Cardioprotective mechanisms in aging

Aging is associated with increased risk of cardiovascular diseases, the leading cause of death worldwide. Despite the great public health importance, there is an incomplete understanding of the critical molecular mechanisms involved in progressive deteriorations in the structure and function of the heart due to aging. Consequently, pharmacological interventions without long-term side effects are lacking and contribute to the growing incidence and prevalence of cardiovascular manifestations, including cardiac hypertrophy and heart failure, thus limiting health span of the elderly. Natural cardioprotective agents that target the cellular processes underlying the development of age-associated deteriorations in the structure and function of the heart (e.g. age- dependent decline in autophagy) hold the promise to combat age-related cardiovascular diseases, such as heart failure. This project aims (1) to explore the cardioprotective effects of a potent natural autophagy-inducer on structural and functional myocardial remodeling during aging using relevant animal models, and to (2) elucidate whether these cardioprotective effects induced by a dietary compound supplementation depend on autophagy and/or other mechanism(s). A comprehensive functional and structural characterization of the cardiac phenotype in aging mice will involve the complementary use of a variety of state-of-the-art techniques, such as echocardiography, hemodynamic measurements, electron microscopy, (sub-)cellular confocal microscopy as well as protein and molecular biology assays. Targeted metabolite- and proteome analyses will be performed to unravel yet unidentified signalling pathways/mechanisms being potentially involved in the cardioprotection. The results from this project will hopefully provide evidence for a novel intervention to prevent age-related decline in cardiovascular function, and thus delay the manifestation of heart failure in an increasingly aging population.

Increased average life expectancy has brought about a global rise of age-related chronic diseases. Among these, cardiovascular disorders pose an enormous burden on public health and economy and their death toll will continue to rise in absence of effective interventions. A recent study conducted by an international team led by Prof. Dr. Simon Sedej (Medical University of Graz) discovered that spermidine, which also naturally occurs in our body and exists in high amounts in certain foods (e.g. wheat germ, soy beans, aged cheese, shiitake mushrooms, green peas, nuts and broccoli amongst others) might turn back the clock on age-related decline in cardiac health. In fact, mice supplemented with the polyamine spermidine in their drinking water had better cardiac function with reversed age-related cardiac hypertrophy. In addition, spermidine improved the energy-producing (mitochondrial) capacity and structural integrity of cardiomyocytes the cardiac muscle cells responsible for contraction and pumping action of the heart. Such improved cardiac health in spermidine- supplemented mice was related to a beneficial effect on their life span as well. When spermidine was administered early in life, it prolonged life span by up to 15%, while later supplementation of spermidine (to already aged mice) increased chances of survival by 10%. In addition to aging, hypertension (i.e. elevated blood pressure) is one of the leading risk factors for cardiovascular disease and mortality. Spermidine administration to a strain of rats that develop hypertension upon salt intake not only delayed the development of hypertension, but also improved cardiac muscle elasticity, and protected the animals from heart and renal failure. Such cardiovascular protective effects of spermidine seem to be primarily mediated through stimulation of autophagy, a self-renewal cellular process - that declines with age - responsible for cleaning up old, damaged, and potentially toxic molecules and organelles. The epidemiological analysis of 829 participants in the Bruneck study (South Tyrol, Italy) revealed that increased dietary spermidine intake is associated with reduced blood pressure and lower risk of heart failure and other cardiovascular diseases. In addition, people consuming a spermidine-rich diet had significantly reduced cardiovascular- related mortality, contributing to reduced overall rate of death. Collectively, our findings provide the first evidence that spermidine protects the heart against aging and disease and extends life span similar to caloric restriction, at least, in preclinical testing. The discovery that spermidine could have profound effects on cardiac health and may even lengthen life is extremely encouraging and deserves attention at a time when the need to reduce the increasing burden of age-related disease is pressing.