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. In this review, we implicate fundamental mechanisms of aging in driving HFpEF and elucidate how caloric restriction mitigates the disease progression. Furthermore, we discuss the potential for pharmacologically mimicking the beneficial effects of caloric restriction in HFpEF using clinically approved and emerging caloric restriction mimetics. We surmise that these compounds could offer novel therapeutic avenues for HFpEF and alleviate the challenges associated with the implementation of caloric restriction and other lifestyle modifications to reduce the burden of HFpEF at a population level.