Gordon J Lithgow
Buck Institute For Research On Aging
Project start date: 2008-02-15
Project end date: 2013-01-31
Sponsored Links Excellgen http://Excellgen.com
PHARMACOLOGY OF LIFESPAN EXTENSION
Gordon J Lithgow
Buck Institute For Age Research, Novato, Ca 94945
Grant 5R01AG029631-03 from National Institute On Aging
Abstract: Aging is the single most important risk factor in human disease in developed countries, and it is thought that an understanding of aging mechanisms would prompt design of rational therapies against age-related diseases. A corollary is that a pharmacological agent that slows aging itself is likely to be effective against a wide spectrum of diseases. To discover what classes of chemical compounds slow aging, we will screen a large and diverse chemical library for extension in the lifespan of the nematode C. elegans. We have developed a number of automated screening methods that exploit C. elegans handling technology. We will also screen a library of compounds generally recognized as safe (GRAS) for extended lifespan to bias our search towards compounds that will prove useful in mammals. We will establish whether the compounds extend lifespan by acting on known pathways and determine their impact on general metabolism and stress resistance. We expect some compounds will prolong lifespan by novel mechanisms in which case we will identify the target proteins. Overall, we aim to identify a range of compounds that slow aging; these compounds will be leads for the development of therapeutics against a range of age-related diseases
Keywords: Address; Affect; Age; Aging; Biology; Body Tissues; C elegans; C.elegans; Caenorhabditis elegans; Chemicals; Complex; Critiques; Developed Countries; Developed Nations; Disease; Disorder; Drugs; Genes; Genetic; Industrialized Countries; Industrialized Nations; Intermediary Metabolism; Length of Life; Libraries; Literature; Longevity; METBL; Mammalia; Mammals; Mammals, General; Measures; Medication; Metabolic Processes; Metabolism; Methods; Modeling; Nematoda; Nematodes; Organelles; Organism; Pathology; Pathway interactions; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacology; Principal Investigator; Programs (PT); Programs [Publication Type]; Proteins; Proxy; Resistance; Risk Factors; Screening procedure; Senescence; Stress; Technology; Testing; Tissues; Toxic effect; Toxicities; age dependent; age related; design; designing; disease/disorder; drug/agent; gene product; human disease; insight; life span; lifespan; living system; mouse model; mutant; novel; pathway; programs; resistant; roundworm; screening; screenings; senescent; small molecule libraries; therapeutic development
Project start date: 2008-02-15
Project end date: 2013-01-31
Budget start date: 15-FEB-2010
Budget end date: 31-JAN-2011
PFA/PA: PA-07-070
5R01AG029631-03 (2010): $369835
Grants awarded to Gordon J Lithgow
CHECKPOINT FUNCTIONS, LIFESPAN DETERMINATION AND NEURODEGENERATION (3 OF 11)
Gordon J Lithgow
Buck Institute For Age Research, Novato, Ca 94945
Grant 5RL1ES016655-04 from Office Of The Director, National Institutes Of Health
Abstract: We have uncovered a novel genetic pathway that determines adult lifespan in the nematode Caenorhabditis elegans. This pathway encodes components of DNA damage/cell cycle checkpoints, which are known to prevent inappropriate cell division. However, because non-dividing cells comprise the C. elegans adult soma, it appears that these checkpoint proteins also control the survival of cells in a postmitotic state. Down-regulation of checkpoint functions in adult C. elegans renders them very stress resistant and extends their lifespan. Through a whole genome RNA interference screen, we determined that many novel genes encode checkpoint functions and influence lifespan. We now propose to determine the mechanism(s) by which these genes act during aging and survival, and whether their functions are conserved in mammals. We will determine the role of lifespan-modulating checkpoint proteins in the survival of nematode neurons, which are crucial regulators of nematode lifespan, mouse cortical neurons, and dopaminergic neurons derived from human embryonic stem cells. We will modulate checkpoint functions in these post-mitotic cells and determine their resistance genotoxic and cytotoxic insults. We will identify chemical compounds that modulate survival through checkpoints, with a view to developing novel interventions into aging and neurological disease. This interdisciplinary project requires expertise in invertebrate aging, mammalian neuroscience, high throughout screening, chemical biology, molecular genetics and stem cell biology
Keywords: 21+ years old; Ablation; Address; Adult; Age; Aged 65 and Over; Aging; Animal Model; Animal Models and Related Studies; Area; Biochemical; Biology; Biology of Aging; C elegans; C.elegans; Caenorhabditis elegans; Cancerous; Cancers; Cell Body; Cell Communication and Signaling; Cell Cycle Arrest; Cell Cycle Checkpoint; Cell Cycle Progression; Cell Death; Cell Signaling; Cell Survival; Cell Viability; Cell division; Cells; Cellular biology; Cellular injury; Chemicals; Complex; DA Neuron; DNA Damage; DNA Injury; DNA Replication; DNA Synthesis; DNA biosynthesis; Development; Discipline; Disease; Disorder; Dopamine neuron; Down-Regulation; Down-Regulation (Physiology); Downregulation; Elderly; Elderly, over 65; Elements; FLR; Face; Failure (biologic function); Foundations; Gametes; Genes; Genetic; Genetic Alteration; Genetic Change; Genetic defect; Genome; Genomics; Germ Cells; Germ Lines; Germ-Line Cells; Hand; Heart; Human; Human, Adult; Human, General; Hydroxycarbamid; Hydroxycarbamide; Interphase Cell; Intervention; Intervention Strategies; Intracellular Communication and Signaling; Invertebrata; Invertebrates; Invertebrates, General; Knowledge; Laboratories; Length of Life; Life; Link; Longevity; Maintenance; Maintenances; Malignant; Malignant - descriptor; Malignant Neoplasms; Malignant Tumor; Mammalia; Mammals; Mammals, General; Mammals, Mice; Man (Taxonomy); Man, Modern; Mice; Mitotic; Molecular Genetic; Molecular Genetics; Mortality; Mortality Vital Statistics; Murine; Mus; Mutation; Nature; Nematoda; Nematodes; Nerve Cells; Nerve Degeneration; Nerve Unit; Nervous System Diseases; Neural Cell; Neurocyte; Neurologic Disorders; Neurological Disorders; Neuron Degeneration; Neurons; Neurosciences; Non-dividing Cell; Organism; Outcome; Pathology; Pathway interactions; Phenotype; Post-Transcriptional Gene Silencing; Post-Transcriptional Gene Silencings; Posttranscriptional Gene Silencing; Posttranscriptional Gene Silencings; Proteins; Quelling; RNA Interference; RNA Silencing; RNA Silencings; RNAi; Regulation; Reproductive Cells; Research; Research Resources; Resistance; Resources; Resting Cell; Risk Factors; Role; Screening procedure; Senescence; Sequence-Specific Posttranscriptional Gene Silencing; Series; Severities; Sex Cell; Signal Transduction; Signal Transduction Systems; Signaling; Stress; System; System, LOINC Axis 4; Testing; Translating; Translatings; Urea, hydroxy-; Work; adult human (21+); advanced age; age dependent; age related; age related neurodegeneration; biological signal transduction; cell biology; cell body (neuron); cell damage; cell injury; cell type; cytotoxic; disease/disorder; dopaminergic neuron; elders; facial; failure; gene product; genome mutation; geriatric; hESC; human ES cell; human ESC; human embryonic stem cell; human stem cells; hydroxyurea; initial cell; interventional strategy; language translation; late life; later life; life span; lifespan; living system; malignancy; model organism; mouse model; mutant; necrocytosis; neoplasm/cancer; nervous system disorder; neural cell body; neural degeneration; neurodegeneration; neurological disease; neuron cell death; neuron loss; neuronal; neuronal cell body; neuronal cell death; neuronal degeneration; neuronal loss; neuronal survival; new therapeutics; next generation therapeutics; novel; novel therapeutics; older adult; older person; pathway; pleiotropism; pleiotropy; prevent; preventing; resistant; response; roundworm; screening; screenings; senescent; senior citizen; sexual cell; social role; soma; stem cell biology; stressor; tool
Project start date: 2007-09-30
Project end date: 2012-06-30
Budget start date: 1-JUL-2010
Budget end date: 30-JUN-2011
PFA/PA: RFA-RM-06-008
5RL1ES016655-04 (2010): $376822
5RL1ES016655-03 (2009): $380628
5RL1ES016655-02 (2008): $380628
PHARMACOLOGY OF LIFESPAN EXTENSION
Gordon J Lithgow
Buck Institute For Age Research, Novato, Ca 94945
Grant 3R01AG029631-02S1 from National Institute On Aging
Abstract: This proposal is in response to the American Recovery and Reinvestment Act 2009(ARRA) and to NOT-OD-09-058. Aging is the single largest risk factor for disease in developed countries. The ongoing demographic change in the American population is greatly increasing the proportion of the population at risk for socially and economically important age-related diseases including Parkinson´s disease (PD), Alzheimer´s disease and cancer. Age-related disease is arguably the single greatest challenge for biomedicine in the 21st Century. Age-related diseases increasingly represent a national emergency; one that may undermine the mid-term benefits of the American Recovery and Reinvestment Act (ARRA). This supplement application addresses the goals of the ARRA by creating two job opportunity and proposing to purchase supplies and equipment from American scientific suppliers. Prompted by our prior discovery of compounds which extend lifespan and protect against stress we proposed in the parent grant to find new compounds that slow aging rates of the nematode C. elegans and determine the mechanisms at play. We expected such work to open new avenues for development of therapeutics for age-related diseases. We have made the striking discovery that a group of compounds commonly used to stain aggregating proteins in neurological disease increase the normal lifespan of C. elegans. Moreover, we find evidence that the compounds, especially thioflavin T (ThT) are slowing in vivo protein aggregate formation. The compounds have been previously used in human clinical studies. We previously discovered that Lithium, commonly used as a drug for the treatment of bipolar disorder, extends C. elegans lifespan. We believe Lithium acts via a distinct mechanism involving epigenetic modifications. We now propose to extend the scope of the grant to investigate the mechanisms at play for both these interesting interventions. It is important to follow BOTH leads at this time because it appears they act by different mechanisms. By pursuing two potential mechanisms to slow aging, we are more likely to find an intervention with significance to human aging and age-related disease. Since Lithium is already a drug in widespread use and ThT has been used in clinical research the likelihood that this proposal will lead to translational research in aging appears high. This request is directly relevant to American Recovery and Reinvestment Act (ARRA) as it calls for the creation of a new job opportunity and the purchase of scientific equipment and supplies from American companies. It also addresses the development of therapeutics for economically important age-related diseases and it directly addresses "healthspan", a strategic priority for the Division of Aging Biology
Keywords: 2-(p-(dimethylamino)phenyl)-3, 6-dimethylbenzothiazolium chloride; Address; Affective Psychosis, Bipolar; Age; Aging; Alzheimer; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer`s; Alzheimer`s Disease; Alzheimers Dementia; Alzheimers disease; American; Amine Oxidase (Flavin-Containing); Amine[{..}]oxygen oxidoreductase (deaminating) (flavin-containing); Apparatus and Instruments; Area; Biology of Aging; Bipolar Disorder; C elegans; C.elegans; Caenorhabditis elegans; Cancers; Chromatin Assembly; Chromatin Modeling; Chromatin Structure; Clinical Research; Clinical Study; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Developed Countries; Developed Nations; Developing Countries; Developing Nations; Disease; Disorder; Drugs; Economics; Emergencies; Emergency Situation; Employee Strikes; Epigenetic; Epigenetic Change; Epigenetic Mechanism; Epigenetic Process; Equipment and Supplies; Flavins; Funding; Gene Expression; Goals; Grant; High Throughput Assay; Histones; Human; Human, General; Idiopathic Parkinson Disease; Industrialized Countries; Industrialized Nations; Intervention; Intervention Strategies; Jobs; L-Lysine; Lead; Length of Life; Less-Developed Countries; Less-Developed Nations; Lewy Body Parkinson Disease; Li+ element; Libraries; Lithium; Longevity; Lysine; MAO; Malignant Neoplasms; Malignant Tumor; Man (Taxonomy); Man, Modern; Medication; Modification; Mono-S; MonoS; Monoamine Oxidase; Nematoda; Nematodes; Nervous System Diseases; Neurologic Disorders; Neurological Disorders; Occupations; Paralysis Agitans; Parkinson; Parkinson Disease; Parkinson`s; Parkinson`s disease; Parkinsons disease; Pb element; Peptides; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacology; Phenotype; Play; Population; Populations at Risk; Post-Transcriptional Gene Silencing; Post-Transcriptional Gene Silencings; Posttranscriptional Gene Silencing; Posttranscriptional Gene Silencings; Primary Parkinsonism; Primary Senile Degenerative Dementia; Professional Postions; Proteins; Psychosis, Manic-Depressive; Quelling; RNA Interference; RNA Silencing; RNA Silencings; RNAi; Recovery; Risk Factors; Science; Screening procedure; Senescence; Sequence-Specific Posttranscriptional Gene Silencing; Staining method; Stainings; Stains; Stress; Strikes; Strikes, Employee; Technology; Testing; Thioflavin T; Third-World Countries; Third-World Nations; Time; Translational Research; Translational Research Enterprise; Translational Science; Tyramine Oxidase; Under-Developed Countries; Under-Developed Nations; Work; adrenalin oxidase; age dependent; age related; amine oxidase (flavin); bipolar affective disorder; dementia of the Alzheimer type; disease/disorder; drug/agent; effective therapy; gene product; heavy metal Pb; heavy metal lead; high throughput screening; in vivo; insoluble aggregate; interest; interventional strategy; life span; lifespan; malignancy; manic depressive disorder; manic depressive illness; neoplasm/cancer; nervous system disorder; neurological disease; novel; parent grant; prevent; preventing; primary degenerative dementia; protein aggregate; public health relevance; response; roundworm; screening; screenings; senescent; senile dementia of the Alzheimer type; therapeutic development; translation research enterprise; tyraminase
Relevance: 7. /Relevance This request is directly relevant to American Recovery and Reinvestment Act (ARRA) as it calls for the creation of a new job opportunity and the purchase of scientific equipment and supplies from American companies. It also addresses the development of therapeutics for economically important age-related diseases and it directly addresses "healthspan", a strategic priority for the Division of Aging Biology
Project start date: 2009-09-30
Project end date: 2011-08-31
Budget start date: 30-SEP-2009
Budget end date: 31-AUG-2011
PFA/PA: PA-07-070
3R01AG029631-02S1 (2009): $438300
ENHANCING INDERDISCIPLINARY RESEARCH IN AGING AND AGE-RELATED DISEASE.
Gordon J Lithgow
Buck Institute For Age Research, Novato, Ca 94945
Grant 5P30AG036467-02 from National Institute On Aging
Abstract: Aging is the single largest risk factor for disease in developed countries. The ongoing demographic change in the American population is greatly increasing the proportion of the population at risk for socially and economically significant age-related diseases. Age-related diseases increasingly represent a national emergency, one that may undermine the long-term benefits of the American Recovery and Reinvestment Act of (ARRA, 2009). This P30 proposal addresses the goals of the ARRA by creating a new research group predicted to grow from three to six personnel over four years. This new research group will collaborate with and significantly enhance the activities of the Interdisciplinary Research Consortium on Geroscience; a group of research projects aiming at understanding the aging component in age-related disease. The new research will have "interdisciplinary training in aging and disease" or "translational research" or "inflammation biology". Funding the application will accelerate the progress of science that provides essential knowledge for the development of effective therapies for age-related diseases, an area of vital to the economic wellbeing of the nation. Change in the American population is greatly increasing the proportion of the population at risk for socially and economically significant age-related diseases. Age-related diseases increasingly represent a national emergency, one that may undermine the long-term benefits of the American Recovery and Reinvestment Act of (ARRA, 2009). This project will help accelerate the progress of science that provides essential knowledge for the development of effective therapies for age-related diseases, an area of vital to the economic wellbeing of the nation
Project start date: 2009-09-30
Project end date: 2011-08-31
Budget start date: 1-SEP-2010
Budget end date: 31-AUG-2011
PFA/PA: RFA-OD-09-005
5P30AG036467-02 (2010): $385922
1P30AG036467-01 (2009): $421304
Interdisciplinary Research Consortium In Geroscience
Gordon J Lithgow, Associate Professor For Age Research
Buck Institute For Age Research
novato, Ca 94945
Grant 8UL1DE019608-02 from National Institute Of Dental & Craniofacial Research IRG: ZRR1
Abstract: Age-related disease is arguably the single greatest challenge for biomedicine in the 21st Century. By 2030 the national healthcare bill is predicted to be four trillion dollars, fully half of which will be required for persons aged 65 and older. Aging is the most important risk factor for human disease in developed countries, and consequently creates an enormous social and economic impact. Our ability to tackle age- related disease is undermined by our lack of understanding of the principles and mechanisms of aging. Aging is a multifaceted and profound biomedical problem that is unlikely to yield to traditional investigative techniques. We propose that only by studying the interface of normal aging and aging diseases, in an interdisciplinary fashion, can we build the knowledge that will facilitate intervention. We propose to initiate a new field ("interdiscipline") called Geroscience that, by analogy to the creation of the field of Neuroscience, will have wide-reaching ramifications for biomedical science, healthcare, the training of future interdisciplinary researchers in Geroscience, and the national response to the many problems associated with the "graying of America." The Buck Institute is an NIH-designated Center of Excellence, the only independent research institute in the U.S. that is focused solely on aging research, and since its very planning and inception has been devoted to interdisciplinary research; therefore, its approaches and operation to date fit extremely well with the NCRR guidelines for the current application. Based on our track record of highly collaborative, cross-discipline activity, our high density of researchers in this new field, and our designation as a Nathan Shock Center of Excellence, we believe that we are uniquely placed to form an Interdisciplinary Research Consortium in Geroscience
Keywords: aging, interdisciplinary collaboration cooperative study NIH Roadmap Initiative tag, clinical research, human subject
Project start date: 2007-09-20
Project end date: 2012-06-30
8UL1DE019608-02 (2008): $886466
3UL1DE019608-02S1 (2008): $194000
Gordon J Lithgow
Buck Institute For Research On Aging
Project start date: 2012-04-01
Project end date: 2014-03-31
INTERDISCIPLINARY RESEARCH CONSORTIUM IN GEROSCIENCE
Gordon J Lithgow
Buck Institute For Age Research, Novato, Ca 94945
Grant 5UL1DE019608-04 from Office Of The Director, National Institutes Of Health
Keywords: Interdisciplinary Research; Interdisciplinary Study; Multidisciplinary Collaboration; Multidisciplinary Research; Study, Interdisciplinary
Project start date: 2007-09-20
Project end date: 2012-06-30
Budget start date: 1-JUL-2010
Budget end date: 30-JUN-2011
PFA/PA: RFA-RM-06-008
5UL1DE019608-04 (2010): $887117
Sponsored Links Excellgen http://Excellgen.com
5UL1DE019608-03 (2009): $891201
3UL1DE019608-03S1 (2009): $194000
1UL1RR024917-01 (2007): $605280