Calorie Restriction Mimetics in the Context of Cardiovascular Disease

The practice of calorie restriction produces a beneficial upregulation of cellular stress responses. In short-lived species such as mice this can produce a dramatic slowing of aging, improvement in health, and extension of life span. The same mechanisms produce similar short-term benefits to health, but not a significant lengthening of life, in species as long-lived a our own, however. Nonetheless, there is considerable interest in calorie restriction mimetics, compounds that can trigger at least some of the same regulatory mechanisms governing cellular stress responses, particularly the operation of autophagy.

Recent years have seen a growing interest in understanding how dietary interventions shape and interact with the most common cardiovascular risk factors, including hypertension, obesity, metabolic syndrome, and diabetes mellitus type 2. Substantial cardiometabolic improvements have been reported with fasting interventions such as reduction in blood pressure, body weight and fat mass, lower blood glucose, and improvement in insulin sensitivity, both in experimental and clinical studies. Although caloric restriction consistently improves several aspects of health, its application has been hampered by poor compliance and adverse side effects on bone health and immune response, especially in the elderly.

An interesting aspect that warrants further attention is the effect of caloric restriction mimetics or dietary interventions aimed at weight loss on the gut microbiome changes in obese patients with diabetes mellitus type 2 or metabolic syndrome. Although these interventions propose beneficial clinical outcomes, their effect on the gut microbiome is only beginning to unfold. Interestingly, a combination therapy of resveratrol and spermidine synergistically induces autophagy at doses which do not trigger effects of the same magnitude if administered alone. At present, however, it remains elusive what is the optimal dose for any of the caloric restriction mimetics that could provide health benefits or protect humans at risk of cardiovascular disease.

Unlike the current drug development approaches that focus on individual diseases in isolation and consider specificity as a desirable outcome in disease prevention and treatment, both caloric restriction mimetics and caloric restriction intercept multiple different targets. Such pleiotropic mode of action appears advantageous in targeting the complex process of aging as the greatest risk factor for cardiovascular diseases and associated comorbid conditions. Thus, dietary interventions should aim to maintain optimum health and prevent cardiovascular diseases by attenuating the molecular causes of biological aging directly.

Non-cell autonomous effects of caloric restriction mimetics and caloric restriction itself, such as the anti-inflammatory or immune modulatory functions, are increasingly viewed as relevant as cell autonomous mechanisms. Taking this into account, more research is needed to ascertain how different forms of fasting and caloric restriction mimetics can be the most favorable to further improve cardiometabolic markers in healthy adults and patients living with or at risk of developing cardiovascular disease. Based on the currently available data, harnessing caloric restriction mimetics or dietary interventions, such as intermittent fasting or the Mediterranean diet represent a promising preventive venue, which might reduce cardiovascular risk and the burden of cardiovascular disease.


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