High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study

Abstract

(1) Background: Spermidine is a biogenic polyamine that plays a crucial role in mammalian metabolism. As spermidine levels decline with age, spermidine supplementation is suggested to prevent or delay age-related diseases. However, valid pharmacokinetic data regarding spermidine remains lacking. Therefore, for the first time, the present study investigated the pharmacokinetics of oral spermidine supplementation. (2) Methods: This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken. Spermidine, spermine, and putrescine were quantified by liquid chromatography–mass spectrometry (LC–MS/MS). The plasma metabolome was investigated using nuclear magnetic resonance (NMR) metabolomics. (3) Results: Compared with a placebo, spermidine supplementation significantly increased spermine levels in the plasma, but it did not affect spermidine or putrescine levels. No effect on salivary polyamine concentrations was observed. (4) Conclusions: This study’s results suggest that dietary spermidine is presystemically converted into spermine, which then enters systemic circulation. Presumably, the in vitro and clinical effects of spermidine are at least in part attributable to its metabolite, spermine. It is rather unlikely that spermidine supplements with doses <15 mg/d exert any short-term effects.

The efflux pumps Rv1877 and Rv0191 play differential roles in the protection of Mycobacterium tuberculosis against chemical stress

“…However, since eukaryotes can already produce Spm, it means they can tolerate a certain level of Spm, as opposed to other antibiotics. Moreover, the introduction of Spm as a food supplement to treat or prevent other disease conditions, further supports the ability of eukaryotes to tolerate an appreciable level of Spm (Senekowitsch et al, 2023). Lastly, because Spm can reduce the MIC of known TB drugs and vice versa (Sao Emani and Reiling, 2023), a high dose may not be required after all, if used in combination with these antibiotics.…”

The central role of DNA damage in immunosenescence

“…Spermidine and other related polyamines may therefore elicit genoprotective effects and alleviate immunosenescence by acting as antioxidants, promoting repair, and reducing ROS burden through increased autophagy. Spermidine supplementation in humans is tolerated at doses tested up to 15 mg/day, though we note that supplementation does not detectably change blood spermidine levels, despite eliciting its beneficial anti-ageing effects (Schwarz et al, 2018;Wirth et al, 2018;Senekowitsch et al, 2023). Current clinical trials investigating whether spermidine supplementation (e.g., NCT05421546, spermidine at 6 mg/day) improves vaccine responses in old people will be greatly informative in translating in vitro studies to population interventions.…”

The Effect of Spermidine Supplementation on Cognitive Function in Adults: A Mini-Review

“…Interestingly, the spermidine supplementation dose used in these trials could be considered low, taking into account that daily intake of spermidine has been estimated to be highly variable between subjects, ranging from 5 to 15mg , currently registered clinical trials are evaluating doses of 4 to 6 mg and that a recent pharmacokinetic study suggested that doses less than 15mg are unlikely to exert any short-term effects. (Senekowitsch et al, 2023). Furthermore, Schwarz 2022, which was methodologically well-designed and had longer follow-up times, used a remarkably low spermidine dose, raising the possibility that the lack of clinical effect may have been associated with the low dose.…”