I used to raise an eyebrow at longevity stacks.

Not the concept — the execution. Rapamycin at 45. NMN capsules sourced from supplement companies with better marketing than manufacturing standards. Resveratrol, which has not survived its own clinical testing. The aesthetics of optimization dressed in the vocabulary of preventive medicine, confident in inverse proportion to the evidence. I am a cardiometabolic physician. Skepticism about this category comes with the job.

And then I looked carefully at what I take every morning.

I had quietly built one. Not from a podcast or a protocol. Incrementally, across years of clinical practice, each addition requiring enough evidence to clear the same bar I apply to a treatment recommendation. A statin I started earlier than most guidelines would have prompted. A fiber supplement I added after a patient asked a question I couldn't answer as well as I wanted. A GLP-1/GIP agonist I wrote about in this newsletter — and the response to that piece made clear how many physicians are navigating the same questions privately that they are not yet comfortable asking out loud.

The organizing framework is healthspan — the years lived in good metabolic, cardiovascular, cognitive, and physical health. I am less interested in adding years at the end than in compressing morbidity into as narrow a window as possible. The six interventions below represent my best current thinking on how to pursue that goal. None of them are on any longevity influencer's recommended list. Several of them cost less than a cup of coffee per day. All of them have earned their place through mechanism and evidence, not momentum.

The cholesterol wars are over. LDL-C is causal, modifiable, and dose-dependently linked to atherosclerotic cardiovascular disease across every analytical method we have brought to the question. What remains underappreciated is that timing is as important as magnitude. Ference and colleagues' 2015 JACC analysis made this case in a way that should permanently change when we start.

The plaque that ruptures at 62 was building in the third decade. This reframes lipid-lowering from "treatment" to "lifetime exposure reduction" — and the compounding logic means earlier, sustained lowering yields disproportionately greater returns. The WOSCOPS 20-year follow-up (Ford et al., Circulation 2016) confirmed the durability: men randomized to pravastatin showed 21% lower cardiovascular mortality two decades later, long after most had discontinued therapy. The IMPROVE-IT trial subsequently confirmed that ezetimibe adds CV event reduction beyond statin monotherapy — precisely what the dual-mechanism Mendelian randomization predicted.

This is why I take both. Not because guidelines mandate it — they don't, at my current LDL level. Because the Mendelian randomization data is telling me something about what my arteries are accumulating in the background while I wait for a guideline threshold to authorize the conversation. I would rather have that conversation with myself now, at a point when early intervention still has time to compound, than revisit it in ten years when the only available option is late treatment.

I added psyllium to my morning routine after a patient asked me, in an otherwise routine follow-up visit, why I wasn't recommending it more consistently. The question was better than my answer. I had been treating fiber as a lifestyle footnote — the thing I mentioned after the things I actually meant. That patient made me go back to the literature, and what I found there earned psyllium a permanent place in the rotation.

Americans average 10–15 grams of dietary fiber per day against a recommended 25–38. The reason psyllium husk earned a spot in the same rotation as two lipid-lowering drugs comes down to mechanism: it operates on a third, independent pathway to the same biological targets.

Viscous soluble fiber forms a gel in the intestinal lumen that traps bile acids, preventing their enterohepatic reabsorption. The liver upregulates LDL receptor expression to compensate — pulling circulating LDL-C from the bloodstream. Additive to statin and ezetimibe pathways. The same gel blunts postprandial glucose absorption, attenuating the insulin response and improving long-term insulin sensitivity. And in the colon, fiber fermentation produces short-chain fatty acids — butyrate, propionate, acetate — that serve as colonocyte fuel, maintain intestinal barrier integrity, and signal satiety through enteroendocrine pathways.

Creatine has a branding problem — it lives in the supplement aisle between protein powders and pre-workouts. The evidence base, however, is more robust than many prescription medications I write. More importantly, the longevity argument for creatine is not about gym performance. It is about the growing body of data connecting skeletal muscle mass and physical capacity to all-cause mortality.

Skeletal muscle is the largest insulin-responsive organ in the body (~80% of postprandial glucose disposal), secretes myokines that regulate inflammation and neuroplasticity, and serves as a direct predictor of metabolic and functional independence. Creatine augments phosphocreatine stores by 20–40%, improving ATP regeneration kinetics during high-intensity effort — making resistance training more productive, lean mass preservation more attainable, and functional decline more resistible.

I was a multivitamin skeptic for most of my career. The category had long felt like nutritional security theater — expensive urine, as the dismissive shorthand goes. What changed my view was the COSMOS trial program — and the evidence has continued to accumulate in ways that have substantially upgraded how I think about this supplement category. What started as a cognitive aging signal has, with the latest COSMOS data, become something considerably more fundamental: direct evidence of biological age deceleration measured at the level of DNA methylation.

This matters in a way that cognitive test scores alone do not. PCGrimAge and PCPhenoAge are not abstract scores — they are second-generation epigenetic clocks that integrate biological signals across multiple organ systems and have been validated as predictors of all-cause mortality that outperform chronological age. Slowing the rate at which these clocks advance is a measurable deceleration of biological aging itself, not a proxy outcome.

The probable mechanism: B12 and folate-mediated homocysteine reduction (elevated homocysteine drives DNA methylation dysregulation and is exquisitely sensitive to B-vitamin status), combined with antioxidant micronutrient support of mitochondrial function. The effect being strongest in those with accelerated biological aging at baseline suggests this is correcting an underlying insufficiency — not augmenting normal biology. COSMOS-Mind was conducted in adults ≥60, but epigenetic age diverges from chronological age gradually over decades. The logical implication is that intervention earlier, not later, is the better bet. I take Centrum Silver because that's what COSMOS used. The honest answer is also that the evidence does not yet tell me whether a different formulation would perform differently.

I have written about my experience with low-dose tirzepatide before in this newsletter, and that piece became the most-read thing I have published here. The resonance wasn’t just curiosity about incretin pharmacology—it was the willingness to say plainly: I take this, and it changed my relationship with food noise and metabolic regulation. And the conversation about who benefits from GLP-1/GIP agonism remains far narrower than it should be.

Here I want to make the mechanistic case for tirzepatide as a longevity intervention — not a weight loss drug, but a metabolic agent with direct anti-atherosclerotic effects that the emerging literature is beginning to characterize at a mechanistic level.

Tirzepatide's dual agonism at GLP-1R and GIPR is not a pharmacological doubling-down on a single pathway. GLP-1 receptor agonism reduces appetite through central hypothalamic and brainstem satiety signaling, slows gastric emptying, and stimulates glucose-dependent insulin secretion. GIPR agonism contributes through distinct adipose tissue energy partitioning effects and central signaling that appear synergistic with — not duplicative of — GLP-1's anorectic action. The result: greater visceral fat reduction, greater insulin sensitization, and superior cardiometabolic improvement relative to GLP-1 monotherapy at equivalent doses.

The SELECT cardiovascular outcomes signal raised the question: what exactly is tirzepatide doing to the arterial wall beyond improving lipids and blood pressure? Kang and colleagues (Archives of Pharmacal Research, 2026) have now provided a mechanistic answer — and it goes directly to the cellular biology of atherosclerosis.

This is preclinical data and requires appropriate humility. ApoE−/− mice are not humans, and translational failures in cardiovascular pharmacology are common. But the mechanism is coherent with the SELECT cardiovascular outcomes signal — and specifically with the finding that approximately one-third of SELECT's MACE reduction preceded significant weight loss. Tirzepatide appears to be doing something to the arterial wall that metabolic improvement alone does not fully explain.

Six interventions. Six distinct primary mechanisms. Three converging on LDL-C through independent additive pathways. One directly targeting the cellular biology of plaque development. One measurably decelerating biological aging at the level of DNA methylation. None of these is a shortcut — they augment a biological foundation that exercise, sleep, and dietary quality must also build.

The thesis is compounding. LDL-C reduction begun earlier accumulates into decades of reduced arterial exposure. Preserved muscle at 45 becomes the reserve capital that prevents falls at 75. Micronutrient support now is protecting against an epigenetic aging trajectory that diverges slowly and silently before it becomes clinically apparent. Visceral adiposity reduction today is the input to tomorrow's metabolic risk calculation.

Notice what is not on this list. No rapamycin — the human longevity evidence remains thin and the immunosuppression risk profile is real. No metformin outside of glycemic indication — the TAME trial is ongoing and I will update my thinking when it reports. No NMN — I am not persuaded the delivery mechanism translates to meaningful tissue-level NAD+ repletion at commercially available doses. No resveratrol — the clinical trial record has not matched the preclinical promise. The absence of items is as deliberate as the presence of items.

I share this not to prescribe — these decisions belong between you and your physician — but because physicians who apply evidence to their own lives have a different kind of credibility than those who simply cite guidelines. Time is the one variable in biological aging that medicine consistently underestimates. It is also the one where early decisions carry the largest eventual returns.