Polyamine supplementation enhances autophagy and reverses age‐related arterial stiffening

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Aging leads to stiffening of large elastic arteries as a result of changes in structural proteins and increased macromolecular damage. Polyamines (PA) play a causal role in survival/longevity and have been reported to induce autophagy, the cellular process of recycling damaged biomolecules. However, the potential for PA to reduce age‐related arterial stiffness is unknown. We studied young (Y: 5 mo, n=7) and old (O: 28–29 mo, n=7) male C57/BL6 mice, and old mice treated with the PA spermidine (OPA: 29 mo, n=7). Aortic pulse wave velocity (aPWV), an index of arterial stiffness, was higher in O vs. Y mice (465 ± 25 vs. 383 ± 21 cm/s, p<0.05). This was associated with ~50% greater aortic levels of both protein carbonyls, an index of oxidative damage, and advanced glycation end products (AGEs), a marker of protein cross‐linking (dot and western blotting, both p<0.05, O vs. Y). PA supplementation (3 mM drinking water × 4w) ameliorated aortic stiffening in old mice (OPA aPWV pre: 482 ± 17 vs. OPA post: 343 ± 14 cm/s, P<0.05) and reversed age‐related increases in protein carbonyls and AGEs. The effects of PA treatment were associated with enhanced autophagy as indicated by an ~20% reduction in acetylation (inhibition) of histone H3, an ~25% increase in expression of the transcription factors AMPK and FOXO3a, and a corresponding increase in LC3‐II and decrease in p62, markers of autophagy and autophagic protein aggregation/damage, respectively (western blotting, all p<0.05, O vs. OPA). These results suggest that PA supplementation may be a novel strategy for reversing age‐related arterial stiffening, perhaps by enhancing autophagic clearance of damaged/aggregated proteins.NIH AG013038, AG039210, HL007822