#21

The Animal Evidence

Parkinson’s models. The data are consistent. A 2026 systematic review and meta-analysis found nicotine significantly reduced apoptosis (RR 0.49), oxidative stress (RR 0.55), and neuroinflammation (RR 0.62), while enhancing dopaminergic neuron survival (RR 1.67). Mechanisms include alpha-synuclein reduction, SIRT6 suppression (a 2018 paper that I co-authored), and microglial modulation via α7 nAChRs.

Alzheimer’s models. Bidirectional. On the amyloid side, Nordberg et al. (2002) showed chronic nicotine reduced plaques by more than 80% in APPsw mice. On the tau side, Oddo et al. (2005) showed increased tau phosphorylation in 3xTg-AD mice. The tau studies used transgenic animals overexpressing human tau at constant doses, and relevance to intermittent, low-dose nicotine in humans without tauopathy is unclear. Neuroprotective effects are far more consistent in Parkinson’s models than Alzheimer’s models.

What About Longevity?

There is limited direct evidence for longevity, but a mechanistic case worth noting. Nicotine activates the cholinergic anti-inflammatory pathway through α7 nAChR stimulation, inhibiting NF-κB signaling. It upregulates BDNF, activates FOXO/DAF-16 pathways (the same longevity pathways targeted by caloric restriction and rapamycin), enhances SOD-3 antioxidant activity, and through SIRT6 suppression may reduce neuroinflammation. The overlap with established longevity pathways is notable, though no human studies have directly tested whether nicotine extends lifespan.

agh, velo 6mg felt really good, but the PATCh feels SO different between brands, I hated zyn’s feel,

u kind of have to take it out a bit quickly

above all, the #1 thing hitting my happiness/functioning is my lack of alertness throughout the day and if I can increase it SOMEHOW without bumping my HR to 120 it will help. I went on concerta 18mg again but concerta 18mg still has issues, so im gonna have to use a complex combination of concerta, caffeine, nicotine, modafinil, music, and maybe adderall xr microdoses to really figure this out

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#22
#23

You ask me what we need to win this war. I answer tobacco as much as bullets. Tobacco is as indispensable as the daily ration; we must have thousands of tons without delay.

General John J. Pershing, 1917

I use nicotine gum if I want a quick mental boost. I use patches occasionally for a more sustained effect. I don’t use it often enough to ge addicted, but I really wouldn’t care if I did. After all I am highly addicted to caffeine.

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#24

I do admire men of conviction. :smile:

#25

Yes. For dendrite shrinkage / arbor loss, NAMPT can matter, but the cleanest story is still mostly:

NAMPT → NAD+ → SIRT1 and related NAD-dependent programs → better dendritic maintenance

Two pieces of evidence point that way. In a mouse model, deleting Nampt from forebrain excitatory neurons caused abnormal CA1 dendritic morphology and reduced dendritic arborization. Separately, in cultured hippocampal neurons, SIRT1 promoted dendritic arborization, and adding NAD+ increased dendritic branching and helped protect against Aβ-induced dendritic dystrophy. So if your worry is “does lower NAMPT plausibly make dendrites less robust?”, the answer is yes, plausibly. And a lot of that benefit may indeed be mediated through NAD+/SIRT1, which means NR/NMN could capture part of it rather than missing it completely. (PMC)

The catch is that NR is not guaranteed to reproduce every local NAMPT effect perfectly. Dendrites and axons are obnoxiously compartmentalized, and neuronal structural maintenance also depends on other NAD-linked systems like the NMNAT2/SARM1 axon-survival pathway, not just NAMPT alone. So I would think of NR/NMN as a reasonable bypass for much of the metabolic pressure, but not as a perfect one-to-one replacement for all neuron-structure biology tied to NAMPT. (PMC)

在 nicotine being upstream of NAMPT directly: surprisingly, yes, there is at least one serious preclinical paper saying so. A 2023 Nature Communications study reported that low-dose nicotine restored age-related declines in NAMPT activity in multiple mouse tissues, including hippocampus and cortex, by promoting SIRT1 binding and deacetylation of NAMPT, and they explicitly said this effect was independent of nicotinic acetylcholine receptors. That is a pretty direct “upstream of NAMPT” claim. But it is still mouse/preclinical biology, not a clean human therapeutic rule. (Nature)

I would not treat that as a practical NAMPT hack, though. Nicotine has obvious addiction liability and broader cardiovascular and autonomic downsides, and the paper’s result does not mean “nicotine is a smart way to fix a NAMPT problem.” It means nicotine can modulate NAMPT activity in at least some biological contexts, not that it is a good intervention for you. (Nature)

So the blunt version is:

  • Dendrite maintenance: yes, lower NAMPT could plausibly worsen it, and a lot of that seems to run through NAD+/SIRT1, which means NR/NMN may help more than you’d think. (PMC)
  • Nicotine upstream of NAMPT: yes, plausibly and even directly in one mouse study, but that is not the same thing as “nicotine is a good NAMPT therapy.” (Nature)

If you’re thinking in intervention terms, NR/NMN makes much more sense than nicotine. Humanity did, in fact, already run the nicotine experiment. Spectacularly mixed reviews.

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