Association of spermidine plasma levels with brain aging in a population‐based study

Abstract

Introduction Supplementation with spermidine may support healthy aging, but elevated spermidine tissue levels were shown to be an indicator of Alzheimer's disease (AD). Methods Data from 659 participants (age range: 21–81 years) of the population‐based Study of Health in Pomerania TREND were included. We investigated the association between spermidine plasma levels and markers of brain aging (hippocampal volume, AD score, global cortical thickness [CT], and white matter hyperintensities [WMH]). Results Higher spermidine levels were significantly associated with lower hippocampal volume (ß = −0.076; 95% confidence interval [CI]: −0.13 to −0.02; q = 0.026), higher AD score (ß = 0.118; 95% CI: 0.05 to 0.19; q = 0.006), lower global CT (ß = −0.104; 95% CI: −0.17 to −0.04; q = 0.014), but not WMH volume. Sensitivity analysis revealed no substantial changes after excluding participants with cancer, depression, or hemolysis. Discussion Elevated spermidine plasma levels are associated with advanced brain aging and might serve as potential early biomarker for AD and vascular brain pathology.

Reduction of spermine synthase enhances autophagy to suppress Tau accumulation

“…The observation of elevated polyamine levels in AD patient brains or plasma [36][37][38][39][40][41] (Fig. 6) also raises questions on the perceived beneficial effect of spermidine supplementation on brain health in human or animal models [11,20,[63][64][65][66][67].…”

“…Under SRS conditions, with complete loss of SMS, there is a significant increase in spermidine and a decrease in spermine levels, which leads to an overall increase in total polyamines [4,9]. Conversely, under AD conditions, with increased SMS and the conversion of spermine to spermidine, both spermidine and spermine levels increase [36][37][38][39][40][41]. The elevated polyamines and their metabolism in these two pathological conditions result in higher levels of oxidative stress [68][69][70] and impaired autophagic flux [29][30][31][32].…”

“…In addition to the above-mentioned roles of polyamines in autophagy regulation, studies have indicated the potential role of polyamines in Tauopathy [10,13,[33][34][35]. Interestingly, similarly as in SRS, polyamine levels are upregulated in brains or plasma/serum of Tauopathy patients or animal models [33,34,[36][37][38][39][40][41]. Manipulating polyamine pathway genes Sat1 and Azin2 has been shown to modulate Tauopathy progression in mouse models [33,34].…”

Reduction of Spermine Synthase Suppresses Tau Accumulation Through Autophagy Modulation in Tauopathy

“…The observation of elevated polyamine levels in AD patient brains or plasma [27,28,[45][46][47]] also raises questions on the perceived beneficial effect of spermidine supplementation on brain health in human or animal models [29,[48][49][50][51]. Different levels of polyamine metabolic activity might contribute to this discrepancy.…”

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

“…However, the role of spermidine in brain aging and age-related cognitive decline is complex. On the one hand, supplementation with spermidine may support healthy aging, while on the other hand, elevated spermidine plasma levels are associated with advanced brain aging, and they might serve as a potential early biomarker for Alzheimer's disease and vascular brain pathology [26].…”