Why not Spermidine?

Spermidine is found naturally in many foods. Blood levels decline with age. Supplementation extends lifespan and healthspan in various species, and lowers mortality in human trials. I have been unable to find toxicity data or any downside to spermidine supplementation, except that the effective dosage may be impractical.

Consistently across species, extra supply of spermidine prolongs the life span in an autophagy-dependent manner and counteracts age-associated pathologies such as cardiovascular disease, neurodegeneration, and cancer.”
— Guido Kroemer in Science [2018

If you haven’t followed Guido Kroemer, you’ll find he’s a wellspring of deep biochemical knowledge. 

Many life extension strategies involve hacking the body’s signaling systems, binding to specific proteins like SIRT or TOR. But spermidine is a small molecule, too simple to have specific signaling properties. Compared to even smaller molecules like H2O2 and NO, it persists in the metabolism long enough to be transported and affect multiple tissues. 

Autophagy is the recycling of damaged organelles (cell parts) and damaged biomolecules, a renewing process that has long been recognized as a necessary process for keeping the body young. Mitochondria are the organelles that generate energy, and ROS are their toxic byproduct. One of the most essential functions of autophagy is the recycling of mitochondria.

Fasting triggers autophagy, and this is part of the reason it is good for us. Longo’s Fasting-Mimicking Diet was designed to promote autophagy. The life extension and other benefits from spermidine are found to result principally from enhanced autophagy. (The way this is determined is to repeat life extension experiments with an autophagy gene disabled, and it is found that spermidine has no benefit [2016].) Spermidine was found to extend lifespan in yeast, worms, flies, and human cell cultures [2009].

Apoptosis=programmed cell death is an essential function for removing senescent and cancerous cells. We need apoptosis, and would be more vulnerable without it, but as we get older, apoptosis develops a “hair trigger”, and cells begin to commit suicide when they’re still healthy and useful. Overactive apoptosis is to blame for sarcopenia – the loss of muscle mass with age. Apoptosis is also implicated in the loss of brain cells that leads to Alzheimer’s Disease. Spermidine dials down apoptosis

Spermidine is an anti-inflammatory, and there is suggestion from animal models that it could relieve arthritis [2016]. This study found a stronger benefit for spermine, which is a metabolic product downstream of spermidine.

Foods with the highest concentrations of spermidine include wheat germ, natto and other soy products, mushrooms, some cheeses, and apples. An ounce of wheat germ or 8 oz of cheese contains 10 mg spermidine. Some of our spermidine comes from the gut microbiome. The probiotic Bifidobacterium LKM512 increased blood levels of spermidine in mice.

Spermidine dosage is curiously missing from some of the most important studies. 

In the mouse lifespan study that produced the best results [2017], mean lifespan was extended by 24%. Spermidine was added to the drinking water of test mice at a concentration of 3mM. Translating to humans is not straightforward, but here’s a rough estimate: If you drank 2 quarts a day of water or other fluids with this concentration of spermidine, you would be getting about 1 gram. To get this from food you would eat 6 pounds of wheat germ daily. The highest-dosage supplement pills I can find have 5 mg, so 1 gram per day = 200 pills. For some other supplements, pills of ½ g or a full g are not hard to find. I don’t know if spermidine is intrinsically expensive or if there is another reason that supplement companies gauge the dosage levels so low.

There are no human studies based on supplementation, but some authors have tried to correlate mortality with estimates of spermidine intake from (self-reported) food surveys. Again, they report results by dividing the test subjects into three groups, comparing highest and lowest (estimated) spermidine intake without specifying quantities [2018]. Mortality was reduced by about 25% in the tercile with highest spermidine intake, corresponding to about 3 years of extra life. Because the correlation is computed based on foods, this result may include confounding errors, as the foods highest in spermidine have other health benefits. 

This Japanese study from 2012 looks for factors that affect longevity across 48 Western countries. Because there are so many variables, the uncertainty is great, but dietary polyamines (including spermidine) stood out as a factor decreasing cardiovascular disease burden (r = -0.355, p = 0.007). 

In elders with mild cognitive impairment, there was an indication of possible memory benefits [2018, 2021]. Two studies suggest benefits for immunosenescence as well [2014, 2015]. 

Here’s an excellent short review, also by Kroemer [2019] as senior author. 

The bottom line

I don’t know why it has taken me so long to discover spermidine, or why it is not more frequently discussed by health gurus and biohackers. This month’s Life Extension magazine calls for trials of multiple combined interventions — an idea which I have advocated since 2018. Spermidine is on top of their list of substances to try in combinations.

I plan to self-experiment with high dosages, based on the very limited data from rodents.

11 thoughts on “Why not Spermidine?

  1. Having read your post, I am left with the following question. What is the dosage you are going to experiment with, and how, given the low dosages available commercially, are you going to procure the necessary amount on an ongoing basis?

  2. Our results did not provide support for the notion that dietary spermidine has beneficial effects on mortality. DOI: 10.1017/S0007114523002465

    We report that higher spermidine blood levels are associated not only with deteriorated brain health but also with less advantageous markers of sleep quality in older adults. doi: 10.1007/s11357-023-00886-3

  3. The other thing to consider is that lab mice are rather good at dealing with toxicity. I wouldn’t assume that you can handle 1 gram of spermidine. It might be fine, but then again, your poor liver might not thank you.

  4. I have been aware of spermidine since more than a decade ago, but have never considered it likely to be of much benefit for aging in reasonably available doses (low mg doses), at least not likely enough to do a lot of research on it.

    AFAIK the animal studies showing benefits use very high doses, far higher than the tiny doses found in supplements or the diet. The amounts found in dietary items are so small and there are so many confounders in studies on dietary intakes that there is no good proof the positive relationship between spermidine rich foods and some measures of health is caused by the spermidine rather than something else. Lastly, Richard Miller of the Intervention Testing Program said that they tested spermidine in mice and found that they didn’t find measurable amounts of it in the blood after ingestion. That’s not encouraging.

    Of course there is a chance that spermidine has some benefits that do not depend on its significant precence in the blood but depend more on its breakdown products. But at such low doses I doubt it. I know there are a few human studies showing potential benefits of low mg doses but I’m not convinced of such doses doing anything significant without seeing much more evidence. There is also a chance that you simply need very high doses (100mg +) to see some significant effects but I don’t recall seeing human studies using such doses and anyways such studies would be practically irrelevant when it’s almost impossible to get such doses through supplements.

  5. I think maybe it would be better to trial at least 15 mg based on this, “ Taking our data into account, those results may have been a consequence of simple underdosing. It is rather unlikely that spermidine supplements with daily doses below 15 mg exert any effect, since even the effect observed in this study was rather small. Thus, in future trials, daily doses of at least 15 mg should be used.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10143675/

    I’ve just never really understood why spermidine would better than rapamycin which is cheaper in doses that we know are effective for autophagy.

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