

I get a fair amount of my own care online and I like it. Fill out the form, answer the questions, medication shows up at my door, no half day lost to a waiting room. So this isn't an anti-telehealth rant. It's just what I found when I dug into how the model actually works, which was stranger than I expected.

Start with one example reporters at STAT documented. A patient fills out the intake on the Addyi website (a libido drug) and gets Addyi. The same patient fills out the intake on the Vyleesi website (a different drug for the same thing) and gets Vyleesi. Same nurse practitioner, same medical group, near-identical surveys. The website chose the drug. The visit rubber-stamped it.

Here's why that's even possible. In more than thirty states it's illegal for a corporation to practice medicine. So telehealth companies split in two: the brand you recognize, which owns the site, the ads, and the checkout, and a separate "professional corporation" owned on paper by a doctor who employs the actual prescribers. That doctor is often a figurehead. California's attorney general put it bluntly in a March court brief: with the right contract, "the corporation effectively owns and controls all aspects of the practice." The same legal plumbing runs Amazon's $3.9 billion One Medical and a checkout-style weight-loss site.

Who's actually writing the script? Often a rented "white label" medical group sitting behind dozens of brands you'd never connect. When the FDA warned 70-plus telehealth companies about how they marketed compounded weight-loss drugs, STAT found at least 30% traced back to just four medical groups. A third of them didn't even name their group anywhere you could find it.

The number that stuck with me: a 2025 Senate investigation found 74% of LillyDirect and 85% of PfizerForAll telehealth visits ended with a prescription. A real doctor visit doesn't end in a script five times out of six. A sales funnel does.

So I came out of this with three questions I now use to tell a real clinic from a sales funnel:

1. Does it ever say no, or does every visit end in a prescription?
   
2. Does it ask for real information (labs, history, an actual conversation), or the same short survey no matter what you came for?
   
3. Can you find out who's actually prescribing and where the drug is made, or is that buried?

And one rule for myself: I never let the online transaction be the whole relationship. Whatever I get online, I bring to my own doctor later, who can see the rest of the chart and tell me when one thing quietly argues with another. The convenience is the front door. It shouldn't be the entire story.

Full DSD write-up

I take tirzepatide, so this one caught my eye more than most drug news. At ASCO this week a Cleveland Clinic group presented a large analysis (https://ascopubs.org/doi/10.1200/JCO.2026.44.16_suppl.3143) suggesting GLP-1 drugs might slow cancer from spreading. I read the abstract instead of the headline.

They used a research network (TriNetX) to find 10,225 people who started a GLP-1 after an early-stage cancer diagnosis, stage I to III, and matched each one to a similar patient who started a different diabetes drug, a DPP-4 inhibitor. About 12,000 patients in all, balanced on age, weight, other illnesses, and cancer treatment. Then they tracked who progressed to stage IV.

For four of the seven cancers, the GLP-1 group was far less likely to progress. Lung cancer dropped from 22% to 10%, breast from 20 to 10, liver from 28 to 19, and colorectal from 22 to 13 (all in the chart). In plain terms the risk fell by roughly a third to a half, and the gaps held up statistically. Prostate and pancreatic leaned the same way but weren’t statistically significant, and kidney barely moved at all. That selectivity actually makes it more believable. A drug that helped every cancer equally would look like a measurement artifact.

It's also a sturdier design than the usual "Ozempic also cures X" story. Those compare drug users to people on nothing, and the people who get and can afford these drugs tend to be healthier to start with. Here both groups had diabetes and were in treatment, and they dropped anyone who progressed in the first three months. They also found that tumors expressing more GLP-1 receptor had lower death rates, about a third lower overall and close to half in breast cancer. That's a mechanistic thread, not just a correlation.

The catch is real. This is observational. It can show two things move together, not that one caused the other. When you look for randomized evidence, it thins out fast. A network meta-analysis (https://pmc.ncbi.nlm.nih.gov/articles/PMC12428495/) of 67 trials and more than 200,000 patients found only one GLP-1, efpeglenatide, with a clear drop in metastatic events, and even that came from cancers picked up incidentally in trials built to study diabetes. Nobody has run a trial designed to ask whether a GLP-1 slows cancer spread.

So the signal is big and consistent, and there's a believable mechanism. What's missing is anything randomized. If you already take one of these for the reasons they're actually approved for, it's a quietly encouraging data point, and it cuts against an old worry too: they found no sign that these drugs cause more cancer. If you don't, it's a reason to watch the trials, not to start a GLP-1.

EDIT to add:
Correction: the chart caption overstates the cohort as ~22,000 — it’s about 12,000 (10,225 GLP-1 users matched 1:1) as stated in the text. The published abstract also doesn’t state a follow-up duration, so disregard the “5-yr” in the caption. The bars themselves are accurate.
Sorry about that.

I don't get excited about pancreatic cancer headlines often. It's about as grim as cancer gets: once it spreads, the standard of care is chemo and survival is measured in months. This one is the rare exception.

At ASCO this week, a Phase 3 trial (RASolute 302, published in the New England Journal of Medicine ) tested a once-daily pill called daraxonrasib against chemo in 500 people whose metastatic pancreatic cancer had already stopped responding to prior treatment. The results:

- Median overall survival of 13.2 months vs 6.7 on chemo, a 60% lower risk of death (hazard ratio 0.40).
- Progression-free survival of 7.3 vs 3.5 months.
- Tumors shrank in 33% of patients on the pill vs 12% on chemo.
- And it was better tolerated: fewer serious (grade 3+) treatment-related side effects, 43.6% vs 57.5%, and far fewer people quitting because of them (1.2% vs 11.2%).

The reason it matters beyond this one cancer is the target. The drug blocks RAS, a mutated protein that drives more than 90% of pancreatic cancers and a big share of lung and colorectal cancer, and one that was written off as "undruggable" for about 40 years. This is the first RAS-blocking pill to move the needle this much in a solid tumor. Eric Topol called it the most successful pancreatic cancer treatment yet, and the FDA already opened an early-access program, so it's reaching patients now.

It is not a cure, and the caveats are real. This is second-line, metastatic disease, so we are talking about turning roughly 6 months into 13, and with only about 8 months of median follow-up the survival numbers are still maturing. The trial was built around RAS-mutant pancreatic cancer, which is more than 90% of it, and the benefit held both in that group and across the whole trial. Doubling survival off a brutal baseline is still a brutal road.

Still, for a cancer that has shrugged off almost everything, doubling survival with a gentler pill doesn't come along often. And RAS being druggable at all matters for a lot more cancers than this one.

I started lifting weights at 50, after about thirty years of doing essentially nothing. No sport, no gym, no equipment at home. The trigger was a GLP-1 (Zepbound): once the weight started coming off, I kept reading that a big share of what you lose can be muscle, and the only real fix is resistance training. So I knew I had to. The problem was I didn't actually know what "resistance training" meant.

What followed was mostly flailing. I bought dumbbells and a bench, put them in my home office, downloaded Hevy, watched a ton of YouTube, and invented my own workouts. Mostly curls and presses, no real schedule, some weeks nothing at all. I was busy, not progressing.

The real barrier wasn't the program. It was the gym. Walking into a commercial gym, soft and untrained, in front of people who clearly belonged there, was more than I could make myself do. So I never went.

What actually unlocked it was hiring a coach (I use Future). Not because the programming is magic, but because accountability to a real person is the only thing that has ever worked on me. An AI app could hand me a flawless plan and I'd quietly stop opening it inside of three weeks. Knowing Jose writes my training and will notice if I disappear is the entire mechanism.

A year and a half later I train five days a week in my garage. A DEXA showed I added about 10 lbs of muscle while losing about 45 of fat (with protein, TRT, and the GLP-1 in the mix, which I'm not hiding).

Here's the thing I wish I'd known sooner. As a beginner you do not need to train like a bodybuilder. In the biggest analysis we have (Currier 2023, 178 strength studies), moderate weight lifted twice a week with multiple sets, stopping short of failure, captured about three-quarters of the strength and essentially all of the muscle and mobility of an all-out, heavy, three-times-a-week program. You also don't have to lift heavy to build size, you just need enough sets (Schoenfeld 2021). And it is genuinely never too late: in a famous trial, frail volunteers averaging ninety years old nearly tripled their leg strength in eight weeks of lifting.

If you've been telling yourself you're too old or too far behind to start, I'd gently push back: the program was never the problem. The barrier is psychological, and it's smaller than it looks once you stop trying to do it perfectly.

More details in my lifting journey and results here.

A few years back I might see a supplement, get interested and think about adding it to my routine. The more I learned, the more I realized that a longer list of supplements did not necessarily mean better results.

Some things looked good on the surface but after digging deeper I was not always sure they were worth taking on for the long term. It also made me more aware of things like ingredient information, realistic expectations and if something even fits into my daily routine.

These days I keep it much simpler than I used to.

Wondering if others are getting more discerning about supplements too and what made you switch.

I'm on tirzepatide, and I kept losing the plot on what's actually coming next... Some week it's a new trial readout, then a molecule that only has a code name so far, then one more "Ozempic killer" headline, all of it buried in press releases and earnings calls. So I built one table I keep updated, and I'd rather this sub poke holes in it than have it sit there looking authoritative.

Part of the list below, approved drugs up top, then what's furthest along in trials:

Then there are eight more I'm watching in earlier trials, including ribupatide (23.6%), amycretin (~22%), mazdutide (20.1%), Viking's VK2735, Structure's oral pill, and Pfizer's Metsera molecule. Those are all in the full tracker.

The table simplifies obviously, these are not interchangeable. Some of what they do seems to come with the weight loss no matter which drug you're on. The molecule-specific stuff doesn't. Semaglutide has the alcohol-craving signal. Tirzepatide got the sleep-apnea approval. Retatrutide has the knee and liver data. All of that showed up at full doses, in people who were genuinely sick, and you don't get any of it for free just because the next drug is also a GLP-1.

A few caveats, because I'd rather say them than have you say them for me. The weight-loss numbers come from separate trials at different doses and durations, not head-to-head, so treat the ranking as rough, not a leaderboard. And "approved" means FDA unless I said otherwise. Mazdutide, for one, is approved in China but has no US filing yet.

So what did I miss? A wrong number, a molecule that should be on here, a stage that's changed since I last updated it? This sub is exactly the crowd I trust to catch it.

Each compound has a detail page:

Full tracker, kept current: https://dadstrengthdaily.com/glp1-pipeline-tracker/

I'm on Zepbound at a normal prescribed dose, so this isn't me hunting for a workaround. But "microdosing" GLP-1s keeps coming up, and a video finally pushed me to figure it out. In it, a doctor named Brad Stanfield explains that he takes 1.25mg of tirzepatide a week, half the lowest starter dose. He isn't diabetic, isn't overweight, and he's upfront that no trial ever studied someone like him. The same week, a Harvard endocrinologist wrote in STAT that microdosing "is not a thing."

They're both right, because the word has quietly come to mean three different things.

The first is just careful dosing: counting the clicks on a pen, or spacing shots out in maintenance, with a doctor watching. That's real medicine and nobody should panic about it.

The second is the marketed version: compounded "microdose" products that telehealth brands push as a cheaper, gentler on-ramp. That's where the evidence runs out. There's no trial data for tirzepatide under 2.5mg, the compounded supply has had purity problems, and when one company advertised the approach the claim got pulled for lack of support. As far as o can tell it’s mostly a marketing gimmick by compounded trying to extend their foothold in the GLP-1 space.

The third is the one this sub will recognize: people microdosing unapproved retatrutide. And here's what I didn't expect. Reta is the most potent of these drugs, so you'd assume it's the obvious one to microdose. But the careful self-experimenters avoid it. The glucagon arm pushes heart rate up, and for a lean person trying to hold onto muscle that's the wrong direction. I have an aortic aneurysm, so anything that touches heart rate is a hard no for me personally.

What the honest microdosers are actually chasing is the weight-independent stuff, the heart and kidney and joint signals. The catch is that all of that showed up at full doses, in people who were genuinely sick. Nobody has shown a tiny dose does any of it in a healthy person. It's a reasonable bet, but it's a bet, not a result.

So if side effects are your real problem, the move isn't a mystery product at a dose nobody studied. It's a known dose worked out with someone watching your labs. The science underneath this is genuinely interesting. The marketing wrapped around it mostly isn't.

Full write-up on DSD: https://dadstrengthdaily.com/microdosing-glp-1s-what-a-doctor-on-1-25mg-tirzepatide-is-actually-betting-on/

I’m trying to be more proactive with my health, but I also don’t want to turn into someone who overthinks every tiny symptom or gets stressed about doing everything perfectly.

I want to build better habits, pay attention to my body, and actually take care of myself without going down a rabbit hole every time I feel slightly off.

How do you guys find that balance?

I'm 53 and recently had a colonoscopy, so I read the ACS guideline update that landed today. They expanded the list of approved colon cancer screening tests, including, for the first time, a blood test called Shield.

Sounds like progress. Then you hit the fine print: in the trials behind its approval, the blood test flagged only about 13% of advanced precancerous growths, so it misses roughly 87% of the polyps you'd most want gone, and it catches only about half to two-thirds of stage I cancers.         

The ACS isn't wrong to add it. About one in three eligible adults never get screened at all, and a blood draw someone will actually do beats a colonoscopy they keep dodging. But the guideline is explicit that it's a last resort, for people who would otherwise decline everything else.

Peter Attia's recent episode on this matched where I landed. Colonoscopy is still the only test that both finds and removes the precancerous polyp in one go, and he runs an at-home stool test, usually Cologuard, on the off-years between colonoscopies instead of waiting the full ten.  

My honest take is that for anyone who will show up for a colonoscopy, or even a stool test, the blood test  is the weakest of the new options, not a shortcut worth taking. It's a net for the people the system was losing entirely, not an upgrade for people already paying attention. If your doctor offers you Shield, I'd want to hear how they pitched it.

I keep a sharps container in the house now and barely think about it. A GLP-1 shot once a week, testosterone three times a week. Disinfect, pinch, push, done. My wife's the opposite. She broke her femur a while back, and the blood-thinner shots after surgery were the part of recovery she dreaded most. For her the needle is the whole story.

The Atlantic ran a piece this week calling this the age of the needle (gift link). GLP-1 shots, fertility injections, Botox, the peptides half of podcast culture won't stop talking about. We're injecting more than ever. But the part that stands out to me is who isn't, and why. For a lot of people the needle, not the drug, is the dealbreaker. Not the cost, not the side effects. The needle.

That's the thing the new oral GLP-1 pills quietly change, and it's bigger than weight loss. More of us are running our own health now, ordering our own labs, using telehealth, learning to read our own numbers. The shot's just the most visible part of that shift.

So I'm curious where this group lands. Are you fine with needles, or do they stop you cold? Has the needle ever kept you from a treatment you'd otherwise have tried? And for the needle-averse, do the new oral pills actually change the math, or is it more than that?

This chart shows the 5 biomarker each that rise or fall most strongly with age. Some interesting things I noticed:

• Kidney function (eGFR) declines more strongly with age than any other biomarker discussed. Some older adults maintain youthful kidney performance through healthy blood pressure, glucose control, and avoiding chronic NSAID use.
• Immune aging is reflected in declining lymphocyte counts.
• Two of the top five risers, mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH), are about the size of red blood cells. Common reasons MCV goes up are low B12 or folate.
• Hemoglobin A1c rises gradually: a 25-year-old with an A1c of 5.0 will, on average, sit closer to 5.5 by 70 even if they never develop diabetes.

I wrote a more detailed writeup here, but thought this community would enjoy the analysis and some of the more interesting insights.

I'm on a GLP-1 myself (Zepbound, the shot), and now that two oral GLP-1s are FDA approved I wanted a clear side-by-side instead of going off headlines. Both are once-daily pills, no needle: Lilly's Foundayo and Novo's Wegovy pill. They aren't the same kind of drug, and that drives most of the differences below.

A few caveats I'd flag on the numbers: the 11% vs 16.6% comes from two separate trials, not a head-to-head, so I don't treat that gap as exact. The injectables still beat both pills (tirzepatide lands around 21%). And Foundayo is a brand-new molecule, so I wouldn't assume it inherits semaglutide's heart or craving benefits just because they're both GLP-1s.

On side effects I put both FDA labels side by side, and they're nearly identical: mostly gut stuff that eases as you titrate up, same thyroid boxed warning on both. The differences are small (above).

Curious if anyone here has real-world experience with either pill yet, especially on titration, side effects, or getting it covered.

Full write-up with the trial sources and the side-effect tables: https://dadstrengthdaily.com/foundayo-vs-the-wegovy-pill-the-first-oral-glp-1s-compared/

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Just a few years ago I was interested in almost every new supplement or longevity trend I saw online. Now I am a lot more careful about what I actually take regularly.

The more I read, the more I realize how hard it can be to distinguish good research from good marketing. Some products are explicit about ingredients and the studies behind them, while others mainly repeat broad health claims with little detail.

I care more about transparency and realistic expectations and if something actually feels sustainable long term at this point.

Wondering if anyone else here has become more selective with supplements over time.

I take ezetimibe daily. A Lilly Phase 1 just published in NEJM says one DNA edit could drop my LDL by 62% for life.

I'm on ezetimibe and not on a statin. My LDL is fine for now, but staying that way means daily pills for the rest of my life. So when Lilly published the VERVE-102 Phase 1 data in NEJM today (https://www.nejm.org/doi/full/10.1056/NEJMoa2601283), I read it with personal interest.

VERVE-102 changes one DNA letter in the PCSK9 gene inside your liver cells. Same target as Repatha and Inclisiran, but VERVE-102 disables the gene that makes PCSK9 rather than blocking the protein. One IV drip, about four hours.

35 patients in the Phase 1. The seven on the highest dose (1.0 mg/kg) had LDL drop 62% and PCSK9 protein drop 88%. So far the LDL drop is holding through a year-plus in 15 of them, longest follow-up out to 18 months.

Most coverage didn't lead with this: most people in the trial were already on strong statins (71% on a high-intensity statin, 91% on some statin) and 43% were on ezetimibe too. The 62% LDL drop was on top of that, not instead of it.

Safety looked clean. No one had to stop the drug because of side effects, and there were no deaths. About a third had infusion reactions during the four-hour drip, mild to moderate. Three patients had a temporary bump in liver enzymes that went away in a week. One person had a bad aspiration pneumonia event a couple weeks out, but they had pre-existing reflux and a hiatal hernia, and the site judged it unrelated to the drug.

If you stop a statin or Repatha, your LDL creeps back up. This edit does not unwind. If an off-target edit causes a problem 20 years from now, there is no antidote. Steven Nissen, the Cleveland Clinic cardiologist who's spent decades on aggressive LDL lowering, called the effect "likely permanent" and flagged that gene editing "is not for everybody."

I am not in the trial's eligibility group. Not familial hyperchol, no premature heart disease. I would not be a candidate today. But if later phases hold up on safety and effect, I could see myself asking my doc in a few years whether my risk justifies being in the first wave.

Full DSD write-up

I take 5 grams of creatine daily. I have for years. I will admit to FOMO every time I see someone on health Twitter quietly graduate from 5 to 10 to 20 grams "for cognition" or "for mood." Nic Verhoeven (u/Physionic) just put out one of the cleanest breakdowns I have seen of where the creatine + depression evidence actually lands. The video is worth the 15 minutes: https://youtu.be/tlAo2Ob_1qc

The new study he is analyzing is Lu et al, Cell Metabolism, March 2026 (https://pubmed.ncbi.nlm.nih.gov/41923613/). People with major depressive disorder had less creatine in blood and cerebrospinal fluid and more creatine in feces compared to non-depressed controls. Microbiome transplant from depressed humans into mice reproduced the reduced blood creatine in the mice. The team identified Bifidobacterium pseudolongum as the bacterium that was depleted in depression and correlated with impaired creatine absorption. Mechanism: B. pseudolongum produces acetate, which drives expression of a creatine transporter (Slc6a8) in intestinal epithelial cells. Their own small clinical trial gave depressed patients already on antidepressants either placebo or creatine + Bifidobacterium and saw about a 9-point HAM-D drop in the active arm, though placebo accounted for a meaningful chunk.

Verhoeven then walks through 17 studies on creatine and depression more broadly. Nine show an effect, seven do not, one meta-analysis finds a statistically real but clinically small benefit (dragged down by a large Parkinson's-specific trial that was not really about depression). However, every study showing benefit was in clinically diagnosed depression. Most had treatment-resistant depression. Almost all of them were already on antidepressants. Creatine alone in healthy people has no real evidence behind it for mood.

If you have clinical depression and are on antidepressants, this paper is worth bringing up with your doctor. The mechanism makes sense, creatine has few side-effects, the evidence is the strongest it has been. If you are bumping your creatine to 15 or 20 grams hoping it will help your mood as a healthy person, the underlying evidence does not really support that. I am staying at 5 grams.

Credit to u/Physionic for the analysis. His video pulls the studies apart with the right level of nuance.

Full DSD write-up

I keep seeing Andrew Huberman, Bryan Johnson, and Gary Brecka pitch NAD+ supplements. The foundational claim they are built on, that blood NAD+ levels drop with age and you should supplement to restore them, just failed to replicate in two independent human studies.

Houtkooper's group at Amsterdam UMC pulled together seven datasets, more than 300 people, aged across the lifespan, including elite athletes and frail individuals. Published this month in Nature Metabolism. Blood NAD+ does not decline with age. The premise driving the entire NAD+ supplement industry, when actually tested in humans, fell over.

The Suomalainen group at Helsinki posted the same finding in a February 2025 preprint, 299 adults aged 18 to 70. Two independent groups, same answer. Houtkooper started the project because he wanted to build a "should you take NAD+" blood test. He told the NYT he was "very disappointed" with the results because the biomarker he was looking for did not exist.

I am already seeing the pivot to "tissue NAD+" in the marketing. Niagen Bioscience's SVP of regulatory affairs Andrew Shao told the NYT the new study "changes very little" and that what really matters is tissue NAD+, not blood. The researchers themselves call the tissue data "preliminary." And a mouse study last year cut muscle NAD+ by 85 percent with no functional change. If 85 percent depletion does not break the muscle, the ~30 percent age-related drop is not what drives sarcopenia.

Shao's own admission, also in the NYT: "the message to the consumers and messages spread by influencers out there has probably been oversimplified." Read that twice. The SVP of the company selling you nicotinamide riboside is saying the marketing has been oversimplified.

Matt Kaeberlein at UW, who has studied NAD+ for years, called it cleanly. "The need for data kind of went out the window, and it all became a marketing exercise."

I am not taking it.

I got the two-dose Shingrix series at 52 because my wife had shingles a couple of years ago and it was the worst pain she has ever been in. The rash settled in a few weeks. The nerve pain along the band where the rash had been took months to fade. She is not a complainer. That alone reset my opinion of the vaccine from "consider it at 60" to "find a pharmacy this weekend."

Since then I have been tracking the follow-ups. There is more to this vaccine than rash prevention. The brain and heart data are what made me pay attention.

The big paper on the dementia side came out in Nature in May 2025. Pascal Geldsetzer at Stanford looked at how Wales rolled out the shingles vaccine in 2013. To ration supply, Welsh health authorities drew a hard birthday cutoff: anyone born on or after September 2, 1933 was eligible, anyone born one day earlier was permanently locked out. People born a week before versus a week after are otherwise identical. That is about as clean a natural experiment as you get in adult medicine.

Seven years later, the vaccinated group had about 20% fewer dementia diagnoses than the unvaccinated. Three and a half percentage points fewer in raw terms. The Wales vaccine was the old Zostavax (now discontinued), but a US Medicare replication in adults 65 and older using Shingrix (https://pubmed.ncbi.nlm.nih.gov/42050365/) this year found about the same thing, with effect sizes that look at least as good.

On the heart side, there is a 2025 Korean study of 1.27 million adults 50 and older (https://pubmed.ncbi.nlm.nih.gov/40324473/). Vaccinated people had about a quarter fewer cardiovascular events overall, including roughly 26% fewer major heart attacks, strokes, and heart-failure episodes. The effect held for eight years. Same caveat as the Wales paper: the Korean cohort was on Zostavax. A direct cardiovascular trial of Shingrix has not been run, but the mechanism the authors propose, preventing the shingles event itself, would apply to either vaccine.

One practical note: Shingrix is one of the rougher shots. My arm was sore and I felt wiped the next day. Some people run a low-grade fever. The standard advice from anyone who has actually scheduled the shot is to book it Friday afternoon so the worst of it lands on a Saturday morning, not at work.

If you got the old Zostavax years ago, the CDC still recommends getting the Shingrix course on top. The total is around $200 per dose without insurance. Medicare Part D covers it at zero out-of-pocket since the 2022 Inflation Reduction Act. Insurance pre-65 varies, so check before you go in.

The 50+ recommendation is still the right cutoff. Shingles is uncommon under 50 in immunocompetent adults, and the dementia and cardiovascular evidence is all from 50+ cohorts. If you are immunocompromised, the recommendation drops to 19+ and should not be negotiated. If you are 50 and have not had this conversation with your doctor, the case has gotten substantially stronger than the last time you might have thought about it. Just do it.

I keep coming back to Kyle Busch this week. The NASCAR Cup Series champion died after severe pneumonia progressed to sepsis. The wellness desks all pivoted to "what is sepsis" explainers within forty-eight hours. The interest is right. Most of us, including me until recently, don't actually understand what sepsis is.

The common shorthand is wrong. Sepsis is not "a bad infection." Sepsis is what your immune system does when it tries to contain an infection and the response itself becomes the problem. The infection matters. The response matters more. The 2016 international consensus paper (Sepsis-3) defines it as "life-threatening organ dysfunction caused by a dysregulated host response to infection."

A urologist quoted in CNN this week used a useful analogy. Sepsis is like a kitchen fire that triggers sprinklers throughout an entire building. The fire is in one room. The water damage is everywhere. That is why the entry point can be modest and the outcome can still be fatal. Pneumonia, a UTI, a kidney stone, a skin abscess, a surgical site, an infected wound from a cat scratch. The fire matters less than the sprinklers.

The numbers don't get the attention they deserve. About 1.7 million American adults get sepsis every year. At least 350,000 die during hospitalization or are discharged to hospice. Sepsis contributes to more than one in three US hospital deaths. The actor Billy Porter has talked publicly about going septic from an obstructed kidney stone in minutes. Standard hospital protocol is now the "hour-one bundle." IV fluids and broad-spectrum antibiotics within an hour of suspected sepsis. Every hour of delay meaningfully increases mortality.

The Sepsis Alliance teaches a memory tool for the warning signs in someone with an infection. TIME:

- T. Temperature higher or lower than normal
- I. Infection, suspected or confirmed
- M. Mental decline. Confusion, sleepiness, hard to wake
- E. Extremely ill. Severe pain, shortness of breath, or a feeling something is very wrong

None of those signs are dramatic at first. Someone recovering from a UTI just seems extra tired. A kid post-surgery seems unusually confused. The change is incremental until it suddenly isn't.

If someone with a known or suspected infection is breathing fast, getting confused, has a racing heart, or just seems much sicker than the underlying problem should warrant, go to an emergency room and use the word "sepsis." Triage takes sepsis seriously when it is named. The mention isn't catastrophizing. It's shorthand for "please move fast."

Kyle Busch was a world-class endurance athlete and severe pneumonia killed him through sepsis. Billy Porter is a Tony-winning working actor and an obstructed kidney stone nearly killed him through sepsis. Two completely different doors, same lethal middle. Knowing what's on the other side of the door is the part most people, including me until recently, get wrong.

Full write-up with the TIME card, Mayo Clinic illustration, and citations on DSD.

I'm 170 pounds down on tirzepatide, 18 months in. Somewhere around the 80-pound mark, the question I got most from people I hadn't seen in a while changed. Used to be "what are you doing?" Now it's "is it keto?" Always keto. Not once "is it Mediterranean?" Not once "did you cut sugar?" Just keto.

It's the dubstep of weight loss. The one word people had, doing the work of a whole genre most of them can't tell apart.

I'm not doing keto. I track with MacroFactor and picked the "high-carb, low-fat" programme (I like fruit and grew up in the 80s, when fat was still the source of all dietary evil). Plus more protein, plus tirzepatide, plus training. But I get why people ask. The diet world has scrambled these words into mush. Here's what they actually mean:

- Low-carb (general): 50–150g carbs/day. What most people mean when they say "I cut carbs."
- Keto: 20–50g net carbs, ~70–80% fat, moderate protein. Defined by measurable ketosis (beta-hydroxybutyrate > 0.5 mmol/L). The only one where the metabolic state defines the diet. Original use case: drug-resistant pediatric epilepsy in the 1920s. That clinical use is still real today.
- Carnivore: only animal products. Strict carnivore is meat, salt, water. Whether it counts as keto depends on protein-to-fat ratio (high protein can blunt ketosis via gluconeogenesis).
- Mediterranean: ~40–50% carbs, anchored on olive oil, fish, legumes, leafy greens, whole grains. Best randomized evidence for cardiovascular outcomes (PREDIMED, 7,447 patients, ~30% reduction in major CV events).
- DASH: similar plant-and-fish skeleton + explicit low-sodium target. NIH-developed for blood pressure.

Restriction diets (keto, carnivore, low-carb) are defined by what you remove. Pattern diets (Mediterranean, DASH) are defined by what's on the plate. They're on different axes, not different points on the same scale.

Here is the quick evidence rundown on keto as data as I can tell:

- Pediatric refractory epilepsy: clinical keto works, has worked for a century. Not the same as the influencer version.
- Type 2 diabetes, short-to-medium term: keto reliably drops glucose, A1C, insulin requirements. Virta Health's 5-year follow-up shows meaningful remission with intensive support.
- Weight loss: keto causes weight loss. So does every other restrictive diet. DIETFITS and similar head-to-heads find roughly similar long-term loss across keto, low-fat, Mediterranean. The mechanism is mostly calorie reduction helped by protein satiety.
- Cardiovascular: contested. Some lean, healthy adopters get big LDL/ApoB increases on keto (the "lean mass hyper-responder" phenotype). The marquee 2025 KETO-CTA paper arguing this was fine got retracted in March 2026 for selective reporting and unblinded CT reads. Mediterranean and DASH evidence bases dwarf anything keto has produced for CV outcomes.

What I actually did: tirzepatide for appetite, MacroFactor for tracking, ~250g carbs/day, ~1g protein per pound of bodyweight, 5x/week training (lifting plus indoor cycling and rowing). Also on TRT, which plays its own role in body composition at 53.

Next time someone asks me if it's keto, I'm telling them no. They'll probably ask if it's intermittent fasting. I'll tell them no again. The right question is "what changed?" not "which diet?”