Integrative Geroscience Project

1. Integrative Geroscience Project Richard Hodes On behalf of: The trans-NIH GeroScience Interest Group (GSIG)

2. Aging is the major risk factor for most chronic diseases Stem Cells Proteostasis Biology of Aging Epigenetics Inflammation Metabolism Immunity Damage (Repair) Stress (Adaptation) Genetics

3. Many chronic diseases are studied individually Vascular Disease Neurological Disease Arthritis CKD Biology of Disease Sarcopenia Cancer Immunity Heart Disease COPD

4. Convergence Biology of Aging Biology of Disease Geroscience

5. Integrative Geroscience Project SCOPE To develop a well-validated set of metrics to assess aging changes that influence multiple age-related morbidities STRATEGY Establish pre-clinical animal models, leveraging data obtained to date from animal and human clinical studies

6. Integrative Geroscience Project WHAT IS NEEDED? • 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

7. Integrative Geroscience Project MAIN DELIVERABLE 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.

8. A Molecular Toolbox for Geroscience Stem Cells Proteostasis Genetics Inflammation Metabolism Immunity Damage (Repair) Stress (Adaptation) Epigenetics

9. A Clinical Toolbox for Geroscience Vascular Disease Neurological Disease Arthritis CKD Sarcopenia Cancer Immunity Heart Disease COPD

10. What can the metrics be used for? In both animal models and humans: • 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.

11. What can the metrics be used for? Intervention HEALTHSPAN METRICS Disease 1 Disease 2 Disease 3 Disease 4 Disease 5 Disease 6 Disease 7 . . . . . - X X

12. INTEGRATED GEROSCIENCE PROJECT (IGP) Timely Lifespan can be modified in mice and other organisms (by behavioral, genetic and pharmacologic means) Rapamycin on TPA-induced skin tumors And when this is done, many aspects of health are concomitantly improved: Rapamycin on Ab in the brain of mouse models Checkleyet al. – Ca Prev. Res (2011) Resveratrol in very fat mice Bauret al. – Nature. (2006) Caccamo et al. – JBC 2010

13. INTEGRATED GEROSCIENCE PROJECT (IGP) Many aging interventions affect multiple health parameters Removal of senescent cells Baker DJ et al. – Nature 479:232 (2011) Eye Cataracts Bone Lordokyphosis Inguinal Adipose Tissue Muscle Sarcopenia Work

14. INTEGRATED GEROSCIENCE PROJECT (IGP) Aging intervention affect multiple health parameters Heterochronic parabiosis Cardiac Hypertrophy Strength & Endurance Smell OLFACTION MUSCLES Stem Cells & Niches Post-injury repair GDF-11 Conboy et al. Nature433: 760 (2005) LEARNING & MEMORY Cognitive function Synaptic plasticity Neuro-vasculature CCL11 Villeda et al. Nature 477: 90 (2011); Villeda et al. Nat Med 20: 659(2014); Sinha et al. Science344: 649 (2014); Katsimpardiet al. Science344: 630 (2014) Loffredo et al. Cell153: 828 (2013)

15. INTEGRATED GEROSCIENCE PROJECT (IGP) Transformative • Better screening for: • Multiple positive effects • Possible adverse effects • Multiple diseases The Translational pipeline

16. INTEGRATED GEROSCIENCE PROJECT (IGP) Transformative Geroscience 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?

17. 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)

18. INTEGRATED GEROSCIENCE PROJECT (IGP) Synergistic and Cross-Cutting Dementia NIA CKD Diabetes NIGMS NIDDK NIAAA NIMH NICHD NINDS Alzheimer’s Cancer Aging Stroke Depression OD NCI CSR NIDCR CVD Osteoporosis NCCAM NIDA NIEHS NIAID NEI NHGRI Asthma COPD NIAMS Arthritis NHLBI NIBIB AP: Maybe cut this out if short of time? They probably already got the idea

19. INTEGRATED GEROSCIENCE PROJECT (IGP) Integrative Geroscience addresses all chronic diseases at once Dementia CVD Sarcopenia CKD Arthritis COPD Chronic Disease Damage Epigenetics Stress Adaptation Diabetes Osteoporosis Neurodegeneration Hearing Stem Cells Vision Frailty Inflammation Metabolism Proteostasis Other Biology

20. GEROSCIENCE INITIATIVE Timeline Human Data Data Coordination Center Animal Data Multi Morbidity Healthspan Interventions VALIDATED METRICS Metrics Lifespan Animal Models Healthspan Consortium Years 01-05 Years 06-10