Autophagy and Spermidine

The molecule spermidine is loaded with a polyamine molecule that prolongs the lifespan of many life forms including mammals when supplemented in the diet.  That molecule is abundantly found in wheat germ and to a lesser extent in grapefruits.

Polyamines are identified as putrescine, spermine and spermidine.  They are synthesized internally from the amino acid ornithine.  Polyamines are also consumed in the diet and play an important role in regulation of cell growth and immune response. [Nutrition 2007]

Biologists excitedly say polyamines found in many foods may reset the body’s 24-hour circadian clock and prolong the healthspan and lifespan of humans.  [Cell Metabolism 2015]

There is a short list of molecules that are deemed to be valid anti-aging agents.  The anti-diabetic drug metformin; the red wine molecule resveratrol; curcumin the molecule derived from turmeric spice; and the immune-suppressant drug rapamycin are frequently cited.  But spermidine, often mentioned with these other molecules, has largely been overlooked, that is, till now. [Nutrition Research Reviews 2015; Biochemical Biophysical Research Communications 2013; Aging Cell 2011]

Spermidine derives its name from spermine, for which spermidine is a precursor.  Spermine was first identified in human semen and hence the name spermidine. [NIPS Journal 1986]

How polyamines like spermidine work

The provision of supplemental spermidine prolongs the life of living organisms often used as models for longevity science. Spermidine is known as a molecule that activates a biological process called autophagy that is believed to be involved in most if not all lifespan-prolonging therapies. [Autophagy2010]

Spermidine is described as a “novel autophagy inducer and longevity elixir.” [Autophagy 2010]

The biological literature is clear—inhibit autophagy and all living organisms age faster. [Cell 2011]

Autophagy, literally “self eating,” is a biological process that is activated when there is not enough food for an organism to survive.  It is well known that limitation of calories to living organisms prolongs their life.  Less food (but not starvation) activates survival mechanisms.  Molecules like resveratrol, curcumin, nicotinamide (vitamin B3 niacin) along with spermidine activate autophagy. [Autophagy 2014]

Lifespan is dependent upon autophagy.  Spermidine, long identified as an agent that promotes autophagy along with resveratrol, is just now gaining public attention. [Journal Cellular Molecular Medicine 2010]  Whether an individual deprives themself of food (calorie restriction), or molecularly mimics calorie restriction, they are activating the same life-prolonging mechanism – cell cleansing autophagy. [Nature Cell Biology 2010]

Cell cleansing

As living cells age cellular waste accumulates in the watery (cytosol) portion of the cell.  Spermidine facilities autophagy, an inner cellular mechanism that cleanses cells from accumulated debris via lysosomal enzymes.  Mutant animals that are defective for autophagy are short-lived.  Autophagy is increased by genetic or molecular manipulation, such as creating a variant of laboratory mice that over-produce Sirtuin1 survival gene protein; or inhibit p53 gene protein; or by provision of an autoimmune suppressing drug, rapamycin; or the red wine molecule resveratrol (both known as anti-aging agents); or by provision of spermidine, a primary polyamine.

Via autophagy polyamines like spermidine extend the lifespan of yeast cells, roundworms, fruit flies and lab mice, all living organisms used in longevity experiments.  Deprivation of spermidine does the opposite: promotes aging. [Acta Pharmacology Sinica 2013]

While it is said there are no human studies involving spermidine, centenarians are known to exhibit healthy levels of polyamines such as spermidine. [Rejuventation Research 2012]

Sudden public attention

Why spermidine is just now making news headlines goes unexplained.

Spermidine’s biological properties are profound.

Spermidine levels are always higher during childhood growth than in adulthood. [Journal Endocrinological Investigation 1982]  The question arises: since this has been known since 1982 (see date of above reference), why haven dietitians been remiss in suggesting spermidine-rich foods or dietary supplements for children and adults?

Drugs or supplements?

While some news sources said wait till synthetic anti-aging drugs are developed that mimic spermidine, other news sources pointed to longevity diets and dietary supplements that are already widely available. [Express UK; Medical Daily]

Polyamines are richly provided in foods such as wheat germ, green pepper, black rice, rice bran, soybeans, oranges, mushrooms and green tea. [Journal Biochemistry 2006]

News reporters chose blue cheese and peas as rich natural sources of spermidine but they are pale sources of spermidine compared to wheat germ.  [Food World News] Wheat germ provides almost 7 times as much spermidine as rice bran, 14 times as much as peas and twice as much as soybeans, all considered rich natural sources of spermidine.

Content of Spermidine in Foods
Food source Polyamine content
(nanomole per gram)
Wheat germ 2440
Soybeans 1090
Rice bran 355
Green tea (leaf) 296
Blue cheese 262
Mango 199
Peas 173
Source: Journal Biochemistry, Volume 139, page 81-90, 2006

Researchers withhold recommendation to supplement the diet with polyamines such as spermidine but they are a ubiquitous component of all diets and supplementation has extended the lifespan of all animals tested. [Cell Metabolism 2015]

A precaution

Because polyamines are required for cellular growth, hence they are widely available in foods, yet in the instance of cancer, high concentrations of polyamines should probably be avoided if there are existing tumors. [World Journal Gastroenterology 2014]  There is no evidence that polyamines promote the development of cancer, but they may promote the growth of an existing tumor just as B vitamins do. [PLoS One 2011]  Polyamines are provided in a wide variety of foods and cannot be entirely eliminated from the diet and are necessary for health.

Spermidine versus resveratrol

Both resveratrol and spermidine activate autophagy. [Journal Cellular Biology 2011]

Polyamines operate in a manner that differs from that of resveratrol. [PLoS One 2011]

Specifically spermidine promotes autophagy by different mechanisms than resveratrol. [Aging 2009]

Spermidine and eye health

Spermidine has been used experimentally to demonstrate its profound effect in promoting health of organs distant from the gut, such as the human eye.

Spermidine promotes the survival of cells in the optic nerve following injury. [Cell Death Disease 2015]  Spermidine may have application in the treatment of glaucoma. [Investigative Ophthalmology Visual Science 2015]  Polyamines like spermidine prevent death of retinal nerve cells. [Journal Neurochemistry2007]  Spermidine (but not its precursor putrescine) protects a layer of cells in the human retina called the retinal pigment epithelium. [Investigative Ophthalmology Visual Science 2007]

However, since polyamines promote cell growth, they have been found to promote abnormal blood vessel growth in the retina and would not be recommended in cases of wet macular degeneration or diabetic retinopathy. [British Journal Ophthalmology 2003; Investigative Ophthalmology Visual Science2002]

Probiotics too

The human body internally produces polyamines.  Age-related reduction in polyamines in the intestines is associated with disruption of intestinal barriers.  Probiotics (Bifidobacterium animalis) are known to increase intestinal polyamine concentrations.

In the animal laboratory the provision of probiotics prolonged the lifespan of mice via reduction of low-grade inflammation made possible by an increase in polyamines. [PLoS One 2011]

The provision of probiotics (Bifidobacterium lactis) has actually been shown to reduce mutagenicity (unfavorable alteration of DNA) in healthy humans. [Mutation Research 2004]

The provision of supplemental selenium (as selenomethionine), a trace mineral, has also been demonstrated to increase polyamine synthesis in laboratory animals. [Amino Acids 2007]

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