Bendera R, Wilson L. The Regulatory Effect of Biogenic Polyamines Spermine and Spermidine in Men and Women. Open J Endocr Metab Dis. 2019;9:35-48. doi:10.4236/ojemd.2019.93004.
Publication Date: "March 2019"
Peer Reviewed: Yes
Study Design: "open-label pilot trial"
Methodology: Saliva samples were collected at baseline, after 30 days of supplementation, and 30 days post-supplementation; hormone levels were measured using salivary hormone assays; endpoints included hormone function changes and symptom assessments using modified Cornell and Kupperman indices
Sample Size: "A total of 15 participants"
Controls Used: "Each 96-well block of samples included two blanks and 11 other control samples."
Dose Used: "Two metered, sublingual doses of spermine and spermidine three times per day for 30 days."
Statistical Significance Declared: "Clinically significant reductions (p-value less than 0.05) in cortisol were seen in 30 days among 83% of male participants and 37% of female participants."
Adverse Events due to Spermidine Supplementation: "There were no adverse events reported or identified from the modified Cornell and Kupperman indices during the treatment phase of this trial or for 30 days post treatment."
Conflict of Interest: "The authors declare no conflicts of interest regarding the publication of this paper."

Madeo F, Eisenberg T, Pietrocola F, Kroemer G. Spermidine in health and disease. Science. 2018;359(6374):eaan2788. doi:10.1126/science.aan2788

Publication Date: "26 Jan 2018"

Peer Reviewed: Yes

Study Design: "Structured Abstract"

Methodology: Conceptual review of spermidine's roles in anti-aging and disease prevention through analysis of existing literature and studies.

Sample Size: Not applicable (review article).

Controls Used: Not applicable (review article).

Dose Used: Not specified in direct quotes within a review article.

Statistical Significance Declared: Not applicable (review article).

Adverse Events due to Spermidine Supplementation: No adverse events related to spermidine supplementation. However, they do state that “Possible contraindications of spermidine administration such as advanced cancer and renal failure have to be defined.”

Conflict of Interest: "F.M., T.E., and G.K. are inventors on a patent application (WO2010081204 A3) submitted by Katholieke Universiteit Leuven that covers the use of spermidine for life-span extension. F.P. and G.K. are inventors on a patent application (WO2015049365 A3) submitted by INSERM (Institut National de la Santé et de la Recherche Médicale), Assistance Publique-Hôpitaux De Paris (APHP), Université Paris Descartes, Université Pierre et Marie Curie (Paris 6), Université Paris Diderot–Paris 7, Université Paris–Sud, Institut Gustave Roussy, that covers the medical use of CRMs."

Yamamoto T, Hinoi E, Fujita H, Iezaki T, Takahata Y, Takamori M, Yoneda Y. The natural polyamines spermidine and spermine prevent bone loss through preferential disruption of osteoclastic activation in ovariectomized mice. Br J Pharmacol. 2012 Jan 17;165(2):469-79. doi: 10.1111/j.1476-5381.2012.01856.x.
Publication Date: "First published: 17 January 2012"
Peer Reviewed: Yes
Study Design: "In this study, we evaluated the pharmacological properties of several natural polyamines on the functionality and integrity of bone in both in vitro and in vivo experiments."
Methodology: Mice subjected to OVX and given oral supplementation of spermidine or spermine. Pre-osteoclasts cultured with RANKL with or without spermidine or spermine. Various assays and histomorphometric analyses performed.
Sample Size: "56 mice were used in this study."
Controls Used: "OVX or sham operation under aseptic environments."
Dose Used: "0.3 or 3 mM every day."
Statistical Significance Declared: "*P < 0.05, **P < 0.01, significantly different from each control value obtained in sham-operated mice."
"#P < 0.05, ##P < 0.01, significantly different from the value obtained in ovariectomized mice."
Adverse Events due to Spermidine Supplementation: Not specifically mentioned.
Conflict of Interest: "No authors have any conflict of interest."

Verri Hernandes V, Dordevic N, Hantikainen EM, Sigurdsson BB, Smárason SV, Garcia-Larsen V, Gögele M, Caprioli G, Bozzolan I, Pramstaller PP, et al. Age, Sex, Body Mass Index, Diet and Menopause Related Metabolites in a Large Homogeneous Alpine Cohort. Metabolites. 2022; 12(3):205. https://doi.org/10.3390/metabo12030205
Publication Date: "24 February 2022"
Peer Reviewed: Yes
Study Design: "A single-site population-based study with a longitudinal lookout"
Methodology: "Linear regression models were fitted separately for each metabolite using its concentration as response variable and sex, age, fasting status and BMI as covariates"
Sample Size: "6872 study participants"
Controls Used: "Quality control (QC) samples: Biocrates p180_QC1 and p180_QC2, an aliquot of the SRM 1950 (Metabolites in Frozen Human Plasma) from NIST (QC NIST STD) as well as an aliquot of the pool of all serum samples of the study (QC CHRIS Pool)"
Dose Used: Not specified.
Statistical Significance Declared: "p-values from all analyses were adjusted for multiple testing using the Bonferroni correction method. Metabolites with an adjusted p-value smaller than 0.05 were considered significant"
Adverse Events due to Spermidine Supplementation: Not explicitly mentioned.
Conflict of Interest: "The authors declare no conflict of interest"

Byun JA, Choi MH, Moon MH, Kong G, Chung BC. Serum polyamines in pre- and post-operative patients with breast cancer corrected by menopausal status. Cancer Lett. 2009;273(2):300-304. doi:10.1016/j.canlet.2008.08.024
Publication Date: "Available online 20 September 2008."
Peer Reviewed: Yes
Study Design: "Evaluation of serum polyamine levels along with operative conditions in both pre- and post-menopausal BCa patients compared to healthy subjects using a validated liquid chromatography–tandem mass spectrometry (LC–MS/MS)."
Methodology: Serum polyamine levels measured by liquid chromatography–mass spectrometry (LC-MS/MS) in breast cancer patients (pre- and post-menopausal) and compared to healthy controls.
Sample Size: "Pre-menopause: 45.6 ± 0.8 years old, n = 58; post-menopause: 55.2 ± 1.1 years old; n = 11", "normal controls (pre-menopause: ages 43.6 ± 0.9 years, n = 45, post-menopause: ages 55.2 ± 1.0 years, n = 18)."
Controls Used: "Age-matched normal controls."
Dose Used: Not applicable (observational study).
Statistical Significance Declared: "1,3-Dap, N-actPut, N-actSpd, and Sp were significantly higher (p < 0.05) in pre-surgery BCa patients than in the controls; N-actPut (p < 0.0005) and Sp (p < 0.005) levels markedly increased."
Adverse Events due to Spermidine Supplementation: Not applicable (observational study).
Conflict of Interest: "All authors does not conflicts of interest."

Yamada T, Park G, Node J, et al. Daily intake of polyamine-rich Saccharomyces cerevisiae S631 prevents osteoclastic activation and bone loss in ovariectomized mice. Food Sci Biotechnol. 2019;28:1241–1245. doi:10.1007/s10068-019-00561-4
Publication Date: "Published: 06 February 2019"
Peer Reviewed: Yes
Study Design: "Ovariectomy-induced mouse model of postmenopausal osteoporosis"
Methodology: UV exposure to isolate yeast strain, oral supplementation to mice, diet intake, water intake, body weight measured, histomorphometric analyses of vertebrae.
Sample Size: "Eight-week-old female ddY mice (n=10)"
Controls Used: "Sham-operated mice"
Dose Used: "5% S. cerevisiae S631 with high concentration of polyamines" and "17β-estradiol (βE2), 5 μg/kg"
Statistical Significance Declared: "p < 0.01" for diet intake, water intake, body weight, BV/TV ratio, Oc.S/BS, BFR
Adverse Events due to Spermidine Supplementation: None declared.
Conflict of Interest: "Junichi Node and Shigeru Hiramoto are employees of Nisshin Pharma Inc. All other authors state that they have no conflicts of interest."

Jimenez Gutierrez GE, Borbolla Jiménez FV, Muñoz LG, Tapia Guerrero YS, Murillo Melo NM, Cristóbal-Luna JM, Leyva Garcia N, Cordero-Martínez J, Magaña JJ. The molecular role of polyamines in age-related diseases: an update. Int J Mol Sci. 2023;24(22):16469. doi:10.3390/ijms242216469.
Publication Date: "Published version of the manuscript"
Peer Reviewed: Yes
Study Design: "review"
Methodology: Literature review of existing studies on polyamines and their effects on aging and related diseases.
Sample Size: Not applicable (review study).
Controls Used: Not applicable (review study).
Dose Used: Not specified in the review.
Statistical Significance Declared: Not specified in the review.
Adverse Events due to Spermidine Supplementation: Not specified in the review.
Conflict of Interest: "The authors declare no conflict of interest."

Kaorop W, Maneechote C, Kumfu S, Chattipakorn S, Chattipakorn N. Spermidine provides cardioprotection in rats with estrogen deprivation through improving cardiometabolic and mitochondrial functions. J Am Coll Cardiol. 2023;81(8 Suppl):1701. doi:10.1016/S0735-1097(23)02145-9.
Publication Date: "March 7, 2023"
Peer Reviewed: Yes
Study Design: "Poster Contributions"
Methodology: Female Wistar rats were divided into groups; ovariectomy was performed; treated with vehicle, spermidine, or estradiol; measurements taken after 8 weeks.
Sample Size: "sham group (n=5) and the estrogen-deprived group (n=15)"
Controls Used: "sham group"
Dose Used: "spermidine (20 mg/kg/day, p.o.)"
Statistical Significance Declared: "* P<0.05 vs. SV" and "† P<0.05 vs. OV"
Adverse Events due to Spermidine Supplementation:: Not specified.
Conflict of Interest: Not specified in the text

Fahrmann, J. F., Vykoukal, J., Fleury, A., Tripathi, S., Dennison, J. B., Murage, E., Wang, P., Yu, C.-Y., Capello, M., Creighton, C. J., Do, K.-A., Long, J. P., Irajizad, E., Peterson, C., Katayama, H., Disis, M. L., Arun, B., & Hanash, S. (2020). Association Between Plasma Diacetylspermine and Tumor Spermine Synthase With Outcome in Triple-Negative Breast Cancer. JNCI: Journal of the National Cancer Institute, 112(6), 607–616. https://doi.org/10.1093/jnci/djz182
Publication Date: "Published: 10 September 2019"
Peer Reviewed: Yes
Study Design: "case-control cohort"
Methodology: "Using liquid chromatography mass spectrometry, polyamine levels were determined in plasma samples from newly diagnosed patients with TNBC (n = 87) and cancer-free controls (n = 115). Findings were validated in plasma samples from an independent prospective cohort of 54 TNBC, 55 estrogen receptor negative (ER−) and progesterone receptor negative (PR−) and HER2 positive (HER2+), and 73 ER+ case patients, and 30 cancer-free control subjects. Gene expression data and clinical data for 921 and 2359 breast cancer tumors were obtained from The Cancer Genome Atlas repository and the Oncomine database, respectively."
Sample Size: "87 TNBC breast cancer cases and 115 cancer-free controls"
Controls Used: "cancer-free controls"
Dose Used: "48-hour treatment with vehicle, putrescine, spermidine, or spermine"
Statistical Significance Declared: "Statistical significance was determined by Wilcoxon rank-sum test P < .05 comparing IC50 values between TNBC and non-TNBC cell lines."
"Plasma DAS value ≥ 1.16, hazard ratio = 3.06, 95% confidence interval [CI] = 1.15 to 8.13, two-sided P = .03."
"top 25th percentile hazard ratio = 2.06, 95% CI = 1.04 to 4.08, one-sided P = .04"
Adverse Events due to Spermidine Supplementation: No adverse events declared.
Conflict of Interest: "The authors declare no conflicts of interest."

Jayachandran M, Kantarci K, Zuk SM, Senjem ML, Gunter JL, Jack CR, Miller VM. White matter hyperintensities and blood platelet reactivity in menopausal women. Alzheimer's Dement. 2014;10(Suppl). doi:10.1016/j.jalz.2014.05.727.

Publication Date: December 2019.

Peer Reviewed: Yes.

Study Design: "three years after they had participated in the Kronos Early Estrogen Prevention Study (KEEPS)"

Methodology: "Volumes of total white matter and WMH were quantified by a semi-automated segmentation algorithm based on fluid attenuated inversion recovery (FLAIR) MR images of the brain in healthy menopausal women (n=44). Platelet reactivity and microvesicle markers of intravascular cellular activation were measured using our established methodologies. Correlations between these markers and the log transformed percentage (WMH volumes/ white matter volume) of WMH were analyzed by multivariate linear regression."

Sample Size: "44"

Controls Used: Not explicitly stated.

Dose Used: Not applicable.

Statistical Significance Declared: "Statistical significance was accepted at P<0.05. WMH load significantly and positively correlated with three measures of platelet activation and cell-cell interactions: the percentage of platelet micro-aggregates in the blood (r=0.31, P=0.0403); platelet dense granule secretion of adenosine triphosphate to thrombin receptor agonist peptide (r=0.41, P=0.0055); and percentage of microvesicles derived from leukocytes (r=0.31, P=0.0397). In contrast, percentage of platelets positive for lymphocyte antigen (CD3, indirect measure of platelet-lymphocyte interaction) was negatively (r=-0.40, P=0.0081) correlated with WMH."

Adverse Events: Not explicitly stated.

Conflict of Interest: Not explicitly stated.

Liu Y, Han Y, Cao L, Wang X, Dou S. Analysis of Main Components and Prospects of Natto. Advances in Enzyme Research. 2021;9:1-9. doi:10.4236/aer.2021.91001.
Publication Date: "2021"
Peer Reviewed: Yes
Study Design: "Review"
Methodology: Analysis and review of existing literature on natto components and their effects on health.
Sample Size: Not applicable (review study).
Controls Used: Not applicable (review study).
Dose Used: Not specified.
Statistical Significance Declared: Not specified.
Adverse Events due to Spermidine Supplementation: Not Specified.
Conflict of Interest: Not specified.

Pavlovska O, Savelyeva O, Pavlovska K. Genitourinary syndrome of menopause and intestinal microbiota. Menopause Review/Przegląd Menopauzalny. 2023;22(4):213-219. doi:10.5114/pm.2023.133828.
Publication Date: "Published online 2023 Dec 18."
Peer Reviewed: Yes
Study Design: comparative observational study.
Methodology: Examination of 65 middle-aged women, divided into two groups, underwent general clinical studies and bacteriological examination of faeces to assess the intestinal microbiota.
Sample Size: "65 middle-aged women"
Controls Used: "Group II included 26 patients who did not have clinical manifestations of GSM."
Dose Used: Not specified in the document.
Statistical Significance Declared: "pIa-II < 0.01," "pIb-II < 0.01," "pIa-II = 0.018," "pIb-II = 0.004," "pIa-II = 0.028," "pIb-II = 0.018," "pIb-II = 0.002," "pIb-II < 0.001," "pIa-II < 0.001."
Adverse Events due to Spermidine Supplementation: No adverse events directly linked to Spermidine supplementation stated.
Conflict of Interest: "The authors report no conflict of interest."

Huynh K. Cardioprotective benefits of dietary spermidine. Nat Rev Cardiol. 2017;14(2):65. doi:10.1038/nrcardio.2016.222.
Publication Date: "17 January 2017"
Peer Reviewed: Yes
Study Design: "prospective, population-based patient cohort study"
Methodology: Oral supplementation of spermidine in mice and rats; transcriptome and proteome analyses; measurement of autophagic flux; comparison with Atg5−/− mice; prospective cohort study in humans.
Sample Size: Not specified
Controls Used: "control mice that received normal drinking water"
Dose Used: "lifelong access to drinking water supplemented with spermidine"
Statistical Significance Declared: Not specified
Adverse Events due to Spermidine Supplementation: "Spermidine-treated Atg5−/− mice also had impaired diastolic and systolic function." (These effects are specific to mice with a cardiomyocyte-specific autophagy defect)
Conflict of Interest: Not specified

Madeo F, Hofer SJ, Pendl T, Bauer MA, Eisenberg T, Carmona-Gutierrez D, Kroemer G. Nutritional Aspects of Spermidine. Ann Rev Nutr. 2020;40:135-159. doi:10.1146/annurev-nutr-120419-015419Publication Date: "Volume publication date August 2020"Peer Reviewed: YesStudy Design: "The prospective Bruneck Study" and "a second, independent cohort in the SAPHIR Study"Methodology: Dietary assessments using scientifically validated FFQs, repeated over 20 years; analysis of dietary intake and mortality correlations; preclinical and clinical trials.Sample Size: "829 participants" in the Bruneck Study; "1,770 healthy unrelated participants" in the SAPHIR StudyControls Used: Placebo groups in clinical trialsDose Used: "Approximately 10 mg of spermidine per day" based on dietary intake estimatesStatistical Significance Declared: "Weakly, but significantly, correlate with improved cognitive performance" and other various correlations with health benefitsAdverse Events due to Spermidine Supplementation: No adverse events directly linked to spermidine supplementation.Conflict of Interest: "D.C.-G., G.K., and F.M. are the scientific cofounders of Samsara Therapeutics...T.P. has equity interests in Samsara Therapeutics...F.M. and D.C.-G. have equity interests in The Longevity Labs (TLL)...T.E. has equity interests in and conducts paid consultancies for TLL...G.K. holds research contracts with Bayer Healthcare, Genentech, GlaxoSmithKline, Institut Mérieux, Kaleido Biosciences, Lytix Biopharma, NuCana, Oncolinx, PharmaMar, Samsara Therapeutics, SOTIO, and Tioma Therapeutics...G.K. is on the Board of Directors of the Bristol Myers Squibb Foundation France...G.K. is a scientific cofounder of everImmune and Therafast Bio."