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.
SummaryFatty acids (FAs) activate and fuel UCP1-mediated non-shivering thermogenesis (NST) in brown adipose tissue (BAT). Release of FAs from intracellular fat stores by adipose triglyceride lipase (ATGL) is considered a key step in NST. Accordingly, the severe cold intolerance of global ATGL knockout (AKO) mice has been attributed to defective BAT lipolysis. Here we show that this conclusion is incorrect. We demonstrate that although the BAT-specific loss of ATGL impairs BAT lipolysis and alters BAT morphology, it does not compromise the β3-adrenergic thermogenic response or cold-induced NST. Instead, NST depends on nutrient supply or lipolysis in white adipose tissue during fasting, suggesting that circulating energy substrates are sufficient to fuel NST. Cold intolerance in AKO mice is not caused by BAT dysfunction as previously suspected but by severe cardiomyopathy. We conclude that functional NST requires adequate substrate supply and cardiac function, but does not depend on ATGL-mediated lipolysis in BAT.
Cardiovascular diseases are the most prominent maladies in aging societies. Indeed, aging promotes the structural and functional declines of both the heart and the blood circulation system. In this review, we revise the contribution of known longevity pathways to cardiovascular health and delineate the possibilities to interfere with them. In particular, we evaluate autophagy, the intracellular catabolic recycling system associated with life- and health-span extension. We present genetic models, pharmacological interventions, and dietary strategies that block, reduce, or enhance autophagy upon age-related cardiovascular deterioration. Caloric restriction or caloric restriction mimetics like metformin, spermidine, and rapamycin (all of which trigger autophagy) are among the most promising cardioprotective interventions during aging. We conclude that autophagy is a fundamental process to ensure cardiac and vascular health during aging and outline its putative therapeutic importance.
Ageing constitutes the most important risk factor for all major chronic ailments, including malignant, cardiovascular and neurodegenerative diseases. However, behavioural and pharmacological interventions with feasible potential to promote health upon ageing remain rare. Here we report the identification of the flavonoid 4,4′-dimethoxychalcone (DMC) as a natural compound with anti-ageing properties. External DMC administration extends the lifespan of yeast, worms and flies, decelerates senescence of human cell cultures, and protects mice from prolonged myocardial ischaemia. Concomitantly, DMC induces autophagy, which is essential for its cytoprotective effects from yeast to mice. This pro-autophagic response induces a conserved systemic change in metabolism, operates independently of TORC1 signalling and depends on specific GATA transcription factors. Notably, we identify DMC in the plant Angelica keiskei koidzumi, to which longevity- and health-promoting effects are ascribed in Asian traditional medicine. In summary, we have identified and mechanistically characterised the conserved longevity-promoting effects of a natural anti-ageing drug.
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