Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults.

Abstract:

:Metformin and exercise independently improve insulin sensitivity and decrease the risk of diabetes. Metformin was also recently proposed as a potential therapy to slow aging. However, recent evidence indicates that adding metformin to exercise antagonizes the exercise-induced improvement in insulin sensitivity and cardiorespiratory fitness. The purpose of this study was to test the hypothesis that metformin diminishes the improvement in insulin sensitivity and cardiorespiratory fitness after aerobic exercise training (AET) by inhibiting skeletal muscle mitochondrial respiration and protein synthesis in older adults (62 ± 1 years). In a double-blinded fashion, participants were randomized to placebo (n = 26) or metformin (n = 27) treatment during 12 weeks of AET. Independent of treatment, AET decreased fat mass, HbA1c, fasting plasma insulin, 24-hr ambulant mean glucose, and glycemic variability. However, metformin attenuated the increase in whole-body insulin sensitivity and VO2 max after AET. In the metformin group, there was no overall change in whole-body insulin sensitivity after AET due to positive and negative responders. Metformin also abrogated the exercise-mediated increase in skeletal muscle mitochondrial respiration. The change in whole-body insulin sensitivity was correlated to the change in mitochondrial respiration. Mitochondrial protein synthesis rates assessed during AET were not different between treatments. The influence of metformin on AET-induced improvements in physiological function was highly variable and associated with the effect of metformin on the mitochondria. These data suggest that prior to prescribing metformin to slow aging, additional studies are needed to understand the mechanisms that elicit positive and negative responses to metformin with and without exercise.

journal_name

Aging Cell

journal_title

Aging cell

authors

Konopka AR,Laurin JL,Schoenberg HM,Reid JJ,Castor WM,Wolff CA,Musci RV,Safairad OD,Linden MA,Biela LM,Bailey SM,Hamilton KL,Miller BF

doi

10.1111/acel.12880

subject

Has Abstract

pub_date

2019-02-01 00:00:00

pages

e12880

issue

1

eissn

1474-9718

issn

1474-9726

journal_volume

18

pub_type

杂志文章,随机对照试验
  • Meta-analysis on blood transcriptomic studies identifies consistently coexpressed protein-protein interaction modules as robust markers of human aging.

    abstract::The bodily decline that occurs with advancing age strongly impacts on the prospects for future health and life expectancy. Despite the profound role of age in disease etiology, knowledge about the molecular mechanisms driving the process of aging in humans is limited. Here, we used an integrative network-based approac...

    journal_title:Aging cell

    pub_type: 杂志文章,meta分析

    doi:10.1111/acel.12160

    authors: van den Akker EB,Passtoors WM,Jansen R,van Zwet EW,Goeman JJ,Hulsman M,Emilsson V,Perola M,Willemsen G,Penninx BW,Heijmans BT,Maier AB,Boomsma DI,Kok JN,Slagboom PE,Reinders MJ,Beekman M

    更新日期:2014-04-01 00:00:00

  • Free radical generation by skeletal muscle of adult and old mice: effect of contractile activity.

    abstract::Oxidative modification of cellular components may contribute to tissue dysfunction during aging. In skeletal muscle, contractile activity increases the generation of reactive oxygen and nitrogen species (ROS). The question of whether contraction-induced ROS generation is further increased in skeletal muscle of the eld...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/j.1474-9726.2006.00198.x

    authors: Vasilaki A,Mansouri A,Van Remmen H,van der Meulen JH,Larkin L,Richardson AG,McArdle A,Faulkner JA,Jackson MJ

    更新日期:2006-04-01 00:00:00

  • Attenuation of ataxia telangiectasia mutated signalling mitigates age-associated intervertebral disc degeneration.

    abstract::Previously, we reported that persistent DNA damage accelerates ageing of the spine, but the mechanisms behind this process are not well understood. Ataxia telangiectasia mutated (ATM) is a protein kinase involved in the DNA damage response, which controls cell fate, including cell death. To test the role of ATM in the...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.13162

    authors: Han Y,Zhou CM,Shen H,Tan J,Dong Q,Zhang L,McGowan SJ,Zhao J,Sowa GA,Kang JD,Niedernhofer LJ,Robbins PD,Vo NN

    更新日期:2020-07-01 00:00:00

  • Neuronal control of lipid metabolism by STR-2 G protein-coupled receptor promotes longevity in Caenorhabditis elegans.

    abstract::The G protein-coupled receptor (GPCR) encoding family of genes constitutes more than 6% of genes in Caenorhabditis elegans genome. GPCRs control behavior, innate immunity, chemotaxis, and food search behavior. Here, we show that C. elegans longevity is regulated by a chemosensory GPCR STR-2, expressed in AWC and ASI a...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.13160

    authors: Dixit A,Sandhu A,Modi S,Shashikanth M,Koushika SP,Watts JL,Singh V

    更新日期:2020-06-01 00:00:00

  • Dysfunction of the unfolded protein response increases neurodegeneration in aged rat hippocampus following proteasome inhibition.

    abstract::Dysfunctions of the ubiquitin proteasome system (UPS) have been proposed to be involved in the aetiology and/or progression of several age-related neurodegenerative disorders. However, the mechanisms linking proteasome dysfunction to cell degeneration are poorly understood. We examined in young and aged rat hippocampu...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/j.1474-9726.2009.00519.x

    authors: Gavilán MP,Pintado C,Gavilán E,Jiménez S,Ríos RM,Vitorica J,Castaño A,Ruano D

    更新日期:2009-12-01 00:00:00

  • Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults: A randomized, double-blind, placebo-controlled, multicenter trial: The MASTERS trial.

    abstract::Progressive resistance exercise training (PRT) is the most effective known intervention for combating aging skeletal muscle atrophy. However, the hypertrophic response to PRT is variable, and this may be due to muscle inflammation susceptibility. Metformin reduces inflammation, so we hypothesized that metformin would ...

    journal_title:Aging cell

    pub_type: 杂志文章,多中心研究,随机对照试验

    doi:10.1111/acel.13039

    authors: Walton RG,Dungan CM,Long DE,Tuggle SC,Kosmac K,Peck BD,Bush HM,Villasante Tezanos AG,McGwin G,Windham ST,Ovalle F,Bamman MM,Kern PA,Peterson CA

    更新日期:2019-12-01 00:00:00

  • Age-related changes in regional brain mitochondria from Fischer 344 rats.

    abstract::Brain mitochondrial function has been posited to decline with aging. In order to test this hypothesis, cortical and striatal mitochondria were isolated from Fischer 344 rats at 2, 5, 11, 24 and 33 months of age. Mitochondrial membrane potential remained stable through 24 months, declining slightly in mitochondria from...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/j.1474-9726.2005.00156.x

    authors: LaFrance R,Brustovetsky N,Sherburne C,Delong D,Dubinsky JM

    更新日期:2005-06-01 00:00:00

  • The histone deacetylase inhibitor butyrate improves metabolism and reduces muscle atrophy during aging.

    abstract::Sarcopenia, the loss of skeletal muscle mass and function during aging, is a major contributor to disability and frailty in the elderly. Previous studies found a protective effect of reduced histone deacetylase activity in models of neurogenic muscle atrophy. Because loss of muscle mass during aging is associated with...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.12387

    authors: Walsh ME,Bhattacharya A,Sataranatarajan K,Qaisar R,Sloane L,Rahman MM,Kinter M,Van Remmen H

    更新日期:2015-12-01 00:00:00

  • A novel kinase regulates dietary restriction-mediated longevity in Caenorhabditis elegans.

    abstract::Although dietary restriction (DR) is known to extend lifespan across species, from yeast to mammals, the signalling events downstream of food/nutrient perception are not well understood. In Caenorhabditis elegans, DR is typically attained either by using the eat-2 mutants that have reduced pharyngeal pumping leading t...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.12218

    authors: Chamoli M,Singh A,Malik Y,Mukhopadhyay A

    更新日期:2014-08-01 00:00:00

  • Mitochondrial mass governs the extent of human T cell senescence.

    abstract::The susceptibility of human CD4+ and CD8+ T cells to senesce differs, with CD8+ T cells acquiring an immunosenescent phenotype faster than the CD4+ T cell compartment. We show here that it is the inherent difference in mitochondrial content that drives this phenotype, with senescent human CD4+ T cells displaying a hig...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.13067

    authors: Callender LA,Carroll EC,Bober EA,Akbar AN,Solito E,Henson SM

    更新日期:2020-02-01 00:00:00

  • DLP1-dependent mitochondrial fragmentation and redistribution mediate prion-associated mitochondrial dysfunction and neuronal death.

    abstract::Mitochondrial malfunction is a universal and critical step in the pathogenesis of many neurodegenerative diseases including prion diseases. Dynamin-like protein 1 (DLP1) is one of the key regulators of mitochondrial fission. In this study, we investigated the role of DLP1 in mitochondrial fragmentation and dysfunction...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.12693

    authors: Li C,Wang D,Wu W,Yang W,Ali Shah SZ,Zhao Y,Duan Y,Wang L,Zhou X,Zhao D,Yang L

    更新日期:2018-02-01 00:00:00

  • Calcium buffering systems and calcium signaling in aged rat basal forebrain neurons.

    abstract::Disturbances of neuronal Ca2+ homeostasis are considered to be important determinants of age-related cognitive impairment. Cholinergic neurons of the basal forebrain (BF) are principal targets of decline associated with aging and dementia. During the last several years, we have attempted to link these concepts in a ra...

    journal_title:Aging cell

    pub_type: 杂志文章,评审

    doi:10.1111/j.1474-9726.2007.00293.x

    authors: Murchison D,Griffith WH

    更新日期:2007-06-01 00:00:00

  • DNA damage response and cellular senescence in tissues of aging mice.

    abstract::The impact of cellular senescence onto aging of organisms is not fully clear, not at least because of the scarcity of reliable data on the mere frequency of senescent cells in aging tissues. Activation of a DNA damage response including formation of DNA damage foci containing activated H2A.X (gamma-H2A.X) at either un...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/j.1474-9726.2009.00481.x

    authors: Wang C,Jurk D,Maddick M,Nelson G,Martin-Ruiz C,von Zglinicki T

    更新日期:2009-06-01 00:00:00

  • FOXO3 targets are reprogrammed as Huntington's disease neural cells and striatal neurons face senescence with p16INK4a increase.

    abstract::Neurodegenerative diseases (ND) have been linked to the critical process in aging-cellular senescence. However, the temporal dynamics of cellular senescence in ND conditions is unresolved. Here, we show senescence features develop in human Huntington's disease (HD) neural stem cells (NSCs) and medium spiny neurons (MS...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.13226

    authors: Voisin J,Farina F,Naphade S,Fontaine M,Tshilenge KT,Galicia Aguirre C,Lopez-Ramirez A,Dancourt J,Ginisty A,Sasidharan Nair S,Lakshika Madushani K,Zhang N,Lejeune FX,Verny M,Campisi J,Ellerby LM,Neri C

    更新日期:2020-11-01 00:00:00

  • Effects and mechanisms of prolongevity induced by Lactobacillus gasseri SBT2055 in Caenorhabditis elegans.

    abstract::Lactic-acid bacteria are widely recognized beneficial host associated groups of the microbiota of humans and animals. Some lactic-acid bacteria have the ability to extend the lifespan of the model animals. The mechanisms behind the probiotic effects of bacteria are not entirely understood. Recently, we reported the be...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.12431

    authors: Nakagawa H,Shiozaki T,Kobatake E,Hosoya T,Moriya T,Sakai F,Taru H,Miyazaki T

    更新日期:2016-04-01 00:00:00

  • Activity of mannose-binding lectin in centenarians.

    abstract::We analyzed MBL2 gene variants in two cohorts of centenarians, octo-nonagenarians and nonagenarians, and in the general population, one from Sardinia Island (Italy), recruited in the frame of the AKea study, and another from Campania (southern Italy), to search for haplotypes related to longevity. We also assessed in ...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/j.1474-9726.2012.00793.x

    authors: Tomaiuolo R,Ruocco A,Salapete C,Carru C,Baggio G,Franceschi C,Zinellu A,Vaupel J,Bellia C,Lo Sasso B,Ciaccio M,Castaldo G,Deiana L

    更新日期:2012-06-01 00:00:00

  • Cytoskeleton stiffness regulates cellular senescence and innate immune response in Hutchinson-Gilford Progeria Syndrome.

    abstract::Hutchinson-Gilford progeria syndrome (HGPS) is caused by the accumulation of mutant prelamin A (progerin) in the nuclear lamina, resulting in increased nuclear stiffness and abnormal nuclear architecture. Nuclear mechanics are tightly coupled to cytoskeletal mechanics via lamin A/C. However, the role of cytoskeletal/n...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.13152

    authors: Mu X,Tseng C,Hambright WS,Matre P,Lin CY,Chanda P,Chen W,Gu J,Ravuri S,Cui Y,Zhong L,Cooke JP,Niedernhofer LJ,Robbins PD,Huard J

    更新日期:2020-08-01 00:00:00

  • Mitochondrial-targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice.

    abstract::Mitochondrial dysfunction plays a key pathogenic role in aging skeletal muscle resulting in significant healthcare costs in the developed world. However, there is no pharmacologic treatment to rapidly reverse mitochondrial deficits in the elderly. Here, we demonstrate that a single treatment with the mitochondrial-tar...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.12102

    authors: Siegel MP,Kruse SE,Percival JM,Goh J,White CC,Hopkins HC,Kavanagh TJ,Szeto HH,Rabinovitch PS,Marcinek DJ

    更新日期:2013-10-01 00:00:00

  • Pharmacological maintenance of protein homeostasis could postpone age-related disease.

    abstract::Over the last 10 years, various screens of small molecules have been conducted to find long sought interventions in aging. Most of these studies were performed in invertebrates but the demonstration of pharmacological lifespan extension in the mouse has created considerable excitement. Since aging is a common risk fac...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/j.1474-9726.2012.00789.x

    authors: Alavez S,Lithgow GJ

    更新日期:2012-04-01 00:00:00

  • Aldose reductase and AGE-RAGE pathways: central roles in the pathogenesis of vascular dysfunction in aging rats.

    abstract::Aging is inevitably accompanied by gradual and irreversible innate endothelial dysfunction. In this study, we tested the hypothesis that accentuation of glucose metabolism via the aldose reductase (AR) pathway contributes to age-related vascular dysfunction. AR protein and activity levels were significantly increased ...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/j.1474-9726.2010.00606.x

    authors: Hallam KM,Li Q,Ananthakrishnan R,Kalea A,Zou YS,Vedantham S,Schmidt AM,Yan SF,Ramasamy R

    更新日期:2010-10-01 00:00:00

  • PAPP-A: a new anti-aging target?

    abstract::This article focuses on the role of PAPP-A in mammalian aging. It introduces PAPP-A and a little of its history, briefly discusses the function of PAPP-A in the insulin-like growth factor (IGF) system and the regulators of PAPP-A expression, and then reviews data concerning PAPP-A in aging and age-related diseases esp...

    journal_title:Aging cell

    pub_type: 杂志文章,评审

    doi:10.1111/j.1474-9726.2010.00630.x

    authors: Conover CA

    更新日期:2010-12-01 00:00:00

  • Dietary restriction of rodents decreases aging rate without affecting initial mortality rate -- a meta-analysis.

    abstract::Dietary restriction (DR) extends lifespan in multiple species from various taxa. This effect can arise via two distinct but not mutually exclusive ways: a change in aging rate and/or vulnerability to the aging process (i.e. initial mortality rate). When DR affects vulnerability, this lowers mortality instantly, wherea...

    journal_title:Aging cell

    pub_type: 杂志文章,meta分析

    doi:10.1111/acel.12061

    authors: Simons MJ,Koch W,Verhulst S

    更新日期:2013-06-01 00:00:00

  • Inhibition of histone acetyltransferase GCN5 extends lifespan in both yeast and human cell lines.

    abstract::Histone acetyltransferases (HATs) are important enzymes that transfer acetyl groups onto histones and thereby regulate both gene expression and chromosomal structures. Previous work has shown that the activation of sirtuins, which are histone deacetylases, can extend lifespan. This suggests that inhibiting HATs may ha...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.13129

    authors: Huang B,Zhong D,Zhu J,An Y,Gao M,Zhu S,Dang W,Wang X,Yang B,Xie Z

    更新日期:2020-04-01 00:00:00

  • A neuroprotective role for the DNA damage checkpoint in tauopathy.

    abstract::ATM and p53, effectors of the DNA damage checkpoint, are generally considered pro-apoptotic in neurons. We show that DNA damage and checkpoint activation occurs in postmitotic neurons in animal models of tauopathy, neurodegenerative disorders that include Alzheimer's disease. Surprisingly, checkpoint attenuation poten...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/j.1474-9726.2011.00778.x

    authors: Khurana V,Merlo P,DuBoff B,Fulga TA,Sharp KA,Campbell SD,Götz J,Feany MB

    更新日期:2012-04-01 00:00:00

  • Sterol regulatory element-binding protein-1c orchestrates metabolic remodeling of white adipose tissue by caloric restriction.

    abstract::Caloric restriction (CR) can delay onset of several age-related pathophysiologies and extend lifespan in various species, including rodents. CR also induces metabolic remodeling involved in activation of lipid metabolism, enhancement of mitochondrial biogenesis, and reduction of oxidative stress in white adipose tissu...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.12576

    authors: Fujii N,Narita T,Okita N,Kobayashi M,Furuta Y,Chujo Y,Sakai M,Yamada A,Takeda K,Konishi T,Sudo Y,Shimokawa I,Higami Y

    更新日期:2017-06-01 00:00:00

  • Relative contribution of V-H+ATPase and NA+/H+ exchanger to bicarbonate reabsorption in proximal convoluted tubules of old rats.

    abstract::With aging, the kidney develops a progressive deterioration of several structures and functions. Proximal tubular acidification is impaired in old rats with a decrease in the activity of brush border Na+/H+ exchange and a fall of H-ion flux measured with micropuncture experiments. In the present work we evaluate the c...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/j.1474-9726.2006.00229.x

    authors: Fiori M,Radrizzani M,Díaz-Sylvester P,Müller A,Corti T,Monserrat A,Amorena C

    更新日期:2006-10-01 00:00:00

  • Experimental insights into age-exacerbated cognitive dysfunction after peripheral surgery.

    abstract::Here I comment on the recent contribution by Barrientos et al. J. Neurosci. 32, 14641-14648 (2012) addressing treatment possibilities for surgery-induced cognitive dysfunction. It has been over 15 years since the publication of a landmark study that indicated age as a major risk factor for postoperative cognitive dysf...

    journal_title:Aging cell

    pub_type: 评论,杂志文章

    doi:10.1111/acel.12066

    authors: Fidalgo AR

    更新日期:2013-06-01 00:00:00

  • A role for the Werner syndrome protein in epigenetic inactivation of the pluripotency factor Oct4.

    abstract::Werner syndrome (WS) is an autosomal recessive disorder, the hallmarks of which are premature aging and early onset of neoplastic diseases (Orren, 2006; Bohr, 2008). The gene, whose mutation underlies the WS phenotype, is called WRN. The protein encoded by the WRN gene, WRNp, has DNA helicase activity (Gray et al., 19...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/j.1474-9726.2010.00585.x

    authors: Smith JA,Ndoye AM,Geary K,Lisanti MP,Igoucheva O,Daniel R

    更新日期:2010-08-01 00:00:00

  • Telomerase reverse transcriptase haploinsufficiency and telomere length in individuals with 5p- syndrome.

    abstract::Telomerase, which maintains the ends of chromosomes, consists of two core components, the telomerase reverse transcriptase (TERT) and the telomerase RNA (TERC). Haploinsufficiency for TERC or TERT leads to progressive telomere shortening and autosomal dominant dyskeratosis congenita (DC). The clinical manifestations o...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/j.1474-9726.2007.00324.x

    authors: Du HY,Idol R,Robledo S,Ivanovich J,An P,Londono-Vallejo A,Wilson DB,Mason PJ,Bessler M

    更新日期:2007-10-01 00:00:00

  • Reduced repression of cytokine signaling ameliorates age-induced decline in hematopoietic stem cell function.

    abstract::Aging causes profound effects on the hematopoietic stem cell (HSC) pool, including an altered output of mature progeny and enhanced self-propagation of repopulating-defective HSCs. An important outstanding question is whether HSCs can be protected from aging. The signal adaptor protein LNK negatively regulates hematop...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/j.1474-9726.2012.00863.x

    authors: Norddahl GL,Wahlestedt M,Gisler S,Sigvardsson M,Bryder D

    更新日期:2012-12-01 00:00:00