RG Adipocytes & Metabolism, Institute for Diabetes & Obesity, Helmholtz Diabetes Center, Helmholtz Center Munich, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany.
German Center for Diabetes Research (DZD), 85764, Neuherberg, Germany.
BMC Biol. 2023 Jul 4;21(1):150. doi: 10.1186/s12915-023-01629-8.
Biological aging is an important factor leading to the development of pathologies associated with metabolic dysregulation, including type 2 diabetes, cancer, cardiovascular and neurodegenerative diseases. Telomere length, a central feature of aging, has additionally been identified as inversely associated with glucose tolerance and the development of type 2 diabetes. However, the effects of shortened telomeres on body weight and metabolism remain incompletely understood. Here, we studied the metabolic consequences of moderate telomere shortening using second generation loss of telomerase activity in mice.
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 to 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, 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. These findings will guide future murine and human aging studies and provide important insights into the age associated development of type 2 diabetes and metabolic syndrome.
生物衰老（biological aging）是导致与代谢失调相关的病理学发展的一个重要因素，包括 2 型糖尿病、癌症、心血管疾病和神经退行性疾病。端粒长度（telomere length），衰老的一个核心特征，也被确定为与葡萄糖耐量和 2 型糖尿病的发展呈负相关。然而，端粒缩短对体重和代谢的影响仍不完全清楚。在这里，我们使用第二代端粒酶活性丧失的小鼠研究了端粒中度缩短的代谢后果。
老年雄性和雌性 G2 Terc-/- 小鼠和对照组的体重和组成、葡萄糖稳态、胰岛素敏感性和代谢活性都进行了特征描述。此外，还对脂肪组织、肝脏和肠道的分子和组织学分析以及微生物组分析进行了补充。我们表明，中度端粒缩短可导致老年雄性和雌性 G2 Terc-/- 小鼠的胰岛素敏感性和葡萄糖耐量提高。这伴随着两性脂肪和瘦体重的减少。从机制上讲，这种代谢改善是由于肠道中膳食脂质摄取减少所致，其特征是小肠肠上皮细胞中脂肪酸转运蛋白的基因表达减少。此外，G2-Terc-/- 小鼠的肠道微生物组组成发生了显著变化，这可能有助于改善葡萄糖代谢。
我们的研究表明，中度端粒缩短可减少肠道脂质吸收，从而导致老年小鼠的肥胖减少和葡萄糖代谢改善。这些发现将指导未来的小鼠和人类衰老研究，并为 2 型糖尿病和代谢综合征的年龄相关发展提供重要的见解。
