Reduced intestinal lipid absorption improves glucose metabolism in aged G2-Terc knockout mice

Biological aging associates with the development of type 2 diabetes, cancer, cardiovascular and neurodegenerative diseases. Similar to aging itself, shortened telomeres also associate with the development of metabolic disease. However, due to the severe pathologies associated with strong telomere shortening in mice, the exact effects of shortened telomeres on metabolic function remain incompletely understood. Here, we studied the metabolic consequences of moderate telomere shortening using second generation loss of telomerase activity in mice. Heterozygous Terc+/- mice were mated to generate wildtype and Terc-/- mice, which were inbred to generate second generation (G2) Terc-/- mice and wildtype controls. Aged male and female G2 Terc-/- mice and controls were characterized with respect to body weight and composition, glucose homeostasis, insulin sensitivity and metabolic activity. This was complemented with molecular and histological analysis of adipose tissue, liver and the intestine as well as microbiota analysis. We show that moderate telomere shortening leads improved insulin sensitivity and glucose tolerance in aged male and female G2 Terc-/- mice. This is accompanied by reduced fat and lean mass in both sexes. Mechanistically, the metabolic improvement results from reduced dietary lipid uptake in the intestine, characterized by reduced gene expression of fatty acid transporters in enterocytes of the small intestine. Furthermore, G2-Terc-/- mice showed significant alterations in the composition of gut microbiota with increased Bifidobacteriaceae and Erysipelotrichaceae, potentially contributing to the improved glucose metabolism. Our study shows that moderate telomere shortening reduces intestinal lipid absorption, resulting in reduced adiposity and improved glucose metabolism in aged mice.