4.8. Clinical and Research Implications
DISEASES
Since spermidine supplementation has been postulated as a possible means of therapeutically targeting several diseases [First, our data demonstrate that a daily dose of 15 mg of spermidine significantly increases blood concentrations of spermine. In previous trials, daily spermidine doses of 0.9–1.2 mg have been used without any change in blood concentrations of polyamines or any clinical efficacy [Second, it can be postulated that the in vitro and clinical effects of spermidine are not solely due to spermidine itself but may also be attributed to its metabolite, spermine, which is formed in the body prior to or in peripheral tissues [Third, the overall view of preclinical and clinical data, including the results presented here, suggests that the mechanisms of intestinal absorption as well as the mechanisms of presystemic spermidine metabolism are different in rodents and humans, thereby directly affecting the biological effects. Therefore, special caution is required when transferring experimental animal data with spermidine to humans. On the other hand, spermine might represent the predominant form of transport of spermidine in the blood, with dietary spermidine being absorbed into enterocytes and intracellularly converted to spermine, which is then extruded into the systemic circulation through the basolateral membrane, followed by reconversion to spermidine in tissues and organs. It is well known that the conversion of spermidine to spermine is not a one-way street but rather possible in both directions [Fourth, oral spermidine intake of 15 mg/d does not affect salivary polyamine concentrations. Preclinical data implying an oropharyngeal effect of spermidine may not be translated into recommendations to supplement spermidine, as effective doses have yet to be determined. Systemic doses of 15 mg/d do not seem to be appropriate for yielding pharmacological concentrations in the saliva.Fifth, our findings challenge the concept of epidemiological spermidine studies based on statistical correlations between the spermidine content of food and biological effects without considering the variability of presystemic spermidine metabolism or dietary spermine intake.