eBriefing

The Biology of Aging: Novel Drug Targets for Neurodegenerative Disease

The Biology of Aging
Reported by
Alan Dove

Posted July 17, 2014

Overview

For most of human history, age-related diseases were irrelevant; the majority of people died long before they could grow old. A few short centuries of science then unleashed a phalanx of lifesaving advances, including vaccines, antibiotics, sanitation, and a secure food supply. As lifespans steadily lengthened, previously rare age-related conditions became more common. For many populations today, old age has become the biggest risk factor for dying.

As a result, scientists are focusing on aging itself, a process that drives numerous health-destroying diseases. While researchers have developed therapies for some of these conditions, including heart disease, diabetes, and arthritis, the neurodegenerative effects of aging have been much harder to treat.

On May 9, 2014, the New York Academy of Sciences hosted a symposium covering basic and applied research on age-related neurodegeneration. Speakers discussed new findings about the mechanisms of aging and described novel strategies for treating Alzheimer's disease and other neurodegenerative conditions. The Biology of Aging: Novel Drug Targets for Neurodegenerative Disease was presented by the Academy's Brain Dysfunction Discussion Group and the Alzheimer's Drug Discovery Foundation.

Use the tabs above to find a meeting report and multimedia from this event.

Presentations available from:
Carmela R. Abraham, PhD (Boston University School of Medicine)
Nir Barzilai, MD (Albert Einstein College of Medicine)
Jerry R. Colca, PhD (Metabolic Solutions Development Company)
Brendan D. Manning, PhD (Harvard School of Public Health)
Richard I. Morimoto, PhD (Northwestern University)
D. Martin Watterson, PhD (Northwestern University Feinberg School of Medicine)


Presented by

  • Alzheimer's Drug Discovery Foundation
  • The New York Academy of Sciences

The Brain Dysfunction Discussion Group is proudly supported by


  • Acorda Therapeutics

Mission Partner support for the Frontiers of Science program provided by Pfizer

Journal Articles

Area-Gomez E, de Groof AJC, Boldogh I, et al. Presenilins are enriched in endoplasmic reticulum membranes associated with mitochondria. Am J Pathol. 2009;175(5):1810-16.

Bachstetter AD, Watterson DM, Van Eldik LJ. Target engagement analysis and link to pharmacodynamic endpoint for a novel class of CNS-penetrant and efficacious p38α MAPK inhibitors. J Neuroimmune Pharmacol. 2014. [Epub ahead of print]

Berk JL, Suhr OB, Obici L, et al. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA. 2013;310(24):2658-67.

Bialas AR, Stevens B. TGF-β signaling regulates neuronal C1q expression and developmental synaptic refinement. Nat Neurosci. 2013;16(12):1773-82.

Borson S, Frank L, Bayley PJ, et al. Improving dementia care: the role of screening and detection of cognitive impairment. Alzheimers Dement. 2013;9(2):151-9.

Byles V, Covarrubias AJ, Ben-Sahra I, et al. The TSC-mTOR pathway regulates macrophage polarization. Nat Commun. 2013;4:2834.

Chang TK, Shravage BV, Hayes SD, et al. Uba1 functions in Atg7- and Atg3-independent autophagy. Nat Cell Biol. 2013;15(9):1067-78.

Dubal DB, Yokoyama JS, Zhu L, et al. Life extension factor klotho enhances cognition. Cell Rep. 2014;7(4):1065-76.

Feldman HH, Haas M, Gandy S, et al. Alzheimer's disease research and development: a call for a new research roadmap. Ann N Y Acad Sci. 2014;1313(1):1-16.

Harrigan GG, Colca J, Szalma S, Boros LG. PNU-91325 increases fatty acid synthesis from glucose and mitochondrial long chain fatty acid degradation: a comparative tracer-based metabolomics study with rosiglitazone and pioglitazone in HepG2 cells. Metabolomics. 2006;2:21-9.

Klionsky DJ, Abdalla FC, Abeliovich H, et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 2012;8(4):445-544.

Klionsky DJ, Baehrecke EH, Brumell JH, et al. A comprehensive glossary of autophagy-related molecules and processes (2nd edition). Autophagy. 2011;7(11):1273-94.

Liu P, Gan W, Inuzuka H, et al. Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis. Nat Cell Biol. 2013;15(11):1340-50.

Liu Y, Tan YL, Zhang X, et al. Small molecule probes to quantify the functional fraction of a specific protein in a cell with minimal folding equilibrium shifts. Proc Natl Acad Sci U S A. 2014;111(12):4449-54.

Mariño G, Niso-Santano M, Baehrecke EH, Kroemer G. Self-consumption: the interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol. 2014;15(2):81-94.

Mehi SJ, Maltare A, Abraham CR, King GD. MicroRNA-339 and microRNA-556 regulate Klotho expression in vitro. Age (Dordr). 2014;36(1):141-9.

Menon S, Dibble CC, Talbott G, et al. Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell. 2014;156(4):771-85.

Milman S, Atzmon G, Huffman DM, et al. Low insulin-like growth factor-1 level predicts survival in humans with exceptional longevity. Aging Cell. 2014. [Epub ahead of print]

Milman S, Schulder-Katz M, Deluty J, et al. Individuals with exceptional longevity manifest a delayed association between vitamin D insufficiency and cognitive impairment. J Am Geriatr Soc. 2014;62(1):153-8.

Morfini GA, Bosco DA, Brown H, et al. Inhibition of fast axonal transport by pathogenic SOD1 involves activation of p38 MAP kinase. PLoS ONE. 2013;8(6):e65235.

Morimoto RI, Cuervo AM. Proteostasis and the aging proteome in health and disease. J Gerontol A Biol Sci Med Sci. 2014;69 Suppl 1:S33-8.

Rappley I, Monteiro C, Novais M, et al. Quantification of transthyretin kinetic stability in human plasma using subunit exchange. Biochemistry. 2014;53(12):1993-2006.

Román GC, Nash DT, Fillit H. Translating current knowledge into dementia prevention. Alzheimer Dis Assoc Disord. 2012;26(4):295-9.

Ryno LM, Genereux JC, Naito T, et al. Characterizing the altered cellular proteome induced by the stress-independent activation of heat shock factor 1. ACS Chem Biol. 2014. [Epub ahead of print]

Schafer DP, Stevens B. Phagocytic glial cells: sculpting synaptic circuits in the developing nervous system. Curr Opin Neurobiol. 2013;23(6):1034-40.

Tucker Zhou TB, King GD, Chen C, Abraham CR. Biochemical and functional characterization of the klotho-VS polymorphism implicated in aging and disease risk. J Biol Chem. 2013;288(51):36302-11.

Vacic V, Ozelius LJ, Clark LN, et al. Genome-wide mapping of identical-by-descent segments in an Ashkenazi Parkinson disease cohort identifies associated haplotypes. Hum Mol Genet. 2014. [Epub ahead of print]

Watterson DM, Grum-Tokars VL, Roy SM, et al. Development of novel in vivo chemical probes to address CNS protein kinase involvement in synaptic dysfunction. PLoS ONE. 2013;8(6):e66226.

Wu LJ, Stevens B, Duan S, MacVicar BA. Microglia in neuronal circuits. Neural Plast. 2013;2013:586426.

Yu A, Shibata Y, Shah B, et al. Protein aggregation can inhibit clathrin-mediated endocytosis by chaperone competition. Proc Natl Acad Sci U S A. 2014;111(15):E1481-90.

Yu WH, Dorado B, Figueroa HY, et al. Metabolic activity determines efficacy of macroautophagic clearance of pathological oligomeric alpha-synuclein. Am J Pathol. 2009;175(2):736-47.

Organizers

Howard Fillit, MD

Alzheimer's Drug Discovery Foundation
website | publications

Howard Fillit, a geriatrician, neuroscientist, and leading expert in Alzheimer's disease, is the founding executive director of the Alzheimer's Drug Discovery Foundation (ADDF). The foundation's mission is to accelerate the discovery and development of drugs to prevent, treat, and cure AD, related dementias, and cognitive aging. Fillit has had a distinguished academic medicine career at The Rockefeller University and Mount Sinai School of Medicine, where he is a clinical professor of geriatrics and medicine and a professor of neurobiology. He is the senior editor of the Textbook of Geriatric Medicine and Gerontology. Fillit was previously the corporate medical director for Medicare at New York Life, responsible for over 125 000 Medicare managed-care members in five regional markets. Fillit has received several awards and honors, including the Rita Hayworth Award for Lifetime Achievement. He also serves as a consultant to pharmaceutical and biotechnology companies, health care organizations, and philanthropies.

Kevin J. Lee, PhD

Lawrence Ellison Foundation
website

Kevin J. Lee is executive director of the Lawrence Ellison Foundation, a philanthropic organization established to support biomedical research on the mechanisms of aging, age-related diseases, and neuroscience and supported by Larry Ellison, founder and CEO of Oracle Corporation. Lee received his PhD in biology from the Massachusetts Institute of Technology. He has over 25 years of research experience in molecular genetics and neurobiology in biotechnology, academic research, and nonprofit settings. Lee previously served as executive vice president of research at Sentigen Biosciences and as a member of the Scientific Review Board of the Simons Foundation Autism Research Initiative. Lee's research employed genetic approaches to learn how neurons in the brain are "wired up" during development to make functional circuits that relay sensory information and control behavior. Lee worked with Dr. Thomas Jessell at the Center for Neurobiology and Behavior at Columbia University, where he studied the specification, axonal projection, and functional connectivity of nerve cells in the spinal cord.

Jennifer Henry, PhD

The New York Academy of Sciences

Jennifer Henry is the director of Life Sciences at the New York Academy of Sciences. Henry joined the Academy in 2009, before which she was a publishing manager in the Academic Journals division at Nature Publishing Group. She also has eight years of direct editorial experience as editor of Functional Plant Biology for CSIRO Publishing in Australia. She received her PhD in plant molecular biology from the University of Melbourne, specializing in the genetic engineering of transgenic crops. As director of Life Sciences, she is responsible for developing scientific symposia across a range of life sciences, including biochemical pharmacology, neuroscience, systems biology, genome integrity, infectious diseases and microbiology. She also generates alliances with organizations interested in developing programmatic content.


Speakers

Carmela R. Abraham, PhD

Boston University School of Medicine
website | publications

Carmela R. Abraham obtained her PhD in neuroscience at Harvard University. She is a professor of biochemistry and of pharmacology and experimental therapeutics at Boston University School of Medicine. Her laboratory studies the molecular mechanisms leading to normal brain aging and the pathological processes that culminate in AD. Using the rhesus monkey as a model for understanding changes that occur during nonpathological aging, her group discovered that the antiaging protein klotho is downregulated with age. The researchers also found that klotho protects neurons against various insults, including the neurotoxic amyloid-β peptide, and induces oligodendrocyte differentiation into myelinating cells, which is particularly important in multiple sclerosis. As part of her translational research, Abraham identified small molecules that enhance klotho expression. She plans to test them in mouse models of AD and MS. Abraham is the recipient of the Temple and Zenith awards from the Alzheimer's Association.

Eric H. Baehrecke, PhD

University of Massachusetts Medical School
website | publications

Eric Baehrecke obtained his PhD from the University of Wisconsin–Madison. He completed a Howard Hughes Medical Institute fellowship at the Life Sciences Research Foundation at the University of Utah. He was a faculty member of the University of Maryland before becoming a professor and vice chair of the Department of Cancer Biology at the University of Massachusetts Medical School. His laboratory studies the mechanisms that regulate autophagy, cell survival, and programmed cell death in the context of normal and abnormal development. The researchers use global genomic approaches, including DNA microarrays, proteomics, and forward genetic screens, to identify genes and proteins involved in programmed cell death and development.

Nir Barzilai, MD

Albert Einstein College of Medicine
website | publications

Nir Barzilai is director of the Institute for Aging Research at the Albert Einstein College of Medicine and director of the Paul F. Glenn Center for the Biology of Human Aging Research and the Nathan Shock Centers of Excellence in the Basic Biology of Aging at the National Institutes of Health. He is the Ingeborg and Ira Leon Rennert Chair of Aging Research; a professor in the Departments of Medicine and Genetics; and a member of the Diabetes Research Center, the Division of Endocrinology and Diabetes, and the Division of Geriatrics. His studies on families with centenarians have provided genetic and biological insights on protection against aging. Several drugs were developed based, in part, on these and similar paradigm-changing studies. Barzilai was awarded over $35 million in NIH funding for these efforts. He is the recipient of numerous awards, including the 2010 Irving S. Wright Award of Distinction in Aging Research. A graduate of the Technion-Israel Institute of Technology in Israel, Barzilai completed his residency in internal medicine at Hadassah Medical Center in Jerusalem and served as chief medic and physician in the Israel Defense Forces.

Jerry R. Colca, PhD

Metabolic Solutions Development Company
website | publications

Jerry Colca is cofounder, part owner, president, and chief scientific officer of Metabolic Solutions Development Company (MSDC). He has spent his professional career studying the endocrine control of metabolism as relates to diabetes. He holds a PhD in physiology and biochemistry from the University of Houston, where he studied the regulation of secretion of pancreatic hormones. His postdoctoral training at Washington University concentrated on the biochemistry of isolated pancreatic islets and the study of stimulus–secretion coupling in the control of metabolism. Colca has studied the mechanism of action of thiazolidinedione (TZD) insulin sensitizers from the early days of their discovery, and is particularly interested in the safety and pharmacology of pioglitazone. In January 2006 he cofounded MSDC with Dr. Rolf Kletzien. The company has two compounds in clinical trials and is making progress in understanding the molecular mechanisms of insulin sensitizers. These efforts have identified a novel mitochondrial target through which insulin sensitizers modify diseases of metabolic dysfunction.

Jeffery W. Kelly, PhD

The Scripps Research Institute
website | publications

Jeffery W. Kelly is the Lita Annenberg Hazen Professor of Chemistry and chairman of the Department of Molecular and Experimental Medicine at Scripps Research Institute. Kelly previously served as vice president of academic affairs and dean of graduate studies at Scripps for nearly a decade. His research is focused on uncovering protein folding principles and on understanding the etiology of protein misfolding and/or aggregation diseases and using this information to develop novel therapeutic strategies. Kelly cofounded FoldRx Pharmaceuticals based on his discovery of tafamidis, approved by the European Medicines Agency and the Japanese authorities to treat familial amyloid polyneuropathy. This first-in-class drug is the first agent that halts neurodegeneration in a human amyloid disease. It also provides the first pharmacological evidence that the process of amyloidogenesis causes the degeneration of post-mitotic tissue. Kelly is also the cofounder of Proteostasis Therapeutics Inc., a company using small molecules to alter the protein homeostasis network to ameliorate several aggregation-associated degenerative diseases as well as loss-of-function diseases. In 2012 Kelly cofounded Misfolding Diagnostics Inc., a San Diego-based company focusing on the early diagnosis of degenerative diseases.

Brendan D. Manning, PhD

Harvard School of Public Health
website | publications

Brendan Manning received his PhD from Yale University and joined the laboratory of Dr. Lewis Cantley at Harvard Medical School for his postdoctoral research. He discovered that tuberous sclerosis complex tumor suppressors are the key molecular connection between the PI3K and mTOR pathways, thereby linking a signaling pathway activated in the majority of human cancers to a nutrient-sensing pathway that controls cell growth and metabolism. In 2004 Manning joined the faculty of the then newly established Department of Genetics and Complex Diseases at Harvard School of Public Health, where he is now a professor and director of the PhD Program in the Biological Sciences in Public Health. His laboratory is unraveling signaling networks that coordinate nutrient availability with metabolic responses, focusing on how the dysregulation of such networks underlies aging and aging-related diseases.

Richard I. Morimoto, PhD

Northwestern University
website | publications

Richard I. Morimoto is the Bill and Gayle Cook Professor of Biology and the director of the Rice Institute for Biomedical Research in the Department of Molecular Biosciences at Northwestern University. He holds a PhD in molecular biology from the University of Chicago and completed a postdoctoral fellowship at Harvard University. His research focuses on the heat shock response, particularly the functions of molecular chaperones and the proteostasis network to maintain cellular health and to respond to challenges from stress, aging, and diseases of protein conformation. These studies provide a molecular basis for the cellular and organismal stress response and its role in aging and age-associated degenerative diseases, including neurodegeneration, metabolic diseases, and cancer. He serves on scientific advisory boards for the University of Heidelberg, the RIKEN Brain Science Institute, the Roswell Park Cancer Institute, BioCity Turku, and the Max Planck Institute. He is a cofounder of Proteostasis Therapeutics Inc., a biotech company working to discover small molecule therapeutics for diseases of protein conformation.

Beth Stevens, PhD

Harvard Medical School
website | publications

Beth Stevens is an assistant professor of neurology at Boston Children's Hospital and Harvard Medical School. She received her PhD in neuroscience in 2003 from the University of Maryland and completed a postdoctoral fellowship at Stanford University School of Medicine. Her research focuses on understanding the mechanisms by which neuron–glia communication helps control the formation, elimination, and plasticity of synapses in health and disease. She is a recipient of awards including the Smith Family Award for Excellence in Biomedical Research, the Dana Foundation Award (Brain and Immunoimaging), and the Ellison Medical Foundation New Scholar in Aging award of the John Merck Scholar Program.

D. Martin Watterson, PhD

Northwestern University Feinberg School of Medicine
website | publications

D. Martin Watterson holds the GD Searle Chair Professorship at Northwestern University, where he founded an academic drug discovery program that has brought CNS drug candidates to preclinical and clinical development. He has served as a department chair, university center director, and curriculum codirector. His academic record is complemented by commercial experience with small business startups, service on several boards, and pharmaceutical industry consulting. Watterson directs an advisory group that assists companies, government agencies, and research institutes in the processes of drug discovery and translation of basic science into clinical products. His previous academic appointments include faculty positions at The Rockefeller University, where he was an Andrew Mellon Fellow, and at Vanderbilt University Medical Center, where he was a professor of pharmacology and an investigator in the Howard Hughes Medical Institute.

Haung Yu, PhD

Columbia University
website | publications

Wai Haung (Ho) Yu received his PhD in pharmacology from the University of Toronto, Canada. He completed a postdoctoral research fellowship at New York University's Nathan Kline Institute, where he was later a clinical instructor and assistant professor before joining the Columbia University Department of Pathology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain. Yu's research looks at the role of protein quality control in neurodegeneration, examining the biological outcomes of protein homeostasis in neurons and the deleterious effects of failed degradation, primarily of aggregate-prone proteins like tau and α-synuclein. Yu's lab is developing novel neuronal assays and identifying new modulators of autophagic and lysosomal activity. He has received recent funding support from the NIH, ADDF, CurePSP, the Alzheimer's Association, and BrightFocus. Yu has served on scientific review boards for the Veteran's Administration, ADDF, and the Weston Foundation in Canada.

Alan Dove

Alan Dove is a science writer and reporter for Nature Medicine, Nature Biotechnology, and Bioscience Technology. He also teaches at the NYU School of Journalism and blogs at http://dovdox.com.

Sponsors

Presented by

  • Alzheimer's Drug Discovery Foundation
  • The New York Academy of Sciences

The Brain Dysfunction Discussion Group is proudly supported by


  • Acorda Therapeutics

Mission Partner support for the Frontiers of Science program provided by Pfizer


Bronze Sponsor

Takeda Pharmaceutical Company Limited

Academy Friend

Lawrence Ellison Foundation

Grant Support

This program is supported in part by a grant from Biogen Idec.