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• mert
• Blog
• May 3, 2026

Sterile Infammaging

The great thing about getting older is that you always have something to talk about with other old people at a dinner table—your medical problems.  And sterile inflammaging:  chronic, low-grade inflammation without an infectious trigger. It’s one of the constant companions of old age and now considered one of the central drivers of aging. What makes it different from “regular” chronic inflammation is its source. There’s no virus, no bacterial infection, no autoimmune misfire to point at. The inflammation is generated from within—by the body’s own aging cells, tissues, and metabolic byproducts.

Most adults over 65 show measurable elevations in inflammatory markers compared to younger people, and these elevations track closely with frailty, disability, and overall mortality. The phenomenon is so consistent across populations that researchers describe it as a near-universal feature of human aging, distinct from acute or pathogen-driven inflammation.  Besides CRP and ESR, the traditional quick and dirty measures of inflammation, there are some new composite measures that combine multiple inflammatory and biological aging signals:

• Interleukin-6 (IL-6)
• TNF-alpha
• Multi-cytokine panels that capture a broader inflammatory signature than any single marker
• DNA methylation clocks (epigenetic age) that correlate with inflammatory burden
• Glycomics, metabolomics, and lipidomics profiles that detect age-related shifts in circulating molecules
• Immune cell profiling—particularly the ratio of naive to memory T cells, and the accumulation of senescent immune cells like clonal GZMK+ CD8+ T cells, which has emerged as a conserved hallmark of inflammaging

What causes it?

Inflammaging results from several aging processes that all happen to feed inflammation.

• Cellular senescence. As cells accumulate damage, some stop dividing but refuse to die. These “zombie” cells secrete a cocktail of inflammatory molecules called the senescence-associated secretory phenotype, or SASP—cytokines, chemokines, proteases, and reactive oxygen species. A small population of senescent cells can inflame an entire tissue, and their numbers grow steadily with age.
• Mitochondrial dysfunction. Aging mitochondria leak more reactive oxygen species and release damaged mitochondrial DNA into the cell. The immune system reads this leaked DNA as a danger signal—essentially mistaking it for bacterial DNA—and mounts an inflammatory response.
• The immune system itself ages. The thymus shrinks, T cell diversity drops, and T cell lineages shift to inflammatory subtypes.  Innate immunity becomes less precise—quicker to inflame, slower to resolve. Aged immune cells are themselves a major source of inflammatory cytokines.
• Gut microbiota changes. With age, the gut barrier becomes more permeable and the microbiome shifts toward more pro-inflammatory species. Bacterial fragments leak into circulation and trigger systemic immune activation.
• Visceral fat—is metabolically active tissue that produces inflammatory signals. The overlap between metabolic disease and inflammaging is so strong that researchers often discuss them together.
• Defective autophagy. Cells lose the ability to efficiently clear damaged proteins and organelles. The cellular debris itself becomes inflammatory.

These mechanisms reinforce each other. Senescent cells damage mitochondria. Damaged mitochondria activate immune cells. Aging immune cells fail to clear senescent cells.

What are the consequences?

Inflammaging is now linked to most major age-related diseases—not as a side effect, but as a contributor.

• Cardiovascular disease. Chronic vascular inflammation drives atherosclerosis, endothelial dysfunction, and stiffening of arteries.
• Neurodegeneration. Inflammatory signaling contributes to Alzheimer’s, Parkinson’s, and age-related cognitive decline. The aging brain shows microglial activation and cytokine elevation that parallels systemic inflammaging.
• Sarcopenia and frailty. Inflammatory cytokines accelerate muscle protein breakdown and impair regeneration.
• Type 2 diabetes and metabolic syndrome. Inflammation interferes with insulin signaling and pancreatic function.
• Cancer. Chronic inflammation creates a tissue environment that favors tumor development and progression.
• Cerebral small vessel disease. Inflammation damages the blood-brain barrier and the small vessels that supply deep brain structures.
• Kidney disease. Inflammaging accelerates fibrosis and impairs kidney regeneration.

Looked at this way, many seemingly separate diseases of aging share a common inflammatory undercurrent. This is part of why interventions targeting inflammaging have such broad potential—they don’t treat one disease, they target an upstream driver of many.

How do we prevent and treat it?

Inflammaging is modifiable. While we can’t stop aging, we can reduce the inflammatory burden, and the evidence here keeps growing.

Lifestyle foundations

The interventions with the strongest and most consistent evidence are also the most accessible.

• Physical activity. Regular exercise lowers IL-6 and CRP, improves immune function, reduces visceral fat, and clears senescent cells from some tissues. Both aerobic and resistance training contribute, and the benefits show up even when exercise begins later in life.
• Anti-inflammatory diet. Diets emphasizing polyphenol-rich plants, omega-3 fatty acids (from fatty fish, walnuts, flax), olive oil, and minimally processed foods consistently lower inflammatory markers. Mediterranean and traditional Japanese eating patterns are the best-studied examples.
• Caloric restriction and intermittent fasting. Both reduce inflammatory signaling, improve metabolic health, and trigger autophagy—the cellular cleanup that clears damaged components before they become inflammatory.
• Sleep.  Inadequate or fragmented sleep elevates inflammatory cytokines within days. Consistent, sufficient sleep is one of the most underrated anti-inflammatory interventions.
• Stress management. Chronic psychological stress activates inflammatory pathways through HPA axis dysregulation. Meditation, social connection, and stress-reduction practices have measurable effects on inflammatory markers.

Emerging pharmaceutical therapies

Not nearly as effective as lifestyle measures, but worth mentioning.

• Senolytics are drugs and natural compounds that selectively eliminate senescent cells. The combination of dasatinib and quercetin has shown promise in early human trials. Fisetin, a flavonoid found in strawberries, is also being studied. The idea is simple: clear the zombie cells, and you remove a major source of SASP-driven inflammation.
• Senomorphics don’t kill senescent cells but suppress their inflammatory output—useful when wholesale removal isn’t feasible.
• Targeted immunomodulators. IL-11 inhibitors, TLR-modulating compounds, and inflammasome-targeted therapies are in development. Not ready for prime time.
• Probiotics and prebiotics. Restoring gut microbial balance can reduce systemic inflammatory load, particularly when combined with dietary fiber.
• Metformin and rapamycin have both shown anti-inflammaging effects in research settings, though their use specifically for healthspan extension remains investigational.
• NAD+ precursors (such as nicotinamide riboside and NMN) support sirtuin function, which helps regulate inflammatory signaling and mitochondrial health.

Medical treatment of inflammaging has its strongest clinical validation in two landmark trials:

• CANTOS (2017) — The first major proof of concept. Over 10,000 patients with prior heart attack and elevated CRP received canakinumab (an IL-1β–blocking antibody) or placebo. The drug lowered hsCRP by 26-41% with no effect on cholesterol. The 150 mg dose reduced the primary endpoint (non-fatal MI, stroke, or cardiovascular death) by 15% over 3.7 years. This was a watershed result — it proved that reducing inflammation alone, independent of lipid-lowering, prevents cardiovascular events. Sadly, all-cause mortality didn’t improve because reduced cancer mortality was offset by an increase in fatal infections — a reminder that suppressing immunity has real costs in older people.
• COLCOT and LoDoCo2 — These trials tested low-dose colchicine (a cheap, generic anti-inflammatory) in heart disease patients. Both showed reductions in atherosclerotic cardiovascular events, but not mortality. In 2023, the FDA approved colchicine 0.5 mg once daily for the secondary prevention of cardiovascular disease — making it the first approved drug specifically for the inflammatory component of heart disease.
• The STAMINA pilot (published 2025) tested dasatinib + quercetin in 12 older adults with mild cognitive impairment and slow gait. It was small, single-arm, and uncontrolled, but: MoCA cognitive scores improved by 1 point on average and by 2 points significantly in those with the lowest baseline scores; stride length tended to improve; no serious adverse events occurred. This is a tiny study and probably not even worth mentioning until larger randomized trials result.

There are no completed trials yet showing that lowering inflammation extends lifespan or broadly improves healthspan in healthy older adults. The evidence we have is almost entirely from people who already have cardiovascular disease. Whether reducing inflammaging in generally healthy aging adults prevents future disease remains an open question being actively tested.

Inflammaging reframes how we think about aging. It suggests that many of the diseases we accept as inevitable consequences of getting older share a common, addressable upstream driver. The same processes that age your immune system are aging your blood vessels, your brain, your muscles, and your metabolism—all at once.

That’s bad news in the sense that the problem is systemic. But it’s also good news: a single intervention that meaningfully lowers inflammation can ripple across multiple organ systems. Exercise, diet, sleep, stress reduction, and emerging targeted therapies hit a shared mechanism.

• mert
• Blog
• May 3, 2026

NAD+: The Cofactor at the Center of Aging

Not a week goes by that I don’t get a question or an IG post or some Huberman / Rogansphere related podcast link about supplementing NAD.  Often from the same individual actually.  Is it worth spending your money to take NMN or NR or niacin or any one of the many varieties of this cofactor?

What NAD+ is and actually does

1. Cellular metabolism:  NAD+ is a coenzyme, meaning it works alongside enzymes rather than acting on its own. It exists in two forms—oxidized (NAD+) and reduced (NADH)—and the cell uses the conversion between them to shuttle electrons. Glycolysis, the citric acid cycle, beta-oxidation of fatty acids: all of them generate ATP only because NAD+ is there to accept electrons and ferry them to the electron transport chain. Without NAD+, mitochondria stop and you don’t make energy.  But most people have enough NAD+.  What is more important is the ratio of NAD+ to NADH.

In a healthy cytoplasm, the free NAD+/NADH ratio is enormous, somewhere on the order of 700:1. In the mitochondrial matrix it is much lower, around 7:1 to 10:1.  If you have lots of NAD+ relative to NADH, oxidativereactions proceed—glucose gets oxidized, fatty acids get burned, electrons flow into the mitochondrial respiratory chain. If you have lots of NADH relative to NAD+, the cell is signaled to stop oxidizing and start storing—fatty acid synthesis, gluconeogenesis from lactate, building rather than breaking down.

Most discussions of metabolic damage focus on oxidative stress—the accumulation of reactive oxygen species. Less appreciated, but possibly equally important in modern disease, is its mirror image: reductive stress, the state of having too much NADH and not enough NAD+.

Chronic overfeeding produces exactly this. When you continuously supply substrate—glucose, fatty acids, amino acids—to a cell that is not actually using much energy, glycolysis and beta-oxidation generate NADH faster than the electron transport chain can dispose of it. The NAD+/NADH ratio collapses. Several things happen as a consequence:  The mitochondria back up. Electron transport slows because complex I cannot offload electrons from NADH fast enough, and the ones that do get loaded tend to leak out as superoxide—the actual source of much of the reactive oxygen species we worry about. Paradoxically, reductive stress causes oxidative stress.

2. DNA Repair: it is believed by some and not by others that the NAD/NADH ratio affects the function of PARPs which are all DNA repair enzymes.  The PARPs (poly-ADP-ribose polymerases) detect DNA damage and recruit repair machinery. Every time a strand break occurs—and in a typical cell this is thousands of times a day—PARPs consume NAD+ to flag the damage. Less NAD means less DNA repair, which means faster aging.
3. The sirtuins (SIRT1 through SIRT7) are deacetylases that remove acetyl groups from histones and other proteins. They are central to the cellular response to caloric restriction, they tune mitochondrial biogenesis, and they regulate the expression of stress-response genes. Sirtuins cannot function without NAD+.
4. Inflammation: CD38, an ectoenzyme present on immune cells and many other tissues, also consumes NAD+. CD38 expression rises substantially with age and with chronic inflammation, and it is now thought to be one of the principal reasons that NAD+ levels fall as we get older.

So NAD+ is being burned through multiple different ways at once—to make energy, to repair DNA, and to fuel an inflammatory enzyme that gets busier with age—while the cell’s capacity to synthesize it appears to decline. Tissue measurements suggest NAD+ levels in skin, muscle, liver, and brain fall by something on the order of 50% between young adulthood and old age. The hypothesis that follows is straightforward: if we can refill the tank, perhaps some of the downstream consequences of low NAD+—mitochondrial dysfunction, impaired DNA repair, chronic inflammation—can be reversed or slowed.

The four oral options

You cannot simply swallow NAD+ and expect it to reach your cells. The molecule is too large and too charged to cross membranes intact; it gets broken down in the gut. So all oral strategies rely on precursors that the body can transport and assemble into NAD+ on the inside.

1. Niacin (nicotinic acid) is the original B3 vitamin, the one that cures pellagra. It enters the Preiss-Handler pathway and is reliably converted to NAD+ in the liver and elsewhere. It is cheap, well-studied, and has the inconvenient property of producing a vasodilatory flush—the prostaglandin-mediated burning, itching sensation that has caused generations of patients to abandon it.
2. Niacinamide (nicotinamide, NAM) is the amide form of niacin. It does not cause flushing because it does not act on the same receptor (GPR109A) that mediates the flush. It is converted to NAD+ via the salvage pathway. The catch: at high doses, niacinamide actually inhibits sirtuins. It is a sirtuin product, and product inhibition is exactly what you would expect. So while niacinamide raises NAD+, it may blunt one of the downstream pathways you are trying to activate.
3. Nicotinamide riboside (NR) is a more recently characterized precursor that bypasses some of the rate-limiting steps in the salvage pathway. Multiple human trials have shown that 300–1000 mg per day of NR reliably raises whole-blood NAD+ levels, is well tolerated, and produces modest improvements in markers like blood pressure and arterial stiffness in older adults.
4. Nicotinamide mononucleotide (NMN) is one step further down the synthesis pathway than NR. The question of whether NMN itself crosses cell membranes or whether it must first be converted back to NR has been debated for years; the practical answer seems to be that oral NMN does raise NAD+ in humans. A randomized trial in middle-aged adults given 250 mg per day showed elevation of blood NAD+ and prevention of an age-related rise in HOMA-IR (an insulin resistance score) seen in the placebo group. A study in older Japanese men using 250 mg per day for twelve weeks showed improvements in muscle function on certain measures.

The honest summary of the oral precursor literature is this: all of them raise NAD+ in blood, the safety profiles look good across studies running up to a year, and the clinical effects on hard outcomes—cardiovascular events, cognitive decline, mortality—have not yet been demonstrated in adequately powered trials. The studies showing improvements tend to be small, of short duration, and heterogeneous in their endpoints. We are still in the phase where we can say with confidence that these compounds do what they say on the tin biochemically, but not yet that they translate into the kind of healthspan extension that the mouse data suggest is possible.

The IV NAD+ DANGER

A growing cottage industry offers intravenous NAD+ at concierge clinics and longevity spas, often at considerable expense. The pitch is appealing—why mess around with precursors when you can deliver the finished molecule directly?

The instinct that something is off about putting a lot of NAD+ into the bloodstream turns out to be biochemically grounded. Inside the cell, NAD+ is one of the most abundant small molecules in metabolism. Outside the cell, it is something else entirely: a damage-associated molecular pattern, or DAMP. When cells lyse from infection, trauma, or necrosis, they spill their NAD+ into the extracellular space, and the immune system reads this as a signal that something has gone wrong. Extracellular NAD+ triggers inflammatory and immune responses.

This explains the well-known side effect profile of IV NAD+: nausea, malaise, abdominal cramping, sweating, anxiety, chest pressure. These are not idiosyncratic reactions—they are predictable consequences of pushing extracellular NAD+ to supraphysiologic concentrations and activating purinergic signaling. The standard clinical workaround is to infuse very slowly, often over four to six hours, which keeps extracellular concentrations from spiking high enough to trigger the worst of it.

A recent retrospective comparison of IV NAD+ versus IV NR in a real-world clinic setting found that NR could be delivered considerably faster with fewer adverse experiences, and neither produced clinically significant changes in liver enzymes or inflammatory markers at 30 days. This is reassuring as far as it goes, but the studies remain small, short, and uncontrolled. There are no randomized controlled trials demonstrating that IV NAD+ produces clinical benefits beyond what oral precursors provide, and the cost differential is enormous. My own view is that the burden of proof for IV NAD+ is on the people charging $800 a session for it, and that burden has not been met.

The Coronary Drug Project

The most provocative piece of clinical evidence in this entire field comes not from a longevity study but from a 1960s cholesterol trial. The Coronary Drug Project enrolled 8,341 men with prior myocardial infarction and randomized them to placebo or one of several lipid-lowering interventions, including 3 grams per day of niacin. The trial ran from 1966 to 1975. At the end of the active treatment period, niacin showed a modest reduction in nonfatal MI but no significant mortality benefit. A reasonable result. The trial closed.

Then in 1985, nine years after everyone had stopped taking the drug, the investigators did a follow-up to determine vital status on the original cohort. What they found was unexpected enough that it has been discussed ever since. All-cause mortality in the niacin group was 11% lower than in the placebo group (52.0% vs 58.2%, p=0.0004). The benefit was present across every major category of death—coronary, other cardiovascular, cancer, and other. Translated into life expectancy, the niacin recipients had gained roughly 1.6 years of additional life. And remember: they had stopped taking the drug almost a decade earlier.

A late, durable, all-cause mortality benefit from a drug discontinued years before is a strange finding. The conventional explanation has been that niacin’s lipid effects produced a slow accrual of cardiovascular benefit. But the cancer mortality reduction and the cross-category nature of the effect have always sat awkwardly with a pure lipid-lowering story. Looked at through an NAD+ lens, the result is more interpretable: a sustained pharmacologic boost of NAD+ during a critical window may have produced cumulative benefits—better DNA repair capacity, better mitochondrial maintenance, lower CD38-driven inflammation—that compounded over the subsequent decade. This is speculative. It is not what the trial was designed to test. But it is the kind of result that makes you take the pathway seriously.

It is worth noting that subsequent niacin trials in the statin era—AIM-HIGH and HPS2-THRIVE—failed to show cardiovascular benefit when niacin was added on top of statin therapy. Whether this reflects a true loss of benefit in the modern lipid-lowered population, or simply the use of formulations and dosing that did not replicate the original CDP exposure, is debated. The CDP result remains the single most striking long-term outcomes signal in the entire NAD+ literature, and it is over forty years old.

Where this leaves us

Cellular NAD+ falls with age. Restoring it in mice produces effects that look a lot like rejuvenation across multiple tissues. In humans, oral precursors reliably raise cellular NAD+ levels, appear safe over the durations studied, and produce small signals in surrogate markers—blood pressure, arterial stiffness, insulin sensitivity, certain measures of muscle function. They have not yet been shown to extend healthspan or lifespan in adequately powered trials, and such trials are difficult to run at the scale and duration required.

For a patient asking what to do today, my reading is roughly this: the case for some form of B3 supplementation in older adults is reasonable, given the favorable safety profile and the mechanistic plausibility. NR and NMN are the most studied of the modern precursors. Niacin remains the only B3 compound with long-term hard outcomes data, and that data is genuinely impressive even if it is decades old; the flush is the price of admission. High-dose niacinamide is probably best avoided as a longevity strategy given its sirtuin inhibition. IV NAD+ is, in my opinion, at best a way to spend money.  At worst, you are doing physical harm to your body.

For young people who are not depleted in NAD, supplementation seems superfluous.  If the ratio is what matters, what should we expect from oral precursors? They certainly raise the total NAD+ pool. But unless you also do something to keep NADH from accumulating, much of the new NAD+ may simply be reduced to NADH by the substrate the cell is already drowning in. You’ll have a bigger pool, with the same unfavorable distribution.  Concentrate instead on raising the NAD / NADH level through exercise and periodic fasting.