Fight Aging!

Researchers have studied calorie restriction as a means to slow aging quite extensively, but organisms are highly complex and there is always more that can be investigated. Here, researchers look in detail at the effects of calorie restriction in mice on the beta cells of the pancreas, necessary for the normal function of insulin metabolism. It is interesting to see mitophagy reduction as a means of increased mitochondrial function, though this could indicate that calorie restriction adjusts mitochondrial activity in ways that extend the functional life span of an individual mitochondrion, thereby less need for mitophagy. The big question regarding research into the mechanisms of calorie restriction is whether this is a useful way to find a basis for drug development aimed at slowing aging, given that long-lived species exhibit a much smaller effect on life span resulting from the practice of calorie restriction, and studies in mice almost certainly overstate benefits that might be obtained in humans.

Caloric restriction (CR) extends organismal lifespan and health span by improving glucose homeostasis mechanisms. How CR affects organellar structure and function of pancreatic beta cells over the lifetime of the animal remains unknown. We investigated these questions by exposing adult mice to mild CR (i.e., 20% restriction) for up to 12 months and applied in vivo and in vitro metabolic phenotyping of beta cell function followed by single cell multiomics and multi-modal high resolution microscopy pipelines (electron, light, mass spectrometry, and isotope microscopy) to investigate how CR modulates beta cell heterogeneity and longevity.

Gene regulatory network analysis links this transcriptional phenotype to transcription factors involved in beta cell identity (Mafa) and homeostasis (Atf6). Imaging metabolomics further demonstrates that CR beta cells are more energetically competent. In fact, high-resolution light and electron microscopy indicates that CR reduces beta cell mitophagy and increases mitochondria mass, increasing mitochondrial ATP generation. Finally, we show that long-term CR delays the onset of beta cell aging and senescence to promote longevity by reducing beta cell turnover. Therefore, CR could be a feasible approach to preserve compromised beta cells during aging and diabetes.

Link: https://doi.org/10.1101/2023.08.23.554369