Clonal haematopoiesis of indeterminate potential (CHIP). Clonal expansion of haematopoietic stem cells that carry certain somatic mutations that confer a cell proliferation advantage. Mitophagy Type of macroautophagy for the removal of damaged or dysfunctional mitochondria.

Rationale: Aging is one of the strongest risk factors for atherosclerosis. Yet whether aging increases the risk of atherosclerosis independently of chronic hyperlipidemia is not known. Objective: To determine if vascular aging before the induction of hyperlipidemia enhances atherogenesis. Methods and Results: We analyzed the aortas of young and aged normolipidemic wild type, disease-free mice and found that aging led to elevated IL (interleukin)-6 levels and mitochondrial dysfunction, associated with increased mitophagy and the associated protein Parkin. In aortic tissue culture, we found evidence that with aging mitochondrial dysfunction and IL-6 exist in a positive feedback loop. We triggered acute hyperlipidemia in aged and young mice by inducing liver-specific degradation of the LDL (low-density lipoprotein) receptor combined with a 10-week western diet and found that atherogenesis was enhanced in aged wild-type mice. Hyperlipidemia further reduced mitochondrial function and increased the levels of Parkin in the aortas of aged mice but not young mice. Genetic disruption of autophagy in smooth muscle cells of young mice exposed to hyperlipidemia led to increased aortic Parkin and IL-6 levels, impaired mitochondrial function, and enhanced atherogenesis. Importantly, enhancing mitophagy in aged, hyperlipidemic mice via oral administration of spermidine prevented the increase in aortic IL-6 and Parkin, attenuated mitochondrial dysfunction, and reduced atherogenesis. Conclusions: Before hyperlipidemia, aging elevates IL-6 and impairs mitochondrial function within the aorta, associated with enhanced mitophagy and increased Parkin levels. These age-associated changes prime the vasculature to exacerbate atherogenesis upon acute hyperlipidemia. Our work implies that novel therapeutics aimed at improving vascular mitochondrial bioenergetics or reducing inflammation before hyperlipidemia may reduce age-related atherosclerosis.

The bioenergetic profile of mitochondria isolated from skeletal muscle is associated with gait speed in older adults. Blood-based bioenergetic profiling is also associated with gait speed and may provide an alternative measure of mitochondrial function.

Blood based bioenergetic profiling strategies are emerging as potential reporters of systemic mitochondrial function; however, the extent to which these measures reflect the bioenergetic capacity of other tissues is not known. The premise of this work is that highly metabolically active tissues, such as skeletal and cardiac muscle, are susceptible to differences in systemic bioenergetic capacity. Therefore, we tested whether the respiratory capacity of blood cells, monocytes and platelets, are related to contemporaneous respirometric assessments of skeletal and cardiac muscle mitochondria. 18 female vervet/African green monkeys (Chlorocebus aethiops sabaeus) of varying age and metabolic status were examined for this study. Monocyte and platelet maximal capacity correlated with maximal oxidative phosphorylation capacity of permeabilized skeletal muscle (R=0.75, 95% confidence interval [CI]: 0.38–0.97; R=0.51, 95%CI: 0.05–0.81; respectively), isolated skeletal muscle mitochondrial respiratory control ratio (RCR; R=0.70, 95%CI: 0.35–0.89; R=0.64, 95%CI: 0.23–0.98; respectively), and isolated cardiac muscle mitochondrial RCR (R=0.55, 95%CI: 0.22–0.86; R=0.58, 95%CI: 0.22–0.85; respectively). These results suggest that blood based bioenergetic profiling may be used to report on the bioenergetic capacity of muscle tissues. Blood cell respirometry represents an attractive alternative to tissue based assessments of mitochondrial function in human studies based on ease of access and the minimal participant burden required by these measures.

SummaryFrailty, a clinical syndrome that typically occurs in older adults, implies a reduced ability to tolerate biological stressors. Frailty accompanies many age‐related diseases but can also occur without overt evidence of end‐organ disease. The condition is associated with circulating inflammatory cytokines and sarcopenia, features that are shared with heart failure (HF). However, the biological underpinnings of frailty remain unclear and the interaction with HF is complex. Here, we describe the inflammatory pathophysiology that is associated with frailty and speculate that the inflammation that occurs with frailty shares common origins with HF. We discuss the limitations in investigating the pathophysiology of frailty due to few relevant experimental models. Leveraging current therapies for advanced HF and current known therapies to address frailty in humans may enable translational studies to better understand the inflammatory interactions between frailty and HF.