Spermidine

Based on the provided literature, the scientific consensus indicates that the natural polyamine spermidine acts as an evolutionarily conserved pro-longevity factor by inducing autophagy across multiple model organisms, including yeast, flies, worms, and mice [1, 2, 4, 8]. Mechanistically, spermidine functions as an acetylase inhibitor that stimulates autophagy independently of SIRT1—specifically through the inhibition of the acetyltransferase EP300—and plays roles in regulating translation, interacting with nucleic acids and proteins, and influencing eIF5A hypusination and TFEB translation [3, 5, 6, 7]. Furthermore, somatic polyamine levels naturally decline with age, and dietary supplementation or the upregulation of luminal polyamines via intestinal microbiota can enhance longevity and delay senescence [4, 8].

Open questions remain regarding the full spectrum of molecular targets, optimal clinical translation strategies, and the precise mechanisms governing how polyamine homeostasis alters tissue-specific aging and disease states in humans [3, 9]. While foundational geroscience frameworks prioritize interventions like spermidine for age-related conditions such as sarcopenia, translating these preclinical findings into validated clinical therapies requires further maturity of evidence [9, 10].