This very readable paper discusses the possible role for ceramides in the processes of aging relevant to declining fitness and muscle function. This is all some steps removed from the fundamental cell and tissue damage that causes aging, however, and is really a discussion of the details of a small snapshot of later, complicated reactions to that damage. That said, it is very representative of most present research into aging by groups that lean towards producing possible therapies. Interventions are planned for later consequences in aging, without addressing the root causes of observed disruptions and alterations.
Aging is associated with a progressive loss of cardiorespiratory fitness, which in turn leads to an increased risk of morbidity and mortality. Cardiorespiratory fitness is defined as maximal oxygen consumption (VO2 peak) during dynamic exercise and is typically measured during a graded exercise test. Using this operational definition, the decline in fitness starts around the age of thirty and continues at approximately 10% per decade. It accelerates even further toward the end of the lifespan, even in healthy persons. Cardiorespiratory fitness is a critical determinant of physical function in older adults and an accurate indicator of cardiovascular and overall health. Thus, maintaining a good level of fitness is fundamental to delaying mobility difficulty and attaining healthy longevity.
Maximal oxygen consumption is largely explained by cardiovascular adaptations in transporting oxygen to muscle as well as mitochondrial adaptations within muscle, to meet the energy demands of physical activity. Recent evidence suggests that the capacity for vasodilatation in the peripheral vasculature also plays an important role in maximal oxygen uptake. The decline in VO2 peak with aging has been primarily attributed to the reductions in muscle oxygen delivery, due to decreased cardiac output, and to the reductions in skeletal muscle oxidative capacity, mainly due to the mitochondrial dysfunction. However, there is a wide interindividual variability in the rate of decline, which is only partially explained by differences in physical activity. Thus, studies of biological correlates of physical fitness are important because they may provide insight as to why some individuals experience an accelerated decline of aerobic capacity. Further, such correlations may serve as clinically valuable prognostic indicators of cardiovascular health, morbidity, and mortality risk.
Ceramides are a ubiquitous group of lipids that consist of a sphingosine linked to a fatty acid. Ceramides are known for their structural role in plasma membranes and also as important signaling molecules involved in many essential cellular processes including inflammation, immune cell trafficking, vascular and epithelial integrity, apoptosis, autophagy, and stress responses. In the circulation, ceramides are transported primarily in low-density lipoproteins (LDL) and very-low-density lipoproteins (VLDL). Previous studies suggested that ceramides increase with age and are associated with accelerated aging and age-related chronic conditions, particularly cardiovascular and metabolic diseases. Treatments targeting ceramides may be potentially very effective for preventing or treating these conditions. For example, elevated plasma ceramides cause vascular endothelial dysfunction by promoting endothelial cell growth arrest, oxidative stress, senescence and death, disrupting insulin signaling and increasing inflammation. Perhaps through these same mechanisms, ceramides may contribute to the early stages of atherosclerosis.
Given the evidence linking ceramide to mechanisms fundamental to cardiovascular health in cell culture and animal studies, we examined the relationships between ceramides and indicators of cardiovascular health in older adults. We applied multiple regression models to test the associations between ceramide species and VO2 peak, while adjusting for age, sex, blood pressure, serum LDL, HDL, triglycerides, and other covariates. We found that higher levels of circulating C18:0, C20:0, C24:1 ceramides and C20:0 dihydroceramides were strongly associated with lower aerobic capacity. The associations held true for both sexes (with men having a stronger association than women) and were unchanged after adjusting for confounders and multiple comparison correction. Interestingly, no significant association was found for C16:0, C22:0, C24:0, C26:0, and C22:1 ceramide species, C24:0 dihydroceramide, or total ceramides. Our analysis reveals that specific long-chain ceramides strongly associate with low cardiovascular fitness in older adults and may be implicated in the pathogenesis of low fitness with aging.