Cardiovascular diseases (CVDs) affecting the heart and blood vessels are a global health concern, and are known to claim millions of lives annually. In China, an estimated 330 million people are affected by CVDs, making it the leading cause of mortality in both urban and rural populations.
An approach for managing and preventing CVDs entails reducing calorie intake to a level that does not cause malnutrition. This practice, known as caloric restriction (CR), has been shown to extend the lifespan of patients and reduce the risk of age-related diseases such as CVDs. These positive implications of CR are speculated to be mediated by sirtuins—a family of nicotinamide adenine dinucleotide (NAD+)-dependent signaling proteins. These proteins are known to play a role in various cellular functions, including the regulation of metabolism, DNA repair, and gene expression. However, the mechanisms underlying the interplay between CR and sirtuins is still not clear.
Now, however, to shed light on the mechanisms through which CR improves cardiovascular health, researchers from China have conducted a thorough review of existing literature. Their study examines the interaction between CR and sirtuins and is published online in the Chinese Medical Journal on 25 March 2024.
Their review reveals that the benefits of CR on cardiovascular health have been well-documented. It has been shown to reduce blood pressure, decrease inflammation, alleviate oxidative stress, and enhance endothelial function. Studies where individuals were assigned to a 25% CR diet for 6 months demonstrated a reduction in cholesterol levels and blood pressure, both of which are risk factors for CVDs. The reduction in fat levels is attributed to a change in energy metabolism brought about by CR, in which enhanced utilization of stored fat in cardiac tissues is favored as an energy source.
Another important aspect influenced by CR is vascular health, which is closely linked to CVDs. The accumulation of plaque in the arteries or thickening of arterial walls can cause CVDs. CR alleviates these conditions by promoting the cellular renewal of the endothelium and preventing the excessive growth of muscle cells in the arterial walls.
The review also states that seven sirtuins that mediate the cardiovascular benefits of CR have been identified based on their location. These include SIRT1, SIRT6, and SIRT7, which are located in the nucleus of the cell and are found to regulate gene expression. Moreover, SIRT3, SIRT4, and SIRT5 are present in the mitochondria, where they maintain mitochondrial function and mitigate oxidative stress. Furthermore, SIRT2 is located in the cytoplasm of the cell and is involved in DNA repair and apoptosis, a type of programmed cell death.
In their review, the researchers also found that in various mouse models, CR increases the expression of these proteins improving both vascular and heart health and even preventing tumor formation. "In experimental studies using murine models, the sirtuins, notably SIRT1, have been shown to mediate the beneficial effects of CR on diverse CVDs, including diabetic cardiomyopathy, myocardial ischemia–reperfusion injury, myocardial fibrosis, atherosclerosis, and abdominal aortic aneurysm," explains Dr. Depei Liu. The increase in SIRT1 is attributed to elevated intracellular NAD+ levels that are induced by CR.
Beyond direct cardiovascular benefits, CR also positively affects other tissues and organs and indirectly contributes to cardiovascular health. It promotes glucose uptake in skeletal muscles, improves glucose production in the liver, and reduces adipose tissue mass. CR also influences the release of specific metabolites from various organs into the cardiovascular system, affecting sirtuin levels. For instance, the researchers noted that CR promotes hydrogen sulfide production, which in turn, enhances sirtuin activity. CR was also found to reverse alterations that occur in non-coding RNAs (ncRNAs) due to aging. These ncRNAs directly target sirtuins and regulate their function.
Despite these revelations, the researchers believe that the complexities of the relationship between CR, sirtuins, and cardiovascular functions calls for further research for clarifying their effects. "Existing studies on sirtuins and CR merely represent the tip of the iceberg. The evidence supporting sirtuins as a sensor or mediator of CR remains insufficient. The distinct functions of each molecule within the family have not been clearly analyzed. Moreover, the conclusions drawn from mouse experiments remain unclear, and further experiments in primates are yet to be conducted," says Dr. Depei Liu.
Going ahead, the researchers suggest using advanced methodologies like single-cell sequencing, high-throughput technologies, and machine learning models to gain a deeper understanding of this complex interplay. These insights, in turn, can pave the way for the development of novel therapeutic strategies aimed at prevention and treatment of CVDs.
