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

Convergence

Biologyof

Disease

Biologyof

Aging

Geroscience

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