Integrative Geroscience Project Richard Hodes On behalf of: The trans-NIH GeroScience Interest Group...
-
Upload
easter-adams -
Category
Documents
-
view
220 -
download
4
Transcript of Integrative Geroscience Project Richard Hodes On behalf of: The trans-NIH GeroScience Interest Group...
Integrative Geroscience ProjectRichard Hodes
On behalf of:The trans-NIH GeroScience Interest Group (GSIG)
Burch, John CSREdwards, Samuel CSRKhalsa, Partap NCCAMHowcroft, Kevin NCIJohnson, Ron NCILee, Jerry NCILi, Xiaoling NCIRodriguez, Henry NCIRowland, Julia NCIShen, Grace NEIFletcher, Colin NHGRIOh, Youngsuk NHLBIPunturieri, Antonello NHLBIHadley, Evan NIAKohanski, Ronald NIASierra, Felipe NIAWise, Bradley NIAMurray, Gary NIAAARegunathan, Soundar NIAAADeckhut, Alison NIAIDErbelding, Emily NIAID
Macchiarini, Francesca NIAIDShott, Joseph NIAIDMcGowan, Joan NIAMSSmith, Theresa NIAMSGrave, Gilman NICHDFrascella, Joe NIDAFrieden, Leslie NIDCRKusek, John NIDDKPawlyk, Aaron NIDDKLawler, Cindy NIEHSRowley-Hill, Joan NIEHSWales, Deborah NIEHSWoychik, Rick NIEHSEvans, Jovier NIMHNiederehe, George NIMHCorriveau, Roderick NINDSTully, Lois NINRWasserman, Joan NINRDwyer, Johanna ODStredrick, Denise OD
Aging is the major risk factor for most chronic diseases
Epigenetics
MetabolismInflammation
Damage(Repair)
Stress(Adaptation)
Genetics
StemCells
Immunity
Proteostasis
Biologyof
Aging
Many chronic diseases are studied individually
Arthritis
Sarcopenia CKD
COPD Heart Disease
Immunity
VascularDiseaseNeurological
Disease
Cancer
Biologyof
Disease
SCOPE
To develop a well-validated set of metrics to assess aging changes that influence multiple
age-related morbidities
Integrative Geroscience Project
STRATEGYEstablish pre-clinical animal models,
leveraging data obtained to date from animal and human clinical studies
WHAT IS NEEDED?
Integrative Geroscience Project
• Data and specimens from:
… longitudinal human cohorts with extensive phenotype characterization.
… comprehensive animal model studies, including interventions.
• Practical animal models that mimic the natural disease processes of aging in human populations.
R. Hodes has requested some data on this last point. This is provided in a separate set of slides
MAIN DELIVERABLE
Integrative Geroscience Project
Validated reliable quantitative metrics of conserved molecular, cellular and
physiological pathways of aging that underlie multiple chronic diseases,
including multimorbidities.
A Pawlik: and validated reliable quantitative metrics to assess them and their modulation.
Epigenetics
Metabolism
Damage(Repair)
Stress(Adaptation)
Genetics
StemCells
Immunity
Proteostasis
A Molecular Toolbox for Geroscience
Inflammation
A Clinical Toolbox for Geroscience
Arthritis
Sarcopenia CKD
COPD Heart Disease
Immunity
VascularDiseaseNeurological
Disease
Cancer
What can the metrics be used for?
• Assessment of overall susceptibility to multiple chronic diseases.
• Screening and testing interventions, including drug repurposing, that might affect multiple chronic conditions, rather than one disease at a time.
• Detecting, in preclinical or early human testing, of potential adverse effects of an intervention designed for one condition on other age-related conditions.
• Assessment of the drivers of multimorbidity.
In both animal models and humans:
What can the metrics be used for?
Intervention
Disease 1 Disease 2 Disease 3 Disease 4 Disease 5 Disease 6 Disease 7 . . . . .
- X X
HEALTHSPAN METRICS
Lifespan can be modified in mice and other organisms (by behavioral, genetic and pharmacologic means)
And when this is done, many aspects of health are concomitantly improved:
INTEGRATED GEROSCIENCE PROJECT (IGP)
Timely
Rapamycin on Ab in the brain of mouse models
Caccamo et al. – JBC 2010
Rapamycin on TPA-induced skin tumors
Checkley et al. – Ca Prev. Res (2011)
Resveratrol in very fat mice
Baur et al. – Nature. (2006)
INTEGRATED GEROSCIENCE PROJECT (IGP)Many aging interventions affect multiple health parameters
Removal of senescent cellsBaker DJ et al. – Nature 479:232 (2011)
EyeCataracts
BoneLordokyphosis
MuscleSarcopenia
Work
InguinalAdipose Tissue
Heterochronic parabiosis
INTEGRATED GEROSCIENCE PROJECT (IGP)Aging intervention affect multiple health parameters
Villeda et al. Nature 477: 90 (2011); Villeda et al. Nat Med 20: 659 (2014); Sinha et al. Science 344: 649 (2014); Katsimpardi et al. Science 344: 630 (2014)
SynapticplasticityNeuro-
vasculature
OLFACTIONMUSCLES
Cognitive function
CardiacHypertrophy
Smell
Post-injury repair
Strength &Endurance
GDF-11
Loffredo et al. Cell 153: 828 (2013)
Conboy et al. Nature 433: 760 (2005)
CCL11
Stem Cells & Niches
LEARNING & MEMORY
Better screening for:• Multiple positive effects • Possible adverse effects• Multiple diseases
INTEGRATED GEROSCIENCE PROJECT (IGP)
Transformative
The Translational pipeline
INTEGRATED GEROSCIENCE PROJECT (IGP)
TransformativeGeroscience shifts the research focus from models of specific diseases to models with multiple diseases.
Most existing laboratory animals acquire multiple chronic diseases with age.
Different laboratory strains within a species display different combinations of chronic conditions, akin to human multimorbidity.
Therefore existing laboratory animals can be used to model human aging when the metric is health and multiple chronic diseases.What are the measures of HEALTH across the
life course?
INTEGRATED GEROSCIENCE PROJECT (IGP)
Transformative
Validated gero-relevant pathways and associated predictive metrics will address the challenging development of new interventions to the chronic diseases of aging by providing:• Pre-clinical models • With improved predictive ability• Ability to target pathways underlying multiple diseases
• Clinical biomarkers • For early safety signals in clinical trials• Segregation of high-risk patients• Precision medicine taking into account the entire healthspan
Slide added by Aaron Pawlik, as a proposal to develop the ideas from the previous slide (see also note on next slide)
Aging
Dementia
COPD
Stroke
CVD
Diabetes
Cancer
Arthritis
Asthma
Osteoporosis
CKD
Depression
Alzheimer’s
NIA
NEI
NCI
NIAID
NIDDK
NINDS
NIAMS
NHGRI
NIEHS
NIGMS
OD
NICHD
NIAAA
NHLBINIBIB
NIDA
NIMH
NIDCR CSR
NCCAM
INTEGRATED GEROSCIENCE PROJECT (IGP)
Synergistic and Cross-Cutting
AP: Maybe cut this out if short of time? They probably already got the idea
Osteoporosis
Sarcopenia
Frailty Vision
Diabetes
Dementia
CKD
ArthritisChronicDisease
COPD
Neurodegeneration
Proteostasis
EpigeneticsDamage
Inflammation
OtherBiology
Metabolism
StemCells
StressAdaptation
Hearing
Geroscience addresses all chronic diseases at once
CVD
INTEGRATED GEROSCIENCE PROJECT (IGP)
Integrative
Years 06-10
Human Data
Animal Data
AnimalModels
Metrics VALIDATEDMETRICS
DataCoordination
Center
HealthspanConsortium
Interventions
MultiMorbidity
Healthspan
Lifespan
Years 01-05
GEROSCIENCE INITIATIVETimeline