We should take into consideration that there are effects from medicines and supplements that don’t follow the population’s average. Just because a very serious side effect only affects 1 out of 100, it does not mean it is insignificant knowledge. On the contrary, it is very valuable, and the focus is to try and find out what that little percentage has in common so we can choose another treatment.
Same goes for a small minority who respond favorably to a treatment when the vast majority of the population does not.
“Importantly, spermidine supplementation enhances immune responses in aged mice, improving tumor cell surveillance and vaccine efficacy. While rapamycin is one of the first pharmacological interventions shown to extend the lifespan of mice, concerns about immunosuppressive side effects of rapamycin have been raised. Indeed, the first clinical indication for rapamycin was immunosuppression in the context of organ transplantation. It is tempting to speculate, yet remains to be demonstrated, that such immunosuppressive effects can be mitigated by co-administering rapamycin with spermidine, by using rapamycin in a discontinuous fashion, or by a combination of both approaches.“
Its not just Richard Miller - its a team of excellent scientists at 3 independent labs… (I think they may all have done the preliminary testing to see blood levels of spermidine). But more importantly they worked with Frank Madeo (the key researcher on Spermidine in Austria) to identify dosing and delivery strategies… so they had the input from the key proponents of spermidine.
Richards’ discussion of Spermidine (queued up in the video below):
If exogenous spermidine is useless, what about boosting endogenous production? Perhaps through providing some kind of substrate to increase production, or take something that will modify some rate limiting pathway or the like? Does the rate of spermidine production decline with age, and can that decline be slowed or prevented?
Speaking just for myself, all I do, is add a tablespoon of wheat germ to my morning cereal/mix five days a week. I know the spermidine fraction is microscopic, but as a natural food source, maybe it makes some kind of functional food difference? Because maybe isolated spermidine supplementation can’t be absorbed, but when the spermidine is present in a natural food matrix, the effect is different when consumed? But ok, I figure if the tiny bit of spermidine does nothing, then maybe other constituents of the wheat germ might be helpful, like vitamin E… and failing all of that, at least I know it provides a small fiber boost, always useful.
The other thing is that the ITP rapamycin and rapamycin+ trials did nothing to add or boost spermidine for the mice, yet they still exhibited life extension, so I’m not sure how much to stress over this.
I particularly valued the comments about the economic interests pushing commercial products. What will happen when there are no more Richard Millers who don’t have a commercial interest?
Hello, may I ask your opinion on this: I have read all topics on spermidine back to the old ones and I am confused: on one hand there are Miller’s & Co experiments showing that spermidine doesnt get into blood or tissue, on the other hand data showing an increase in spermine level upon 15 mg/d oral supplementation. The 2024 article shows the role of spermidine in the rapamycine effect on mTOR but does not mention spermine. Does spermine play a role ? Because if so, oral supplementaion would make sense. Thank you
Spermidine supplementation using the spermidine-rich plant extract did not significantly alter whole-blood polyamine concentrations in humans and mice at most concentrations. The absence of changes of polyamine levels in the blood may be due to the fast absorption/metabolism rate of polyamines from the intestinal lumen into solid tissues, as observed in an ex vivo rat model by Uda and colleagues [18].
The Japanese, on the other hand, state the following:
Although the blood spermidine/spermine ratio in mice did not change after increased polyamine intake,this ratio did decrease in human volunteers. The difference in blood spermidine/spermine ratio between mice and human volunteers might be due to a species difference, differences in the ratios of spermine/spermidine loaded, and differences in the intestinal environment such as endogenous flora.
Same findings as Miller, with regard to mice, and spermidine in blood.
The above also shows differing conclusions of the Europeans versus the Japanese. The Europeans think it is the fast absorption/metabolism rate that makes it hard to detect in blood. The Japanese posit that it is a specie difference between mice and humans, that explain their findings - spermidine increase in humans, no change in mice.
Other researchers, instead of focusing on blood levels like Miller, look to effects, after spermidine supplementation.
Lifespan extension in mammals
Lifelong spermidine supplementation via drinking water is sufficient to prolong the lifespan of adult female and male mice90. Similar effects were observed for spermine but not for putrescine90.
Spermidine also sufficed to prolong the lifespan of pre-aged 18-month-old mice90 and short-lived male mice with progeria (Zmpste24−/− mice)171 .
Likewise, daily injections late in life caused a nonsignificant lifespan extension in mice102 and polyamine-enriched food prolonged the lifespan of aging mice172 , suggesting that the mode of administration is of little importance for the longevity effects.
Interestingly, the upregulation of intestinal polyamine production in 14-month-old mice by feeding the prebiotic arginine combined with the probiotic bifidobacteria LKM512 (equipped with the enzymatic machinery to convert arginine into spermidine) is sufficient to prolong lifespan and reduce the incidence of age-related diseases173 ,174 .
While the cardioprotective effects of spermidine could mechanistically be linked to autophagy90, only one mechanistic lifespan study has been conducted in mammalian models. In the study by Yue et al., lifespan extension and autophagy induction by spermidine feeding were abolished in autophagy-deficient male Map1s-knockout mice52.
Fewer studies have been carried out on rats: in salt-sensitive Dahl rats, spermidine exerts systemic cardioprotective effects90. One study found no impact on life expectancy but a significant healthspan-extending effect in middle-aged male Sprague-Dawley rats175.
LKM512 again. Seems to be a good supplement. We discussed this earlier. It a yogurt bacterium.
So if the endogenous spermidine/spermine production is being chased, ingesting the LKM512 yogurt should be considered. The bacterium is also known as BB12, commercially available as Stonyfield probiotic yogurt.
You can make your own yogurt with the capsules below.
That’s a good approach. Outcome studies is where it’s at. That said, study design is also critical. The ITP uses three separate labs, uses genetically diverse mice, and eschewes using short lived and genetically screwed up animals.
That’s a glaring issue here in many studies. Short lived species (MK’s 900 day mice rule), accellerated aging, salt-sensitive rats and other screwed up animals. You never know if the intervention isn’t simply compensating for the defects in the animals, and is useless in normal ones. A pillow tied around the head prolongs life! Quick, let’s get some pillows… but first, how does it work? Well, in our study we randomly divided people into two groups. One with pillows around the head, one without. It was a randomized and double blinded. Both groups were repeatedly hit in the head with a hammer by an industrial robot. After ten days we looked at the results. The group with a pillow around the head (our intervention!) had a 70% survival rate, the group without the pillow had a 1% survival rate. Now, we will go out into the world and announce that pillows around the head have longer lifespans.
So, if your genes are altered so you die or age prematurely, or salt kills you, our supplement will show a longer lifespan! Same relevance to the public as pillows tied around the head - if not hammered by a robot, you can ignore the pillow as a lifespan extending intervention.
