Jasmine W Larrick

Inflammaging, the increase of proinflammatory processes with increasing age, has multiple mechanisms from increasing numbers of senescent cells secreting cytokines to changes in metabolic processes. Alterations of oxygen metabolism with aging, especially decreased levels of O ₂ with age resulting from endocrine and cardiovascular dysfunction as well as desensitization of cellular response to hypoxia, may exacerbate inflammaging, which in turn creates further oxygen metabolic dysfunction. During aging, decline in levels of erythrocyte 2,3-bisphosphoglycerate (2,3-BPG), BPG mutase, and adenosine A2B receptor, a key adenosine signaling receptor that can augment 2,3-BPG expression, may fail to protect sensitive brain tissue from subtly reduced O ₂ levels, in turn resulting in increased numbers of activated microglia and secretion of proinflammatory cytokines, ultimately promoting inflammaging and senescence of endothelial cells. Interventions to restore O ₂ levels directly or via increasing 2,3-BPG may help promote cognitive health in old age, but significant work to quantify the degree of reduced O ₂ during aging in mammals, and especially humans, needs to be pursued.

Intermittent fasting (IF) is the practice of restricting food intake for 12–48 hours per fasting cycle over a prolonged period of time. Previous study shows beneficial health effects such as weight loss and lower risk for cardiometabolic diseases. Although reduced calorie intake may account for some of the observed benefits of IF, exact mechanisms are still unclear. Recent evidence indicates that IF may lead to remodeling and increased taxonomic diversity in the human gut microbiome. In particular, the Lachnospiraceae family of anaerobic bacteria increased during fasting. This family, in the order Clostridiales, promotes butryogenesis in the gut, a process that is associated with healthful metabolic and prolongevity effects. IF-associated alterations to the microbiome may play a key role in the metabolic and potential healthspan-enhancing benefits of IF and dietary restriction.

Until recently, the mechanism of adaptive thermogenesis was ascribed to the expression of uncoupling protein 1 (UCP1) in brown and beige adipocytes. UCP1 is known to catalyze a proton leak of the inner mitochondrial membrane, resulting in uncoupled oxidative metabolism with no production of adenosine triphosphate and increased energy expenditure. Thus increasing brown and beige adipose tissue with augmented UCP1 expression is a viable target for obesity-related disorders. Recent work demonstrates an UCP1-independent pathway to uncouple mitochondrial respiration. A secreted enzyme, PM20D1, enriched in UCP1+ adipocytes, exhibits catalytic and hydrolytic activity to reversibly form N-acyl amino acids. N-acyl amino acids act as endogenous uncouplers of mitochondrial respiration at physiological concentrations. Administration of PM20D1 or its products, N-acyl amino acids, to diet-induced obese mice improves glucose tolerance by increasing energy expenditure. In short-term studies, treated animals exhibit no toxicity while experiencing 10% weight loss primarily of adipose tissue. Further study of this metabolic pathway may identify novel therapies for diabesity, the disease state associated with diabetes and obesity.