Ferroptosis is a recently characterized cell death phenotype resulting from iron-catalyzed peroxidation of polyunsaturated fatty acid phospholipids. Increased dysfunctional iron metabolism is thought to lead to increased levels of iron and ferroptosis, which in turn leads to cell and organismal death at least in the nematode Caenorhabditis elegans. Drugs that block lipid peroxidation or scavenge intracellular iron extend healthspan and lifespan in C. elegans independently of other mechanisms such as the daf-1/daf-16 (insulin/insulin-like growth factor 1 [IGF-1]) pathway, but unlike many aging mechanisms do not alter temporal scaling across the life cycle of C. elegans, but rather act at specific late points in the organism's life history, temporarily blocking execution of critical dysfunction that results in listless worms. As such, inhibition of ferroptosis may be a means to extend healthspan and treat frailty and possibly neurodegenerative diseases that have a reported role for iron dyshomeostasis. However, a significant effort to understand ferroptosis in the context of mammalian and human biology is necessary. For example, some tumors block ferroptosis to survive. The constraints of balancing iron metabolism are significant and will require careful consideration in any drug development program.

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.

Advancing age is the biggest risk factor for development for the major life-threatening diseases in industrialized nations accounting for >90% of deaths. Alzheimer's dementia (AD) is among the most devastating. Currently approved therapies fail to slow progression of the disease, providing only modest improvements in memory. Recently reported work describes mechanistic studies of J147, a promising therapeutic molecule previously shown to rescue the severe cognitive deficits exhibited by aged, transgenic AD mice. Apparently, J147 targets the mitochondrial alpha-F1-ATP synthase (ATP5A). Modest inhibition of the ATP synthase modulates intracellular calcium to activate AMP-activated protein kinase to inhibit mammalian target of rapamycin, a known mechanism of lifespan extension from worms to mammals.

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.

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