Mobbs Lab

Aging & Metabolism

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Research

Our laboratory studies mechanisms linking lifespan with age-related diseases, and particularly mechanisms by which dietary restriction increases lifespan and concomitantly delays age-related diseases across a wide range of species and diseases, even engineered diseases.  Based on great progress in elucidating these mechanisms, the laboratory is increasingly turning to drug discovery, focusing on Alzheimer’s Disease and other age-related diseases in which overactive innate immunity is implicated.

Mobbs Laboratory

Charles V Mobbs, PhD
Professor, Neuroscience, Endocrinology, Geriatrics, Pharmacology and Therapeutics Discovery
Location:
Lab: Hess 10-301
Office: Hess 9-119
Email:
charles.mobbs@mssm.edu
Phone:
Office: 212.824.8923
Lab: 212.824.9168

Ongoing Projects

DRUG DISCOVERY: ALZHEIMER’S AND OTHER AGE-RELATED DISEASES

Continue to develop several novel classes of compounds that mimic effects of dietary restriction to inhibit overactive innate immunity (common to essentially all age-related diseases) and also inhibit in vivo Aβ toxicity (a model for Alzheimer’s Disease), likely by impacting metabolic architecture (e.g., reducing glycolysis and increasing alternate substrate utilization).

AGING

Reversing diabetic and age-related impairments with a ketogenic diet.
Reversing age-related impairments by activating the “glucose-switch” gene pattern
Reversing age-dependent deleterious changes in gene expression

OBESITY

Reversing obesity and diabetes caused by hypothalamic CBP inhibition.
Reversing obesity and diabetes with a ketogenic diet.
Reversing obesity due to impairments in glucose-sensing

DIABETES

Reversing diabetic complications with drugs that block glucose neurotoxicity
Reversing diabetic complications with a ketogenic diet

Hypotheses

A key observation about the nature of age-related impairments is that these impairments accrue over time, reflecting a cumulative and apparently irreversible process. We have now discovered the molecular mechanism of this “molecular memory” effect and shown that it applies to all age-related diseases that are influenced by dietary restriction. Specifically this molecular memory effect promotes the deleterious molecular architecture entailing increased glycolysis and reduced alternative substrate metabolism, which is reversed by dietary restriction, mediated by enhanced ketogenesis and subsequent enhancement of Cbp activity. In particular this process explains the cumulative development of diabetic complications, and implies that both age-related impairments and diabetic complications can not only be slowed (as with dietary restriction) but can actually be reversed, by blocking glucose metabolism more effectively than can be done with dietary restriction. We have actually accomplished this reversal of diabetic and age-related impairments with a ketogenic diet, and are now developing drugs that similarly reverse age-related impairments.

Protocols

Mice

Genetic engineering (transgenic and knockout); Genetic manipulation by in vivo gene transfer: AAV and nanoparticles; Complete metabolic phenotyping: Food intake, activity, metabolic architecture (indirect calorimetry, temperature telemetry, flux analysis, metabolomics, gene expression by RNAseq.

Caenorhabditis elegans

Assessement of lifespan, sensitivity to oxidative stress, obesity, functional analysis by high-throughput RNAi, high-throughput drug discovery.

Cell culture

Viability; metabolic architecture; gene expression (RNAseq); innate immune responses

Research Questions

What causes aging and age-related diseases, including obesity, diabetes, and Alzheimer’s Disease? The metabolic mystery: obesity and diabetes (a surfeit of nutritional resources) accelerate many age-related diseases, and dietary restriction (a dearth of nutritional resources) slows down aging itself and delays or eliminates almost all age-related diseases. What’s up with that? Can we develop drugs to mimic the protective effects of dietary restriction? (Yes!) Our laboratory uses molecular (including RNAseq, chromatin analysis and RNA interference), histological, behavioral, electrophysiological, and metabolic measurement methods to assess the basic mechanisms by which hypothalamic neurons sense and regulate metabolic state (including body weight and food intake), and how these mechanisms are implicated in metabolic diseases and during aging. Considering that almost all major pathologies are protected by dietary restriction, the mechanisms underlying the metabolic mystery may be considered among the most compelling in biomedical science. We really don’t understand why food intake should lead to diseases, but many lines of evidence suggest neuroendocrine mechanisms. We have studied in some detail the nature of the hypothalamic neurons which are sensitive to nutrition and which in turn regulate metabolic state, and we have thus begun to define a “nutritional field” of neurons which contain overlapping domains sensitive to different nutrients and which regulate different aspects of metabolism. Of particular interest is that the maximum overlap of these nutritional sensors (e.g., of glucose and leptin) may occur within POMC neurons, which we now believe play a critical role in regulating glucose metabolism and energy balance. This is particularly interesting because the POMC neurons are among the most sensitive to decline during aging and we have shown that transgenic enhancement of neuronal POMC completely corrects diabetes and other impairments in genetically obese mice. We have also discovered a common molecular pathway, entailing the histone acetylase Creb-binding protein (Cbp) that is required for the protective effects of dietary restriction and other molecular pathways to increase lifespan and delay age-related diseases. Pharmacological activation of this pathway increases lifespan and protects against neurodegenerative diseases, and the same complex in the hypothalamus predicts lifespan and obesity in mice. We have further developed high-throughput systems for drug discovery which has led to the discovery of a novel class of compounds that delay impairments in an animal model of Alzheimer’s Disease and other age-related pathologies, and inhibits overactivity of the innate immune system which is implicated in most (essentially all) age-related diseases. We are in the process of assessing efficacy of these compounds in a wide variety of age-related diseases and are planning our first clinical trials with our key clinical collaborator, the neurosurgeon Dr. Christopher Kellner.

Featured

Society for Science Regeneron Science Talent Search 2021

Second Place 

Prize: $175,000

Noah Getz, Age: 17
Bronx High School of Science, NY

Project Title: A Novel High Throughput Method for Prescreening Drugs: Using Machine Learning to Predict Phenothiazines That Reduce TNF-ALPHA Secretion with Applications for Alzheimer’s Disease and COVID-19 Treatment

For his research where he adjusted the way computer models identify promising pharmaceutical compounds, which could make the discovery of new drugs faster and less expensive. Noah’s method treats classification as an information retrieval task, similar to the ranking results from a browser search. When he tested his model, it identified two drugs that might dramatically reduce the levels of an inflammation marker implicated in both Alzheimer’s disease and COVID-19.

Top 300 Scholar

Charles Brown, Age: 17
Ossining High School, NY

Project Title: The Validation of Electrodermal Activity as an Objective Measurement of Generalized Anxiety Disorder in Adolescents

Ko F, Isoda F, Mobbs C. Laparotomy in Mice Induces Blood Cell Expression of Inflammatory and Stress Genes. Journal of interferon & cytokine research.  2015 Apr;35(4):302-12. doi: 10.1089/jir.2014.0031. Epub 2014 Nov 19. Surgical trauma induces immune and stress responses although its effects on postsurgical inflammatory and stress gene expression remain poorly characterized. This study sought to improve current scientific knowledge by investigating the effects of laparotomy on mouse blood cell inflammatory and stress gene expression.

AGS 2023 annual scientific meeting, Long Beach, CA

Sharna Saha

CEYE Student

Travel stipend for top scoring student first author and presenter abstract

Title: Targeting metabolic genes wit RNAi and drugs to delay Alzheimer’s pathology using the model organism Caenorhabditis elegans

Damian Gonzalez

Associate Researcher

Top scoring student first author and presenter abstract

Title: Phenothiazines increase lifespan and are protective in 2 C. elegans models of aging related diseases

2023 Regeneron International Science and Engineering Fair

Finalist 

Kun-Hyung Roh

Project Title: Novel Pharmacogenetic methodology for the identification of first in class mechanisms of phenothiazine derivatives to delay and rescue Alzheimer’s disease pathology in C. elegans

Publications

2023

Novel compound inhibits glycolysis, proteotoxicity, inflammation, and impairments in animal models of Alzheimer’s, Huntington’s, and stroke: Aging as a consequence of glycolysis https://doi.org/10.1101/2023.06.12.544352

2022

Asche-Godin SL, Graham ZA, Israel A, Harlow LM, Huang W, Wang Z, Brotto M, Mobbs C, Cardozo CP, Ko FC. RNA-sequencing reveals a gene expression signature in skeletal muscle of a mouse model of age-associated post-operative functional decline. J Gerontol A Biol Sci Med Sci. 2022 Feb 17:glac043. 

Litke R, Vicari J, Huang BT, Gonzalez D, Grimaldi N, Sharma O, Ma G, Shapiro L, Yoon Y, Kellner C, Mobbs C. Diets, genes, and drugs that increase lifespan and delay age-related diseases: Role of nutrient-sensing neurons and Creb-binding protein. Pharmacol Biochem Behav. 2022 Jul 19;219:173428. 

Asche-Godin SL, Graham ZA, Israel A, Harlow LM, Huang W, Wang Z, Brotto M, Mobbs C, Cardozo CP, Ko FC. RNA-sequencing Reveals a Gene Expression Signature in Skeletal Muscle of a Mouse Model of Age-associated Postoperative Functional Decline. J Gerontol A Biol Sci Med Sci. 2022 Oct 6;77(10):1939-1950. 

Knobel P*, Litke R*, Mobbs CV. Biological age and environmental risk factors for dementia and stroke: Molecular mechanisms. Front Aging Neurosci. 2022 Dec 22;14:1042488. 

2021

Schwartz EKC, Sosner EN, Desmond HE, Lum SJ, Sze JY, Mobbs CV. Serotonin and Dopamine Mimic Glucose-Induced Reinforcement in C. elegans: Potential Role of NSM Neurons and the Serotonin Subtype 4 Receptor. Front Physiol. 2021 Dec 20;12:783359.

2018

Mobbs CV. Glucose-Induced Transcriptional Hysteresis: Role in Obesity, Metabolic Memory, Diabetes, and Aging. Front Endocrinol (Lausanne). 2018;9:232. Published 2018 May 28. doi:10.3389/fendo.2018.00232

Marcellino BK, Ekasumara N, Mobbs CV. Dietary Restriction and Glycolytic Inhibition Reduce Proteotoxicity and Extend Lifespan via NHR-49. Curr Neurobiol. 2018;9(1):1–7.

Lieber AC, McNeill IT, Scaggiante J, et al. Biopsy During Minimally Invasive Intracerebral Hemorrhage Clot Evacuation [published online ahead of print, 2018 Dec 24]. World Neurosurg. 2018;S1878-8750(18)32881-X. doi:10.1016/j.wneu.2018.12.058

2017

Moreno CL, Mobbs CV. Epigenetic mechanisms underlying lifespan and age-related effects of dietary restriction and the ketogenic diet. Mol Cell Endocrinol. 2017;455:33–40. doi:10.1016/j.mce.2016.11.013

Michaelides M, Miller ML, DiNieri JA, et al. Dopamine D2 Receptor Signaling in the Nucleus Accumbens Comprises a Metabolic-Cognitive Brain Interface Regulating Metabolic Components of Glucose Reinforcement. Neuropsychopharmacology. 2017;42(12):2365–2376. doi:10.1038/npp.2017.112

2016

Moreno CL, Yang L, Dacks PA, Isoda F, Deursen JM, Mobbs CV. Role of Hypothalamic Creb-Binding Protein in Obesity and Molecular Reprogramming of Metabolic Substrates. PLoS One. 2016;11(11):e0166381. Published 2016 Nov 10. doi:10.1371/journal.pone.0166381

Yang J, Huang T, Song WM, et al. Discover the network underlying the connections between aging and age-related diseases. Sci Rep. 2016;6:32566. Published 2016 Sep 1. doi:10.1038/srep32566

Moreno CL, Ehrlich ME, Mobbs CV. Protection by dietary restriction in the YAC128 mouse model of Huntington’s disease: Relation to genes regulating histone acetylation and HTT. Neurobiol Dis. 2016;85:25–34. doi:10.1016/j.nbd.2015.09.012

Devarakonda K, Mobbs CV. Mechanisms and significance of brain glucose signaling in energy balance, glucose homeostasis, and food-induced reward. Mol Cell Endocrinol. 2016;438:61–69. doi:10.1016/j.mce.2016.09.012

Mobbs CV. Orphaned No More? Glucose-Sensing Hypothalamic Neurons Control Insulin Secretion. Diabetes. 2016;65(9):2473–2475. doi:10.2337/dbi16-0027

2015

Ko F, Isoda F, Mobbs C. Laparotomy in Mice Induces Blood Cell Expression of Inflammatory and Stress Genes. Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research. 2014. doi: 10.1089/jir.2014.0031. PubMed PCMID: 25406893

2013

Mobbs CV, Moreno CL, Poplawski M. Metabolic mystery: aging, obesity, diabetes, and the ventromedial hypothalamus. Trends Endocrinol Metab. 2013. doi: 10.1016/j.tem.2013.05.007. PubMed PMID: 23791973; PubMed Central PMCID: 23791973.

Mobbs CV, Moreno C. Hypothalamic EphA5 Facilitates Counterregulatory Responses: Possible Role for Bidirectional Signaling Leading to Bistability That Enhances Responsiveness to Hypoglycemia. Diabetes. 2013;62(4):1014-6. Epub 2013/03/23. doi: 62/4/1014 [pii]10.2337/db12-1735. PubMed PMID: 23520275; PubMed Central PMCID: 3609568.

Kim ES, Isoda F, Kurland I, Mobbs CV. Glucose-induced metabolic memory in Schwann cells: prevention by PPAR agonists. Endocrinology. 2013;154(9):3054-66. doi: 10.1210/en.2013-1097. PubMed Central PMCID: 23709088.

Moreno C, Yang L, Dacks P, Isoda F, Poplawski M, Mobbs CV. Regulation of peripheral metabolism by substrate partitioning in the brain. Endocrinol Metab Clin North Am. 2013;42(1):67-80. doi: 10.1016/j.ecl.2012.11.007. PubMed Central PMCID: 23391240.

Dacks PA, Moreno CL, Kim ES, Marcellino BK, Mobbs CV. Role of the hypothalamus in mediating protective effects of dietary restriction during aging. Front Neuroendocrinol. 2013;34(2):95–106. doi:10.1016/j.yfrne.2012.12.001

Kefaloyianni E, Lyssand JS, Moreno C, Delaroche D, Hong M, Fenyo D, Mobbs CV, Neubert TA, Coetzee WA: Comparative proteomic analysis of the ATP-sensitive K(+) channel complex in different tissue types. Proteomics 13:368-378, 2013

Mobbs CV, Mastaitis J, Isoda F, Poplawski M. Treatment of diabetes and diabetic complications with a ketogenic diet. J Child Neurol. 2013;28(8):1009–1014. doi:10.1177/0883073813487596

2012

Yang L, Isoda F, Yen K, Kleopoulos SP, Janssen W, Fan X, Mastaitis J, Dunn-Meynell A, Levin BE, McCrimmon R, Sherwin R, Musatov S, Mobbs CV. Hypothalamic Fkbp51 is induced by fasting and elevated hypothalamic expression promotes obese phenotypes. Am J Physiol Endocrinol Metab. 2012. Epub 2012/02/10. doi: ajpendo.00474.2011 [pii] 10.1152/ajpendo.00474.2011. PubMed Central PMCID: 22318949.

Schwartz E, Mobbs CV. Hypothalamic BDNF and obesity: found in translation. Nat Med. 2012;18(4):496-7. Epub 2012/04/07. doi: nm.2716 [pii] 10.1038/nm.2716. PubMed Central PMCID: 22481407.

Dacks PA, Moreno CL, Kim ES, Marcellino BK, Mobbs CV. Role of the hypothalamus in mediating protective effects of dietary restriction during aging. Front Neuroendocrinol. 2012. Epub 2012/12/25. doi: S0091-3022(12)00063-5 [pii]10.1016/j.yfrne.2012.12.001. PubMed Central PMCID: 23262258.

Moreno C, Yang L, Dacks P, Isoda F, Poplawski M, Mobbs CV. Regulation of peripheral metabolism by substrate partitioning in the brain. Endocrinol Metab Clin North Am. 2013;42(1):67-80. doi: 10.1016/j.ecl.2012.11.007. PubMed Central PMCID: 23391240.

Mobbs C, Moreno C, Kim E, Ekasumara N, Marcellino B: Neuroprotection by dietary restriction and the Ppar transcription complex. Translational Neuroscience 3:234-241, 2012

2011

Poplawski MM, Mastaitis JW, Mobbs CV. Naloxone, but not valsartan, preserves responses to hypoglycemia after antecedent hypoglycemia: role of metabolic reprogramming in counterregulatory failure. Diabetes. 2011;60(1):39-46. Epub 2010/09/03. doi: db10-0326 [pii]10.2337/db10-0326. PubMed Central PMCID: 3012195.

Poplawski MM, Mastaitis JW, Isoda F, Grosjean F, Zheng F, Mobbs CV. Reversal of diabetic nephropathy by a ketogenic diet. PLoS One. 2011;6(4):e18604. Epub 2011/05/03. doi: 10.1371/journal.pone.0018604. PubMed Central PMCID: 21533091.

Lublin A, Isoda F, Patel H, Yen K, Nguyen L, Hajje D, Schwartz M, Mobbs C. FDA-Approved Drugs that Protect Mammalian Neurons from Glucose Toxicity Slow Aging Dependent on Cbp and Protect Against Proteotoxicity. PLoS One. 2011;6(11):e27762. Epub 2011/11/25. doi: 10.1371/journal.pone.0027762PONE-D-11-16976 [pii].; PubMed Central PMCID: 3218048.

Diano S, Liu ZW, Jeong JK, Dietrich MO, Ruan HB, Kim E, Suyama S, Kelly K, Gyengesi E, Arbiser JL, Belsham DD, Sarruf DA, Schwartz MW, Bennett AM, Shanabrough M, Mobbs CV, Yang X, Gao XB, Horvath TL. Peroxisome proliferation-associated control of reactive oxygen species sets melanocortin tone and feeding in diet-induced obesity. Nat Med. 2011;17(9):1121-7. Epub 2011/08/30. doi: nm.2421 [pii]10.1038/nm.2421. Central PMCID: 21873987.

2010

Yen K, Mobbs CV. Evidence for only two independent pathways for decreasing senescence in Caenorhabditis elegans. Age (Dordr). 2010;32(1):39-49. Epub 2009/08/08. doi: 10.1007/s11357-009-9110-7. 19662517; PubMed Central PMCID: 2829647.

Poplawski MM, Mastaitis JW, Yang XJ, Mobbs CV. Hypothalamic responses to fasting indicate metabolic reprogramming away from glycolysis toward lipid oxidation. Endocrinology. 2010;151(11):5206-17. Epub 2010/10/01. doi: en.2010-0702 [pii] 10.1210/en.2010-0702. PubMed Central PMCID: 2954726.

Publications Preceding 2010

See Here

About Dr. Mobbs

Training

EDUCATION

B.S. Biology 1978
Massachusetts Institute of Technology, Cambridge, MA

Ph.D. Cell/Molecular Biology 1984
University of Southern California
Mentor: Caleb Finch, Ph.D.

POSTDOCTORAL TRAINING

NIH Post-doctoral Fellowship 1984-1988
Rockefeller University, NY
Mentor: Donald Pfaff, Ph.D.

Current Funding

Delay of Alzheimer’s phenotypes by interventions that increase lifespan.

R01AG062303  09/30/18-09/29/2023  Role: PI

Integrative Network Modeling of Cognitive Resilience to Alzheimer’s Disease

R01AG057907 09/15/2017-05/31/2022  Role:sub-project; Bin Zhang communicating PI

Honors/Service

HONORS

1974:  National Merit Scholar
1975:  McDermott Scholar (MIT)
1979:  Best Teaching Assistant Award (USC)
1981, 1983:  Sigma Xi Graduate Student Research Award
1982:  George Sacher Award, Best Student Paper
1985:  Grass Fellowship, Cold Spring Harbor Laboratory
1989:  Glenn Foundation Fellow
1993:  Mentor, Brookdale Foundation
2005:  Ellison Medical Foundation Senior Fellow
2010: Outstanding mentorship, Mount Sinai School of Medicine
2012: Glenn Award for Research in Biological Mechanisms of Aging

SERVICE

1988: National Academy of Sciences Committee on Aging
1990-1994: Editorial Board, Mechanisms of Aging and Development
1992-1996: Research and Development Committee, VAMC
1992-1996: Institutional Animal Review Committee, VAMC
1992-1996: Co-director, Molecular Diagnostics Core Lab, VAMC
1994-present: Reviewer, American Federation for Aging Research
1997-present: Co-founder of Annual Endocrinology of Aging Symposium
1996-present: Co-editor, “Interdisciplinary Topics in Gerontology”, Karger
1999-2004: Endocrinology Study Section, NIH (Ad hoc)
2002-2004: Metabolism Study Section, NIH (Ad Hoc)
2002-2005: Canadian Institute of Nutrition, Metabolism and Diabetes Review Committee
2004-2006: Cellular Aspects of Diabetes and Obesity Study Section (Ad Hoc)
2004-2006: Integrated Physiology of Obesity and Diabetes (CADO) (Ad Hoc)
2003: Panel on Complications, Juvenile Diabetes Foundation (JDFI)
2003-present: Scientific Review Committee, Juvenile Diabetes Foundation
2005-2008: Medical Review Committee American Diabetes Association
2005-2009: Editorial Board, Endocrinology
2006-present: Editorial Board, Obesity Research
2006-present: Associate Editor, Obesity and Metabolism
2006-2008: Integrated Physiology of Obesity and Diabetes (Charter)
2006-2009: Steering Committee, Endocrine Society
2006-2009: Endocrine Society Steering Committee
2008-present: Special Emphasis Study Sections
2005-2009: Interventions Testing Program Access Committee, NIA
2009-2019: Chair, Interventions Testing Program Access Committee, NIA
2020: Cellular Mechanisms in Aging and Development Review Committee

Courses Taught

Responsible Conduct in Research

Biology of Aging

Neuroscience of Aging

Drug Discovery

Integrated Metabolism

Foundations of Biomedical Research

Meet the Team

Rachel Litke, MD, PhD

Postdoctoral Fellow

rachel.litke@mssm.edu

Damian Gonzalez

Associate Researcher

damian.gonzalez@icahn.mssm.edu

Sharna Saha

CEYE Student

Kun-Hyung Roh

High School Student

Nicolle Palacios

High School Student

Recent Alumni

2019

James Vicari, PhD student ISMMS

Bik Tzu Huang, PhD student ISMMS

2021

Nick Grimaldi, MS

Fatou M’Baye, Undergraduate Student BU

Noah Getz, Undergraduate Student MIT

2022

Lila Shapiro, Undergraduate Student Wellesley

Ojee Sharma, MS, Clinical Research coordinator ISMMS

2023

Santeh Cox, MS,

Brandon Clarke, MS, PhD student UNC