Fight Aging!

Researchers have shown that depleting the amino acid arginine produces some of the effects of calorie restriction, including loss of fat tissue and upregulation of autophagy. In this open access paper, researchers use a few different approaches to this end to illustrate that this may be a viable strategy for improved health. As is the case for all calorie restriction mimetics, it is worth recalling that (a) effects on long-term health and life span in short-lived species are larger than those in long-lived species, and (b) the actual practice of calorie restriction will usually be more effective than an intervention that targets only some of the many mechanisms involved.

Intermittent fasting and caloric restriction (IF and CR) are effective therapies against obesity and its complications, including non-alcoholic fatty liver disease (NAFLD), dyslipidemia, and insulin resistance, in mice and in humans. However, intensive lifestyle modifications are rarely sustainable in real-world settings. We previously found that the hepatocyte response to glucose deprivation is sufficient to mimic several key therapeutic effects of generalized IF and CR on hepatic steatosis, hepatic inflammation, and insulin resistance, in part by inducing hepatocyte autophagic flux and secretion of the anti-diabetic hepatokine, FGF. We thus set out here to leverage this pathway against metabolic disease. Clinically, this approach is of particular interest, because hepatocyte glucose transport and its downstream pathways are amenable to pharmacological therapy.

We previously identified the arginine ureahydrolase, arginase 2 (ARG2), as a hepatocyte glucose withdrawal-induced factor. Induction of ARG2 is sufficient to exert part of the therapeutic metabolic sequelae of caloric restriction. Subsequent data further demonstrated that arginase 1 and arginase 2 polymorphisms determine circulating arginine levels in arginine-supplemented and unsupplemented dietary contexts. Together, the data initiated the hypothesis that augmenting arginine catabolism can modulate host arginine status - and thereby therapeutically direct energy metabolism.

Here, we demonstrate that conferred arginine iminohydrolysis by the bacterial virulence factor and arginine deiminase, arcA, promotes mammalian energy expenditure and insulin sensitivity and reverses dyslipidemia, hepatic steatosis, and inflammation in obese mice. Extending this, pharmacological arginine catabolism via pegylated arginine deiminase (ADI-PEG 20) recapitulates these metabolic effects in dietary and genetically obese models. These effects require hepatic and whole-body expression of the autophagy complex protein BECN1 and hepatocyte-specific FGF21 secretion. The data thus reveal an unexpected therapeutic utility for arginine catabolism in modulating energy metabolism by activating systemic autophagy, which is now exploitable through readily available pharmacotherapy.

Link: https://doi.org/10.1016/j.xcrm.2021.100498