Aging & Metabolism Research Program

Metabolism produces the building blocks and energy necessary for life through an elegant series of dynamically regulated biochemical transformations. Defects in metabolism arise as we age. Scientists in the Aging and Metabolism Research Program have a common interest in the metabolic basis of age-related disease and in extending the health of our aging population.

Our investigators study a variety of age-related diseases integrated across multiple organ systems, including heart failure, diabetic cardiomyopathy, macular degeneration, osteoarthritis, sarcopenia, and neurodegenerative disorders. Common among these afflictions are alterations in cellular metabolism and energy production. Mitochondria are intracellular organelles that play an essential role in metabolism and in the response of cells to physiologic and pathophysiologic stress. The laboratories that comprise our Program investigate distinct aspects of mitochondrial and cellular metabolism, identifying alterations that occur with age that are exacerbated by obesity and diabetes. Associated defects in energy homeostasis, cellular and mitochondrial quality control, production and removal of toxic free radical species, and the inflammatory response are explored to define underlying causes of diseases that primarily afflict the elderly. Together, these multidisciplinary approaches create a synergistic, collaborative, and creative environment that fosters discovery and training.

2020

Brown JL, Lawrence MM, Ahn B, Kneis P, Piekarz KM, Qaisar R, Ranjit R, Bian J, Pharaoh G, Brown C, Peelor FF 3rd, Kinter MT, Miller BF, Richardson A, Van Remmen H. Cancer cachexia in a mouse model of oxidative stress. J Cachexia Sarcopenia Muscle, 2020 September, PMID: 32918528

Bhaskaran S, Pollock N, C Macpherson P, Ahn B, Piekarz KM, Staunton CA, Brown JL, Qaisar R, Vasilaki A, Richardson A, McArdle A, Jackson MJ, Brooks SV, Van Remmen H. Neuron-specific deletion of CuZnSOD leads to an advanced sarcopenic phenotype in older mice. Aging Cell:e13225, 2020 September, PMID: 32886862

Miller BF, Thyfault JP. Exercise-Pharmacology Interactions: Metformin, Statins, and Healthspan. Physiology (Bethesda) 35:338-347, 2020 September, PMID: 32783612

Eyster CA, Matsuzaki S, Newhardt MF, Giorgione JR, Humphries KM. Diabetes induced decreases in PKA signaling in cardiomyocytes: The role of insulin. PLoS One 15:e0231806, 2020 August, PMID: 32817622, PMCID: PMC7444578

Pharaoh G, Brown JL, Sataranatarajan K, Kneis P, Bian J, Ranjit R, Hadad N, Georgescu C, Rabinovitch P, Ran Q, Wren JD, Freeman W, Kinter M, Richardson A, Van Remmen H. Targeting cPLA2 derived lipid hydroperoxides as a potential intervention for sarcopenia. Sci Rep 10:13968, 2020 August, PMID: 32811851, PMCID: PMC7435184

Wolff CA, Lawrence MM, Porter H, Zhang Q, Reid JJ, Laurin JL, Musci RV, Linden MA, Peelor FF 3rd, Wren JD, Creery JS, Cutler KJ, Carson RH, Price JC, Hamilton KL, Miller BF. Sex differences in changes of protein synthesis with rapamycin treatment are minimized when metformin is added to rapamycin. Geroscience, 2020 August, PMID: 32761290

Howell RD, Dominguez-Lopez S, Ocañas SR, Freeman WM, Beckstead MJ. Female mice are resilient to age-related decline of substantia nigra dopamine neuron firing parameters. Neurobiol Aging 95:195-204, 2020 August, PMID: 32846275

Hossen MN, Wang L, Chinthalapally HR, Robertson JD, Fung KM, Wilhelm S, Bieniasz M, Bhattacharya R, Mukherjee P. Switching the intracellular pathway and enhancing the therapeutic efficacy of small interfering RNA by auroliposome. Sci Adv 6:eaba5379, 2020 July, PMID: 32743073, PMCID: PMC7375829

Chiao YA, Zhang H, Sweetwyne M, Whitson J, Ting YS, Basisty N, Pino LK, Quarles E, Nguyen NH, Campbell MD, Zhang T, Gaffrey MJ, Merrihew G, Wang L, Yue Y, Duan D, Granzier HL, Szeto HH, Qian WJ, Marcinek D, MacCoss MJ, Rabinovitch P. Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice. Elife 9, 2020 July, PMID: 32648542, PMCID: PMC7377906

Van Pelt DW, Vechetti IJ Jr, Lawrence MM, Van Pelt KL, Patel P, Miller BF, Butterfield TA, Dupont-Versteegden EE. Serum extracellular vesicle miR-203a-3p content is associated with skeletal muscle mass and protein turnover during disuse atrophy and regrowth. Am J Physiol Cell Physiol, 2020 July, PMID: 32639875, PMCID: PMC7500218

Lawrence MM, Van Pelt DW, Confides AL, Hettinger ZR, Hunt ER, Reid JJ, Laurin JL, Peelor FF 3rd, Butterfield TA, Miller BF, Dupont-Versteegden EE. Muscle from aged rats is resistant to mechanotherapy during atrophy and reloading. Geroscience, 2020 June, PMID: 32588343

Olson AL, Humphries K. Recent advances in understanding glucose transport and glucose disposal. F1000Res 9, 2020 June, PMID: 32595948, PMCID: PMC7315251

Zhao M, Kao CS, Arndt C, Tran DD, Cho WI, Maksimovic K, Chen XXL, Khan M, Zhu H, Qiao J, Peng K, Hong J, Xu J, Kim D, Kim JR, Lee J, van Bruggen R, Yoon WH, Park J. Knockdown of genes involved in axonal transport enhances the toxicity of human neuromuscular disease-linked MATR3 mutations in Drosophila. FEBS Lett, 2020 June, PMID: 32515490

Sataranatarajan K, Pharaoh G, Brown JL, Ranjit R, Piekarz KM, Street K, Wren JD, Georgescu C, Kinter C, Kinter M, Freeman WM, Richardson A, Van Remmen H. Molecular changes in transcription and metabolic pathways underlying muscle atrophy in the CuZnSOD null mouse model of sarcopenia. Geroscience, 2020 May, PMID: 32394347, PMCID: PMC7394980

Yap ZY, Strucinska K, Matsuzaki S, Lee S, Si Y, Humphries K, Tarnopolsky MA, Yoon WH. A biallelic pathogenic variant in the OGDH gene results in a neurological disorder with features of a mitochondrial disease. J Inherit Metab Dis, 2020 May, PMID: 32383294

Wolff CA, Reid JJ, Musci RV, Bruns DR, Linden MA, Konopka AR, Peelor FF, Miller BF, Hamilton KL. Corrigendum to: Differential Effects of Rapamycin and Metformin in Combination With Rapamycin on Mechanisms of Proteostasis in Cultured Skeletal Myotubes. J Gerontol A Biol Sci Med Sci 75:892, 2020 April, PMID: 32302402, PMCID: PMC7164524

Griffin TM, Lories RJ. Cracking the code on the innate immune program in OA. Osteoarthritis Cartilage, 2020 April, PMID: 32278072

Groennebaek T, Nielsen J, Jespersen NR, Botker HE, de Paoli FV, Miller BF, Vissing K. Utilization of biomarkers as predictors of skeletal muscle mitochondrial content after physiological intervention and in clinical settings. Am J Physiol Endocrinol Metab, 2020 April, PMID: 32255679

Miller BF, Reid JJ, Price JC, Lin HL, Atherton PJ, Smith K. CORES OF REPRODUCIBILITY IN PHYSIOLOGY: THE USE OF DEUTERATED WATER FOR THE MEASUREMENT OF PROTEIN SYNTHESIS. J Appl Physiol (1985), 2020 March, PMID: 32213116

Sun C, Sakashita H, Kim J, Tang Z, Upchurch GM, Yao L, Berry WL, Griffin TM, Olson LE. Mosaic Mutant Analysis Identifies PDGFRα/PDGFRβ as Negative Regulators of Adipogenesis. Cell Stem Cell, 2020 March, PMID: 32229310, PMCID: PMC7214206

Piekarz KM, Bhaskaran S, Sataranatarajan K, Street K, Premkumar P, Saunders D, Zalles M, Gulej R, Khademi S, Laurin J, Peelor R, Miller BF, Towner R, Van Remmen H. Molecular changes associated with spinal cord aging. Geroscience, 2020 March, PMID: 32144690, PMCID: PMC7205981

Lawrence MM, Van Pelt DW, Confides AL, Hunt ER, Hettinger ZR, Laurin JL, Reid JJ, Peelor FF 3rd, Butterfield TA, Dupont-Versteegden EE, Miller BF. Massage as a mechanotherapy promotes skeletal muscle protein and ribosomal turnover but does not mitigate muscle atrophy during disuse in adult rats. Acta Physiol (Oxf):e13460, 2020 March, PMID: 32125770, PMCID: PMC7293583

Griffin TM, Batushansky A, Hudson J, Lopes EBP. Correlation network analysis shows divergent effects of a long-term, high-fat diet and exercise on early stage osteoarthritis phenotypes in mice. J Sport Health Sci 9:119-131, 2020 March, PMID: 32099720, PMCID: PMC7031811

Ehrlicher SE, Stierwalt HD, Miller BF, Newsom SA, Robinson MM. Mitochondrial adaptations to exercise do not require Bcl2-mediated autophagy but occur with BNIP3/Parkin activation. FASEB J, 2020 February, PMID: 32030805

Quarles E, Basisty N, Chiao YA, Merrihew G, Gu H, Sweetwyne MT, Fredrickson J, Nguyen NH, Razumova M, Kooiker K, Moussavi-Harami F, Regnier M, Quarles C, MacCoss M, Rabinovitch PS. Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment. Aging Cell 19:e13086, 2020 February, PMID: 31823466, PMCID: PMC6996961

Cardoso AC, Lam NT, Savla JJ, Nakada Y, Pereira AHM, Elnwasany A, Menendez-Montes I, Ensley EL, Petric UB, Sharma G, Sherry AD, Malloy CR, Khemtong C, Kinter MT, Tan WLW, Anene-Nzelu CG, Foo RS, Nguyen NUN, Li S, Ahmed MS, Elhelaly WM, Abdisalaam S, Asaithamby A, Xing C, Kanchwala M, Vale G, Eckert KM, Mitsche MA, McDonald JG, Hill JA, Huang L, Shaul PW, Szweda LI, Sadek HA. Mitochondrial Substrate Utilization Regulates Cardiomyocyte Cell Cycle Progression. Nat Metab 2:167-178, 2020 February, PMID: 32617517, PMCID: PMC7331943

Gunning AC, Strucinska K, Muñoz Oreja M, Parrish A, Caswell R, Stals KL, Durigon R, Durlacher-Betzer K, Cunningham MH, Grochowski CM, Baptista J, Tysoe C, Baple E, Lahiri N, Homfray T, Scurr I, Armstrong C, Dean J, Fernandez Pelayo U, Jones AWE, Taylor RW, Misra VK, Yoon WH, Wright CF, Lupski JR, Spinazzola A, Harel T, Holt IJ, Ellard S. Recurrent De Novo NAHR Reciprocal Duplications in the ATAD3 Gene Cluster Cause a Neurogenetic Trait with Perturbed Cholesterol and Mitochondrial Metabolism. Am J Hum Genet, 2020 January, PMID: 32004445, PMCID: PMC7010973

Griffin TM, Friedman JE. How can parental obesity promote OA across generations? Nat Rev Rheumatol, 2020 January, PMID: 31949286

2019

Groennebaek T, Sieljacks P, Nielsen R, Pryds K, Jespersen NR, Wang J, Carlsen CR, Schmidt MR, de Paoli FV, Miller BF, Vissing K, Bøtker HE. Effect of Blood Flow Restricted Resistance Exercise and Remote Ischemic Conditioning on Functional Capacity and Myocellular Adaptations in Patients With Heart Failure. Circ Heart Fail 12:e006427, 2019 December, PMID: 31830830

Dai DF, Liu Y, Basisty N, Karunadharma P, Dastidar SG, Chiao YA, Chen T, Beyer RP, Chin MT, Maccoss M, La Spada AR, Rabinovitch PS. Differential effects of various genetic mouse models of the mechanistic target of rapamycin complex I inhibition on heart failure. Geroscience 41:847-860, 2019 December, PMID: 31650481, PMCID: PMC6925086

Dominguez-Lopez S, Sharma R, Beckstead MJ. Neurotensin receptor 1 deletion decreases methamphetamine self-administration and the associated reduction in dopamine cell firing. Addict Biol:e12854, 2019 November, PMID: 31742874

Pharaoh G, Owen D, Yeganeh A, Premkumar P, Farley J, Bhaskaran S, Ashpole N, Kinter M, Van Remmen H, Logan S. Disparate Central and Peripheral Effects of Circulating IGF-1 Deficiency on Tissue Mitochondrial Function. Mol Neurobiol, 2019 November, PMID: 31732912, PMCID: PMC7060968

Rangaraju V, Lewis TL Jr, Hirabayashi Y, Bergami M, Motori E, Cartoni R, Kwon SK, Courchet J. Pleiotropic Mitochondria: The Influence of Mitochondria on Neuronal Development and Disease. J Neurosci 39:8200-8208, 2019 October, PMID: 31619488, PMCID: PMC6794931

Newhardt MF, Batushansky A, Matsuzaki S, Young ZT, West M, Chin NC, Szweda LI, Kinter M, Humphries KM. Enhancing cardiac glycolysis causes an increase in PDK4 content in response to short term high fat diet. J Biol Chem, 2019 September, PMID: 31562244, PMCID: PMC6851294

Zhu S, Makosa D, Miller B, Griffin TM. Glutathione as a mediator of cartilage oxidative stress resistance and resilience during aging and osteoarthritis. Connect Tissue Res:1-14, 2019 September, PMID: 31522568, PMCID: PMC6884680

Griffin TM, Scanzello CR. Innate inflammation and synovial macrophages in osteoarthritis pathophysiology. Clin Exp Rheumatol 37 Suppl 120:57-63, 2019 September, PMID: 31621560, PMCID: PMC6842324

Zyla K, Larabee CM, Georgescu C, Berkley C, Reyna T, Plafker SM. Dimethyl fumarate mitigates optic neuritis. Mol Vis 25:446-461, 2019 August, PMID: 31523122, PMCID: PMC6707756

Ahn B, Smith N, Saunders D, Ranjit R, Kneis P, Towner RA, Van Remmen H. Using MRI to measure in vivo free radical production and perfusion dynamics in a mouse model of elevated oxidative stress and neurogenic atrophy. Redox Biol 26:101308, 2019 August, PMID: 31470261, PMCID: PMC6831885

Yang X, Brobst D, Chan WS, Tse MCL, Herlea-Pana O, Ahuja P, Bi X, Zaw AM, Kwong ZSW, Jia WH, Zhang ZG, Zhang N, Chow SKH, Cheung WH, Louie JCY, Griffin TM, Nong W, Hui JHL, Du GH, Noh HL, Saengnipanthkul S, Chow BKC, Kim JK, Lee CW, Chan CB. Muscle-generated BDNF is a sexually dimorphic myokine that controls metabolic flexibility. Sci Signal 12, 2019 August, PMID: 31409756, PMCID: PMC7219567

Miller BF, Baehr LM, Musci RV, Reid JJ, Peelor FF 3rd, Hamilton KL, Bodine SC. Muscle-specific changes in protein synthesis with aging and reloading after disuse atrophy. J Cachexia Sarcopenia Muscle, 2019 July, PMID: 31313502, PMCID: PMC6903438

Borcherding DC, Siefert ME, Lin S, Brewington J, Sadek H, Clancy JP, Plafker SM, Ziady AG.. Clinically-approved CFTR modulators rescue Nrf2 dysfunction in cystic fibrosis airway epithelia. J Clin Invest 130, 2019 May, PMID: 31145101, PMCID: PMC6668689

Delacruz RGC, Sandoval IT, Chang K, Miller BN, Reyes-Uribe L, Borras E, Lynch PM, Taggart MW, Hawk ET, Vilar E, Jones DA. Functional characterization of CNOT3 variants identified in familial adenomatous polyposis adenomas. Oncotarget 10:3939-3951, 2019 June, PMID: 31231471, PMCID: PMC6570471

Pharaoh G, Sataranatarajan K, Street K, Hill S, Gregston J, Ahn B, Kinter C, Kinter M, Van Remmen H. Metabolic and Stress Response Changes Precede Disease Onset in the Spinal Cord of Mutant SOD1 ALS Mice. Front Neurosci 13:487, 2019 May, PMID: 31213966, PMCID: PMC6554287

Sieljacks P, Wang J, Groennebaek T, Rindom E, Jakobsgaard JE, Herskind J, Gravholt A, Møller AB, Musci RV, de Paoli FV, Hamilton KL, Miller BF, Vissing K. Six Weeks of Low-Load Blood Flow Restricted and High-Load Resistance Exercise Training Produce Similar Increases in Cumulative Myofibrillar Protein Synthesis and Ribosomal Biogenesis in Healthy Males. Front Physiol 10:649, 2019 May, PMID: 31191347, PMCID: PMC6548815

Batushansky A, Lopes EBP, Zhu S, Humphries KM, Griffin TM. GC-MS Method for Metabolic Profiling of Mouse Femoral Head Articular Cartilage Reveals Distinct Effects of Tissue Culture and Development. Osteoarthritis Cartilage, 2019 May, PMID: 31136803, PMCID: PMC6702098

Miller BF, Pharaoh GA, Hamilton KL, Peelor FF, Kirkland JL, Freeman WM, Mann SN, Kinter M, Price JC, Stout MB. Short-term calorie restriction and 17α-estradiol administration elicit divergent effects on proteostatic processes and protein content in metabolically active tissues. J Gerontol A Biol Sci Med Sci, 2019 May, PMID: 31074767, PMCID: PMC7164531

Tschumi CW, Daszkowski AW, Sharpe AL, Trzeciak M, Beckstead MJ. A history of ethanol drinking increases locomotor stimulation and blunts enhancement of dendritic dopamine transmission by methamphetamine. Addict Biol:e12763, 2019 May, PMID: 31062485, PMCID: PMC6832768

Tarantini S, Valcarcel-Ares MN, Toth P, Yabluchanskiy A, Tucsek Z, Kiss T, Hertelendy P, Kinter M, Ballabh P, Süle Z, Farkas E, Baur JA, Sinclair DA, Csiszar A, Ungvari Z. Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice. Redox Biol 24:101192, 2019 April, PMID: 31015147, PMCID: PMC6477631

Ahn B, Ranjit R, Premkumar P, Pharaoh G, Piekarz KM, Matsuzaki S, Claflin DR, Riddle K, Judge J, Bhaskaran S, Satara Natarajan K, Barboza E, Wronowski B, Kinter M, Humphries KM, Griffin TM, Freeman WM, Richardson A, Brooks SV, Van Remmen H. Mitochondrial oxidative stress impairs contractile function but paradoxically increases muscle mass via fibre branching. J Cachexia Sarcopenia Muscle 10:411-428, 2019 April, PMID: 30706998, PMCID: PMC6463475

Reid JJ, Linden MA, Peelor FF, Miller RA, Hamilton KL, Miller BF. Brain Protein Synthesis Rates in the UM-HET3 Mouse Following Treatment with Rapamycin or Rapamycin with Metformin. J Gerontol A Biol Sci Med Sci, 2019 March, PMID: 30864661

Newman AH, Cao J, Keighron JD, Jordan CJ, Bi GH, Liang Y, Abramyan AM, Avelar AJ, Tschumi CW, Beckstead MJ, Shi L, Tanda G, Xi ZX. Translating the atypical dopamine uptake inhibitor hypothesis toward therapeutics for treatment of psychostimulant use disorders. Neuropsychopharmacology, 2019 March, PMID: 30858517, PMCID: PMC6785152

Piccart E, Tschumi CW, Beckstead MJ. Acute and subchronic PCP attenuate D2 autoreceptor signaling in substantia nigra dopamine neurons. Eur Neuropsychopharmacol 29:444-449, 2019 March, PMID: 30686631, PMCID: PMC6421099

Wolff CA, Reid JJ, Musci RV, Linden MA, Konopka AR, Peelor FF, Miller BF, Hamilton KL. Differential Effects of Rapamycin and Metformin in Combination with Rapamycin on Mechanisms of Proteostasis in Cultured Skeletal Myotubes. J Gerontol A Biol Sci Med Sci, 2019 March, PMID: 30820523, PMCID: PMC6909916

Tschumi CW, Beckstead MJ. Diverse actions of the modulatory peptide neurotensin on central synaptic transmission. Eur J Neurosci 49:784-793, 2019 March, PMID: 29405480, PMCID: PMC6078827

Deepa SS, Van Remmen H, Brooks SV, Faulkner JA, Larkin L, McArdle A, Jackson MJ, Vasilaki A, Richardson A. Accelerated sarcopenia in Cu/Zn superoxide dismutase knockout mice. Free Radic Biol Med 132:19-23, 2019 February, PMID: 30670156, PMCID: PMC6405207

Sivasami P, Poudel N, Munteanu MC, Hudson J, Lovern P, Liu L, Griffin T, Hinsdale ME. Adipose tissue loss and lipodystrophy in xylosyltransferase II deficient mice. Int J Obes (Lond), 2019 February, PMID: 30778123

Konopka AR, Miller BF. Taming expectations of metformin as a treatment to extend healthspan. Geroscience, 2019 February, PMID: 30746605, PMCID: PMC6544683

Pearsall EA, Cheng R, Matsuzaki S, Zhou K, Ding L, Ahn B, Kinter M, Humphries KM, Quiambao AB, Farjo RA, Ma JX. Neuroprotective effects of PPARα in retinopathy of type 1 diabetes. PLoS One 14:e0208399, 2019 February, PMID: 30716067, PMCID: PMC6361421

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. Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. Aging Cell 18:e12880, 2019 February, PMID: 30548390, PMCID: PMC6351883

Batushansky A, Matsuzaki S, Newhardt MF, West MS, Griffin TM, Humphries KM. GC-MS metabolic profiling reveals fructose-2,6-bisphosphate regulates branched chain amino acid metabolism in the heart during fasting. Metabolomics 15:18, 2019 January, PMID: 30830475, PMCID: PMC6478396

Coen PM, Musci RV, Hinkley JM, Miller BF. Mitochondria as a Target for Mitigating Sarcopenia. Front Physiol 9:1883, 2019 January, PMID: 30687111, PMCID: PMC6335344

Qaisar R, Bhaskaran S, Ranjit R, Sataranatarajan K, Premkumar P, Huseman K, Van Remmen H. Restoration of SERCA ATPase prevents oxidative stress-related muscle atrophy and weakness. Redox Biol 20:68-74, 2019 January, PMID: 30296699, PMCID: PMC6174848

Aging and Metabolism Research Program
Oklahoma Medical Research Foundation
825 NE 13th Street, MS 21
Oklahoma City, OK 73104

Phone: (405) 271-7570
Fax: (405) 271-1437
Email: Jeannie-Evans@omrf.org