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Spermidine: endogenous autophagy-bringer and longevity-inducer

Article
August 19, 2022
By
Olena Mokshyna, PhD.

Spermidine, found in blue and aged cheeses, mushrooms, legumes, and whole grains, is essential for tissue regeneration and cell growth, and proliferation.

Spermidine: endogenous autophagy-bringer and longevity-inducer

 

Compound description

 

Spermidine is a small positively charged polyamine compound synthesized within many living organisms and was initially isolated from semen. With age, the spermidine levels tend to drop (1). 

In diet, sources of spermidine include blue and aged cheeses, mushrooms, legumes, and whole grains (2). Depending on food choices, the average daily nutritional intake of spermidine varies from ~7 to 25 mg and more, with the highest amounts in the Mediterranean diet (3).

 

Properties

 

In the organism, spermidine, as well as other polyamines, is involved in several crucial cellular functions and helps maintain cell homeostasis (4). It is essential for tissue regeneration and cell growth, and proliferation. Through synchronizing an array of ATPase (adenosine triphosphatase, enzymes used by cells to harness energy), spermidine maintains the potential of cellular membranes and controls the intracellular pH (6). 

Spermidine attracts much interest due to being a natural autophagy-inducer shown to promote autophagy in yeast, flies, worms (7), and mammalian cell cultures (8). Autophagy is a natural self-degradation process employed by cells to clear the “debris” of dysfunctional proteins and organelles. In this regard, spermidine shares the effect of caloric restriction and can thus be considered caloric restriction mimetic (CRM). Cells treated with spermidine demonstrate changes in multiple proteins, pointing to the complex mechanism of its action (9). Not every detail of this complicated cross-talk has been yet studied, but several main pathways are known. Spermidine, similarly to some other CRMs, can inhibit mTOR (mammalian target of rapamycin) and activate AMPK (5’ adenosine monophosphate-activated protein kinase) (10). Both these processes may further facilitate autophagic response and have been extensively associated with longevity. Spermidine is also able to induce mitophagy through PINK1 (Parkin-signaling pathway, through which the mitochondrial quality control occurs) (11) and directly inhibit other autophagy-inducing proteins (12). Long-term effects of spermidine may also be explained by its impact on gene expression, particularly upregulation of the FOXO3 gene (forkhead box O3 gene, one of the so-called longevity genes) (13).

Other processes in which spermidine plays a role (14) include control of apoptosis (programmed cell death), tumor growth, immune and inflammation responses, neuromodulation, and neuroprotection.

 

Use as a supplement

The ability of spermidine to induce autophagy and act as CRM led to the intense focus on its potential anti-aging effect. Dietary supplementation of spermidine was shown to prolong life- and healthspan (7) in several animal models (including flies, yeast, and mice). Simultaneously, it was able to inhibit oxidative stress in aging mice and protect them from cardiovascular disease (15). Though a majority of literature is limited to the model organisms, a prospective population-based study (16) reported that high nutritional spermidine intake is connected to reduced overall, cancer-related, and cardiovascular mortality. Notably, the connection remained significant even after correcting for other factors, such as body mass index, physical activity, and socioeconomic status. Observational studies have shown that healthy nonagenarians and centenarians tend to maintain higher concentrations of whole-blood spermidine and spermine (17). Another study addressed a decrease in cognitive performance, one of the most prominent age-related conditions. Elevated spermidine intake was shown to increase cognitive function in mice and to correlate with cognitive performance in humans (18). Nevertheless, future research is needed to fully understand the mechanisms and establish an optimal regimen of spermidine supplementation. 

 

Dosage, recommendations, and side effects

 

Due to spermidine being an endogenous compound, it has a good safety profile with low toxicity and strong efficacy at even moderate concentrations. Life-long supplementation seems to have no adverse effects in mice (19), and a clinical trial in elderly humans showed no strong adverse effects after three months (20). Additionally, it was shown that a 2-months polyamine-rich diet was well-tolerated in human volunteers (21).

Nevertheless, spermidine should be used with caution with any existing health conditions and avoided by patients with advanced cancer (due to the possible tumorigenesis influence) and renal problems. If you have any doubts about this supplement, please consult your healthcare provider.

In our Marketplace, you can find spermidine from wheat germ from the DoNotAge vendor with a recommended dosage of 8 mg/serving (two capsules).

 

References

 

1.         Scalabrino G, Ferioli ME. Polyamines in mammalian ageing: An oncological problem, too? A review. Mech Ageing Dev. 1984 Aug;26(2–3):149–64.

2.         Atiya Ali M, Poortvliet E, Strömberg R, Yngve A. Polyamines in foods: development of a food database. Food Nutr Res. 2011 Jan;55(1):5572.

3.         Zoumas-Morse C, Rock CL, Quintana EL, Neuhouser ML, Gerner EW, Meyskens FL. Development of a Polyamine Database for Assessing Dietary Intake. J Am Diet Assoc. 2007 Jun;107(6):1024–7.

4.         Carvalho FB, Mello CF, Marisco PC, Tonello R, Girardi BA, Ferreira J, et al. Spermidine decreases Na+,K+-ATPase activity through NMDA receptor and protein kinase G activation in the hippocampus of rats. Eur J Pharmacol. 2012 Jun;684(1–3):79–86.

5.         Eisenberg T, Knauer H, Schauer A, Büttner S, Ruckenstuhl C, Carmona-Gutierrez D, et al. Induction of autophagy by spermidine promotes longevity. Nat Cell Biol. 2009 Nov;11(11):1305–14.

6.         Morselli E, Mariño G, Bennetzen MV, Eisenberg T, Megalou E, Schroeder S, et al. Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome. J Cell Biol. 2011 Feb 21;192(4):615–29.

7.         Bennetzen MV, Mariño G, Pultz D, Morselli E, Færgeman NJ, Kroemer G, et al. Phosphoproteomic analysis of cells treated with longevity-related autophagy inducers. Cell Cycle. 2012 May;11(9):1827–40.

8.       Mariño G, Pietrocola F, Eisenberg T, Kong Y, Malik SA, Andryushkova A, et al. Regulation of Autophagy by Cytosolic Acetyl-Coenzyme A. Mol Cell. 2014 Mar;53(5):710–25.

9.       Qi Y, Qiu Q, Gu X, Tian Y, Zhang Y. ATM mediates spermidine-induced mitophagy via PINK1 and Parkin regulation in human fibroblasts. Sci Rep. 2016 Jul;6(1):24700.

10.       Pietrocola F, Lachkar S, Enot DP, Niso-Santano M, Bravo-San Pedro JM, Sica V, et al. Spermidine induces autophagy by inhibiting the acetyltransferase EP300. Cell Death Differ. 2015 Mar;22(3):509–16.

11.       Chrisam M, Pirozzi M, Castagnaro S, Blaauw B, Polishchuck R, Cecconi F, et al. Reactivation of autophagy by spermidine ameliorates the myopathic defects of collagen VI-null mice. Autophagy. 2015 Dec 1;11(12):2142–52.

12.       Madeo F, Eisenberg T, Pietrocola F, Kroemer G. Spermidine in health and disease. Science. 2018 Jan 26;359(6374):eaan2788.

13.       Eisenberg T, Abdellatif M, Schroeder S, Primessnig U, Stekovic S, Pendl T, et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med. 2016 Dec;22(12):1428–38.

14.       Kiechl S, Pechlaner R, Willeit P, Notdurfter M, Paulweber B, Willeit K, et al. Higher spermidine intake is linked to lower mortality: a prospective population-based study. Am J Clin Nutr. 2018 Aug 1;108(2):371–80.

15.       Pucciarelli S, Moreschini B, Micozzi D, De Fronzo GS, Carpi FM, Polzonetti V, et al. Spermidine and Spermine Are Enriched in Whole Blood of Nona/Centenarians. Rejuvenation Res. 2012 Dec;15(6):590–5.

16.       Schroeder S, Hofer SJ, Zimmermann A, Pechlaner R, Dammbrueck C, Pendl T, et al. Dietary spermidine improves cognitive function. Cell Rep. 2021 Apr;35(2):108985.

17.       Kibe R, Kurihara S, Sakai Y, Suzuki H, Ooga T, Sawaki E, et al. Upregulation of colonic luminal polyamines produced by intestinal microbiota delays senescence in mice. Sci Rep. 2015 May;4(1):4548.

18.       Schwarz C, Stekovic S, Wirth M, Benson G, Royer P, Sigrist SJ, et al. Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline. Aging. 2018 Jan 8;10(1):19–33.

19.       Soda K, Kano Y, Sakuragi M, Takao K, Lefor A, Konishi F. Long-Term Oral Polyamine Intake Increases Blood Polyamine Concentrations. J Nutr Sci Vitaminol (Tokyo). 2009;55(4):361–6.

 

Spermidine: endogenous autophagy-bringer and longevity-inducer

 

Compound description

 

Spermidine is a small positively charged polyamine compound synthesized within many living organisms and was initially isolated from semen. With age, the spermidine levels tend to drop (1). 

In diet, sources of spermidine include blue and aged cheeses, mushrooms, legumes, and whole grains (2). Depending on food choices, the average daily nutritional intake of spermidine varies from ~7 to 25 mg and more, with the highest amounts in the Mediterranean diet (3).

 

Properties

 

In the organism, spermidine, as well as other polyamines, is involved in several crucial cellular functions and helps maintain cell homeostasis (4). It is essential for tissue regeneration and cell growth, and proliferation. Through synchronizing an array of ATPase (adenosine triphosphatase, enzymes used by cells to harness energy), spermidine maintains the potential of cellular membranes and controls the intracellular pH (6). 

Spermidine attracts much interest due to being a natural autophagy-inducer shown to promote autophagy in yeast, flies, worms (7), and mammalian cell cultures (8). Autophagy is a natural self-degradation process employed by cells to clear the “debris” of dysfunctional proteins and organelles. In this regard, spermidine shares the effect of caloric restriction and can thus be considered caloric restriction mimetic (CRM). Cells treated with spermidine demonstrate changes in multiple proteins, pointing to the complex mechanism of its action (9). Not every detail of this complicated cross-talk has been yet studied, but several main pathways are known. Spermidine, similarly to some other CRMs, can inhibit mTOR (mammalian target of rapamycin) and activate AMPK (5’ adenosine monophosphate-activated protein kinase) (10). Both these processes may further facilitate autophagic response and have been extensively associated with longevity. Spermidine is also able to induce mitophagy through PINK1 (Parkin-signaling pathway, through which the mitochondrial quality control occurs) (11) and directly inhibit other autophagy-inducing proteins (12). Long-term effects of spermidine may also be explained by its impact on gene expression, particularly upregulation of the FOXO3 gene (forkhead box O3 gene, one of the so-called longevity genes) (13).

Other processes in which spermidine plays a role (14) include control of apoptosis (programmed cell death), tumor growth, immune and inflammation responses, neuromodulation, and neuroprotection.

 

Use as a supplement

The ability of spermidine to induce autophagy and act as CRM led to the intense focus on its potential anti-aging effect. Dietary supplementation of spermidine was shown to prolong life- and healthspan (7) in several animal models (including flies, yeast, and mice). Simultaneously, it was able to inhibit oxidative stress in aging mice and protect them from cardiovascular disease (15). Though a majority of literature is limited to the model organisms, a prospective population-based study (16) reported that high nutritional spermidine intake is connected to reduced overall, cancer-related, and cardiovascular mortality. Notably, the connection remained significant even after correcting for other factors, such as body mass index, physical activity, and socioeconomic status. Observational studies have shown that healthy nonagenarians and centenarians tend to maintain higher concentrations of whole-blood spermidine and spermine (17). Another study addressed a decrease in cognitive performance, one of the most prominent age-related conditions. Elevated spermidine intake was shown to increase cognitive function in mice and to correlate with cognitive performance in humans (18). Nevertheless, future research is needed to fully understand the mechanisms and establish an optimal regimen of spermidine supplementation. 

 

Dosage, recommendations, and side effects

 

Due to spermidine being an endogenous compound, it has a good safety profile with low toxicity and strong efficacy at even moderate concentrations. Life-long supplementation seems to have no adverse effects in mice (19), and a clinical trial in elderly humans showed no strong adverse effects after three months (20). Additionally, it was shown that a 2-months polyamine-rich diet was well-tolerated in human volunteers (21).

Nevertheless, spermidine should be used with caution with any existing health conditions and avoided by patients with advanced cancer (due to the possible tumorigenesis influence) and renal problems. If you have any doubts about this supplement, please consult your healthcare provider.

In our Marketplace, you can find spermidine from wheat germ from the DoNotAge vendor with a recommended dosage of 8 mg/serving (two capsules).

 

References

 

1.         Scalabrino G, Ferioli ME. Polyamines in mammalian ageing: An oncological problem, too? A review. Mech Ageing Dev. 1984 Aug;26(2–3):149–64.

2.         Atiya Ali M, Poortvliet E, Strömberg R, Yngve A. Polyamines in foods: development of a food database. Food Nutr Res. 2011 Jan;55(1):5572.

3.         Zoumas-Morse C, Rock CL, Quintana EL, Neuhouser ML, Gerner EW, Meyskens FL. Development of a Polyamine Database for Assessing Dietary Intake. J Am Diet Assoc. 2007 Jun;107(6):1024–7.

4.         Carvalho FB, Mello CF, Marisco PC, Tonello R, Girardi BA, Ferreira J, et al. Spermidine decreases Na+,K+-ATPase activity through NMDA receptor and protein kinase G activation in the hippocampus of rats. Eur J Pharmacol. 2012 Jun;684(1–3):79–86.

5.         Eisenberg T, Knauer H, Schauer A, Büttner S, Ruckenstuhl C, Carmona-Gutierrez D, et al. Induction of autophagy by spermidine promotes longevity. Nat Cell Biol. 2009 Nov;11(11):1305–14.

6.         Morselli E, Mariño G, Bennetzen MV, Eisenberg T, Megalou E, Schroeder S, et al. Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome. J Cell Biol. 2011 Feb 21;192(4):615–29.

7.         Bennetzen MV, Mariño G, Pultz D, Morselli E, Færgeman NJ, Kroemer G, et al. Phosphoproteomic analysis of cells treated with longevity-related autophagy inducers. Cell Cycle. 2012 May;11(9):1827–40.

8.       Mariño G, Pietrocola F, Eisenberg T, Kong Y, Malik SA, Andryushkova A, et al. Regulation of Autophagy by Cytosolic Acetyl-Coenzyme A. Mol Cell. 2014 Mar;53(5):710–25.

9.       Qi Y, Qiu Q, Gu X, Tian Y, Zhang Y. ATM mediates spermidine-induced mitophagy via PINK1 and Parkin regulation in human fibroblasts. Sci Rep. 2016 Jul;6(1):24700.

10.       Pietrocola F, Lachkar S, Enot DP, Niso-Santano M, Bravo-San Pedro JM, Sica V, et al. Spermidine induces autophagy by inhibiting the acetyltransferase EP300. Cell Death Differ. 2015 Mar;22(3):509–16.

11.       Chrisam M, Pirozzi M, Castagnaro S, Blaauw B, Polishchuck R, Cecconi F, et al. Reactivation of autophagy by spermidine ameliorates the myopathic defects of collagen VI-null mice. Autophagy. 2015 Dec 1;11(12):2142–52.

12.       Madeo F, Eisenberg T, Pietrocola F, Kroemer G. Spermidine in health and disease. Science. 2018 Jan 26;359(6374):eaan2788.

13.       Eisenberg T, Abdellatif M, Schroeder S, Primessnig U, Stekovic S, Pendl T, et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med. 2016 Dec;22(12):1428–38.

14.       Kiechl S, Pechlaner R, Willeit P, Notdurfter M, Paulweber B, Willeit K, et al. Higher spermidine intake is linked to lower mortality: a prospective population-based study. Am J Clin Nutr. 2018 Aug 1;108(2):371–80.

15.       Pucciarelli S, Moreschini B, Micozzi D, De Fronzo GS, Carpi FM, Polzonetti V, et al. Spermidine and Spermine Are Enriched in Whole Blood of Nona/Centenarians. Rejuvenation Res. 2012 Dec;15(6):590–5.

16.       Schroeder S, Hofer SJ, Zimmermann A, Pechlaner R, Dammbrueck C, Pendl T, et al. Dietary spermidine improves cognitive function. Cell Rep. 2021 Apr;35(2):108985.

17.       Kibe R, Kurihara S, Sakai Y, Suzuki H, Ooga T, Sawaki E, et al. Upregulation of colonic luminal polyamines produced by intestinal microbiota delays senescence in mice. Sci Rep. 2015 May;4(1):4548.

18.       Schwarz C, Stekovic S, Wirth M, Benson G, Royer P, Sigrist SJ, et al. Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline. Aging. 2018 Jan 8;10(1):19–33.

19.       Soda K, Kano Y, Sakuragi M, Takao K, Lefor A, Konishi F. Long-Term Oral Polyamine Intake Increases Blood Polyamine Concentrations. J Nutr Sci Vitaminol (Tokyo). 2009;55(4):361–6.

 

Article reviewed by
Dr. Ana Baroni MD. Ph.D.
SCIENTIFIC & MEDICAL ADVISOR
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Dr. Ana Baroni MD. Ph.D.

Scientific & Medical Advisor
Quality Garant

Ana has over 20 years of consultancy experience in longevity, regenerative and precision medicine. She has a multifaceted understanding of genomics, molecular biology, clinical biochemistry, nutrition, aging markers, hormones and physical training. This background allows her to bridge the gap between longevity basic sciences and evidence-based real interventions, putting them into the clinic, to enhance the healthy aging of people. She is co-founder of Origen.life, and Longevityzone. Board member at Breath of Health, BioOx and American Board of Clinical Nutrition. She is Director of International Medical Education of the American College of Integrative Medicine, Professor in IL3 Master of Longevity at Barcelona University and Professor of Nutrigenomics in Nutrition Grade in UNIR University.

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