Specific targeting of adipose tissue metabolism is superior to caloric restriction in treating obesity-related HFpEF.

Obesity is a modifiable major driver of heart failure with preserved ejection fraction (HFpEF), the most common and rapidly increasing form of heart failure. Current metabolic therapies, such as caloric restriction and incretin-based drugs, have shown promise in treating obesity-related HFpEF. However, these interventions neither specifically nor selectively improve adipose tissue metabolism, which is a key etiological factor in HFpEF that may offer a pathway to safer and more effective treatment strategies.

Sirtuin 4 accelerates heart failure development by enhancing reactive oxygen species-mediated profibrotic transcriptional signaling.

Aims: Sirtuin 4 (SIRT4) is a mitochondrially-localized stress-responsive NAD-dependent deacetylase predominantly regulating energy metabolism and reactive oxygen species (ROS) homeostasis. Overexpression of SIRT4 aggravates angiotensin-induced cardiac hypertrophy, however underlying mechanisms remain incompletely elucidated. To current study was designed to explore mechanisms underlying adverse effects of increased SIRT4 levels in the heart following pressure overload.

NAD repletion restores cardioprotective autophagy and mitophagy in obesity-associated heart failure by suppressing excessive trophic signaling.

Macroautophagy/autophagy is markedly inhibited in the hearts of elderly obese patients with heart failure and preserved ejection fraction (HFpEF). However, the therapeutic relevance and underlying signaling mechanisms of the decline of autophagy in HFpEF remain unclear. We observed that therapeutic nicotinamide adenine dinucleotide (NAD) repletion via nicotinamide supplementation restores cardioprotective autophagy and mitophagy in preclinical models of obesity-related HFpEF.

Mechano-energetic uncoupling in heart failure.

Heart failure (HF) is a major global and life-threatening disease. Despite advances in therapies, the prevalence of HF is increasing owing to an ageing population and the pervasive pandemic of obesity and metabolic disorders, which have transformed the pathophysiology of HF. Changes in cardiac energy metabolism and the related energy deficit crucially contribute to the severity and type of HF.

Roadmap for alleviating the manifestations of ageing in the cardiovascular system.

Ageing of the cardiovascular system is associated with frailty and various life-threatening diseases. As global populations grow older, age-related conditions increasingly determine healthspan and lifespan. The circulatory system not only supplies nutrients and oxygen to all tissues of the human body and removes by-products but also builds the largest interorgan communication network, thereby serving as a gatekeeper for healthy ageing.

Phosphorylation of CRYAB induces a condensatopathy to worsen post-myocardial infarction left ventricular remodeling.

Protein aggregates are emerging therapeutic targets in rare monogenic causes of cardiomyopathy and amyloid heart disease, but their role in more prevalent heart-failure syndromes remains mechanistically unexamined. We observed mislocalization of desmin and sarcomeric proteins to aggregates in human myocardium with ischemic cardiomyopathy and in mouse hearts with post-myocardial infarction ventricular remodeling, mimicking findings of autosomal-dominant cardiomyopathy induced by the R120G mutation in the cognate chaperone protein CRYAB. In both syndromes, we demonstrate increased partitioning of CRYAB phosphorylated on serine 59 to NP40-insoluble aggregate-rich biochemical fraction.

Caloric restriction and its mimetics in heart failure with preserved ejection fraction: mechanisms and therapeutic potential.

The global increase in human life expectancy, coupled with an unprecedented rise in the prevalence of obesity, has led to a growing clinical and socioeconomic burden of heart failure with preserved ejection fraction (HFpEF). Mechanistically, the molecular and cellular hallmarks of aging are omnipresent in HFpEF and are further exacerbated by obesity and associated metabolic diseases. Conversely, weight loss strategies, particularly caloric restriction, have shown promise in improving health status in patients with HFpEF and are considered the gold standard for promoting longevity and healthspan (disease-free lifetime) in model organisms.

Lean ZSF1 rats in basic research on heart failure with preserved ejection fraction.

Aims: ZSF1 obese rats harbouring two mutant leptin receptor alleles (Lepr and Lepr) develop metabolic syndrome and heart failure with preserved ejection fraction (HFpEF), making them a widely used animal model in cardiometabolic research. Studies using ZSF1 rats have contributed significantly to the elucidation of pathophysiological mechanisms underlying HFpEF and therapeutic strategies against this multi-organ syndrome. In contrast, hybrid, lean ZSF1 rats (L-ZSF1) do not develop HFpEF and generally serve as controls, disregarding the possibility that the presence of one mutant Lepr allele might affect left ventricular ejection fraction (LVEF), diastolic dysfunction and other relevant HFpEF parameters, such as N-terminal pro-brain natriuretic peptide (NT-proBNP) levels and cardiac inflammation, which could increase during disease manifestation.

Phosphorylation of CRYAB Induces a Condensatopathy to Worsen Post-Myocardial Infarction Left Ventricular Remodeling.

Protein aggregates are emerging therapeutic targets in rare monogenic causes of cardiomyopathy and amyloid heart disease, but their role in more prevalent heart failure syndromes remains mechanistically unexamined. We observed mis-localization of desmin and sarcomeric proteins to aggregates in human myocardium with ischemic cardiomyopathy and in mouse hearts with post-myocardial infarction ventricular remodeling, mimicking findings of autosomal-dominant cardiomyopathy induced by R120G mutation in the cognate chaperone protein, CRYAB. In both syndromes, we demonstrate increased partitioning of CRYAB phosphorylated on serine-59 to NP40-insoluble aggregate-rich biochemical fraction.

A surge in endogenous spermidine is essential for rapamycin-induced autophagy and longevity.

Acute nutrient deprivation (fasting) causes an immediate increase in spermidine biosynthesis in yeast, flies, mice and humans, as corroborated in four independent clinical studies. This fasting-induced surge in spermidine constitutes the critical first step of a phylogenetically conserved biochemical cascade that leads to spermidine-dependent hypusination of EIF5A (eukaryotic translation initiation factor 5A), which favors the translation of the pro-macroautophagic/autophagic TFEB (transcription factor EB), and hence an increase in autophagic flux. We observed that genetic or pharmacological inhibition of the spermidine increase by inhibition of ODC1 (ornithine decarboxylase 1) prevents the pro-autophagic and antiaging effects of fasting in yeast, nematodes, flies and mice.

Risks and Benefits of Intermittent Fasting for the Aging Cardiovascular System.

Population aging and the associated increase in cardiovascular disease rates pose serious threats to global public health. Different forms of fasting have become an increasingly attractive strategy to directly address aging and potentially limit or delay the onset of cardiovascular diseases. A growing number of experimental studies and clinical trials indicate that the amount and timing of food intake as well as the daily time window during which food is consumed, are crucial determinants of cardiovascular health.

Loss of lysosomal acid lipase results in mitochondrial dysfunction and fiber switch in skeletal muscles of mice.

Objective: Lysosomal acid lipase (LAL) is the only enzyme known to hydrolyze cholesteryl esters (CE) and triacylglycerols in lysosomes at an acidic pH. Despite the importance of lysosomal hydrolysis in skeletal muscle (SM), research in this area is limited. We hypothesized that LAL may play an important role in SM development, function, and metabolism as a result of lipid and/or carbohydrate metabolism disruptions.

Metabolic control of mitophagy.

Mitochondrial dysfunction is a major hallmark of ageing and related chronic disorders. Controlled removal of damaged mitochondria by the autophagic machinery, a process known as mitophagy, is vital for mitochondrial homeostasis and cell survival. The central role of mitochondria in cellular metabolism places mitochondrial removal at the interface of key metabolic pathways affecting the biosynthesis or catabolism of acetyl-coenzyme A, nicotinamide adenine dinucleotide, polyamines, as well as fatty acids and amino acids.

Hallmarks of cardiovascular ageing.

Normal circulatory function is a key determinant of disease-free life expectancy (healthspan). Indeed, pathologies affecting the cardiovascular system, which are growing in prevalence, are the leading cause of global morbidity, disability and mortality, whereas the maintenance of cardiovascular health is necessary to promote both organismal healthspan and lifespan. Therefore, cardiovascular ageing might precede or even underlie body-wide, age-related health deterioration.

The impact of moderate endurance exercise on cardiac telomeres and cardiovascular remodeling in obese rats.

Introduction: Hypercaloric nutrition and physical inactivity cause obesity, a potential driver of myocardial apoptosis and senescence that may accelerate cardiac aging. Although physical activity reduces mortality, its impact on myocardial aging is insufficiently understood. Here we investigated the effects of a hypercaloric high-fat diet (HFD) and regular exercise training on cardiac cells telomeres and histomorphometric indices of cardiac aging.

Cardiac PI3K p110α attenuation delays aging and extends lifespan.

Phosphoinositide 3-kinase (PI3K) is a key component of the insulin signaling pathway that controls cellular me-tabolism and growth. Loss-of-function mutations in PI3K signaling and other downstream effectors of the insulin signaling pathway extend the lifespan of various model organisms. However, the pro-longevity effect appears to be sex-specific and young mice with reduced PI3K signaling have increased risk of cardiac disease.

Acetylation and phosphorylation changes to cardiac proteins in experimental HFpEF due to metabolic risk reveal targets for treatment.

Aims: Despite the high prevalence of heart failure with preserved ejection fraction (HFpEF), the pathomechanisms remain elusive and specific therapy is lacking. Disease-causing factors include metabolic risk, notably obesity. However, proteomic changes in HFpEF are poorly understood, hampering therapeutic strategies.

Spermidine overrides INSR (insulin receptor)-IGF1R (insulin-like growth factor 1 receptor)-mediated inhibition of autophagy in the aging heart.

Although attenuated IGF1R (insulin-like growth factor 1 receptor) signaling has long been viewed to promote longevity in model organisms, adverse effects on the heart have been the subject of major concern. We observed that IGF1R is overexpressed in cardiac tissues from patients with end-stage non-ischemic heart failure, coupled to the activation of the IGF1R downstream effector AKT/protein kinase B and inhibition of ULK1 (unc-51 like autophagy activating kinase 1). Transgenic overexpression of human IGF1R in cardiomyocytes from mice initially induces physiological cardiac hypertrophy and superior function, but later in life confers a negative impact on cardiac health, causing macroautophagy/autophagy inhibition as well as impaired oxidative phosphorylation, thus reducing life expectancy.

Effects of Short Term Adiponectin Receptor Agonism on Cardiac Function and Energetics in Diabetic Mice.

Objective: Impaired cardiac efficiency is a hallmark of diabetic cardiomyopathy in models of type 2 diabetes. Adiponectin receptor 1 (AdipoR1) deficiency impairs cardiac efficiency in non-diabetic mice, suggesting that hypoadiponectinemia in type 2 diabetes may contribute to impaired cardiac efficiency due to compromised AdipoR1 signaling. Thus, we investigated whether targeting cardiac adiponectin receptors may improve cardiac function and energetics, and attenuate diabetic cardiomyopathy in type 2 diabetic mice.