Cardioprotection and lifespan extension by the natural polyamine spermidine

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.

Spermidine: a physiological autophagy inducer acting as an anti-aging vitamin in humans?

“…Furthermore, spermidine exhibits anti-inflammatory and antioxidant properties, enhances mitochondrial metabolic function and respiration, promotes chaperone activity and improves proteostasis [4]. Intriguingly, external supplementation of spermidine exerts various beneficial effects on aging and age-related disease in a variety of model organisms, including mice [5,6]. For example, spermidine feeding extends lifespan across species [5,7,8], promotes cardio- [5] and neuroprotection [9–11], stimulates antineoplastic immune response [12] and may avoid immunosenescence by stimulating memory T-cell formation [13,14].…”

“…Intriguingly, external supplementation of spermidine exerts various beneficial effects on aging and age-related disease in a variety of model organisms, including mice [5,6]. For example, spermidine feeding extends lifespan across species [5,7,8], promotes cardio- [5] and neuroprotection [9–11], stimulates antineoplastic immune response [12] and may avoid immunosenescence by stimulating memory T-cell formation [13,14]. Many of these anti-aging properties have been causally linked to the capacity of spermidine to ensure proteostasis through the stimulation of cytoprotective macroautophagy [15–17].…”

“…Importantly, the genetic impairment of autophagy abrogates the beneficial effects of spermidine on longevity of yeast, flies and worms [7]. Moreover, in mice, the cardioprotective and immunosurveillance-associated anticancer effects of spermidine are lost when autophagy is inhibited in myocardial or cancer cells, respectively [5,12]. …”

“…Spermidine shows no adverse effects during life-long administration in mice [5], and a currently ongoing clinical trial on supplementation of spermidine-rich plant extracts to elderly persons indicates good safety and tolerability [40]. Recently, for the first time, an epidemiological study has reported a positive association between nutritional spermidine uptake and human health span and lifespan [38].…”

Spermidine promotes nucleus pulposus autophagy as a protective mechanism against apoptosis and ameliorates disc degeneration

“…Oral supplementation of spermidine is capable of extending the lifespan of mice and exerts cardioprotective effects by reducing cardiac hypertrophy and preserving diastolic function in aged mice. These effects are mediated in part by control of autophagic flux 16. Recently, it was demonstrated that spermidine could stimulate autophagy in various tissues including the brain,17 eye18 and heart 19.…”