The practice of calorie restriction slows aging across the board. Near every known measure of aging is diminished in calorie restricted mice, and it produces significant health gains in humans. While the short term benefits of calorie restriction are quite similar in all mammals, the long term gain in life span is only large in short-lived species. Understanding why this is the case will require a near complete understanding of cellular metabolism as a whole. Researchers can pinpoint key controlling mechanisms, but the interaction between cellular metabolism and the pace of aging is enormously complex, and far from fully mapped. This is one of the reasons why progress towards calorie restriction mimetic drugs has been so painfully slow and expensive.
The example here is one of many in which calorie restriction is shown to reduce the extent of an issue that accompanies aging. Chronic inflammation is a dysregulation of the immune system and associated signaling that has serious consequences over time, accelerating the progression of all of the common age-related conditions. It is particularly damaging in the context of blood vessel walls, where the immune cells known as macrophages gather in attempts to clean up the deposits of cholesterol associated with atherosclerosis. Inflammation is well known to speed up the growth of the atherosclerotic plaques that ultimately cause a stroke or heart attack. Less of it is a good thing.
Aging exponentially increases the incidence of morbidity and mortality of quintessential cardiovascular disease mainly due to arterial proinflammatory shifts at the molecular, cellular, and tissue levels within the arterial wall. Calorie restriction (CR) in rats improves arterial function and extends both health span and life span. How CR affects the proinflammatory landscape of molecular, cellular, and tissue phenotypic shifts within the arterial wall in rats, however, remains to be elucidated.
Aortae were harvested from young (6-month-old) and old (24-month-old) Fischer 344 rats, fed ad libitum and a second group maintained on a 40% CR beginning at 1 month of age. Histopathologic and morphometric analysis of the arterial wall demonstrated that CR markedly reduced age-associated intimal medial thickening, collagen deposition, and elastin fractionation/degradation within the arterial walls. Immunostaining/blotting showed that CR effectively prevented an age-associated increase in the density of platelet-derived growth factor, matrix metalloproteinase type II activity, and transforming growth factor beta 1 and its downstream signaling molecules, phospho-mothers against decapentaplegic homolog-2/3 (p-SMAD-2/3) in the arterial wall. In early passage cultured vascular smooth muscle cells isolated from AL and CR rat aortae, CR alleviated the age-associated vascular smooth muscle cell phenotypic shifts, profibrogenic signaling, and migration/proliferation in response to platelet-derived growth factor.
In conclusion, CR reduces matrix and cellular proinflammation associated with aging that occurs within the aortic wall and that are attributable to platelet-derived growth factor signaling. Thus, CR reduces the platelet-derived growth factor-associated signaling cascade, contributing to the postponement of biological aging and preservation of a more youthful aortic wall phenotype.