#1

Acute nutrient deprivation (fasting) causes an immediate increase in spermidine biosynthesis in yeast, flies, mice and humans, as corroborated in four independent clinical studies. This fasting-induced surge in spermidine constitutes the critical first step of a phylogenetically conserved biochemical cascade that leads to spermidine-dependent hypusination of EIF5A (eukaryotic translation initiation factor 5A), which favors the translation of the pro-macroautophagic/autophagic TFEB (transcription factor EB), and hence an increase in autophagic flux. We observed that genetic or pharmacological inhibition of the spermidine increase by inhibition of ODC1 (ornithine decarboxylase 1) prevents the pro-autophagic and antiaging effects of fasting in yeast, nematodes, flies and mice. Moreover, knockout or knockdown of the enzymes required for EIF5A hypusination abolish fasting-mediated autophagy enhancement and longevity extension in these organisms. Of note, autophagy and longevity induced by rapamycin obey the same rule, meaning that they are tied to an increase in spermidine synthesis. These findings indicate that spermidine is not only a “caloric restriction mimetic” in the sense that its supplementation mimics the beneficial effects of nutrient deprivation on organismal health but that it is also an obligatory downstream effector of the antiaging effects of fasting and rapamycin.

Full Open Access Paper:

https://www.tandfonline.com/doi/full/10.1080/15548627.2024.2396793

6 Likes
#2

Looks like rapamycin plus spermidine would be optimal. Eat your aged cheese during rapamycin days.

Importantly, spermidine supplementation enhancesimmune responses in aged mice, improving tumor cell sur-veillance and vaccine efficacy. While rapamycin is one of thefirst pharmacological interventions shown to extend the life-span of mice, concerns about immunosuppressive side effectsof rapamycin have been raised. Indeed, the first clinical indi-cation for rapamycin was immunosuppression in the contextof organ transplantation. It is tempting to speculate, yet remains to be demonstrated, that such immunosuppressiveeffects can be mitigated by co-administering rapamycin withspermidine, by using rapamycin in a discontinuous fashion,or by a combination of both approaches.

4 Likes
#3

Spermidine intake doesn’t increase serum levels of spermidine.

But even if it did, we would need to test that hypothesis because the body is really complex.

6 Likes
#4

I had a bit of a look at this. Cells have some form of homeostasis on polyamines (spermidine etc) which operates on the cellular membrane, but can manufacture them where needed starting with arginine. Hence a mechanism which may work towards facilitating mitophagy would be to ensure adequate levels of arginine. (possibly and SAMe)

Arginine → Ornithine + Urea (Arginase)
Ornithine → Putrescine (Ornithine decarboxylase (ODC))
Putrescine → Spermidine (Spermidine synthase)

The last step requires decarboxylated S-adenosylmethionine which comes from S-adenosylmethionine (aka SAMe). Hence that may be also part of the process.

#5

We’ve discussed that earlier, in several threads, including discussion of a video of Michael Lustgarten.

Your referenced study was posted several times earlier. The article itself says:

Conclusions: This study’s results suggest that dietary spermidine is presystemically converted into spermine, which then enters systemic circulation. Presumably, the in vitro and clinical effects of spermidine are at least in part attributable to its metabolite, spermine. It is rather unlikely that spermidine supplements with doses <15 mg/d exert any short-term effects.

The study dosed volunteers for five days.

This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken.

Your referenced study was done in 2023. The Japanese study below on human volunteers and mice was done in 2009. The study asked the volunteers to take natto for 26 weeks.

https://www.jstage.jst.go.jp/article/jnsv/55/4/55_4_361/_pdf/-char/en

1 Like
#6

Yes, past discussions on spermidine here:

#7

Thanks for the study! Mmmm unless I’m reading it incorrectly the study you provided showed that spermidine supplementation in humans did not increase the serum levels.

1 Like
#8

The Japanese found that spermine concentration increased. Same conclusion in your referenced study.

(4) Conclusions: This study’s results suggest that dietary spermidine is presystemically converted into spermine, which then enters systemic circulation. Presumably, the in vitro and clinical effects of spermidine are at least in part attributable to its metabolite, spermine. It is rather unlikely that spermidine supplements with doses <15 mg/d exert any short-term effects.

Same statement made by Dr. Richard Miller in the video at 26:56,that spermidine gets converted into its metabolite, spermine.

The Japanese interest in spermine is revealed by the following statement:

We have shown that the changes in polyamine concentrations, especially spermine directly affect the function of immune cells.

#9

There are interesting subsets of metabolites such as the polyamines which are continually being converted into each other. To what extent cytosolic levels can be changed exogenously is, however, unsure.

#10

Why not do it the easy way? Fast for 24 hours to kick start spermadine production and then take your Rapamycin dose.

2 Likes
#11

https://www.sciencedirect.com/science/article/pii/S0002916522029306?via%3Dihub

Higher spermidine intake is linked to lower mortality: a prospective population-based study

The above is an associational study, and measures mortality rates. This mathematician persuaded me not to disregard associational studies.

#12

Sorry, but I don’t know why you talk about spermine now, I thought we were trying to increase spermidine levels. The fact that the body converts it in spermine before absorption doesn’t help with the hypothesis that we should eat spermidine to help rapamycin.

Maybe spermine is enough to help? Who knows. Until we test combining Rapa with Spermidine, we can not draw any conclusions for those studies.

1 Like
#13

Ok. I have read the paper twice, and have a few thoughts. I am not a medical professional, so I may be misunderstanding a few things. The paper stated that Endogenous spermadine production is essential. This makes me think that exogenous spermadine from a supplement may be less relevant, or even completely irrelevant. The author’s stated,

“The strategic combination of rapamycin with spermidine in a sophisticated rhythmic fashion holds promise as a novel approach to maximizing therapeutic efficacy while minimizing adverse effects.”

We often observe on this forum that we do not know the optimum dosage or dosage timing for Rapamycin. Adding spermadine to the mix complicates matters, but could be more important than our favorite weekly vs every other week discussion.

I usually take Rapamycin in the morning with a tin of sardines or an avocado. I then fast until the next day. Perhaps it would be better to fast for 24 hours to kick start endogenous spermadine production and then take Rapamycin. I could then eat a few hours later if desired knowing that the Rapamycin is blocking the leucine signal to raise Mtor. Of course a 3 day fast might be better, but I don’t want to lose muscle mass.

3 Likes
#14

Would liposomal spermidine delivery make a difference? Spermidine (Liposomal) 90 Ct. – Renue By Science