Calorie restriction is perhaps the most studied of all interventions known to slow aging, and yet undergoing calorie restriction changes so much of metabolism that it remains a challenge to understand which of the countless mechanisms involved are important. It is clearly the case that the cellular maintenance processes of autophagy are critical, as researchers have shown that when autophagy is sabotaged via genetic engineering, calorie restriction no longer produces its well-known benefits to health and longevity. Beyond that, different research groups peer intently at very localized portions of cell and tissue biochemistry, and seem likely to continue doing that well into the era in which calorie restriction, and the entire concept of slowing aging via metabolic adjustment, is surpassed by rejuvenation therapies based on periodic repair of the molecular damage that causes aging.
Endothelin-1 (ET-1) is a potent vasoconstrictor synthesized by vascular endothelial cells that is normally present at low plasma concentrations. ET-1 plays a significant role in kidney physiology and pathology, highlighted by the fact that ET-1 transgenic mice undergo spontaneous kidney fibrosis even in the absence of hypertension. Ageing is associated with an increase in ET-1 levels in the renal vasculature. Elevated ET-1 can increase reactive oxygen species (ROS), which in turn can increase the uptake of oxidized low-density lipoprotein (ox-LDL) by increasing the expression of its cognate receptor lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), cumulatively contributing to endothelial dysfunction. Indeed, pre-clinical studies with endothelin receptor antagonists have shown promising results in alleviating ageing-induced impairment of renal function.
Caloric restriction (CR) can reduce the ageing process and related organ dysfunction in most species. CR without malnutrition is a dietary regimen that delays ageing and extends the lifespan. More importantly, studies in mice and rat models of ageing have shown that CR exerts significant cerebrovascular protective effects, improves cortical microvascular density and endothelial function, and counteracts ageing-induced alterations in renal function, including glomerulosclerosis and alterations in glomerular filtration. CR also improved vascular health by eliciting changes in the levels of circulating neuroendocrine factors.
Given this background, the objective of the current study was to investigate whether CR counteracts ageing-induced alterations in renal function and inflammatory cytokines by impacting ET-1 levels. We found that ET-1 messenger RNA (mRNA) and protein expression were increased ex vivo in the renal artery segments of 12-month-old rats compared to 2-month-old rats, which was reversed when rats were subjected to CR. Functional assays showed that CR alleviated renal dysfunction and decreased the expression of pro-inflammatory cytokines by decreasing ET-1 expression.