Supplementation of spermidine at 40 mg/day has minimal effects on circulating polyamines: An exploratory double-blind randomized controlled trial in older men

• Published in: Nutrition research (New York, N.Y.) Vol. 132; pp. 1 - 14
• Main Authors: Keohane, Patrick, Everett, Jeremy R., Pereira, Rui, Cook, Chad M., Blonquist, Traci M., Mah, Eunice
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2024
• Subjects: Aged; Antiaging; Autophagy; Cardiovascular; Dietary Supplements; Double-Blind Method; Human dose; Humans; Longevity; Male; Middle Aged; Natural; Polyamines; Safety; Spermidine; Spermidine - administration & dosage; Spermidine - blood; Spermidine - pharmacology; PP; Human dose; AE; Cardiovascular; CI; Longevity; Natural; Autophagy; mITT; FFQ; SD; Antiaging; LC-MS; hpSPD; BW; Spermidine; NOAEL; hsCRP; Safety; BMI; ELISA
• ISSN: 0271-5317; 1879-0739; 1879-0739
• DOI: 10.1016/j.nutres.2024.09.012

•First human study of a novel, high-purity spermidine-trihydrochloride supplement.•40 mg/day of high-purity spermidine supplement for 28 days is safe in healthy men.•Wide safety margin in preclinical toxicology studies supports dosing at 40 mg/day.•Surprisingly little effect on circulating polyamine homeostasis dosing at 40 mg/day.•Methodological assay limits hinder detecting possible subtle changes in polyamines. This study represents the first investigation into the safety of a novel, high-purity spermidine trihydrochloride supplement (hpSPD) in humans. Spermidine, a natural compound found in various foods, has demonstrated potential health benefits in animal and epidemiological studies. However, evidence from clinical trials and safety evaluations of spermidine supplements is limited because pure spermidine for human administration has not been available. In this randomized, double-blind, within-subject and placebo-controlled trial, 37 healthy men (age 50–70 years; body mass index, 18.5–28 kg/m2) were administered either hpSPD or a placebo. We hypothesized that 7-day and 28-day dosing of 40 mg/day of hpSPD would have minimal effects on safety, although metabolic and polyamine homeostasis has not previously been examined at this dosage level. Consistent with our hypothesis, 40 mg/day hpSPD did not result in any significant changes in clinical, lipids, chemistry, or hematological parameters compared to placebo. Compliance was high, and no study product-related adverse events were reported. Substantial changes in serum and urine polyamine concentrations were not observed following hpSPD supplementation, suggesting effective homeostatic control of full-dose highly purified spermidine supplements with no evidence of adaptation of spermidine metabolism at 40 mg/day. These findings suggest that hpSPD at 40 mg/day for up to 28 days is safe and well-tolerated in healthy older men. The study is consistent with preclinical results and provides important evidence supporting the safety of high-purity spermidine supplementation, enabling further research with single-molecule spermidine to investigate its potential biology for improving human health. This trial was registered at clinicaltrials.gov (NCT05459961). Spermidine shows potential health benefits, but clinical evidence is limited because of the lack of pure spermidine supplements. This first safety study of a novel hpSPD in humans found that intake of hpSPD at 40 mg/day for up to 28 days by healthy older men resulted in no significant adverse effects compared to placebo, supporting its safety in humans. Serum and urine polyamine levels changed minimally, suggesting effective homeostatic control. Abbreviation: hpSPD, high-purity spermidine trihydrochloride supplement. [Display omitted]