1. Introduction
SARS-CoV-2 infections, neurodegenerative disorders, cancer, PTS, infection, necrosis, cognitive decline
SARS-COV-2 INFECTION, PROLIFERATION, NEURODEGENERATIVE DISORDERS, CANCER, INFECTION, NECROSIS, DISEASES
These authors contributed equally to this work.(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.Spermidine is a biogenic polyamine that plays a crucial role in cellular homeostasis, cell growth, proliferation, and autophagy [Polyamines (including spermidine) in the gastrointestinal lumen originate from food, intestinal microbiota, pancreatic-biliary secretions, and degraded intestinal cells [The average daily nutritional intake of spermidine in European countries varies from approximately 10 to 15 mg [To date, little is known about the mechanisms of intestinal absorption, presystemic metabolism, and the kinetics of polyamine transport systems in humans [Luminal polyamines are (at least in part) actively imported into intestinal epithelial cells (IECs) through the polyamine transport system (PTS) [Spermidine has an autophagy-inducing effect that makes it highly interesting for preclinical research [Most prominent translational research with spermidine has focused on its possible efficacy in the context of brain health/aging, oncology, and SARS-CoV-2 infections. Regarding brain health and aging, spermidine-induced autophagy has been postulated to exert protective effects on neurodegenerative disorders and subjective cognitive decline and also to slow aging processes even in humans [In fact, the administration of exogenous spermidine extends the lifespan in various models of aging through epigenetic modifications, autophagy induction, and necrosis suppression [In oncology, due to its direct link with oncogenes, polyamine metabolism has long been a target for potential cancer therapeutic agents [Recently, in vitro data revealed that an infection with SARS-CoV-2 leads to the viral inhibition of spermidine synthase; as a result, the intracellular spermidine concentration decreases, and autophagy as a cellular defense mechanism is reduced [To probe these preclinical data in future clinical trials, detailed knowledge of spermidine pharmacokinetics is essential. Since SARS-CoV-2 replicates predominantly in the pharynx during the initial phase of infection, saliva concentrations of spermidine (as well as spermine and putrescine) after oral intake of spermidine are of major interest. Therefore, in addition to the blood plasma concentrations, we also analyzed the respective saliva concentrations. To the best of our knowledge, the concentrations of spermidine, spermine, and putrescine in saliva after oral intake of spermidine have never been investigated before.Thus, to foster translational research with spermidine, we determined the pharmacokinetics of orally administered spermidine, its precursor putrescine, and its metabolite spermine, as well as the effect of its multiple-day administration on the steady-state concentrations in blood and saliva in healthy volunteers.Additionally, also for the first time, we investigated the effect of orally administered spermidine on the human plasma metabolome using nuclear magnetic resonance (NMR) spectroscopy because spermidine has been postulated to act as a calorie restriction mimetic (CRM) in humans, which would imply effects on the plasma concentrations of various metabolites [