Location: Cleveland Clinic Main Campus
Aging is a major driving force behind disability, metabolic decline, and death. What exactly are the causes of aging and how to stop it have been questions posed by humans for most of history. From single celled model organisms to humans, dietary restriction has proven to be a potent, simple, and cost effective intervention to delay or dampen the onset of aging related pathologies. Dietary restriction offers significant endocrine, metabolic, stress resistance, and longevity benefits. Elusive are the mechanisms, molecules, pathways and triggers that account for these benefits. The lab’s purpose is to untangle the mechanisms and interactions between aging, nutrition, metabolism and stress resistance. This will provide a better understanding of these basic biological processes and ultimately give rise to clinical applications for safely, effectively, and efficiently improving healthspan and lifespan.
The general focus and goals of the lab are to: 1) Better understand the hormonal and nutritional regulation of endogenous hydrogen sulfide (H2S) production and metabolism in various tissues and cells, 2) Elucidate the mechanisms on an organismal, tissue, cellular, and molecular level as to which H2S effects a plethora of biological pathways giving rise to both negative and positive health related endpoints, and 3) Cultivate clinically applicable interventions utilizing diet, exercise, and pharmaceuticals to harness endogenous H2S production for beneficial health outcomes such as increased stress resistance, metabolic fitness, and lifespan.
Specially, the lab looks at the transcriptional, translational and enzymatic regulation of the mammalian H2S generating enzymes cystathionine gamma lyase (CGL), cystathionine beta synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MST). Perturbations of these enzymes have been linked to hypertension, neurodegenerative diseases, osteoporosis, and the inability to positively respond to dietary restriction. We study the regulation and function of these enzymes under conditions that promote extraordinary health & longevity (e.g. during dietary/sulfur amino acid restriction, decreased growth hormone signaling, and exercise) or aging-related pathologies (e.g. atherosclerotic diets, aging, inflammation, genotoxic stress). Additionally, we study the mechanistic roles H2S, or the lack of, plays in promoting or preventing iron induced damamge in the blood diseases sickle cell anemia and hemochromatosis. The work done in the lab addresses a significant gap in our understanding between health, aging and endogenous H2S metabolism with implications for clinical applications and interventions.
Silver, D.; Lathia, J.*; Hine, C*. Hydrogen sulfide operates as a glioblastoma suppressor and is lost under high fat diet. Molecular and Cellular Oncology (accepted 2021). *co-senior/corresponding authors
Yang, J.; Link, C.; Henderson, Y.; Bithi, N.; and Hine, C. Peripubertal Bisphenol A Exposure Imparts Detrimental Age-Related Changes in Body Composition, Cognition, and H2S Production Capacities. Antioxidants & Redox Signaling (accepted 2021)
Buffenstein, R.; Amarosa, V.; Andziak, B.; Avdieiev, S.; Azpurua, J.; Marker, AJ.; Bennett, NC.; Brieno-Enriquez, MA.; Bronner, GN.; Coen, C.; Delaney, MA.; Dengler-crish, CM.; Edrey, Y.; Faulkes, CG.; Frankel, D.; Friedlander, G.; Gibney, PA.; Gorbunova, V.; Heffner, R.; Hine, C.; Holmes, MM.; Jarvis, JUM.; Kawamura, Y.; Kenyon, C.; Khaled, WT.; Kiusui, T.; Kissil, J.; Lagestee, S.; Larson, J.; Lauer, A.; Lavrenschenko, LA.; Lee, A.; Levitt, JB.; Lewin, GR.; Lewis, KN.; Mason, MJ.; McCloskey, D.; McMahon, M.; Miura, K.; Mogi, K.; Narayan, V.; O'Connor, TP.; Oiwa, Y.; Okanoya, K.; Park, TJ,; Place, NJ;, Podshivalova, K.; Pamenter, ME.; Pyott, SJ.; Reznick, J.; Ruby, JG.; Salmon, AB.; Santos-Sacchi, J.; Sarko, D.; Seluanov, A.; Shepard, A.; Smith, M.; Storey, KB.; Tian, X.; Vice, EN.; Viltard, M.; Watarai, A.; Wyvial, E.; Zemlemerova, ED.; Zions, M.; and Smith, ESJ. The naked truth: a comprehensive clarification and classification of current ‘myths' in naked mole-rat biology. Biological Reviews (Cambridge Philosophical Society) (accepted 2021).
Hine, C.; Yang, J.; Zhang, A.; Llarena, N.; Link, C. H2S Supplementation and Augmentation: Approaches for Healthy Aging. Part of the comprehensive collection titled “Hydrogen Sulfide: Chemical Biology Basics, Detection Methods, Therapeutic Applications, and Case Studies,” edited by Mike Pluth, PhD, University of Oregon, which is part of the ongoing “Wiley Series in Drug Discovery and Development”. (accepted 2021).
Silver, D.; Roversi, G.; Bithi, N.; Wang, S.; Neumann, C.; Troike, K.; Ahuja, G.; Reizes, O.; Brown, JM.; Hine, C.*.; Lathia, J.* Severe Consequences of a high-lipid diet include hydrogen sulfide dysfunction and enhanced aggression in glioblastoma. Journal of Clinical Investigation (JCI) (2021). *co-senior/corresponding authors.
Bithi, N.; Link, C.; Henderson, Y.; Kim, S.; Yang, J.; Li, L.; Wang, R.; Willard, B.; and Hine, C. Dietary restriction transforms the mammalian protein persulfidome in a tissue-specific and cystathionine gamma-lyase-dependent manner. Nature Communications 12, 1745 (2021)
Henderson, Y.; Bithi, N.; Link, C.; Yang, J.; Schugar, R.; Llarena, N.; Brown, JM.; and Hine, C. Late-life intermittent fasting decreased aging-related frailty and increases renal hydrogen sulfide production in a sexually dimorphic manner. GeroScience (Journal of the American Aging Association) (2021)
Jonsson, W.; Margolies, N.; Mirek, E.; Zhang, Q.; Linden, M.; Hill, C.; Link, C.; Bithi, N.; Zalma, B.; Levy, J.; Pettit, A.; Miller, J.; Hine, C.; Morrison, C.; Gettys, T.; Miller, B.; Hamilton, K.; Wek, R.; and Antony, T. Physiologic responses to dietary sulfur amino acid restriction in mice are influenced by Atf4 status and biological sex. The Journal of Nutrition (2021).
Llarena, N.; Hine, C. Reproductive longevity and aging: geroscience approaches to maintain long-term ovarian fitness. The Journal of Gerontology Series A: Biological Sciences Vol. 76, No. 9, 1551-1560 (2020). doi: 10.1093/gerona/glaa204. Selected as Editor’s Choice in the special issue “Intersection of Reproductive and Aging Biology
Zhou, H.; Wang, H.; Yu, M.; Schugar, R.; Qian, W.; Tang, F.; Liu, W.; Yang, H.; McDowell, R.; Zhao, J.; Gao, J.; Dongre, A.; Carmen, J.; Yin, M.; Drazba, J.; Dent, R.; Hine, C.; Chen, YR.; Smith, J.; Fox, P.; Brown, JM.; Li, X. IL-1 induces mitochondrial translocation of IRAK2 to suppress oxidative metabolism in adipocytes. Nature Immunology 21, 1219-1231 (2020)
Wilkie, S.; Mulvey, L.; Sands, W.; Marcu, D.; Carter, R.; Morton, N.; Hine, C.; Mitchell, J.; Selman, C. Strain-specificity in the hydrogen sulphide signaling network following dietary restriction in recombinant inbred mice. GeroScience (Journal of the American Aging Association) 42, 801-812 (2020).
Yang, J.; Minkler, P.; Grove, D. Wang, R.; Willard, B.; Dweik, R.; Hine, C. Non-enzymatic hydrogen sulfide production from cysteine in blood is catalyzed by iron and vitamin B6. Communications Biology, Vol. 2, Article number: 194 (2019).
Gokarn, R.; Solon-Biet, S.M.; Cogger, V.C.; Cooney, G.J.; Wahl, D.; McMahon, A.C.; Mitchell, J.R.; Mitchell, S.J.; Hine, C.; de Cabo, R.; Raubenheimer, D.; Simpson, S.J.; Le Couteur, D.G. Long-term Dietary Macronutrients and Hepatic Gene Expression in Aging Mice. The Journal of Gerontology Series A (2018).
Hine, C.; Zhu, Y.; Hollenberg, A.; Mitchell, J. Dietary and Endocrine Regulation of Endogenous H2S Production: Implications for Longevity. Antioxidants and Redox Signaling Vol. 28, Issue 16: 1483-1502 (2018).
Longchamp, A.; Mirabella, T.; Arduini, A.; MacArthur, M.; Das, A.; Trevino-Villarreal, J.H.; Hine, C.; Ben-Sahra, I.; Knudsen, N.; Brace, L.; Reynold, J.; Mejia, P.; Tao, M.; Sharma, G.; Wang, R.; Corpataux, JM.; Haefliger, JA.; Ahn, KH,; Lee, CH.; Manning, B.; Sinclair, D.; Chen, C.; Ozaki, CK.; Mitchell, J. Amino Acid Restriction Triggers Angiogenesis via GCN2/ATF4 Regulation of VEGF and H2S Production. Cell 173(1): 117-129 (2018).
Hine, C. TOR at the Core of Impaired Regeneration. Science Translational Medicine Vol. 10, Issue 422 (2018).
Alfaras, I.; Mitchell, S.; Mora, H.; Lugo, D.; Warren, A.; Navas-Enamorado, I.; Hoffmann, V.; Hine, C.; Mitchell, J.; Le Couteur, D.; Cogger, V.; Bernier, M.; de Cabo, R. Health Benefits of Later-Onset Metformin Treatment Every Other Week in Mice. NPJ Aging and Mechanism of Disease 3 (16): 1-13 (2017).
Hine, C. An Antioxidant to Attenuate Aortic Aging. Science Translational Medicine Vol. 9, Issue 416 (2017).
Hine, C. Delaying Methylation Drift with Diet. Science Translational Medicine Vol. 9, Issue 410 (2017).
Hine, C.; Mitchell, J. Endpoint or Kinetic Measurement of Hydrogen Sulfide Production Capacity in Tissue Extracts. Bio-Protocol Vol. 7, Issue 13: 1-18 (2017).
Hine, C. Evading Sepsis with Exercise. Science Translational Medicine Vol. 9, Issue 404 (2017).
Hine, C. Conjugation does not Conquer all in Cancer Nanotherapy. Science Translational Medicine Vol. 9, Issue 398 (2017).
Hine, C.; Kim, H.; Zhu, Y.; Harputlugil, E.; Longchamp, A.; Matos, M. Ramadoss, P.; Bauerle, K.; Asra, J.; Ozaki, C.; Cheng, S.; Singha, S.; Ahn, K.; Kimmelman, A.; Fisher, F.; Pissios, P.; Withers, D.; Selman, C.; Wang, R.; Yen, K.; Longo, V.; Cohen, P.; Bartke, A.; Kopchick, J.; Miller, R.; Hollenberg, A.; Mitchell, J. Hypothalamic-Pituitary Axis Regulates Hydrogen Sulfide Production. Cell Metabolism 25(6): 1320-1333 (2017).
Hine, C. Rapamycin Keeps the Reproductive Clock Ticking. Science Translational Medicine Vol. 9, Issue 392 (2017).
Hine, C. A Paternal Diet for Offspring Success? Science Translational Medicine Vol. 9, Issue 386 (2017).
Nikonorova, I.; Al-Baghdadi, R.; Mirek, E.; Wang, Y.; Goudie, M.; Wetstein, B.; Dixon, J.; Hine, C.; Mitchell, J.; Adams, C.; Wek, R. Anthony, T. Obesity Challenges the Hepatoprotective Function of the Integrated Stress Response to Asparaginase Exposure in Mice. The Journal of Biological Chemistry 292(16): 6786-6798 (2017).
Hine, C. The Importance of Staying Small. Science Translational Medicine Vol. 9, Issue 380 (2017).
Mitchell, SJ; Madrigal-Matute, J; Scheibye-Knudsen, M; Fang, E; Aon, M; González-Reyes, JA; Cortassa, S; Kaushik, S; Gonzalez-Freire, M;, Patel, B;, Wahl, D; Ali, A; Calvo-Rubio, M; Burón, MI Guiterrez, V; Ward, TM; Palacios, HH; Cai, H; Frederick, DW; Hine, C; Broeskamp, F; Habering, L; Dawson, J; Beasley, TM; Wan, J; Ikeno, Y; Hubbard, G; Becker, KG; Zhang, Y; Bohr, VA; Longo, DL; Navas, P; Ferrucci, L; Sinclair, DA; Cohen, P; Egan, JM; Mitchell, JR; Baur, JA; Allison, DB; Anson, RM; Villalba, JM; Madeo, F; Cuervo, AM; Pearson, KJ; Ingram, DK; Bernier, M; de Cabo, R. Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice. Cell Metabolism 23(6):1093-112 (2016).
Longchamp, A; Tao, Ming; Bartelt, A; Ding, Kui; Lynch, L; Hine, C; Corpataux, J; Kristal, B; Mitchell, J; Ozaki, CK. Surgical Injury Induces Local and Distant Adipose Tissue Browning. Adipocyte 5(2):163-74 (2015).
Robertson, L; Trevino-Villarreal, J; Mejia, P; Grondin, Y; Harputlugil, E; Hine, C; Vargas, D; Zheng, H; Ozaki, CK; Kristal, B; Simpson, S; Mitchell, J. Protein and Calorie Restriction Contribute Additively to Protection from Renal Ischemia Reperfusion Injury Partly via Leptin Reduction in Male Mice. The Journal of Nutrition 145(8):1717-27 (2015).
Mejia, P; Trevino-Villarreal, J.H.; Hine, C; Harputlugil, E; Lang, S; Calay, E; Rogers, R; Wirth, D; Duraisingh, M; Mitchell, J. Dietary Restriction Protects Against Experimental Cerebral Malaria via Leptin Modulation and T-cell mTORC1 Suppression. Nature Communications 6:6050 (2015).
Hine, C; Mitchell, J. Calorie Restriction and Methionine Restriction in Control of Endogenous Hydrogen Sulfide Production by the Transsulfuration Pathway. Experimental Gerontology 68:26-32 (2015).
Hine, C; Harputlugil, E; Zhang, Y; Ruckenstuhl, C; Lee, BC; Brace, L; Longchamp, A; Trevino-Villarreal, J; Mejia, P; Ozaki, CK; Wang, R; Gladyshev, V; Madeo, F; Mair, W; Mitchell, J. Endogenous hydrogen sulfide production is essential for dietary restriction benefits. Cell 160(1-2):132-44 (2015).
Harputlugil, E; Hine, C; Vargas, D; Robertson, L; Manning, B; Mitchell, J. The TSC Complex Is Required for the Benefits of Dietary Protein Restriction on Stress Resistance in vivo. Cell Reports 8(4):1160-70 (2014).
Hine, C; Mitchell, J. Saying No to Drugs: Fasting Protects Hematopoietic Stem Cells from Chemotherapy and Aging. Cell Stem Cell 14(6):704-5 (2014).
Hine, C; Li, H; Xie, L; Mao, Z; Seluanov, A; Gorbunova, V. Regulation of Rad51 Promoter. Cell Cycle 13(13):2038-45 (2014).
Tian, X*; Azpurua, J*; Hine, C*; Vaidya, A; Myakishev-Rempel, M; Ablaeva, J; Mao, Z; Nevo, E; Gorbunova, V; Seluanov, A. High-molecular-mass Hyaluronan Mediates the Cancer Resistance of the Naked Mole Rat. Nature 499(7458):346-9 (2013).
Hine, C; Mitchell, J. NRF2 and the Phase II Response in Acute Stress Resistance Induced by Dietary Restriction. Published in the special issue “Mechanisms of Aging and Longevity”, edited by David Lombard. Journal of Clinical and Experimental Pathology S4(4) (2012).
Gorbunova, V; Hine, C; Tian, X; Ablaeva, J; Gudkov, AV; Nevo, E; Seluanov, A. Cancer Resistance in the Blind Mole Rat is Mediated by Concerted Necrotic Cell Death Mechanism. PNAS 109(47):19392-6 (2012).
Fong, V; Osterbur, M; Capella, C; Kim, Y; Hine, C; Seluanov, A; Gorbunova, V; Dewhurst, S. Adenoviral Vector Driven by a Minimal Rad51 Promoter is Selective for p53-Deficient Tumor Cells. PLoS One 6(12):e28714 (2011).
Hine, C; Seluanov, A; Gorbunova, V. Rad51 Promoter Targeted Gene Therapy is Effective for in vivo Visualization and Treatment of Cancer. Molecular Therapy 20(2):347-55 (2011).
Mao, Z; Hine, C; Tian, X; Van Meter, M; Au, M; Vaidya, A; Seluanov, A; Gorbunova, V. SIRT6 Promotes DNA Repair Under Stress by Activating PARP. Science 332(6036):1443-6 (2011).
Seluanov, A; Hine, C; Azpurua, J; Feigenson, M; Bozzella, M; Mao, Z; Catania, K Gorbunova, V. Hypersensitivity to Contact Inhibition Provides a Clue to Cancer Resistance of Naked Mole-Rat. PNAS 106(46):19352-7 (2009).
Hine, C; Seluanov, A; Gorbunova, V. Use of the Rad51 Promoter for Targeted Anti-Cancer Therapy. PNAS 105(52):20810-5 (2008).
Seluanov, A; Hine, C; Bozzella, M; Hall, A; Sasahara, T; Ribeiro, A; Catania, K; Presgraves, D; Gorbunova, V. Distinct Tumor Suppressor Mechanisms Evolve in Rodent Species that Differ in Size and Lifespan. Aging Cell 7(6):813-23 (2008).
Gorbunova, V; Seluanov, A; Mao, Z; Hine, C. Changes in DNA Repair During Aging. Nucleic Acids Research 35(22):7466-74 (2007).
Seluanov, A; Chen, Z; Hine, C; Sasahara, T; Ribeiro, A Catania, K; Presgraves, D; Gorbunova, V. Telomerase Activity Coevolves with Body Mass, Not Lifespan. Aging Cell 6(1):45-52 (2007).
Drs. Lathia, Silver and Hine report that a high-fat diet causes hydrogen sulfide dysfunction and leads to more severe disease with poorer outcomes among preclinical glioblastoma models.
Dr. Hine discovered that every-other-day fasting helped improve metabolic, muscular and cognitive fitness among aged preclinical models, suggesting possible utility as a clinical intervention to increase healthy years and prevent or delay cognitive decline.