[Abstract unavailable

Ageing results from complex genetically and epigenetically programmed processes that are elicited in part by noxious or stressful events that cause programmed cell death. Here, we report that administration of spermidine, a natural polyamine whose intracellular concentration declines during human ageing, markedly extended the lifespan of yeast, flies and worms, and human immune cells. In addition, spermidine administration potently inhibited oxidative stress in ageing mice. In ageing yeast, spermidine treatment triggered epigenetic deacetylation of histone H3 through inhibition of histone acetyltransferases (HAT), suppressing oxidative stress and necrosis. Conversely, depletion of endogenous polyamines led to hyperacetylation, generation of reactive oxygen species, early necrotic death and decreased lifespan. The altered acetylation status of the chromatin led to significant upregulation of various autophagy-related transcripts, triggering autophagy in yeast, flies, worms and human cells. Finally, we found that enhanced autophagy is crucial for polyamine-induced suppression of necrosis and enhanced longevity.

No abstract

28Aging is associated with an increased risk of cardiovascular disease and death. Here we 29show that oral supplementation of the natural polyamine spermidine extends the lifespan of 30 mice and exerts cardioprotective effects, reducing cardiac hypertrophy and preserving 31 diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy 32 and mitochondrial respiration, and it also improved the mechano-elastical properties of 33 cardiomyocytes in vivo, coinciding with increased titin phosphorylation and suppressed 34 subclinical inflammation. Spermidine feeding failed to provide cardioprotection in mice that 35 lack the autophagy-related protein Atg5 in cardiomyocytes. In Dahl salt-sensitive rats that 36 were fed a high-salt diet, a model for hypertension-induced congestive heart failure, 37 spermidine feeding reduced systemic blood pressure, increased titin phosphorylation and 38 prevented cardiac hypertrophy and a decline in diastolic function, thus delaying the 39 progression to heart failure. In humans, high levels of dietary spermidine, as assessed from 40 food questionnaires, correlated with reduced blood pressure and a lower incidence of 41 cardiovascular disease. Our results suggest a new and feasible strategy for the protection 42 from cardiovascular disease. 43Author's manuscript to Eisenberg et al.