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

Missios P, Zhou Y, Guachalla LM, von Figura G, Wegner A, Chakkarappan SR, Binz T, Gompf A, Hartleben G, Burkhalter MD, Wulff V, Günes C, Sattler RW, Song Z, Illig T, Klaus S, Böhm BO, Wenz T, Hiller K, Rudolph KL - Nat Commun (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Cooperation Group of the Leibniz Institute for Age Research-Fritz-Lipmann-Institute (FLI) Jena with the University of Ulm, 89081 Ulm, Germany.

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.

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Related in: MedlinePlus

Glucose supplementation rescues mitochondrial mass and increases oxygen consumption and ATP levels in G3 mTerc−/− mice.12–15 month old G3 mTerc−/− mice with weight loss on normal ad libitum diet and age-matched mTerc+/+ mice were analyzed under continuous exposure to normal ad libitum diet or 2 weeks after switching to a glucose enriched diet (+Glc): (a–d,g,f) Histograms showing (a) the mitochondrial DNA (mtDNA) copy number in the indicated tissues, (b) the expression of PGC-1α and PGC-1β in the indicated tissues, (c) hepatic citrate synthase (CS) expression, (d) hepatic cytochrome c oxidase levels (COX), (f) oxygen consumption of freshly isolated haemtopoietic cells (Lin-negative), and (g) ATP-levels of freshly isolated haemtopoietic cells (Lin-negative). Data in all histograms are shown as relative expression levels/numbers with data for mTerc+/+ mice on normal ad libitum diet being set to 1. (a-d,g) n=4–6 mice per group, (f) n=9–17 mice per group. (e) Representative western blot analysis of OXPHOS enzymes ((NDUFA (CI), 30 kDa su (CII), ATPα (CV), Core 2 (CIII)) in liver homogenates. All statistical data were assessed using Student’s t-test and are presented as mean±s.e.m. *P<0.05, **P<0.01, ***P<0.001.
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f5: Glucose supplementation rescues mitochondrial mass and increases oxygen consumption and ATP levels in G3 mTerc−/− mice.12–15 month old G3 mTerc−/− mice with weight loss on normal ad libitum diet and age-matched mTerc+/+ mice were analyzed under continuous exposure to normal ad libitum diet or 2 weeks after switching to a glucose enriched diet (+Glc): (a–d,g,f) Histograms showing (a) the mitochondrial DNA (mtDNA) copy number in the indicated tissues, (b) the expression of PGC-1α and PGC-1β in the indicated tissues, (c) hepatic citrate synthase (CS) expression, (d) hepatic cytochrome c oxidase levels (COX), (f) oxygen consumption of freshly isolated haemtopoietic cells (Lin-negative), and (g) ATP-levels of freshly isolated haemtopoietic cells (Lin-negative). Data in all histograms are shown as relative expression levels/numbers with data for mTerc+/+ mice on normal ad libitum diet being set to 1. (a-d,g) n=4–6 mice per group, (f) n=9–17 mice per group. (e) Representative western blot analysis of OXPHOS enzymes ((NDUFA (CI), 30 kDa su (CII), ATPα (CV), Core 2 (CIII)) in liver homogenates. All statistical data were assessed using Student’s t-test and are presented as mean±s.e.m. *P<0.05, **P<0.01, ***P<0.001.

Mentions: Previous studies revealed that telomere dysfunction leads to impairments in mitochondrial biogenesis and function by activating p53/p21-dependent signalling67. In agreement with these studies, 12- to 15-month-old G3 mTerc−/− mice that lost body weight on normal diet exhibited impaired mitochondrial biogenesis in various tissues (such as liver, skeletal muscle and haematopoietic cells) as indicated by reduction in mitochondrial DNA (mtDNA) copy number (Fig. 5a and Supplementary Fig. 2B) and reduced expression of transcriptional regulators of mitochondrial biogenesis (Fig. 5b). In line with reductions in mtDNA, the expression of mitochondrial enzymes (cytochrome c oxidase and citrate synthase) were reduced in liver lysates of 12- to 15-month-old G3 mTerc−/− mice with weight loss on normal diet compared with mTerc+/+ mice (Fig. 5c,d).


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

Missios P, Zhou Y, Guachalla LM, von Figura G, Wegner A, Chakkarappan SR, Binz T, Gompf A, Hartleben G, Burkhalter MD, Wulff V, Günes C, Sattler RW, Song Z, Illig T, Klaus S, Böhm BO, Wenz T, Hiller K, Rudolph KL - Nat Commun (2014)

Glucose supplementation rescues mitochondrial mass and increases oxygen consumption and ATP levels in G3 mTerc−/− mice.12–15 month old G3 mTerc−/− mice with weight loss on normal ad libitum diet and age-matched mTerc+/+ mice were analyzed under continuous exposure to normal ad libitum diet or 2 weeks after switching to a glucose enriched diet (+Glc): (a–d,g,f) Histograms showing (a) the mitochondrial DNA (mtDNA) copy number in the indicated tissues, (b) the expression of PGC-1α and PGC-1β in the indicated tissues, (c) hepatic citrate synthase (CS) expression, (d) hepatic cytochrome c oxidase levels (COX), (f) oxygen consumption of freshly isolated haemtopoietic cells (Lin-negative), and (g) ATP-levels of freshly isolated haemtopoietic cells (Lin-negative). Data in all histograms are shown as relative expression levels/numbers with data for mTerc+/+ mice on normal ad libitum diet being set to 1. (a-d,g) n=4–6 mice per group, (f) n=9–17 mice per group. (e) Representative western blot analysis of OXPHOS enzymes ((NDUFA (CI), 30 kDa su (CII), ATPα (CV), Core 2 (CIII)) in liver homogenates. All statistical data were assessed using Student’s t-test and are presented as mean±s.e.m. *P<0.05, **P<0.01, ***P<0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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f5: Glucose supplementation rescues mitochondrial mass and increases oxygen consumption and ATP levels in G3 mTerc−/− mice.12–15 month old G3 mTerc−/− mice with weight loss on normal ad libitum diet and age-matched mTerc+/+ mice were analyzed under continuous exposure to normal ad libitum diet or 2 weeks after switching to a glucose enriched diet (+Glc): (a–d,g,f) Histograms showing (a) the mitochondrial DNA (mtDNA) copy number in the indicated tissues, (b) the expression of PGC-1α and PGC-1β in the indicated tissues, (c) hepatic citrate synthase (CS) expression, (d) hepatic cytochrome c oxidase levels (COX), (f) oxygen consumption of freshly isolated haemtopoietic cells (Lin-negative), and (g) ATP-levels of freshly isolated haemtopoietic cells (Lin-negative). Data in all histograms are shown as relative expression levels/numbers with data for mTerc+/+ mice on normal ad libitum diet being set to 1. (a-d,g) n=4–6 mice per group, (f) n=9–17 mice per group. (e) Representative western blot analysis of OXPHOS enzymes ((NDUFA (CI), 30 kDa su (CII), ATPα (CV), Core 2 (CIII)) in liver homogenates. All statistical data were assessed using Student’s t-test and are presented as mean±s.e.m. *P<0.05, **P<0.01, ***P<0.001.
Mentions: Previous studies revealed that telomere dysfunction leads to impairments in mitochondrial biogenesis and function by activating p53/p21-dependent signalling67. In agreement with these studies, 12- to 15-month-old G3 mTerc−/− mice that lost body weight on normal diet exhibited impaired mitochondrial biogenesis in various tissues (such as liver, skeletal muscle and haematopoietic cells) as indicated by reduction in mitochondrial DNA (mtDNA) copy number (Fig. 5a and Supplementary Fig. 2B) and reduced expression of transcriptional regulators of mitochondrial biogenesis (Fig. 5b). In line with reductions in mtDNA, the expression of mitochondrial enzymes (cytochrome c oxidase and citrate synthase) were reduced in liver lysates of 12- to 15-month-old G3 mTerc−/− mice with weight loss on normal diet compared with mTerc+/+ mice (Fig. 5c,d).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Cooperation Group of the Leibniz Institute for Age Research-Fritz-Lipmann-Institute (FLI) Jena with the University of Ulm, 89081 Ulm, Germany.

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.

Show MeSH
Related in: MedlinePlus