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One of the most interesting nutritional factors to fight aging is a unique amino acid known as spermidine. As its name suggests, spermidine was first discovered in human semen in 1678 by the famous Dutch scientist Anton Van Leeuwenhoek, commonly known as "the Father of Microbiology." Spermidine is very important to sperm function, but it also plays a significant role in cells throughout the body.
Spermidine fights the aging process through a variety of biological mechanisms. But it is spermidine's role as an enhancer of a process called autophagy and the function of mitochondria, the energy-producing compartments of cells, that are the key factors that produce its significant anti-aging effects that this article will discuss.
The practical application of these effects is using a spermidine-rich diet or spermidine supplementation as an anti-aging strategy.
Spermidine administration extends lifespan in aging models and in animal studies, whether given throughout their lives or later in life. In humans, maintaining spermidine levels throughout the lifespan contributes to living longer. The blood levels of spermidine and its metabolite spermine in people between 60 and 80 years old were lower than in people below the age of 50 years. Still, interestingly, people older than 90 have levels similar to people below 50. This finding implies a correlation between higher spermidine levels and longer life.
Spermidine plays a critical role in cellular function and survival. It is needed to activate key molecules involved in:
Spermidine also plays a significant role in the immune response and the antioxidant system, especially in protecting membrane lipids and DNA.
Additionally, spermidine activates a master metabolism switch, an enzyme known as AMP-activated protein kinase (AMPk). The activity of AMPk plays a major role in energy metabolism and is also tied to life expectancy. With aging, cellular AMPk activation decreases, leading to insulin resistance, liver impairment, accumulation of abdominal (visceral) fat, and loss of muscle mass (sarcopenia). The activation of AMPk may be a critical anti-aging effect of spermidine.
However, regarding its anti-aging effects, most research has focused on spermidine as an enhancer of autophagy and mitochondrial function.
Autophagy translates to "self-eating." It is a cellular cleansing process where accumulated waste products are delivered to compartments in cells known as lysosomes so that they can be destroyed and potentially reused.
Autophagy is the cell's quality control process to dispose of cellular garbage, debris, microorganisms, and unwanted compounds, as well as reuse compounds that can be salvaged.
The science and importance of autophagy is a relatively new discovery. In 2016, Japanese biologist Yoshinori Ohsumi won the 2016 Nobel Prize in Physiology or Medicine for his discoveries of the mechanisms of autophagy.
Enhanced autophagy has been found in exceptionally healthy centenarian humans and appears to be a key target for living a healthier, longer life. Genetics plays a role in autophagy, but it can be influenced considerably by the expression of autophagy genes through diet, lifestyle, and dietary supplements. Spermidine is establishing itself as a key dietary factor to enhance autophagy function.
Spermidine enhances autophagy via its actions on various genes that promote autophagy, including the autophagy gene (ATG5). People who overexpress this gene may live longer. The expression of ATG5 is reduced in response to oxidative and free radical damage, as well as by reduced mitochondrial function. Hence, spermidine appears to reverse the impact of these factors on suppressing autophagy.
In addition to evidence from experimental studies showing spermidine intake may increase longevity, there are also human studies showing a higher spermidine intake is linked to a lower overall mortality rate.
In other words, higher spermidine intake may increase longevity, which means living a longer and healthier life. Spermidine also shows promise in protecting against aging, especially in the brain, heart, liver, joints, and muscles. These tissues are especially susceptible to the detrimental effects of aging. By enhancing autophagy, spermidine combats aging in these tissues and others.
Impaired autophagy accelerates aging by increasing oxidative damage. It also leads to loss of control in building cellular proteins, decreases cellular energy production by inhibiting mitochondrial function, and creates other biochemical challenges associated with an increased rate of cellular aging. These effects hit every tissue of the body, especially the brain, since it is the most metabolically active tissue. Aging-related decline in autophagy is also responsible for sarcopenia – the progressive loss of muscle mass and strength associated with aging.
One of the keys to helping your body's ability to deal with cellular debris is to prevent their formation and accumulation in the first place. A state of chronic, low-grade inflammation characterizes accelerated human aging. This process is called inflammaging, and inflammation also leads to reduced autophagy.
There are a few triggers of inflammaging, such as poor blood sugar control and lack of key dietary factors that fight inflammation, such as omega-3 fatty acids, polyphenol-rich foods like berries, other fruit, green leafy vegetables, carotenoid-rich vegetables, etc.
With inflammaging, mitochondrial function is reduced primarily because of damage and stress caused by free radicals and pro-oxidants. This leads to a greater formation of cellular garbage within the cell itself. Hence, the term "garb-aging" is also used to describe the effects of either excess accumulation of cellular garbage, reduced autophagy, or a combination of both. Spermidine may help to prevent garb-aging by acting as both an antioxidant and enhancing autophagy.
Spermidine is found in many foods but in small quantities. Wheat germ, whole grains, legumes, soy foods, and mushrooms provide the highest content. Aged cheeses and fermented foods are also good sources, along with chicken or beef liver.
The estimated daily intake of spermidine for adults in the United States and Europe is approximately 12.5 mg per day. Three tablespoons of wheat germ provide about 5 mg of spermidine or about 40% of the typical daily intake.
In addition to dietary intake, spermidine is also formed in the body. One route is through the amino acid ornithine via its metabolite putrescine. This route involves converting putrescine to spermidine through the enzyme spermidine synthase. Spermidine can be transformed into spermine and reconverted back to spermidine. While spermidine, spermine, and putrescine are interconverted, spermidine is the predominant and most crucial polyamine to human cellular physiology.
Gut bacteria can also produce spermidine and other polyamines. Since not all gut bacteria produce polyamines, different microbiome compositions may lead to more favorable spermidine production. In the intestinal lining, spermidine has several beneficial effects, including increased cellular longevity, recovery of injured intestinal epithelial, and improved cellular energetics.
Spermidine supplementation is a viable way to boost spermidine intake. Interestingly, when healthy volunteers ingested 15 mg per day of spermidine, it significantly increased spermine levels in blood plasma, but it did not affect spermidine or putrescine levels. Spermine is transported in the blood to body tissues, where much of it is converted back to spermidine. Spermine possesses some benefits as well.
In addition to considerable experimental and human studies indicating a higher spermidine intake prevents age-related cognitive decline, there have also been several clinical trials with wheat germ extracts concentrated for spermidine content showing positive results in elderly patients with declining memory and cognitive function.
The most recent double-blind study focused on the effect of spermidine intake on 85 subjects between 60 and 96 years old from 6 nursing homes. One group received a grain roll (roll A), with each roll A providing 3.3 mg of spermidine. The second group received rolls baked with wheat bran instead of wheat germ (roll B), which provided 1.9 mg of spermidine per roll. In addition to memory tests, blood samples were taken to measure spermidine levels. Results demonstrated a clear link between spermidine intake, blood levels of spermidine, and improved cognitive performance and memory. Based on the results and blood measurements, the minimum daily dosage of spermidine required to show improvement was calculated to be 3.3 mg (roughly two tablespoons of wheat germ). This determination has proved to be very important.
Another double-blind, randomized, placebo-controlled pilot trial showed three months of spermidine supplementation prevented memory loss in elderly subjects at a dosage of 1.2 mg spermidine per day. These encouraging results led to a 12-month randomized controlled trial known as the SmartAge Trial to determine the impact of spermidine supplementation on brain function and associated biomarkers in patients affected with cognitive decline over a more extended period. However, the daily dosage of spermidine was only 0.9 mg per day in this study, and no statistically significant improvements were noted in the SmartAge Trial. As mentioned above, the threshold for positive effects with spermidine supplementation is estimated at 3.3 mg per day. Hence, the dosage was not sufficient to produce a noticeable benefit.
There is another study with spermidine intake that is important to discuss regarding brain health. The study looked at spermidine intake and adherence to the Mediterranean Diet in older subjects with cognitive decline. The study looked at structural measurements of the brain with the help of (magnetic resonance imaging (MRI). Typically, as many people age, there is a loss of critical structural changes in the brain, such as total brain volume, hippocampal volume, and cortical thickness.
Higher spermidine intake was positively associated with improved structural measurements in all of these. It enhanced the benefits seen with the Mediterranean Diet on maintaining brain health during the aging process.
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By Dr. Michael Murray, N.D. 
