Longevity & Mitochondrial Health

NAD After 40: You Don't Have a Supply Problem. You Have a Drain Problem.

Every bottle, every peptide vial and every IV bag in this category is selling you the same side of the equation — more going in. Almost nothing that actually changed in your cells after forty is on that side.

A man sat down across from me with a manila folder. Inside were receipts for eleven NAD IV infusions run over four months. Just under four thousand dollars. Nobody had measured his NAD before the first bag went in, and nobody measured it after the eleventh. He wanted to know whether he should book the next round.

I asked him three things. What is your waist measurement. What was your last hs-CRP. How many days a week do you train against resistance.

He could not answer any of them. That is not a knock on the man, it is a knock on how this category gets sold. He had been handed the most expensive lever in the building and never shown the free ones bolted to the wall behind it. And here is the part that should bother you more than the four thousand dollars: even if every claim on that clinic's wall had been true, the infusion was aimed at the wrong half of the problem.

What NAD actually does, in the order that matters

Two jobs. Only one of them creates a level.

NAD is not fuel. It is a carrier. In the Krebs cycle it strips electrons off the food you ate and hands them to the electron transport chain, which is where the actual ATP gets made. In that job NAD is not used up. The same molecule cycles through thousands of times a day, loaded and unloaded like a forklift. If that were NAD's only job, you would never need to think about your "level" at all.

The second job is what changes everything. NAD is also a substrate — raw material that gets cleaved apart and destroyed. Sirtuins consume it doing metabolic and repair signaling. PARP enzymes consume it repairing damaged DNA. CD38, sitting on the surface of immune cells, consumes it as part of inflammatory signaling. Every time one of those fires, an NAD molecule is broken and has to be rebuilt from scratch.

That is what creates a balance you can actually run low on. Two flows — what you build and what you burn — and your level at any moment is the difference. Muscle and brain are the two most mitochondria-dense tissues you own, which is why this shows up first as the last third of a long effort and as the four o'clock fog, usually in that order. Now notice which flow the market has decided to sell you.

The peptide aisle, and what is actually being sold there

Three compounds, one honest scoreboard

This is where the money is moving right now, so let me take the three you will be offered one at a time.

5-Amino-1MQ

Sold in peptide catalogs. It is not a peptide — it is a small molecule that inhibits NNMT, the enzyme in the right-hand column above. Credit where it is due: the logic is sound and it aims at the correct side of the ledger. Block NNMT, stop methylating nicotinamide out of the pool, keep more substrate available for salvage. In diet-induced obese mice it reduced body weight, white fat mass and fat cell size without changing food intake.¹⁶

That is a mouse. As of this writing there are no published human clinical trials of 5-Amino-1MQ — not a small one, not a weak one, none. Every efficacy figure you will read comes from rodents or cell culture, and it is not on the FDA's 503A bulk substances list, so there is no lawful compounding pathway for it either. When a compound is marketed years ahead of its first human trial, the marketing is the product.

MOTS-c

This one genuinely is a peptide — sixteen amino acids, encoded in mitochondrial DNA rather than nuclear DNA, which is legitimately interesting biology. It activates AMPK, the cell's fuel-sensing switch, and gets called an exercise mimetic because your body makes more of it when you train.

The human evidence is one program. CohBar's CB4211, an analogue rather than the native peptide, ran a Phase 1a/1b study in which twenty participants with obesity and elevated liver fat received 25 mg subcutaneously daily or placebo for twenty-eight days. It met its safety endpoint, and development was discontinued afterward.¹⁷ That is a tolerability finding in twenty people, not an efficacy finding. There is no completed Phase 2 or Phase 3 program for native MOTS-c and no FDA approval.

And here is the part that should end the conversation, because it is sitting in plain sight. MOTS-c gets called an exercise mimetic for a reason: your own muscle manufactures it when you exercise. Reynolds and colleagues put healthy men on a stationary bicycle and biopsied their quadriceps before and after. Endogenous MOTS-c in skeletal muscle rose roughly twelve-fold after a single session and was still elevated four hours later. Circulating MOTS-c rose about 1.6-fold during the ride itself.¹⁸

Twelve-fold. From one bout of cycling. Measured in human muscle tissue — which is more than the injectable version has ever demonstrated in a human efficacy trial of any size.

So there are two ways to raise your MOTS-c. The first is a compound with no completed efficacy trial and no approved indication, bought through a gray market at a recurring monthly cost and injected on a schedule you would have to maintain indefinitely, because a mimetic only mimics for as long as you keep paying for it. That is not a treatment. That is a subscription to a signal.

The second is a bicycle. It is free, it works today, and it does not arrive alone. Training delivers the MOTS-c signal and the adaptation that signal exists to produce — plus strength, VO₂ max, bone density, insulin sensitivity, blood pressure, sleep quality, mood, and an all-cause mortality curve that no vial in this category has ever moved. The peptide sells you one line of the message. The work sends the whole letter, and it signs it.

I say something to patients who come in looking for the way around this, and I will say it here. Learn to enjoy the work. Not tolerate it. Not white-knuckle it for eight weeks every January. Learn to actually enjoy it, the way you would learn to enjoy anything worth being competent at, because that is the only version that survives contact with a real life. The man who gets there never needs the lifetime sentence of injections. The man who does not will keep buying the mimetic until the day he can no longer afford it, and he still will not have the legs. That is not a moral judgment. It is a straightforward question about which of the two you can still be doing at seventy.

In July 2026 the FDA's Pharmacy Compounding Advisory Committee voted 7 to 5 to recommend MOTS-c for the 503A bulk substances list, one of six peptides it advanced over the written objection of the agency's own scientists.¹⁹ Read that carefully. A committee recommendation is not approval, it is not binding, and rulemaking has to follow before anything changes. It says a panel thought pharmacies should be allowed to compound it. It says nothing about whether it works.

NAD+ by IV or injection

Here is the one that cost my patient four thousand dollars, and here is the biochemistry nobody at the front desk explains. NAD+ is a large, polar dinucleotide. It does not cross the cell membrane intact. Outside the cell it is degraded — NAD+ and NMN are both broken down extracellularly to nicotinamide riboside, which is the form that actually enters the cell and gets rebuilt into NAD.²⁰

So the bag is a slow, uncomfortable, expensive way to deliver a downstream molecule you can also swallow. Slow is not a figure of speech. A retrospective review of clients at a commercial infusion clinic compared four consecutive days of 500 mg NAD+ IV against 500 mg nicotinamide riboside IV. The NAD+ group reported moderate to severe gastrointestinal symptoms, elevated heart rate and chest pressure, and their infusions had to be run at an average of about 96 minutes to be tolerated. The nicotinamide riboside group reported mild tingling and cramping and averaged 37 minutes.²¹ Worth noting who ran it: most of the authors are affiliated with the commercial wellness company that administered the infusions. I am citing it anyway, because the tolerability finding runs against the more expensive product they sell.

I have said before that peptides and signaling molecules are often volume knobs turned up in a body that cannot hear them. That is the shape of the problem here too. The compound in this entire category with the most human dose-response data behind it is the boring one you can put in your mouth. That is not a marketing position. That is just where the trials are.

And the other letter: NR versus NMN

One phosphate group, and a great deal of noise

The other thing you will be sold is not a peptide at all, and it deserves a straight answer because it is the direct competitor to what I make. Nicotinamide mononucleotide — NMN — is nicotinamide riboside with a phosphate group attached. One step closer to NAD on the pathway diagram. That single fact is the entire marketing case for it, and it is worth understanding why the biochemistry does not read the way the diagram does.

The phosphate is a liability, not a shortcut. A charged phosphate group does not cross a cell membrane. The mainstream position, supported by isotope and enzymatic work, is that extracellular NMN gets dephosphorylated by the enzyme CD73 back into nicotinamide riboside, and it is the riboside that then enters the cell through nucleoside transporters and gets built into NAD.²⁰ The molecule marketed as being one step ahead has to take a step backward first. A direct NMN transporter, Slc12a8, was reported in mouse intestine in 2019²² and challenged in the same journal within months on the grounds that the analytical methods did not support the assignment.²³ It has not been established in human tissue. That debate is not settled, and I am not going to pretend it is.

Where NMN is genuinely stronger than I am comfortable glossing over. Yoshino and colleagues gave 250 mg of NMN daily for ten weeks to twenty-five postmenopausal women with prediabetes who were overweight or obese, and measured a real improvement in skeletal muscle insulin sensitivity using the hyperinsulinemic-euglycemic clamp — the gold-standard method, not a surrogate marker.²⁴ That is a positive functional outcome in the exact domain where the nicotinamide riboside trials came back empty. If you are keeping an honest scoreboard, NMN has a point on the board that NR does not have.

Read one line further, though, and it turns strange: muscle NAD content did not change. The outcome improved and the biomarker did not, which is the precise mirror image of the NR trials, where the biomarker moved and the outcome did not. Twenty-five women is also a small trial, and nobody has replicated that clamp result at scale.

And nobody has run the race. There is no head-to-head human trial of nicotinamide riboside against NMN. None — not at matched doses, not at any doses. Anyone who tells you flatly that one form is superior is handing you an opinion in a lab coat, and often an opinion with a financial address attached, because both camps have one. Charles Brenner, an author on the dose-response trial this product is built around, owns stock in and advises the company that makes the branded NR material. The researchers who reported the Slc12a8 transporter hold a patent on it. I would rather give you both of those disclosures myself than have you find them later and wonder what else I left out.

So why did I build on nicotinamide riboside? Not because I can prove it wins. Because it is where the dose-response curve is. Somebody ran 100, 300 and 1,000 mg against placebo in 140 people and published what happened at each rung, and that is what let me set a serving on a number instead of on a hunch. NMN has no published equivalent of that curve. When one exists and it beats this, I will say so here and I will change the formula. Until then I would rather build on the molecule with the map than the molecule with the better story.

One practical footnote, because it affects what is on the shelf. The FDA excluded NMN from the dietary supplement definition in late 2022 under the drug preclusion clause, then reversed that position in September 2025 and confirmed the ingredient is lawful. It is legal to sell today. But it spent roughly three years being sold inside a regulatory gray zone, which is a fair reason to ask any NMN brand harder-than-usual questions about sourcing and third-party identity testing on material produced in that window.

The honest complication

Three places this category oversells — including my side of it

First: "your NAD drops fifty percent by fifty." You have seen that number. I cannot trace it to a controlled human measurement, and I am not going to repeat it. What can be traced is thinner and more specific. Massudi and colleagues measured NAD in pelvic skin from forty-nine people ranging from newborn to seventy-seven and found a strong negative correlation with age — a correlation in one tissue, in a small sample, not a percentage per decade.¹ Zhu and colleagues used phosphorus-31 magnetic resonance spectroscopy to measure NAD inside living human brain and found genuine age-dependent reductions in NAD+ and in the NAD+/NADH redox potential.² A 2025 review in Nature Metabolism looked at the whole human literature and concluded the tissue data are sparse and the decline is not uniform.³

And it gets sharper. In 2026 the same group quantified NAD+ across seven independent human cohorts and found that whole blood NAD+ stayed remarkably stable with age and across lifestyle interventions — while still rising in response to nicotinamide riboside, exactly as expected.⁴ Sit with that. Blood NAD is a good readout of whether a precursor is working, and a poor readout of how old your cells are. Anyone selling you a fingerstick NAD test as a biological age clock is running ahead of the evidence.

Second: oral precursors get dismantled before they arrive. Using isotope tracing, Liu and colleagues showed that orally administered nicotinamide riboside does not reach tissues with the nicotinamide-ribose bond intact — it is broken down to nicotinamide first, and in whole blood the half-life of NR is roughly three minutes.⁵ That does not mean it fails: Elhassan gave older adults 1,000 mg daily for twenty-one days and measured a genuinely augmented NAD metabolome in muscle biopsies, with an anti-inflammatory transcriptomic signature alongside it.¹² It means the picture implied by most labels — a capsule of NAD sliding neatly into your mitochondria — is wrong, and the real route is messier and more indirect than the marketing.

Third, and this is the one my own industry buries: the biomarker moved and most outcomes did not. Dollerup ran 2,000 mg per day for twelve weeks in obese, insulin-resistant men and found no improvement in insulin sensitivity.¹³ A follow-up found no change in muscle mitochondrial respiration, content or morphology.¹⁴ Remie gave 1,000 mg daily for six weeks and likewise found no improvement in mitochondrial function or insulin sensitivity.¹⁵ Martens found trends toward lower systolic blood pressure and reduced aortic stiffness that did not survive statistical correction.⁹ That is the scoreboard, and it belongs here as plainly as the good numbers do.

So why do I still take it every morning? Because the drain explanation predicts that exact pattern. Hand a precursor to someone whose consumption side was never the limiting factor and you will move a biomarker and change nothing else — not because the nutrient failed, but because you supplied more of something that was not the bottleneck. Most of these trials enrolled people for whom it was not. That is a design problem, not a verdict.

The free levers

Every one of these is on the outflow side. None of them costs anything.

1. Train against resistance, and keep the aerobic base

   This is not a consolation prize, it is the strongest lever on the page. NAMPT is the rate-limiting enzyme of the salvage pathway, the dominant NAD-building route in muscle. Athletes carry roughly twice the skeletal muscle NAMPT of sedentary adults, and three weeks of training raised NAMPT protein by 127 percent in previously sedentary subjects.¹⁰ In adults fifty-five and over, twelve weeks of aerobic training raised muscle NAMPT by 28 percent and twelve weeks of resistance training raised it by 30 percent.¹¹

   And here is the line from that second study I keep coming back to: across the whole cohort, the single best predictor of NAMPT level was VO₂ peak. Aerobic fitness predicted NAD-building capacity better than age did.

2. Get the visceral fat off

   Senescent cells accumulate in visceral fat and liver with age. The inflammatory factors they secrete drive resident macrophages to proliferate and express CD38 — the enzyme at the top right of the ledger — which then locally destroys NAD.⁷ Mice lacking CD38 are protected from age-related NAD decline altogether.⁶ Read that in reverse and you get the practical version: abdominal fat is not sitting there passively while your NAD falls. It is participating.

3. Lower the chronic inflammatory load

   Same enzyme, upstream of it. Sleep debt, alcohol, periodontal disease, untreated sleep apnea, a diet built on industrial seed oil and refined starch — these are inflammatory inputs, and inflammation is what turns on the NAD-consuming machinery. Fix the inputs first. Where the load stays elevated after the free work is done, that is where a formula like INFLA-MEND has a job, and not one minute before.

4. Stop volunteering DNA damage

   PARP enzymes are the other major consumer, and they fire in proportion to DNA damage. Unprotected sun, tobacco and heavy alcohol all raise that draw. The same paper that found NAD falling with age in human skin found DNA damage rising alongside it, with PARP activity tracking too.¹ Fewer insults, smaller withdrawal.

5. Sleep on a schedule, and eat enough protein

   NAMPT expression follows a circadian rhythm, so an erratic sleep-wake cycle degrades the timing of your own NAD synthesis. And the de novo pathway starts with tryptophan, which sets a floor on the entire left-hand column. A man chasing NAD on 60 grams of protein a day has a more basic problem to solve.

Work those five for ninety days and you have moved most of the ledger without buying anything. I would rather you do that and never order from me than skip it and order twice. If you only ever act on the free half of this article, it was worth writing.

Where targeted support earns its place

Accelerator, not substitute

Now the inflow side, because it is real and it is measurable. Oral nicotinamide riboside raises human NAD in a dose-dependent way, and that finding has held up across independent groups for years.

The trial worth knowing is Conze, Brenner and Kruger, 2019 — randomized, double-blind, placebo-controlled, 140 healthy overweight adults aged 40 to 60, eight weeks. Whole blood NAD+ rose 22 percent at 100 mg per day, 51 percent at 300 mg, and 142 percent at 1,000 mg. The increases appeared within two weeks and held for the rest of the study, with no flushing and no significant difference in adverse events versus placebo.⁸ Disclosure, since I raised the point above: that trial used ChromaDex's branded material, and Charles Brenner, one of its authors, is affiliated with the company. The second, Martens and colleagues, ran 500 mg twice daily for six weeks in adults aged 55 to 79 and measured roughly a 60 percent increase in NAD+ in peripheral blood mononuclear cells versus placebo, well tolerated.⁹

Both of those regimens land on the same daily number: 1,000 mg of nicotinamide riboside chloride. That is the dose NAD Catalyst was built around — 500 mg per capsule, two capsules daily, so the serving sits on the top rung of the published dose-response curve rather than a fraction of it. One with breakfast and one with dinner is the exact split the six-week trial used.

Now the part that normally gets left out. The formula also carries 150 mg of ATP per capsule, 300 mg at the daily serving — below the 400 mg per day used in the oral ATP performance trials, and I am not going to tell you 300 does what 400 did. It is there as adenine nucleotide substrate inside an NAD formula, not as a standalone performance dose. The magnesium is 20 mg daily, a cofactor amount in a well-absorbed chelated form, not a magnesium protocol, and it will not correct a deficiency. Most adults over forty need a real mineral strategy alongside this rather than instead of it, which is why I run Catalyst Electrolyte on training days.

If you want to work both directions at once: NAD Catalyst supplies the coenzyme substrate, and MitoHealth works on the mitochondria doing the carrying. Different jobs, same system. That is a stack, not an admission that either one is short.

Honest expectations

What this will not do

• It will not feel like a stimulant. If week one feels like nothing, that is the expected result, not a bad batch.
• It will not fix insulin resistance. Trials at twice this dose for three times this duration did not. That job belongs to training, body composition and diet.
• It will not close the drain. If your visceral fat and inflammatory load are where they were a year ago, you are filling a tub with the plug out. This is the sentence I most want you to keep.
• It will not hand your thirties back. Nothing in a capsule does, and any label implying otherwise is telling you something about the company rather than the molecule.
• It will not out-argue a ninety-day test. Two bottles is a fair trial. If nothing has changed in energy, recovery or training capacity by then, stop. I would rather you cycle off something that is not working than keep buying it out of hope. That applies to mine.

Back to the folder

I did not tell that man to stop taking NAD precursors. I told him to stop paying for the wrong half of the equation. We ran labs. His hs-CRP was elevated and his fasting insulin was well above where it should have been for a man who described himself as healthy. Both of those sit directly upstream of the enzymes that were emptying his NAD faster than any bag could fill it.

He started lifting three days a week and got the waist down. Ninety days later the inflammatory marker had dropped and, more to the point, the machinery that had been shredding his NAD was running quieter. Then — then — a daily precursor at the researched dose became a multiplier on something worth multiplying, and NAD Catalyst went into his morning at two capsules, where it has stayed.

That is the order, and it has always been the order: foundation, then cofactors, then targeted support. The reason this industry keeps selling it backward is that the last step is the only one it can put in a bottle.

You are not managing a scheduled decline. You are at halftime holding a scouting report most men never bother to read, and the second half is where the game gets decided. Go plug the drain. Then fill the pool.

Stay Strong,

Dr. Andreas

Dr. Andreas Boettcher, B.S., D.C., C.F.M.P.

Ironman Triathlete · Master's Men's Physique Competitor