Acamedic Employment and research experience
Summary of Research Program
Our laboratory develops and tests metabolic-based therapies, including calorie restricted diets, ketogenic diets, exogenous ketogenic agents and metabolic-based drugs that target specific pathways linked pathophysiologically with seizure disorders, neurodegenerative diseases, metabolic dysregulation, cancer, muscle wasting and exercise performance. To investigate the mechanism of these pathologies we use a variety of in vivo and in vitro techniques, including radio-telemetry (EEG, EMG), electrophysiology, fluorescence microscopy, confocal microscopy, atomic force microscopy (AFM), electron microscopy, histology, biochemical assays, metabolomics, toxicology, in vivo bioluminescence imaging, spectrophotometry, behavioral testing and motor function testing. Our work has adapted and utilized radio-telemetry, confocal microscopy and AFM for use inside environmental chambers. These tools allow us to conduct whole-animal, tissue and cellular studies under a broad range of oxygen concentrations and gas pressures to simulate extreme environments or cellular hypoxia/ischemia. Our past and current projects, supported by the Department of Defense (DoD) and Office of Naval Research (ONR), have identified cellular and molecular correlates of CNS oxygen toxicity (CNS-OT) seizures, a phenomenon which limits the capability of Special Operations (SpecOps) diving. Our efforts have focused specifically on measuring neuronal excitability, reactive oxygen species (ROS) production, biomarkers of oxidative stress and global blood and tissue metabolomics.
In 2009 we became interested in understanding the anticonvulsant and neuroprotective mechanism of nutritional ketosis and developed exogenous ketones that produce therapeutic levels of blood ketone. Therapies developed and tested include naturally-derived and synthetic agents that induce hyperketonemia independent of calorie restriction or carbohydrate restriction. The ketogenic diet is the standard of care for drug-resistant and refractory seizures resulting from a variety of etiologies. The brain’s ability to use exogenous ketone bodies for fuel has not been exploited therapeutically, and evidence suggests that therapeutic ketosis confers protection against seizures, hypoglycemia and neurodegenerative disorders by numerous mechanisms, including supporting brain energy metabolism. In addition to neurological disorders, metabolic-based therapies can target cancer metabolism, which derives energy primarily from glycolysis and substrate level phosphorylation. Due to mitochondrial defects, most cancer cells lack the metabolic flexibility to generate ATP from ketones. Our goal is to develop and test therapies that exploit the metabolic defects of cancer by targeting cancer-specific glycolytic metabolism (e.g. Warburg effect) and develop “press pulse” protocols enhance the efficacy existing cancer therapies. Independent of energy metabolism, our more recent work has shown that the ketone β-hydroxybutyrate is an inhibitor of NOD-like receptor family pyrin domain-containing protein (NLRP3) inflammasome, which suppresses inflammation. An emerging area of interest for me is developing metabolic-based therapies that improve health biomarkers linked to obesity, insulin resistance, type-2 diabetes, wound healing and exercise performance and resilience. Our in vitro and in vivo studies continue to validate the efficacy, mechanism of action and safety of metabolic therapies (diet supplements, drugs), including exogenous ketones, with pharmacokinetic and toxicology studies. Our data has produced remarkable results in animal models of seizures and cancer, and current efforts have focused on moving these metabolic-based therapies into human clinical trials.
1. Somlyai G, Collins QT, Meuillet EJ, Hitendra P, D’Agostino DP, Boros LG. Structural homologies between phenformin, lipitor and gleevec aim the same metabolic oncotarget in leukemia and melanoma. Oncotarget; DOI: 10.18632/oncotarget.16238
2. Seyfried TN; Yu G; Maroon JC; D’Agostino DP. (2017) Press-Pulse: A Therapeutic Strategy for the Metabolic Management of Cancer. Nutrition and Metabolism (London) (2017) Feb 23;14:19.
3. Ari C. Canfield CE; Copes N, Poff AM, Fiorelli TN, Landon CS, Goldhagen CR, Mavromates N, D’Agostino DP. (2017) Biochemical alterations in Amyotrophic Lateral Sclerosis (ALS) Mouse Model resulted from the Deanna Protocol Supplement Complex. Metabolomics 13:55; DOI 10.1007/s11306-017-1183-1
4. Ari C, Kovacs Z, Juhasz G, Murdun C, Goldhagen CR, Koutnik A, Poff AM, Kesl SL, D’Agostino DP. (2016) Exogenous ketone supplements reduce anxiety-related behavior in Sprague-Dawley and Wistar Albino Glaxo/Rijswijk rats. Frontiers Molecular Neuroscience; 9: 137. doi: 10.3389/fnmol.2016.00137
5. Poff, A. M., Kernagis, D. and D'Agostino, DP. 2016. Hyperbaric Environment: Oxygen and Cellular Damage versus Protection. Comprehensive Physiology. 7:213–234.
6. Egan B, D'Agostino DP. (2016) Fueling Performance: Ketones Enter the Mix. Cell Metabolism. Sep 13;24(3):373-5. doi: 10.1016/j.cmet.2016.08.021
7. Ciarlone SL; Grieco JC, D'Agostino DP, Weeber E. Ketone ester supplementation attenuates seizure activity, and improves behavior and hippocampal synaptic plasticity in an Angelman syndrome mouse model. Neurobiology of Disease (2016) Dec;96:38-46. doi: 10.1016/j.nbd.2016.08.002.
8. Wilson JM, Lowery RP, Sharp MH, Shields K, Roberts MD, De Souza EO, Joy JM, Ormes J, Rauch JT, Silva J, Volek JS, D'Agostino DP. (2016) The Effects of Ketogenic Dieting on Body Composition, Strength, Power, and Hormonal Profiles in Resistance Training Males. Accepted: Journal of Strength and Conditioning Research (JSCR-08-6651R2)
9. Colquhoun RJ, Gai1 CM, Walters J, Brannon A, Kilpatrick MW, D’Agostino DP; Campbell BI. Comparison of Powerlifting Performance in Trained Males Using Traditional and Flexible Daily Undulating Periodization. (2016) J Strength Cond Res. 2017 Feb;31(2):283-291. DOI: 10.1519/JSC.01500
10. Kesl SL, Poff AM, Ward NP, Fiorelli TN, Ari C, Van Putten AJ, Sherwood JW, Arnold P, D’Agostino DP. (2015) Effects of exogenous ketone supplementation on blood ketone, glucose, triglyceride, and lipoprotein levels in Sprague–Dawley rats. Nutrition and Metabolism; 2016 Feb 4;13:9. doi: 10.1186/s12986-016-0069-y
11. Ari C, D’Agostino DP. Contingency checking and self-directed behaviors in giant manta rays: do fish have self-awareness? Journal of Ethology, May 2016, Volume 34, Issue 2, pp 167-174.
12. Viggiano A, Pilla R, Arnold P, Marcellino M, D’Agostino DP, Zeppa P, Coppola G. Different calorie restriction treatments have similar anti-seizure efficacy. Seizure-European Journal of Epilepsy; 2016 Feb;35:45-9. doi: 10.1016/j.seizure.2016.01.003
13. Boros L, D’Agostino DP, Katz HE, Roth JP, Meuillet EJ, Somlyati G. Submolecular regulation of cell transformation by deuterium depleting water exchange reactions in the tricarboxylic acid substrate cycle. Medical Hypotheses 87 (2016) 69–74; DOI: http://dx.doi.org/10.1016/j.mehy.2015.11.016
14. Poff A, Ward N, Seyfried T, Arnold P, D’Agostino DP. A novel non-toxic metabolic therapy – ketogenic diet, ketone supplementation, and hyperbaric oxygen – elicit potent anti-cancer effects in vitro and in vivo. PloS One. 2015 Jun 10;10(6):e0127407. DOI: 10.1371/journal.pone.0127407
15. Viggiano A, Pilla R, Arnold P, Marcellino M, D’Agostino DP, Coppola G. (2015) Anticonvulsant properties of an oral ketone ester in a pentylenetetrazole-model of seizure. Brain Res. 2015 May 27. pii: S0006-8993(15)00425-4. DOI: 10.1016/j.brainres.2015.05.023.
16. Youm Y, Nguyen K, Grant RW, Golgberg EL, Bodogai M, Kim D, D’Agostino DP, Planavsky N, Lupfer C, Kanneganti TD, Kang S, Horvath TL, Fahmy TM, Crawford PA, Biragyn A, Alnemri E, Dixit VD. "Ketone body β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nature Medicine, 2015 Mar;21(3):263-9 DOI: 10.1038/nm.3804.
17. Ari, C., Poff, A.M., Held, H.E., Landon, C.S., Goldhagen, C.R., Mavromates, N., D’Agostino, DP. Metabolic therapy with Deanna Protocol Supplementation Delays Disease Progression and Extends Survival in Amyotrophic Lateral Sclerosis (ALS) Mouse Model. PLoS One. 2014 Jul 25;9(7):e103526. DOI: 10.1371/journal.pone.0103526
18. Seyfried T, Flores R, Poff AM, D’Agostino DP, Mukherjee P. Metabolic therapy: A new paradigm for managing malignant brain cancer. Cancer Letters. 2014;356(2): 289-300. DOI: 10.1016/j.canlet.2014.07.015.
19. Seyfried TN, Marsh J, Mukherjee P, Zuccoli G, D’Agostino DP. Could Metabolic Therapy Become a Viable Alternative to the Standard of Care for Managing Glioblastoma? Oncology & Hematology Review, 2014;10(1):13–20. DOI: 10.17925/USN.2014.10.01.48
20. Seyfried TN, Poff A, D’Agostino DP. Cancer as a Metabolic Disease: Implications for Novel Therapeutics. Carcinogenesis. 2014, Mar;35(3):515-27. DOI: a10.1093/carcin/bgt480.
21. Poff A, Ari C, Seyfried TN, D’Agostino DP. Ketone Supplementation Decreases Tumor Cell Viability and Prolongs Survival of Mice with Metastatic Cancer. International Journal of Cancer: 2014 Oct. 1;135(7):1711-20. DOI: 10.1002/ijc.28809
22. Brownlow ML, Benner L, Benner L, Joly-Amando A, Azam S, D’Agostino DP, Gordon MN, Morgan D. Calorie restriction, but not ketogenic diet, improves cognition in models of Alzheimer's pathology. Alzheimers’s and Dementia. 2013 9(4): P160. DOI: 10.1016/j.jalz.2013.05.240
23. Brownlow ML, Benner L, D’Agostino DP, Gordon MN, Morgan D. Ketogenic diet improves motor performance but not cognition in two mouse models of Alzheimer's pathology. PLoS One. 2013 Sep 12;8(9):e75713. DOI: 10.1371/journal.pone.0075713.
24. Poff A, Ari C, Seyfried TN, D’Agostino, DP. The Ketogenic Diet and Hyperbaric Oxygen Therapy Prolong Survival in Mice with Systemic Metastatic Cancer. PLoS One., 2013; 8 (6): e65522 DOI: 10.1371/journal.pone.0065522
25. D’Agostino, D.P., Pilla, R., Held, H.E., Landon, C.S., Puchowicz, M., Brunengraber, H., Ari, C., Arnold, P. and Dean, J.B. Therapeutic ketosis with ketone ester delays central nervous system oxygen toxicity seizures in rats. AJP Regulatory, Integrative and Comparative Physiology, 2013 May 15;304(10):R829-36. DOI: 10.1152/ajpregu.00506.2012.
26. Paoli A, Grimaldi K, D'Agostino D, Cenci L, Moro T, Bianco A, Palma A. Ketogenic diet does not affect strength performance in elite artistic gymnasts. Journal of International Society Sports Nutrition. 2012 July 26;9(1):34, DOI: 10.1186/1550-2783-9-34
27. D'Agostino DP, McNally H, Dean JB. Hyperbaric atomic force microscopy (AFM) and fluorescence microscopy for biological applications. Journal of Microscopy; Jan 12; 245 (3), 2012. DOI: 10.1111/j.1365-2818.2011.03599.x. PMID: 22455392
28. D'Agostino DP, McNally H, Dean JB. Development and testing of hyperbaric atomic force microscopy (AFM) for biological applications. Microscopy and Microanalysis, 2011. vol. 16, issue S2, pp. 1042-1043. DOI: 10.1017/S1431927610057739.
29. D'Agostino DP, Olson JE, Dean JB. Acute hyperoxia increases lipid peroxidation and induces plasma membrane blebbing in human U87 glioblastoma cells. Neuroscience; 2009; Mar 31;159(3):1011-22. DOI: 10.1016/j.neuroscience.2009.01.062. PMID: 19356685
30. D’Agostino DP, Mazza EM, Neubauer JA. (2008) Heme oxygenase is necessary for the excitatory response of cultured neonatal rat rostral ventrolateral medulla neurons. AJP Regulatory, Integrative and Comparative Physiology. 2009. Jan;296(1):R102-18. 10.1152/ajpregu.90325 PMID: 18971354
31. D'Agostino DP, Colomb DG Jr, Dean JB. Effects of hyperbaric gases on membrane nanostructure and function in neurons. J Appl Physiol. 2009 Mar;106(3):996-1003 Review. PMID: 18818382. DOI: 10.1152/japplphysiol.91070.2008.
32. D’Agostino DP, Putnam RW, and Dean JB. Superoxide (·O2-) production in CA1 neurons of rat hippocampal slices exposed to graded levels of oxygen. Journal of Neurophysiology. 2007. Aug;98(2):1030-41. PMID: 17553943