Spermidine: Benefits, Foods, Supplements & Side Effects

Jay Campbell

By Jay Campbell

July 13th, 2022

 

Anti-aging compounds come and go faster than the latest iPhone.

Most of them are bunk, the few with promise need many more studies to validate their benefits to human health, and the rare ones with promise are the compounds you’ve already heard me talk about.

So it takes nothing short of a miracle for me to even consider looking at a brand new compound… let alone dedicate an entire article to it.

Which is why I’m thrilled to be doing my usual Jay Campbell deep-dive on a compound called Spermidine.

On top of lifespan-extending benefits not limited to a mere test tube, it already shows practical applications towards fat loss and hair growth.

This article will tell you about the multiple spermidine benefits and how you can get your hands on the world’s cleanest supply of it.

What is Spermidine?

Spermidine is a compound that belongs to a group of molecules known as “polyamines”:

“Polyamine is an organic compound consists of 2 or more amino groups (-NH2). Polyamines are synthesized in cells and play essential role in the proliferation and development of mammalian cells. In addition, polyamines have been shown to exert protein synthesis, antioxidant activity, anti-allergenic effect, and suppression on glycation process”

“…There are more than 20 type of polyamines present in the human body. Spermidine, spermine and putrescine are the most prevalent polyamine present in all living organisms. The synthesis of polyamine is highest in cells of foetus and newborns due to its cell proliferative property. It was found that polyamines are loaded in breast milk.”

Due to spermidine prevalent presence in almost every single tissue in our body, the only question is where you will not find it.

Spermidine is made through a cascade of enzymatic reactions that starts from the amino acid arginine:

Polyamines | Chaim Kahana's Lab

(Source)

But just like many of the essential compounds in our body, spermidine concentrations gradually decrease with age… with one small exception:

“tissue concentrations of spermidine decline in an age-dependent manner in both model organisms and humans.  This may account for decreased autophagy and drive the onset of age-associated diseases.

A remarkable exception to this decline in spermidine levels are healthy nonagenarians and centenarians, who retain whole-blood concentrations reminiscent of younger (middle-aged) individuals

The optimal concentration of spermidine in humans to maintain optimal autophagy levels for healthy aging, however, still needs further investigation.”

Fortunately, the age-associated decline is easily reversible and I’ll tell you how.

First, let’s see why it is in our best interest to care about spermidine production.

Spermidine Benefits

With nearly 14,000 papers dating all the way back to 1927, listing all of the spermidine benefits would take multiple books.

But what we can do is highlight all of the major ones that are most worth your attention.

Autophagy

This is the primary way through which spermidine exerts all of its health effects, thus the main pathway through which spermidine works in the body.

I was going to create a separate section for spermidine’s mechanism of action but felt it was more appropriate to put it here.

Before I talk about how spermidine induces autophagy, first you have to know exactly what autophagy is:

“Autophagy is well known to control the mass of individual cells because it constitutes the most efficient pathway for the degradation of cytosolic proteins and protein aggregates, as well as the sole pathway for the digestion and recycling of cytoplasmic organelles. 

Thus, in response to nutrient starvation or different external stimuli, cells reduce their biomass in an autophagy-dependent fashion, accessorily degrading macromolecules into the building blocks of adaptive responses, as well as into substrates of energy-producing reactions.”

Effectively we’re talking about a form of cell renewal.

As I mentioned in my article on cellular senescence, autophagy helps to “decrease oxidative stress, increase genomic stability (which aids in the prevention of cancer), increase metabolism, and increase the elimination of waste.”

It’s this very same process that allows caloric restriction (i.e. intermittent fasting) to have benefits for both health and longevity.

With that out of the way, here’s a short description of HOW spermidine activates autophagy:

“… [Spermidine] induces autophagy through the inhibition of several acetyltransferases, including EP300, one of the main negative regulators of autophagy.

Its potency has been recently quantified to be equivalent to that of rapamycin, an FDA-approved immunosuppressant with protective and autophagy-stimulatory properties.

Importantly, the genetic impairment of autophagy abrogates the beneficial effects of spermidine on longevity of yeast, flies and worms “

The initial discovery of spermidine to induce longevity in yeast was a significant scientific landmark as Resveratrol and Rapamycin were the only other two compounds in existence circa 2009 to do so (AND extend said benefits to flies and human cells).

Even more interesting is how resveratrol and spermidine have similar yet distinct mechanisms that converge towards inducing autophagy:

“Although resveratrol and spermidine ignite autophagy through distinct mechanisms, these compounds stimulate convergent pathways that culminate in concordant modifications of the acetylproteome.

Both agents favor convergent deacetylation and acetylation reactions in the cytosol and in the nucleus, respectively. Both resveratrol and spermidine were able to induce autophagy in cytoplasts (enucleated cells)

At doses at which neither resveratrol nor spermidine stimulated autophagy alone, these agents synergistically induced autophagy

Let’s take a look at some of the more groundbreaking applications of spermidine’s autophagy-inducing abilities.

Weight Loss

Believe it or not, there is a negative correlation between spermidine uptake in humans and rate of obesity, independent of diabetic status:

“Daily spermidine intake was calculated from the NHANES dietary data and nutrient database for polyamine intake.

Pearson correlation was performed to assess the relationship between spermidine intake and the parameters associated with obesity. Daily intake of spermidine was negatively correlated with BMI, waist circumference and the homeostatic model assessment of insulin resistance (HOMA-IR) index and fasting serum glucose, fasting insulin, and HbA1c levels.

Moreover, as BMI and WASTE increases, daily spermidine intake decreased. Importantly, the high glucose, insulin, HOMA-IR and HbA1c are generally associated with lowered spermidine intake.”

The paper quoted suggests that one of the possible mechanisms for doing so involves improving the function of gut microbiota within diet-induced obese mice.

Other mechanisms include targeting “brown” fat (which uses your body fat to create heat):

“Spermidine is orally administrated into high-fat diet (HFD)-fed mice. The weight gain, insulin resistance, and hepatic steatosis are attenuated by oral spermidine in HFD-fed mice, accompanied by an alleviation of white adipose tissue inflammation. Oral spermidine promotes BAT activation and metabolic adaptation of skeletal muscle in HFD-fed mice, evidenced by UCP-1 induction and CREB activation in both tissues.”

Along with improving key biomarkers:

“Spermidine administration lowered fat mass and plasma lipid profile in HFD-induced obese mice without affecting body weight. In addition, spermidine attenuated hepatic steatosis by regulating lipid metabolism and enhancing antioxidant capacity.

Moreover, spermidine reduced adipose tissue inflammation by decreasing inflammatory cytokine and chemokines expression, and these results might contributed to the enhanced thermogenic gene expression in brown adipose tissue”

For the diabetics who feel left out, don’t worry — there are multiple animal studies showing increased glucose tolerance and insulin sensitivity upon a spermidine intervention with or without exercise.

Dr. Elizabeth Yurth talks more about Spermidine and weight loss in the video below:

Hair Growth

It turns out that spermidine may have vastly unexplored potential in the field of hair loss.

This was evident as early as 1997, when scientists discovered how important polyamines are essential for hair follicle function/growth and fiber composition:

Surprisingly, spermidine itself had some effect in reversing the inhibition of enzymes needed to synthesize polyamines

“Addition of spermidine to the media overcame this inhibition but spermine had no effect. Further evidence that spermine is not required for normal follicle function was provided by incubating follicles with the specific inhibitor of spermine synthase, n-butyl-1,3-diaminopropane. This inhibitor, even at high concentrations, had no effect on fiber growth in vitro.

Spermidine partially overcame the growth depression that occurred in follicles cultured in methionine-deficient media, suggesting that part of the requirement for methionine is for spermidine synthesis in the follicle. These investigations provide strong evidence that the polyamines in general, and spermidine in particular, play a major role in hair growth.”

Later on, cell culture studies revealed that spermidine does more than this and is actually essential for human hair growth:

“We have studied the effects of the prototypic polyamine, spermidine (0.1–1 µM), on human scalp HFs [hair follicles] and human HF epithelial stem cells in serum-free organ culture. Under these conditions, spermidine promoted hair shaft elongation and prolonged hair growth (anagen).

Spermidine also upregulated expression of the epithelial stem cell-associated keratins K15 and K19, and dose-dependently modulated K15 promoter activity in situ and the colony forming efficiency, proliferation and K15 expression of isolated human K15-GFP+ cells in vitro”

A closely-related analog, alpha-methylspermidine, is also being investigated as it is more metabolically stable than spermidine (which has the downside of being easily converted into other polyamines).

We don’t have much outside of in vitro studies, but so far it reliably grows hair follicles and even has some anti-inflammatory properties that can serve useful for inflammation-driven scalp diseases.

However… we’re fortunate enough to have a few human studies demonstrating spermidine as far more than a one-trick pony.

A randomized double-blind study published in 2011 had 100 healthy males take a placebo or a spermidine supplement every day for 90 days straight.

Spermidine was able to prolong the anagen (growth) phase of the normal hair growth cycle after results were obtained at three and six months of the protocol:

“The spermidine-based nutritional supplement increased the number of anagen V–VI HFs after three months of treatment, accompanied by increased Ki-67, a marker for cellular proliferation, and decreased c-Kit, a marker for apoptosis, levels.

All results were also significantly better when compared to the placebo group. The pull test remained negative after six months in all patients receiving the spermidine supplement, while 68% of the subjects in the placebo group had a positive pull test.”

No details were given about the specific composition of the spermidine supplement, so there’s no way to know exactly how much subjects took on a daily basis.

This same mystery appears to be present in a 2018 paper from an Italian dermatology journal where researchers claimed to have run a double-blind clinical trial using a topical mixture of Sandalore and N1-methylspermidine.

We don’t know the exact composition of this mixture, and since I couldn’t find the full study, here’s what is reported after this mixture was used in 60 men and women suffering from telogen effluvium:

“…the clinical trials performed confirmed the safety and anti hair loss efficacy of the lotion reporting a reduction of hair loss (modified wash test) and hair growth stimulation as evaluated by hair density, hair shaft diameter, % of anagen hair and Hair Mass Index increase after 3 months of treatment.

The lotion efficacy remained statistically significant for the above-mentioned parameters, with the exception of hair lost during wash, also 3 months after the end of treatment.”

The good news is we have one clinical study from 2003 sponsored by a supplement company where they actually tried using spermidine in healthy men and women with telogen effluvium between the ages of 18 and 60:

“In a first step, the active substance was tested alone (0.5 mg), in combination with other ingredients and against placebo. The active substance is spermidine…. In addition, spermidine was administered together with the ingredients methionine, vitamin C, vitamin E, calcium pantotenate, zinc, polyphenols from red grape peels, vitamin B6, copper, folic acid, and biotin as a complete food supplement. The trade name is Biogenina®.

The microscopy assessment (trichogram) of the follicles showed a 17% increase in anagen phase for the spermidine-supplemented group, a 20% increase for the Biogenina group, and an 8% increase in the placebo group. The pull test to assess the resistance of hair stem to traction was unchanged in the placebo group and improved by 63% in the spermidine-supplemented group and by 94% in the Biogenina group at two months.

In addition, a wash test was performed. The hair loss was unchanged in the placebo group and decreased by 39% in the spermidine-supplemented group and by 67% in the Biogenina group at two months.

(You can click here to get a full PDF copy of the study)

Could this ingredient be a new part of the infamous Auxano Grow formula that’s helped thousands of men and women permanently reverse hair loss and stimulate hair growth?

I can’t say for sure, but at least one other company has attempted to patent spermidine as a hair loss treatment!

Improving Cognitive Function

Spermidine can also help us stay smarter in old age, but it does so by reducing the chances of neurodegenerative disease instead of directly boosting cognitive performance.

A 2018 randomized controlled trial found that older adults (60-80 years old) experiencing cognitive decline noticed significant improvements in memory performance after 3 months of taking a plant extract supplement daily consisting of 1.2 mg spermidine:

“Memory performance was moderately enhanced in the spermidine group compared with placebo at the end of intervention [contrast mean = .17, 95% confidence interval (CI): -.01, .35, Cohen’s d = .77, 95% CI: 0, 1.53].

Mnemonic discrimination ability improved in the spermidine-treated group with a medium effect size (mean difference = -.11, 95% CI: -.19, -.03, Cohen’s d = .79, 95% CI: .01, 1.55). A similar effect was not found in the placebo-treated group (mean difference = .07, 95% CI: -.13, .27, Cohen’s d = -.20, 95% CI: -.94, .54).”

In a separate trial published in 2020 involving a larger group of adults (except this time with mild to moderate dementia), oral supplementation of 2-3 mg spermidine daily by eating a grain roll:

“The results demonstrated a clear correlation between the intake of spermidine and the improvement in cognitive performance in subjects with mild and moderate dementia in the group treated with the higher spermidine dosage.

The most substantial improvement in test performance was found in the group of subjects with mild dementia with an increase of 2.23 points (p = 0.026) in the mini mental state examination (MMSE) and 1.99 (p = 0.47) in phonematic fluidity. By comparison, the group which had a lower spermidine intake showed consistent or declining cognitive performance.”

What’s funny is that this effect ties back directly to spermidine’s ability to induce autophagy, which works to tackle neuroinflammation and neurotoxicity in the brain.

It’s one of the few effects of spermidine seen consistently in several species: In mice via crossing the blood-brain barrier, boosting mitochondrial function in Drosophila, and associated with lower risk for cognitive impairment in humans when spermidine uptake is higher.

Anti-Aging and Longevity

I want to finish off this section by highlighting two studies that show how spermidine is unquestionably linked to a longer life.

The first study showed not only that in rats, but also provided protection from heart disease:

“…dietary supplementation of spermidine given to wild-type mice leads to an extension of lifespan that is associated with a decrease in cardiac hypertrophy and a delay of age-induced diastolic dysfunction.

The authors also elegantly demonstrate that spermidine confers protection of the elasticity and mechanosensitivity function of cardiomyocytes, at least in part, through structural preservation of the cytoskeleton and the myofibrils, attenuation of inflammation and preservation of mitochondrial respiration, all of which are essential for the maintenance of cardiac health during aging.

The authors further show that the treatment of old male and female mice with spermidine late in life is effective at extending their lifespans.”

(The full study can be found here)

The authors of this study briefly mention a correlation they found between high levels of food-obtained spermidine in humans and lower blood pressure, but nothing on human lifespan.

That’s where this second two-decade study of +800 individuals comes in:

“The study revealed that a higher intake of spermidine was associated with lower blood pressure and reduced risk of heart failure and other cardiovascular diseases (a composite of acute coronary artery disease, stroke, and vascular death).

Furthermore, overall and cardiovascular-related mortality was reduced in those subjects consuming higher amounts of spermidine in their diet, even after correcting for possible confounding factors, such as caloric intake, age, sex, body mass index, diabetes, hypertension, physical activity, smoking, and alcohol consumption.

More recently, the safety of spermidine administration to the elderly was examined in a pilot clinical trial recruiting patients with a subjective cognitive decline”

(Full study can be found here)

If that’s not a way to end off the “benefits” section of an article, I don’t know what is.

How to Increase Spermidine

If you want to know how to increase spermidine, the answer is surprisingly simple and can be summarize in one neat infographic:

Figure

(Source)

And to quote the paper I grabbed this image from:

“Possible routes to counteract the age-induced decline of spermidine levels. With old age, endogenous spermidine concentrations diminish due to alterations in one or several factors that determine the bioavailability of the substance in the body.

This detrimental decline may be counteracted by ingesting polyamine-rich food items, polyamine-enriched plant extracts, synthetic spermidine, or by stimulating polyamine synthesis in the gut microbiome through supplementation of prebiotics or probiotics.”

This article is going to focus on (a) foods and (b) supplements.

Don’t get overwhelmed — you’ll find that being fully optimized already has you taken care on the first part.

Foods High in Spermidine

So what are the foods high in spermidine?

According to the Swedish Food Database, here are the top 12 dietary sources of spermidine (in mg/portion):

  • Cooked soybean – 9.7
  • Green peas – 9.1
  • Pear – 6.6
  • Lentil soup – 5.5
  • Mushroom – 4.4
  • Red beans – 3.7
  • Broccoli – 3.6
  • Cauliflower – 3.0
  • Chicken/steak – 2.2
  • Popcorn – 2.1
  • Cheese – 2.0
  • Cooked potato – 1.8

Or viewed in a more graphical format:

An external file that holds a picture, illustration, etc. Object name is FNR-55-5572-g001.jpg

(Source – Mean polyamine content for each food group, the white bars represent spermidine)

Does this look familiar?

It should, because it looks like a diet mostly focused on plants and legumes.

This is not to say you should be ditching meat, but just know you’re not going to get your day’s worth of spermidine from ground beef and protein shakes.

If you eat a diet as per these recommendations, you should generally notice a significant difference over time:

“Definitely. It has been reported that consumption of spermidine rich food leads to enhancement of the polyamine – spermidine or spermine – concentration in the blood after three month. So, a change in diet towards spermidine rich food might be effective.

High concentrations of spermidine are for example available in wheat germs, mushrooms, strongly fermented cheese, meat, green salad, and pears.”

Looks like Grandma was right all along — if it didn’t grow from the ground, don’t eat it!

Spermidine Supplementation

While you can gorge yourself silly on spermidine-rich foods, sometimes it’s a lot easier to get your daily intake through smart spermidine supplementation.

Before I introduce where exactly you should be sourcing spermidine from, let me tell you what NOT to do.

You should absolutely avoid any supplement where the spermidine is provided in the form of a “wheat germ extract”, such as the one below:

This is the oldest scam in the supplement industry — use the excuse of a proprietary formula or a “blend” to hide how much of the most important active ingredient(s) you are using.

Case in point — anti-aging expert David Sinclair used to tell people that he was experimenting with ONE GRAM of spermidine a day.

Except if you look at what he’s taking, his actual daily dose of spermidine is 1000x smaller:

“…when we look at the company he’s invested in, Longevity Labs, who’s first product is a spermidine supplement under the brand SpermidineLIFE. We see that the daily dose of 1 gram (800 mg) of wheat germ, actually only contains 1 milligram (mg) of spermidine.

You can see this on their site if you scroll to ingredients. Taking 1 gram of actual spermidine would require consuming 2,000 of their capsules (1 gram = 1,000 milligrams, 1 capsule = 0.5 mg of spermidine).”

Therefore, I highly suggest you sign up for the Spermidine pre-launch being offered by my #1 peptides vendor Limitless Life Nootropics and use code JAY15 at the checkout cart for 15% off!

They’re going to be releasing an ultra-pure liquid form that blows the competition away with respect to purity and potency.

But for a limited time, you can get it on backorder until it is officially available around August 7th.

For a 15 mL solution containing 90 mg of spermidine, half a milliliter gets you 3 mg!

Spermidine Dosage

So if we ignore basic errors and assume we’re going to do this the right way, what is the best spermidine dose to take?

Based on what I have seen from the human clinical trials and extrapolations from animal data, I would say a good starting spermidine dosage is anywhere between 1-3 mg of spermidine a day. 

Here’s the geeky details if you want to see how I reached that conclusion:

“Based on the preclinical data, maximum safe dosage in humans was calculated using the NOAEL of 5 g/kg bodyweight from the murine model, mouse-to-human interspecies factor of 12.3 and factor 10 as safety distance between sub-chronic and chronic application.

As a result, doses of up to 41 mg/kg bodyweight or 2.8 g extract containing 3.4 mg spermidine for the average person weighing 70 kg were set as the expected upper safety limit for the treatment.”

Keep in mind this is from a study where older adults suffering from cognitive decline were the subjects, so there’s no telling if a biohacker could safely get away with taking higher doses consistently.

Spermidine Side Effects

In theory, spermidine’s status as a naturally-occurring compound essential for human life should automatically make it safe.

But let’s not assume and turn to what the most comprehensive study on spermidine safety for humans says:

“In the human cohort (participants with subjective cognitive decline, n=30, 60 to 80 years of age), a 3-month randomized, placebo-controlled, double-blind Phase II trial was conducted with supplementation of the spermidine-rich plant extract (dosage: 1.2 mg/day).

No differences were observed between spermidine and placebo-treated groups in vital signs, weight, clinical chemistry and hematological parameters of safety, as well as in self-reported health status at the end of intervention. Compliance rates above 85% indicated excellent tolerability.

The data demonstrate that spermidine supplementation using a spermidine-rich plant extract is safe and well-tolerated in mice and older adults.”

Side effects have not been inherently reported, but the absence of evidence isn’t necessarily the evidence of absence.

There’s a big difference between spermidine supplementation and spermidine levels already present in your body from nutrition and general healthy living.

We’ll have to wait and see what emerging data says, but rest assured that spermidine side effects aren’t going to be a serious concern for any biohacker.

Conclusion: Spermidine Is More Than A Funny Name

Spermidine would have never gotten my attention if it wasn’t for people in my private inner circle bringing it up to me several times.

But I am thankful they explained all of the spermidine benefits in detail and why it should be worthy of your attention.

Alongside compounds like NAD+ and Metformin, I now have something to add to my essential stack of anti-aging supplements.

***UPDATE*** Monica and I have been using it for two weeks now and we both notice an increase in energy.

We are both in a summer ‘shred phase’ and it also appears to be optimizing or enhancing autophagy/hormesis.

More information will be forthcoming, because IT IS who I AM.

As always…

Raise Your Vibration To Optimize Your Love Creation!

PS – For first-priority notice on all the anti-aging compounds I’m experimenting with long before I ever mention them to my readers or email subscribers, join The Fully Optimized Health Private Membership Group.

It’s your greatest opportunity to fully optimize your health and gain total access to me and my network of high-level men and women living their highest and best life.

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