NMN + CD38 increases lifespan in males!

#41

I am taking Apigenin already for sleep benefits (35mg of Lipo Agigenin from Renue, supposed to be as good as 100mg due to 90% bioavailability), but I am intrigued with the CD38 inhibition : Your linked paper estimates it will takes 0.9g - 4.5g / day of pure Apigenin (based on 30% bioavailability) to achieve the required plasma concentration for CD38 inhibition. 1g/day of Apigenin from DoNotAge comes to around $2/day, not cheap but worth it if it inhibits CD38 and raises NAD+ levels without all the risks that come with NMN/NR raising NAD+ levels too high. Of course if it takes 5g/day ($10/day) that would be unaffordable for most folks as a way to raise NAD+.

I am thinking of getting 2 Jinfinity NAD test kits and doing a test before starting 1g/day of Apigenin and retesting NAD after 2 months.

Update : I misread the original article : It requires the 0.9g -4.5g dosage every 8 hours, 3x/day, since the half life of Apigenin is only 4 hours.

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#42

I personally wouldn’t take apigenin on the basis of thinking it will inhibit CD38 but if you do a NAD test before and after that would be very interesting and would help give some evidence as to whether it is having any effect at all. Please post the results here if you try that. Good luck.

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#43

I think Micheal Lustgarten, who have the conquer aging or die trying youtube chanel has basically pretty much proven that Apigenin does not inhibit CD38. That episode was a month or so ago. And the cosept that CD38 inhibition will increase NAD is a theory that is yet to be proven true.

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#44

This wikipaedia article CD38 claims that the ultimate cause of age related CD38 elevation (and hence NAD depletion) are believed to be senescent immune cells that accumulate in visceral fat:

Macrophages are believed to be primarily responsible for the age-related increase in CD38 expression and NAD+ decline.[56] Cellular senescence of macrophages increases CD38 expression.[56] Macrophages accumulate in visceral fat and other tissues with age, leading to chronic inflammation.[57] The inflammatory transcription factor NF-κB and CD38 are mutually activating.[56] Secretions from senescent cells induce high levels of expression of CD38 on macrophages, which becomes the major cause of NAD+ depletion with age.[58]

Based on that using a senolytic like Fisetin might also be effective in suppressing CD38 and raising NAD. So I plan to order the 4-pack of NAD tests from Jinfinity (they offer a 10% discount of you order 4 tests) and test the effectiveness of Fisetin and Apigenin sequentially (along with ruling out any effect of alpha17-estradiol):

Mar 10: First NAD test : 24.3 uM

Mar 10 : Start 3 days of Fisetin 1.5g/day (Renue 150mg Liposomal Fisetin x 10 + LEF Senolytic Activator 3 capsules), around 20mg/kg of body weight of bioavailable Fisetin per day, equivalent to around 4g/day of regular Fisetin with 40% bioavailability. Split in 2 equal doses at 6am and 6pm.

Mar 13: Second NAD test (to see if Fisetin had any effect on NAD) + LEF blood test panel with estradiol (regular and sensitive), T, DHT, IGF1, LH+FSH (to monitor status before starting 17alpha-E2) : NAD= 28.1 uM, IGF1= 138 ng/ml, Total T= 579 ng/dL, Free T= 6.7 pg/ml, DHT = 18 ng/dL (ref=30-85), Estradiol(ECLIA)= 26.9 pg/ml, Estradiol (LC/MS/MS)= 26 pg/ml, LH= 16.4 mIU/ml (ref=1.7-8.6), FSH= 51.5 mIU/ml (ref= 1.5-12.4).

Mar 13: Start dermal 17alpha-E2 0.25mg, 2x/day (10am, 10pm) expected to absorb around 50ug/day. Also 1g DoNotAge Apigenin + 70mg Renue Lipo Apigenin, 3x/day (6am, 2pm, 10pm).

Apr 7-10 : 3 days of Lipo Fisetin 1.5g/day.

Apr 10 : Third NAD test to see if Apigenin (+ 17alpha-E2) had any effect on NAD over and above Fisetin. Will also take a panel of LEF blood tests including T+E2(sens)+DHT+FSH+LH+IGF1 to monitor effect of 17alpha-E2.

After getting results of 3rd NAD test, if NAD level is adequate (40-50 uM) see if Apigenin can be dialed back to reduce cost (or discontinued if it had no effect). If NAD is still low will consider adding Lipo NMN 250mg/day.

May 5-7 : 3 days of Fisetin 1.5g/day

May 8 : Fourth NAD test

Update 3/14/2023 : Raised my dosage of Apigenin to 1g every 8 hours and changed my schedule a bit so Fisetin is used half way between my every other week Rapamycin (20mg) to minimize interference.

Update 3/22/2023 : Added blood test results from 3/10/2023. Summary: 3 days of 1.5g/day of Lipo Fisetin raised NAD+ from 24.3uM to 28.1uM. Normal NAD+ for 20-40 year olds are 40-50uM.

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#45

No changes, but I am very interested to hear the results though!

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#46

Added my first 2 NAD+ test results :

  1. NAD+ increased from 24.3uM to 28.1uM after 3 days of 1.5g/day of Lipo Fisetin. So there was the expected effect to increase NAD+, but it did not restore youthful levels of 40-50 uM.
  2. Baseline Hormone levels (for the next stage) are normal except:

A. DHT was low: expected due to taking Dutasteride for enlarged prostate.
B. Testosterone is back from being at the low end of normal on Oct 20, 2022 (around 280 ng/dL, same as for the last several years) to youthful levels of 579 ng/dL on Mar 13, 2023 : I suspect my use of 20mg Rapamycin every other week for the last 2 months may be responsible.
C. FSH and LH are both very high : I have never measured these before and was wondering if anyone has any idea what that means. Theory says my Pituitary is trying to stimulate production of Testosterone : Could this be how Rapamycin raises Testosterone (and Estrogen in women) to more youthful levels ?

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#47

My 3rd NAD+ test result from April 10 : 22.7 uM

So taking 1g of Apigenin (+ 70mg of Lipo Apigenin) 3x per day for 28 days actually lowered my NAD+ level from 28.1uM to 22.7 uM. I conclude that even at this relatively high dosage level Apigenin is not able to block CD38.

I have lowered my dosage of Apigenin back to just 35mg of Lipo Apigenin + 250mg of DNA Apigenin 3x per day, but added Renue Lipo NMN (250mg) + Renue Lipo NR (300mg) + Renue Lipo Quercetine (150mg) + Renue Lipo Trans-Resveratrol (125mg) per day and will retest NAD+ on May 10.

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#48

Based on your n=1 experiment, it appears Apigenin may be snake oil. Or at least not effective in humans. That’s one supplement I will hold off on. That helps.

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#49

N=1 verdict on effect of NMN.

None.

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#50

Still another reason not to waste your money on NMN
Personally, I have been taking the expensive brand of NMN sublingually at a dose of ~1 ½ to 2 grams daily for ~ 8 weeks. No change was noticed either subjectively or in the results of my latest blood work.

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#51

My suspicion for a while now, all the scientific papers on NMN the last couple of years has been grasping at straws to put it mildly. supplement companies and YouTubers love it though, NMN and Resveratrol, two things that does nothing for anti aging…is pumped to be the best anti aging strategy, go figure.

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#52

Low dose nicotine?

https://www.nature.com/articles/s41467-023-36543-8

Nicotine rebalances NAD+ homeostasis and improves aging-related symptoms in male mice by enhancing NAMPT activity

Previous studies showed that supplementing NAD+ precursors, such as nicotinamide mononucleotide (β-NMN), nicotinamide riboside (NR), nicotinamide (NAM), or Niacin (NA), were efficient for anti-aging8,9,10. In mammalian cells, most NAD+ precursors were “reclaimed” to NAD+ via the rate-limiting enzyme nicotinamide phosphoribosyl transferase (NAMPT) of the salvage pathway. As NAMPT activity decreases with age, it results in NAD+ depletion and cognitive impairment11. Consequently, the NAMPT enhancers can effectively increase NAD+ levels and prevent neuronal degeneration12,13,14. Moreover, supplementing the high active extracellular NAMPT (eNAMPT) also increases NAD+ biogenesis and aging-related symptoms15,16,17. Therefore, the enhancement of NAMPT activity could be a potential strategy for preventing aging and age-associated diseases arising from NAD+ decline11,18,19.

Interestingly, nicotine is a secondary metabolite of the NAD+ biosynthesis and the NAD+ pathway is also coordinately regulated with nicotine biosynthesis20,21. Furthermore, the NAD+ salvage pathway is conserved across a variety of species, including bacteria, plants, yeasts, and mammals20. Consequently, we hypothesized that nicotine may play a role in the NAD+ salvage pathway. It has been discovered that minuscule amounts of nicotine, as an activator of NAD+ biogenesis, can markedly improve NAMPT activity and NAD+ synthesis, leading to improved glucose metabolism and cognitive function, as well as aging symptoms, in male mice.

Vape liquid provides nicotine.

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#53

I suppose it has to do with dose, but nicotine is bad for blood vessels. I wouldn’t vape it. Maybe use a small chunk of a patch or chew a tiny piece of gum.

I grew a few tobacco plants in my garden once just for the hell of it. Touching the leaves gives you a little nicotine. Great plants to grow! Knew a guy that smoked and he made them into cigarettes.

#54

I meant drink the vape liquid. I have to check if it is edible. Probably is.

If not, there would be the nicotine gums, for those who want to stop smoking.

#55

Nicotinamide extends replicative lifespan of human cells

https://onlinelibrary.wiley.com/doi/full/10.1111/j.1474-9726.2006.00234.x

Summary

We found that an ongoing application of nicotinamide to normal human fibroblasts not only attenuated expression of the aging phenotype but also increased their replicative lifespan, causing a greater than 1.6-fold increase in the number of population doublings. Although nicotinamide by itself does not act as an antioxidant, the cells cultured in the presence of nicotinamide exhibited reduced levels of reactive oxygen species (ROS) and oxidative damage products associated with cellular senescence, and a decelerated telomere shortening rate without a detectable increase in telomerase activity. Furthermore, in the treated cells growing beyond the original Hayflick limit, the levels of p53, p21WAF1, and phospho-Rb proteins were similar to those in actively proliferating cells. The nicotinamide treatment caused a decrease in ATP levels, which was stably maintained until the delayed senescence point. Nicotinamide-treated cells also maintained high mitochondrial membrane potential but a lower respiration rate and superoxide anion level. Taken together, in contrast to its demonstrated pro-aging effect in yeast, nicotinamide extends the lifespan of human fibroblasts, possibly through reduction in mitochondrial activity and ROS production.

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#56

In another thread, World_Traveler says he takes nicotinamide and riboside powder to make his own precursor.

There is evidence for that approach, below:

The increase is modest, maybe because the doses used in the study are conservative - 240 mg nicotinamide plus 1 gram riboside powder, twice a day.

Compared with the mild increase in NAD+ level, an unexpectedly dramatic increase in NADP+ concentration was observed (Figure 2b). Significant within-group increases of 19.1%, 27.6%, and 19.6% were recorded with RiaGev group at Days 3, 5, and 8 over baseline, respectively (p ≤ 0.008). The NADP+ concentrations for the RiaGev group are also significantly greater than that of Placebo group at Day 5 and 8 (p ≤ 0.04).

Don’t know what the effect of hefty doses (that World_Traveler takes) would be.

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#57

Nicotinamide Adenine Dinucleotide Augmentation in Overweight or Obese Middle-Aged and Older Adults: A Physiologic Study

If one clicks “Show More” on authors, included as co-author is derided-guy-number-one for many members here - David Sinclair.

Body weight (difference −1.9 [−3.3, −0.5] kg, P = .008); diastolic blood pressure (difference −7.01 [−13.44, −0.59] mmHg, P = .034); total cholesterol (difference −26.89 [−44.34, −9.44] mg/dL, P = .004), low-density lipoprotein (LDL) cholesterol (−18.73 [−31.85, −5.60] mg/dL, P = .007), and nonhigh-density lipoprotein cholesterol decreased significantly more in the MIB-626 (microcrystalline β-nicotinamide mononucleotide ) group than placebo.

Due process.

Below is the Jan 2023 study on NR.

Nicotinamide riboside improves muscle mitochondrial biogenesis, satellite cell differentiation, and gut microbiota in a twin study

There are 17 authors. If you expand it, co-author is the Sinclair nemesis, Charles Brenner.

https://www.science.org/doi/10.1126/sciadv.add5163

NR boosted whole-blood NAD+ levels by 2.3-fold

In conclusion, NR supplementation is a potential treatment option to be tested in individuals with decreased muscle mitochondrial biogenesis and dysbiosis. As possible adverse effects, we report a declining muscle satellite cell number and a possibility for impaired glucose metabolism. As patients with chronic muscle disease typically exhibit satellite cell dysfunction, muscle performance and regeneration are important endpoints to be monitored in future NR clinical trials. Overall, our data underscore the role of NR as a potent modifier of systemic NAD+ levels, muscle mitochondrial biogenesis, satellite cell function, DNA methylation, and the gut microbiota in humans. Notably, NR modulated these metabolic processes similarly in both leaner and heavier cotwins, i.e., regardless of BMI.

I’m not into muscle-building. I prefer to try to improve TC, LDL, and blood pressure.

Maybe it is snake oil. But I have unfinished doses of NMN that I have parked somewhere. It is what accountants call sunk-in cost. So will dig them up and restart dosing.

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#58

I have been using NR on and off, primarily because it is made by a US company and it helps. NMN is mostly sourced from China I believe and so are most of the earlier research. Sinclair is using NMN and has said NMN is superior to NR. But at a molecular level, it does not quite make sense to me NMN is better than NR, as Brenner has stated many times.

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#59

I like NMN. I just finished a 25 hour trip from Hong Kong to the USA. Took 1 g of NMN and no jet lag. For those of you who travel, you know how rare that is. IMHO NMN is great for keeping my energy levels up.

As for helping me live longer, I am unsure. But it has its uses.

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#60

When did you take 1g of NMN - before the flight or after?