Calorie Restriction Improves Pancreatic Function in Aging Mammals
Beta cells in the pancreas produce insulin and are essential to the regulation of glucose metabolism. Dysfunction in this cell population causes diabetes, whether the origin is autoimmune destruction of beta cells (type 1 diabetes) or senescence of beta cells brought on by obesity (type 2 diabetes). Aging also impairs beta cell function through some of the same mechanisms, such as cellular senescence and constant, unresolved inflammatory signaling. The practice of calorie restriction slows aging, albeit to a greater degree in short-lived species than in long-lived species, and so it is not surprising to see that calorie restriction attenuates this aspect of degenerative aging.
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. Here, we used single nucleus transcriptomics to show that CR increases the expression of genes for beta cell identity, protein processing, and organelle homeostasis. Gene regulatory network analysis link 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.