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Associations Between 146 Nutrients and All-cause Mortality

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I thought this was really informative for those trying to maximize healthspan and lifespan.

If you go to this paper:

"Spermidine: A physiological autophagy inducer acting as an anti-aging vitamin in humans?" by Madeo, et.al.


and look up the supplemental tables (you can download them if you are interested).

"Supplemental Figure 4. Associations between 146 Nutrients and All-cause Mortality. P values were derived from Cox models with adjustment for age, sex, and the ‘caloric ratio’ and are based on 2540 diet records assessed in 829 participants. Spermidine was the nutrient most significantly associated with the risk of death. Nutrients are displayed as hollow circles (inverse association) or as solid black circles (direct association)"

I attahced the Table showing that the #1 Nutrient directly associated with risk of Death was Spermidine, Followed by Manganese and #3 was Folate.

Nutrients and ACM.png


Some (vegan) foods high in Spermidine include Spinach, Apples, Pears, Mangos, Bananas, Green Peas, Broccoli, Cauliflower, Mushrooms, Potatoes, Carrots and there are many others listed therein.

Edited by Clinton
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I have actually been wondering about my Manganese intake, which hovers around 400% of RDA (mostly from berries, pulses and grains).

Folate is about 140% of RDA from food sources Actually, depending on how much folate there is in my home-made water kefir, it might be considerably higher, as I drink about a liter and a half daily (crazy, I know :).

Haven't been paying attention to Spermidine since Cronometer doesn't cover it, but assume my intake is adequate.

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Spermidine is the only thing (afaik) that can upregulate  autophagy outside decreasing mTor.

And everything with the ability to increase lifespan also seems to increase autophagy... so spermidine might be one of the very few things worth ensuring you get plenty of- I don’t believe it’s available in supplemental form.

It occurs naturally in the body but decreases with age.

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This looks like a good  review. Lots of info in the full text.

Polyamines in Food (2019)



The polyamines spermine, spermidine, and putrescine are involved in various biological processes, notably in cell proliferation and differentiation, and also have antioxidant properties. Dietary polyamines have important implications in human health, mainly in the intestinal maturation and in the differentiation and development of immune system. The antioxidant and anti-inflammatory effect of polyamine can also play an important role in the prevention of chronic diseases such as cardiovascular diseases. In addition to endogenous synthesis, food is an important source of polyamines. Although there are no recommendations for polyamine daily intake, it is known that in stages of rapid cell growth (i.e., in the neonatal period), polyamine requirements are high.

Additionally, de novo synthesis of polyamines tends to decrease with age, which is why their dietary sources acquire a greater importance in an aging population. Polyamine daily intake differs among to the available estimations, probably due to different dietary patterns and methodologies of data collection. Polyamines can be found in all types of foods in a wide range of concentrations. Spermidine and spermine are naturally present in food whereas putrescine could also have a microbial origin. The main polyamine in plant-based products is spermidine, whereas spermine content is generally higher in animal-derived foods.

This article reviews the main implications of polyamines for human health, as well as their content in food and breast milk and infant formula. In addition, the estimated levels of polyamines intake in different populations are provided.


It's interesting to take a closer look at the de novo synthesis of polyamines and the role of gut microbiata:


The de novo synthesis of polyamines in the organism begins with the formation of putrescine from the amino acid ornithine, catalyzed by the enzyme ornithine decarboxylase (ODC) (Figure 2). Putrescine is converted to spermidine by spermidine synthase through the addition of a propylamine group derived from the decarboxylation of S-adenosyl-methionine. Subsequently, spermidine is transformed into spermine by spermine synthase, which adds a second propylamine group (2, 4, 7, 12, 17).




The interconversion of polyamines is a cyclic process that controls their turnover and regulates intracellular homeostasis (Figure 2). This process begins with the acetylation of any of the three polyamines, which is catalyzed by an N-acetyl-transferase enzyme with the participation of acetyl coenzyme-A. Subsequently, the enzyme polyamine oxidase (PAO) removes a propylamine group, and putrescine is obtained from the acetylated metabolite of spermidine, or spermidine from the acetylated metabolite of spermine (2, 10, 12, 17, 18).

The elimination of polyamines from the organism is carried out by the oxidative deamination of a primary amino group, mainly by the action of diamine oxidase (DAO) and PAO. Both enzymes can act on polyamines and their acetylated derivatives (2, 4, 7, 10, 17).

Besides endogenous synthesis, polyamines also have an exogenous origin, mainly food and breast milk (2).

In addition, gut microbiota is also described as a source of polyamines, mainly forming in the large intestine (2, 19, 20). Some recent studies have been linked different intestinal microbial species with the synthesis of these compounds (20). However, more information is still needed on the capability to form polyamines of the gut microbiota and the corresponding biosynthetic pathways. Finally, intestinal and pancreatic secretions and catabolism products of intestinal cells also contribute to the polyamines in the gut (2). Polyamines are absorbed in the duodenum and in the first portion of the jejunum by various mechanisms, including transcellular (through passive diffusion and transporters) and paracellular pathways (2, 4, 21). Polyamines are partly metabolized in the intestinal wall before reaching the blood circulation, and those that pass into the circulation are distributed throughout the organism and captured by the tissues, where they can undergo interconversion reactions.


Endothelial Function is improved by Inducing Microbial Polyamine Production in the Gut (2019)



We investigated the effect of consuming yogurt containing B. animalis subsp. lactis and Arg on endothelial function in healthy adults. Endothelial dysfunction increases the risk of developing cardiovascular disease [37]. Key RHI values <1.67 indicate endothelial dysfunction [22,23]. Here, the RHI increased from 1.50 to 1.81 after Bifal + Arg YG consumption, suggesting that Bifal + Arg YG intake restored endothelial function to normal levels. Moreover, blood pressure and cardiovascular disease are closely related, with systolic and diastolic blood pressure higher than 115 mmHg and 75 mmHg, respectively, being associated with an increased risk of disease development [38]. In the Bifal + Arg YG group, blood pressure decreased to near the baseline level, suggesting that the consumption of this yogurt improved blood pressure. Endothelial function and blood pressure strongly influence each other, and both deteriorate during atherosclerosis progression [39]. Therefore, simultaneous improvement in both parameters is not surprising and indicates that Bifal + Arg YG intake might help prevent the early process of atherosclerosis development. However, the observed changes in blood pressure could also be related to changes in smooth muscle cell reactivity and arterial compliance; further studies are needed to clarify this effect.

Colonic cells can absorb putrescine [40], which is utilized for spermidine and spermine biosynthesis [41]. Previously, we demonstrated that oral Arg administration in rats increased both fecal putrescine and blood spermidine concentration [15]. Moreover, various physiological activities of polyamines depend on the magnitude of their polarity [42]. Thus, although considerably substantial changes in spermidine and spermine levels induce autophagy, minor changes in putrescine levels do not [43,44]. Therefore, the improvement in endothelial function might be mediated by a putrescine-induced increase in serum spermidine biosynthesis. Blood spermidine-induced autophagy might be involved in both blood pressure reduction [5] and endothelial function improvement in mice [45], supporting our results.

Thus, Bifal + Arg YG intake may induce microbial putrescine production, which is absorbed from the intestinal lumen and transported into the blood. Consequently, spermidine is biosynthesized, which promotes autophagy in endothelial cells, thereby improving endothelial function. [ETC.]




Consuming yogurt containing B. animalis subsp. lactis and Arg may prevent or reduce the risk of atherosclerosis by upregulating blood spermidine levels, which subsequently induces autophagy. This is an innovative approach for the production of a desired bioactive metabolite derived from the gut microbiome to enhance endothelial function in humans.


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On 8/5/2018 at 2:10 AM, Todd Allen said:

I've been under the impression that cultured foods are generally very healthy.   However, I never looked deeply into the subject.  I've started reading about the polyamines often found in high quantities in these foods and they are a mixed bag.  Some such as spermidine are considered CR mimetics with nearly reserveratrol levels of hype and others such as putrescine are subjects of Dr. Greger scare videos.  https://www.crsociety.org/topic/16861-cultured-foods-elixirs-or-poisons/?tab=comments#comment-29531


Here's an example of a Greger "scare video":  Carcinogenic Putrescine

Greger cites a study that finds that putrescine may have carcinogenic effects,  and that, he claims,  the highest levels of putrescine are found in   canned tuna and sardines.  [He doesn't mention the very high putrescine levels found in fermented soy in the study, or the fact that citrus fruits (oranges, grapefruits/ juices) have very high levels as well.]

Anyway,  from the study he cites: Toxicological Effects of Dietary Biogenic Amines


[...]Although   non-direct   toxic   effects   have   been   described   for   putrescine   and   other   polyamines, their role in the regulation of cell growth, proliferation and the maturation of the GIT [14, 78] means the amounts present in the latter need be tightly regulated; a disturbed equilibrium could lead to the dysregulation of certain physiological functions (Table  1).  Polyamines  and  their  metabolising  enzymes  are  tightly  linked  to  the  proliferation  of  neoplasms  in  the  GIT,  and  there  is  increasing  evidence  that  putrescine  and spermidine have a role in promoting the malignant transformation of cells [78, 79]. Among the several biochemical alterations seen in such cells, one of the most consistent is  the  change  in  the  intracellular  polyamine  content.  Colorectal  cancer  cells  have  a  higher  polyamine  content  than  the  adjacent  mucosa  or  equivalent  normal  tissue  [80],  highlighting the possible importance of exogenous putrescine in their development [79].

Further, the transport of putrescine from the intestine to the blood is enhanced by high concentrations  of  the  same  [81].  In  fact,  it  is  recommended  that  the  dietary  intake  of  putrescine  be  reduced  in  patients  with  familial  adenomatous  polyposis;  in  a  murine  model  dietary  putrescine  increased  the  malignancy  grade  of  adenomas  [82]. 

Elevated  concentrations  of  putrescine  have  also  been  detected  in  gastric  carcinomas  caused  by  Helicobacter   pylori.   Putrescine   levels   are   restored   if   the   microbial   infection   is   eliminated [83]. Putrescine  can  also  interact  with  certain  pathogenic  microorganisms  since  it  is  an  essential component in their outer structure, and has been reported related to virulence factors   in   many   Gram   positive   and   Gram   negative   pathogens   [83].  

Exogenous   putrescine  can  activate  the  swarming  phenotype  needed  for  pathogenesis  in  some  Proteus mirabilis mutants [84]. 

Apart  from  a  direct  effect  in  promoting  the  transformation  of  cells,  histamine  and  polyamines  subjected  to  heat  can  give  rise  to  secondary  amines  that  can  combine  with  nitrites,  their  salts  generating  nitrosamines  of  known  carcinogenic,  mutagenic  and  teratogenic  activity  [85,  86].  This  is  of  particular  importance  in  some  fermented  meat  products to which nitrates and nitrites are added as preservative.

That study cites this article:

Polyamines and Cancer: Old Molecules, New Understanding (2004)



Polyamines are naturally occurring organic cations found in plants, animals andmicrobes. They are formed by the enzymatic decarboxylation of the amino acidsornithine or arginine.

Ornithine decarboxylase (ODC) is the first enzyme in the polyamine synthesis pathway in mammals and is the target for difluoromethylornithine (DFMO), a substrate analogue and specific inhibitor that irreversibly inactivates ODC when it binds to the active site ofthe enzyme.

ODCand several other polyamine metabolic proteins are essential for normal cell andtissue functions, including growth, development and tissue repair. ODC and polyamine content are increased in many cancers arising from epithelial tissues, suchas the skin and colon.

Polyamines exert their effects in eukaryotic cells in part by regulating specific gene expression.

In murine and human colonic mucosal tissue, ODC is negatively regulated by the adenomatous polyposis coli (APC) tumour-suppressor gene.APCis mutated ordeleted in the germline of people with familial adenomatous polyposis (FAP), a geneticsyndrome associated with a high risk of colon cancer.APCis also mutated or deleted insomatic colon epithelial cells in most sporadic, or non-genetic, forms of colon cancer.

Loss of APC function causes an increase in ODC activity and polyaminebiosynthesis, and tumour formation in ApcMin/+mice, a murine model of human FAP.Treatment ofApcMin/+mice with DFMO suppresses intestinal tumour formation.

Several non-steroidal anti-inflammatory drugs (NSAIDs), the use of which isassociated with decreased risk of epithelial cancers, activate the transcription ofspermidine/spermine N1-acetyltransferase, the first enzyme in the polyamine catabolicpathway. Experimental studies indicate that combinations of DFMO and NSAIDs arepotent inhibitors of colon and intestinal cancer development in murine models.

Clinical studies have shown that DFMO is well tolerated and can prevent thedevelopment of precancerous lesions in the skin. Several large randomized trialsinvolving the skin, colon and other organ sites are underway.


A more recent paper:

Amino acids in cancer (2020)



[...]Amino acid catabolism produces metabolic inter-mediates affecting tumor cell growth and survival. Polyamines (putrescine, spermine, and spermidine) might be the best-known metabolites to promote tumor proliferation and aggressiveness 65. Polyamine synthesis starts from arginine conversion to ornithine through the action of arginase, which is then decarboxylated by the rate-limiting step enzyme, ornithine decarboxylase (ODC), to produce putrescine (Fig.2b).  Decarboxylated S-adenosylmethionine, catalyzed by S-adenosylmethionine decarboxylase(AMD)66, then donates its propyl amine moiety to putrescine and spermidine for the formation of spermidine and spermine, respectively (Fig.2b)67.

Elevated polyamine levels have been observed in patients with cancer. Polyamines and their metabolites in urine andplasma can be useful in both cancer diagnosis and asmarkers of tumor progression in lung and liver can-cers68,69. Polyamines affect numerous processes in tumorigenesis, in part by regulating specific gene expression transcriptionally. As charged cations at physiological pH, polyamines can associate with nucleicacids, which in turn can affect global chromatin structure as well as specific DNAprotein interactions, leading to impacts on gene transcription. Post transcriptional aspects of polyamine-mediated gene regulation are associated with the eukaryotic translation initiation factor5A (eIF5A), whose expression/function is strongly correlated with unfavorable prognostic implications for severalcancers7375. The spermidine-derived amino acid hypu-sine, a unique eIF5A post translational modification of lysine residue 50, is essential for eIF5A functions.Polyamines also exist as a polyamine-RNA complex. Polyamine binding to RNA leads to structural changes,which stimulate and increase the effiency of protein synthesis


However, this study makes a critical point:

Dietary polyamine intake and colorectal cancer risk in postmenopausal women (2015)



To our knowledge, this is the first study of the association between dietary polyamines and risk of CRC and CRC-specific mortality in a large, average-risk population of postmenopausal women. Contrary to our a priori hypothesis, we observed no significant dose-response relation between dietary polyamines and risk of CRC or CRC-specific mortality in fully adjusted models. Before full adjustment, total polyamine intake ≥179.67 μmol/d (quintiles 2–5) was consistently associated with 9–20% decreased risk of CRC. After adjustment for dietary covariates, these associations were not always significant, although point estimates were consistent across all models and quintiles. These dietary covariates included dietary folate equivalents and fiber, whose food sources strongly overlapped with those of polyamines and may have resulted in overadjustment of the model. Overall, our data suggest modest, nonsignificant decreased risk of CRC in individuals with average-to-high polyamine intakes or, conversely, modest increased risk of individuals with very-low polyamine intakes.

Our findings are supported by animal and human studies that suggested effects of dietary polyamines are dependent on background risk of CRC. Similar to previous dietary polyamine studies (4, 18), we showed that citrus fruits are the largest contributor of polyamines to the diet of postmenopausal US women. In ecological studies, the Mediterranean diet, which includes high citrus fruit intake, is associated with protection against the development of diseases including CRC (55).

In experimental animal models, high-polyamine diets delayed aging (56), and putrescine was shown to mediate the effect of probiotics on longevity in mice through direct inhibitory effects on colonic cell senescence (17, 53). In contrast, low-polyamine diets were shown to delay wound healing (57) and inhibit growth (13). In humans at high risk of CRC (adenomatous polyp formers), we previously showed that dietary polyamines increased risk of adenomatous polyp recurrence (4). Similarly, mice initiated with a chemical colorectal carcinogen showed an increase in the severity of premalignant colorectal aberrant crypt foci and adenomatous polyps when exposed to a high-polyamine diet (45, 46, 56). However, these carcinogen-treated animals had fewer aberrant crypt foci in the intestinal tract when they kept receiving low-polyamine diets (13, 46), and a high-polyamine diet before carcinogen treatment decreases tumor incidence (56).

Overall, our observations are consistent with the notion suggested by the literature that the effect of dietary polyamines is to promote health in low-risk colorectums, and polyamines may promote carcinogenesis in colorectums that experienced an initiating event.


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  • 11 months later...
On 2/17/2021 at 5:41 PM, Clinton said:

The highest food source by far for spermidine is wheat germ.

Does anyone here consume wheat germ??

it’s very inexpensive and just 2TBSP per day would provide considerable spermidine.

Interesting. I personally try not to eat wheat often, because while I have never had any symptoms, I am genetically predisposed to Celiac disease.  It's probably not a real issue and I still eat bread, pasta or pizza occasionally, but on daily basis I make do with flax, chia and steel-cut oats.

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