Glucose substitution prolongs maintenance of energy homeostasis and lifespan of telomere dysfunctional mice.

Pavlos Missios,Thomas Illig,Tina Wenz,K Lenhard Rudolph,Anne Gompf,Luis Miguel Guachalla,Götz Hartleben,Sundaram Reddy Chakkarappan,Zhangfa Song,Guido Von Figura,Yuan Zhou,Veronika Wulff,Martin D Burkhalter,Karsten Hiller,André Wegner ,Tina M Binz ,Bernhard Böhm ,Rui Wang-Sattler ,К Schimrigk ,Çagatay Güneş

doi:10.1038/ncomms5924

Abstract

DNA damage and telomere dysfunction shorten organismal lifespan. Here we show that oral glucose administration at advanced age increases health and lifespan of telomere dysfunctional mice. The study reveals that energy consumption increases in telomere dysfunctional cells resulting in enhanced glucose metabolism both in glycolysis and in the tricarboxylic acid cycle at organismal level. In ageing telomere dysfunctional mice, normal diet provides insufficient amounts of glucose thus leading to impaired energy homeostasis, catabolism, suppression of IGF-1/mTOR signalling, suppression of mitochondrial biogenesis and tissue atrophy. A glucose-enriched diet reverts these defects by activating glycolysis, mitochondrial biogenesis and oxidative glucose metabolism. The beneficial effects of glucose substitution on mitochondrial function and glucose metabolism are blocked by mTOR inhibition but mimicked by IGF-1 application. Together, these results provide the first experimental evidence that telomere dysfunction enhances the requirement of glucose substitution for the maintenance of energy homeostasis and IGF-1/mTOR-dependent mitochondrial biogenesis in ageing tissues.

Highlights

DNA damage and telomere dysfunction shorten organismal lifespan
A possible explanation for these findings indicates that G3 mTerc À / À mice continue to depend on increased glucose substitution to maintain energy homeostasis via elevated glucose metabolism in both glycolysis and tricarboxylic acid (TCA) cycle activity
Compared with wild-type mice, progeroid mice with dysfunctional telomeres show increases in energy consumption characterized by compensatory increases in ATP levels, oxygen consumption rates (OCRs) and glucose metabolism via glycolysis and the TCA cycle

Summary

Introduction

DNA damage and telomere dysfunction shorten organismal lifespan. Here we show that oral glucose administration at advanced age increases health and lifespan of telomere dysfunctional mice. The beneficial effects of glucose substitution on mitochondrial function and glucose metabolism are blocked by mTOR inhibition but mimicked by IGF-1 application Together, these results provide the first experimental evidence that telomere dysfunction enhances the requirement of glucose substitution for the maintenance of energy homeostasis and IGF-1/mTOR-dependent mitochondrial biogenesis in ageing tissues. Based on the findings that telomere dysfunction impairs mitochondrial functionality and that induction of senescence increases the energy demand of cells, it is possible that the accumulation of DNA damage would lead to changes in dietary requirements of ageing tissues. The study shows that telomere dysfunction increases the energy demand of telomere dysfunctional cells and glucose content of normal diet becomes limiting for the maintenance of energy homeostasis at the organismal level In this context, the substitution of glucose leads to a significant extension of the lifespan of the mice by stimulating glycolysis, IGF-1/mTOR-dependent mitochondrial biogenesis and oxidative glucose metabolism

Methods

Results

Conclusion