Basic Biology of Aging at the University of Washington

Program Project: Mitochondrial Antioxidants, Aging and Healthspan

This program project makes an integrated and interactive effort to examine the role of mitochondria and mitochondrial ROS in health and aging, with the hypothesis that mitochondrial targeted interventions are capable of resisting age-related disease and improving health and function in multiple organ systems in mammals. Progress on understanding how to deliver these benefits could substantially enhance human healthspan.

Project 1: Mitochondrial ROS and Cardiac Aging
Project 2: Mitochondrial Mutations, Aging and Neurodegenerative Diseases
Project 3 Mitochondrial ROS, Aging, and Cancer
Project 4: Mitochondrial-Targeted Antioxidants, aging and AZT in Skeletal Muscle Dysfunction

Core A: Administration
Core B: Mouse Core
Core C: Proteomics
Core D: Mitochondrial ROS, Aging and novel mitoprotective peptides

Project 1: Mitochondrial ROS and Cardiac Aging
Project Leader: Peter Rabinovitch

Project 1 examines effects mitochondrial ROS on cardiac aging and hypertrophy. Over three million Americans suffer from congestive heart failure. It is the most common reason for hospital admission in older individuals and the most common reason for transfer to a nursing facility. Studies by Project 1 indicate that both mitochondrial targeted catalase (mCAT, an antioxidant) and SS-tetrapeptide therapeutics are protective against cardiac aging, diastolic dysfunction, hypertrophy and failure. Understanding the mechanisms behind these protective effects and translating it to pharmacotherapy may help to prevent, or even reverse, age-related ventricular modeling and its negative physiological consequences.

Key Publications:

 

  1. Dai DF, Chiao YA, Marcinek DJ, Szeto HH, Rabinovitch PS. Mitochondrial oxidative stress in aging and healthspan. Longev Healthspan. 2014 May 1;3:6. doi: 10.1186/2046-2395-3-6. eCollection 2014.   PMCID: PMC4013820
  2. Dai DF, Johnson SC, Villarin JJ, Chin MT, Nieves-Cintrón M, Chen T, Marcinek DJ, Dorn GW 2nd, Kang YJ, Prolla TA, Santana LF, Rabinovitch PS. Mitochondrial Oxidative Stress Mediates Angiotensin II-Induced Cardiac Hypertrophy and Galphaq Overexpression-Induced Heart Failure. Circ Res. 2011, 108(7):837-46. PMCID: PMC3785241
  3. Dai DF, Hsieh EJ, Liu Y, Chen T, Beyer RP, Chin MT, Maccoss MJ, Rabinovitch PS. Mitochondrial proteome remodeling in pressure-overload induced heart failure: the role of mitochondrial oxidative stress. Cardiovasc Res. 2011 Oct 19. PMCID: PMC3243039
  4. Dai D-F, Chen T, Szeto H, Nieves-Cintrón M, Summer V, Santana LF, Rabinovitch PS. Mitochondrial targeted antioxidant peptide ameliorates hypertensive cardiomyopathy. J. American Coll. Cardiol., 2011 Jun 28;58(1):73-82 PMCID: PMC3742010
  5. Dai DF, Rabinovitch PS, Ungvari Z. Mitochondria and Cardiovascular Aging. Circulation Research. 2012 Apr 13;110(8):1109-24. PMID: 22499901
  6. Dai DF, Hsieh EJ, Liu Y, Chen T, Beyer RP, Chin MT, Maccoss MJ, Rabinovitch PS. Mitochondrial proteome remodeling in pressure-overload induced heart failure: the role of mitochondrial oxidative stress. Cardiovasc Res. 2012 Jan 1;93(1):79-88 PMCID: PMC3243039
  7. Dai DF, Hsieh EJ, Chen T, Menendez LG, Basisty NB, Tsai L, Beyer RP, Crispin DA, Shulman NJ, Szeto HH, Tian R, MacCoss MJ, Rabinovitch PS. Global proteomics and pathway analysis of pressure-overload-induced heart failure and its attenuation by mitochondrial-targeted peptides. Circ Heart Fail. 2013 Sep 1;6(5):1067-76. PMCID: PMC3856238

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Project 2: Mitochondrial Mutations, Aging and Neurodegenerative Diseases
Project Leader: Lawrence Loeb

The goal of Project 2 is to determine the mechanism for the generation of mitochondrial DNA mutations during normal aging and in age-associated diseases. Neurodegenerative diseases are associated with an age-dependent accumulation of DNA damage, and Project 2 uses these as models to understand the molecular mechanisms responsible for the increase in mitochondrial DNA  mutations and homoplasmy in aging and disease and to test whether the ability of mitochondrial  therapeutics can protect the CNS from damage.

Key Publications:

  1. Kennedy SR, Salk JJ, Schmitt MW, Loeb LA. Ultra-sensitive sequencing reveals an age-related increase in somatic mitochondrial mutations that are inconsistent with oxidative damage. PLoS Genet. 2013 Sep;9(9):e1003794. PMCID: PMC3784509
  2. Kennedy SR, Loeb LA, Herr AJ. Somatic mutations in aging, cancer and neurodegeneration. Mech Ageing Dev. 2012 Apr;133(4):118-26. PMCID: PMC3325357
  3. Loeb LA. Human cancers express mutator phenotypes: origin, consequences and targeting. Nat. Rev. Cancer, 2011 Jun 11;11(6): 450-57. PMID:21593786
  4. Ladiges W, Wanagat J, Preston BD, Loeb LA, and Rabinovtich P. A mitochondrial view of aging, reactive oxygen species and metastatic cancer. Aging Cell. 2010 Aug; 9(4): 462-465. PMID:20456297
  5. Kamath-Loeb AS, Shen JC, Loeb LA. Werner Syndrome exonuclease facilitates DNA degradation and high fidelity DNA polymerization by human DNA polymerase delta. J Biol Chem. 2012 Apr 6;287(15):12480-90. PMCID: PMC3320997
  6. Kamath-Loeb, A., Loeb, L.A., and Fry, M. (2011) The Werner Syndrome protein is distinguished from the Bloom Syndrome protein by its capacity to tightly bind diverse DNA structures. PLoS One. 2012;7(1):e30189. PMCID: PMC3260238
  7. Schmitt MW, Kennedy SR, Salk JJ, Fox EJ, Hiatt JB, Loeb LA. Detection of ultra-rare mutations by next-generation sequencing. Proc Natl Acad Sci U S A. 2012 Sep 4;109(36):14508-13. PMCID: PMC3437896

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Project 3 Mitochondrial ROS, Aging, and Cancer
Project Leader: Warren Ladiges

This project is based on the concept that  mitochondrial targeted therapeutics can reduce the progression of age-associated cancer in mice with the aim of investigating the mechanisms and developing clinical intervention applications.   The connection of cancer and aging through mitochondria  was motivated by observations that mCAT mice have reduced epithelial cancers with age and are resistant to several experimental cancer models. This connection has great translational implications, as it suggests the possibility that pharmacologic mitochondrial protective drug therapy might attenuate cancer progression or metastasis.

Key Publications:

  1. Goh J, Enns L, Fatemie S, Hopkins H, Morton J, Pettan-Brewer C, Ladiges W. Mitochondrial targeted catalase suppresses invasive breast cancer in mice.BMC Cancer, 2011 May 23;11:191. PMCID: PMC3123323
  2. Cullen SJ, Fatemie S, Ladiges W. Breast tumor cells primed by endoplasmic reticulum stress remodel macrophage phenotype. Am J Cancer Res. 2013;3(2):196-210. PMCID: PMC3623838
  3. Pettan-Brewer C, Morton J, Coil R, Hopkins H, Fatemie S, Ladiges W. B16 melanoma tumor growth is delayed in mice in an age dependent manner. Pathobiol Aging Age Relat Dis. 2012;2 PMCID: PMC3424493
  4. Ladiges WC, Wanagat J, Preston B, Loeb LA, Rabinovitch PS, A mitochondrial view of aging, reactive oxygen species and metastatic cancer. Aging Cell, 2010 Aug;9(4):462-5. PMC20456297
  5. Goh J, Tsai J, Bammler TK, Farin FM, Endicott E, Ladiges WC. Exercise training in transgenic mice is associated with attenuation of early breast cancer growth in a dose-dependent manner. PLoS One. 2013 Nov 27;8(11):e80123. PMCID: PMC3842299
  6. Enns L, Ladiges W. Mitochondrial redox signaling and cancer invasiveness. J Bioenerg Biomembr. 2012 Dec;44(6):635-8. PMID: 22886605; NIHMSID: 547472

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Project 4: Mitochondrial-Targeted Antioxidants, aging and AZT in Skeletal Muscle Dysfunction
Project Leaders: David Marcinek & Joachim Voss

Project 4 examines the effect of oxidative stress on mitochondrial energetics in aging skeletal muscle and how the anti-HIV drugs AZT/3TC may potentiate muscle aging, weakness and fatigue. Sarcopenia of aging and side effects of NRTI treatment on skeletal muscle mitochondrial function share many characteristics, potentially related through mitochondrial dysfunction. Together these represent one of the oldest and newest problems of the aging population.

Key Publications:

  1. Dai DF, Chiao YA, Marcinek DJ, Szeto HH, Rabinovitch PS. Mitochondrial oxidative stress in aging and healthspan. Longev Healthspan. 2014 May 1;3:6. doi: 10.1186/2046-2395-3-6. eCollection 2014.   PMCID: PMC4013820
  2. Conley KE, Amara CE, Bajpeyi S, Costford SR, Murray K, Jubrias SA, Arakaki L, Marcinek DJ, Smith SR. Higher mitochondrial respiration and uncoupling with reduced electron transport chain content in vivo in muscle of sedentary versus active subjects. J Clin Endocrinol Metab. 2013 Jan;98(1):129-36. PMCID: PMC3537085
  3. Marcinek DJ, Siegel MP. Targeting redox biology to reverse mitochondrial dysfunction. Aging (Albany NY). 2013 Aug;5(8):588-9. PMCID: PMC3796210
  4. Siegel MP, Kruse SE, Percival JM, Goh J, White CC, Hopkins HC, Kavanagh TJ, Szeto HH, Rabinovitch PS, Marcinek DJ. Mitochondrial-targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice. Aging Cell. 2013 Oct;12(5):763-71. PubMed PMCID: PMC3772966
  5. Siegel MP, Wilbur T, Mathis M, Shankland EG, Trieu A, Harper ME, and Marcinek DJ. Impaired adaptability of in vivo mitochondrial energetics to acute oxidative insult in aged skeletal muscle.Mech Ageing Dev 133: 620-628, 2012. PMCID: PMC3456966

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Core A: Administration
Core Leader: Peter Rabinovitch

The goal of Core A is to provide overall direction, internal and external review, administrative and statistical support to the PO1.

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Core B: Mouse Core
Core Leader: Warren Ladiges

Core B is designed to provide an animal core in that all 4 projects propose to use mice.  Consolidation of animal resources focused on maximizing efficiency and minimizing costs is essential to the success of the program project. Specialized phenotyping assays will be expertly performed to distinguish phenotypic differences not easily discernible by gross observations, especially in aging cohorts.

Key Publications:

  1. Pettan-Brewer C, Touch DV, Wiley JC, Hopkins HC, Rabinovitch PS, Ladiges WC. A novel radial water tread maze tracks age-related cognitive decline in mice. Pathobiol Aging Age Relat Dis. 2013 Oct 4;3. PMCID: PMC3791354
  2. Goh J, Ladiges WC. A novel long term short interval physical activity regime improves body composition in mice. BMC Res Notes. 2013 Feb 19;6:66. PMCID: PMC3599771
  3. Dai DF, Hsieh EJ, Chen T, Menendez LG, Basisty NB, Tsai L, Beyer RP, Crispin DA, Shulman NJ, Szeto HH, Tian R, MacCoss MJ, Rabinovitch PS. Global proteomics and pathway analysis of pressure-overload-induced heart failure and its attenuation by mitochondrial-targeted peptides. Circ Heart Fail. 2013 Sep 1;6(5):1067-76. PMCID: PMC3856238
  4. Siegel MP, Wilbur T, Mathis M, Shankland EG, Trieu A, Harper ME, Marcinek DJ. Impaired adaptability of in vivo mitochondrial energetics to acute oxidative insult in aged skeletal muscle. Mech Ageing Dev. 2012 Sep-Oct;133(9-10):620-8. PMCID: PMC3456966
  5. Fatemie S, Goh J, Pettan-Brewer C, Ladiges W. Breast tumors in PyMT transgenic mice expressing mitochondrial catalase have decreased labeling for macrophages and endothelial cells. Pathobiol Aging Age Relat Dis. 2012;2. PMCID: PMC3417526

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Core C: Proteomics
Core Leader: Michael MacCoss

The goal of Core C is to provide access to cutting edge proteomics technologies for the P01 studies. These include: 1) unbiased detection of differences in protein abundance between proteomes; 2) targeted analysis of protein abundance for mitochondrial proteins of interest; 3) global measurement of individual mitochondrial protein half-lives.

Key Publications:

  1. Dai DF, Hsieh EJ, Chen T, Menendez LG, Basisty NB, Tsai L, Beyer RP, Crispin DA, Shulman NJ, Szeto HH, Tian R, MacCoss MJ, Rabinovitch PS. Global proteomics and pathway analysis of pressure-overload-induced heart failure and its attenuation by mitochondrial-targeted peptides. Circ Heart Fail. 2013 Sep 1;6(5):1067-76. PMCID: PMC3856238

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Core D: Mitochondrial ROS, Aging and novel mitoprotective peptides
Core Leader: Hazel Szeto

Core D provides SS peptides for the needs of all Research Projects and assists investigators in the use of single dose and chronic dosing of the peptides. The Core has been instrumental in mechanistically relating SS peptide structure to function, particularly though defining the interaction of SS peptides with cardiolipin and cytochrome c. 

Key Publications:

 

 

  1. Szeto HH and Birk AV: Serendipity and the discovery of novel compounds that restore mitochondrial plasticity. Clin Pharmacol Ther. 96:672-683, 2014. PMID: 25188726.
  2. Birk AV, Chao WM, Bracken C, Warren JD and Szeto HH: Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis. Br J Pharmacol, 171:2017-2028, 2014.  PMCID: PMC3976619.
  3. Birk AV, Liu S, Soong Y, Mills W, Singh P, Warren JD, Seshan SV, Pardee JD, Szeto HH. The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin. J Am Soc Nephrol. 2013 Jul;24(8):1250-61. PMCID: PMC3736700.
  4. Birk AV, Chao WM, Bracken C, Warren JD, Szeto HH. Targeting Mitochondrial Cardiolipin and the Cytochrome C/Cardiolipin Complex to Promote Electron Transport and Optimize Mitochondrial Atp Synthesis. Br J Pharmacol. 2013 Oct 18;PubMed PMID: 24134698.
  5. Dai DF, Chen T, Johnson SC, Szeto H, Rabinovitch PS. Cardiac aging: from molecular mechanisms to significance in human health and disease. Antioxid Redox Signal. 2012 Jun 15;16(12):1492-526. PMCID: PMC3329953.
  6. Dai DF, Hsieh EJ, Chen T, Menendez LG, Basisty NB, Tsai L, Beyer RP, Crispin DA, Shulman NJ, Szeto HH, Tian R, MacCoss MJ, Rabinovitch PS. Global proteomics and pathway analysis of pressure-overload-induced heart failure and its attenuation by mitochondrial-targeted peptides. Circ Heart Fail. 2013 Sep 1;6(5):1067-76. PMCID: PMC3856238.
  7. Siegel MP, Kruse SE, Percival JM, Goh J, White CC, Hopkins HC, Kavanagh TJ, Szeto HH, Rabinovitch PS, Marcinek DJ. Mitochondrial-targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice. Aging Cell. 2013 Oct;12(5):763-71. PMCID: PMC3772966.
  8. Szeto HH. First-In-Class Cardiolipin Therapeutic to Restore Mitochondrial Bioenergetics. Br J Pharmacol. 2013 Oct 10;PubMed PMID: 24117165.

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