NIA Science Advances

Richard J. Hodes, M.D.Director

National Institute on Aging

Visit from Friends of the NIAOctober 7, 2016

NIA Science Advances 2016 Update

NATIONAL INSTITUES OF HEALTHNational Institute on Aging

Organizational Structure

Office of the DirectorRichard J. Hodes, M.D.Marie A. Bernard, M.D.

Intramural Research Program

Luigi Ferrucci, M.D., Ph.D.Michele K. Evans, M.D.

Division of Extramural Activities

Robin Barr, D.Phil.Chyren Hunter, Ph.D.

Division of Aging Biology

Felipe Sierra, Ph.D.Ronald Kohanski, Ph.D.

Division of Geriatrics and Clinical Gerontology

Evan Hadley, M.D.Winifred K. Rossi, M.A.

Division of Behavioral and Social Research

John Haaga, Ph.D.Georgeanne Patmios, M.A.

Division of Neuroscience Eliezer Masliah, M.D.

Creighton Phelps, Ph.D.

Intramural Research Program

• 10 Intramural Laboratories• Core facilities• Home of the BLSA and HANDLS

Is Metformin the Magic Elixir for Aging?

Metformin

Dicer

miRNAs

AGE

Dicer

SA-β-Gal

Mock Metformin

SenescenceMarkersp16, p21SASP

Metformin decreases cellular senescenceHooten, T et al. (2016) Aging Cell 15(3): 572-81.

Role of Myelin in Human Brain Function

Myelin

MR image of human brain

Nerve axon microstructure

Myelination is an important feature of-Brain development -The pathophysiology of CNS disorders:

* Multiple sclerosis* Phenylketonuria* Schizophrenia* Epilepsy * Alzheimer's disease

Myelin sheathsRapid conduction of nerve impulses

Bouhrara, M et al. (2016). Neuroimage 127:456-471.

Mapping Myelin in Human BrainMRI scanner

Image acquisition

A series of images

covering the whole brain volume area

- We have developed a new method for high resolution myelin mapping

- Whole brain coverage can be achieved in less than 15 min

- An important step toward understanding the relationship between myelination in mild cognitive impairment and Alzheimer’s disease.

MR Images

Conventional Method New Method* Bouhrara, M et al. (2016). Neuroimage 127:456-471.

Higher midlife adiposity is associated with earlier age at onset (AAO) of AD

Midlife BMI and AAO of Alzheimer’s Disease (AD) (N=142)

Relationship between 10th percentile survival time for Alzheimer’s dementia (AD) and midlife BMI with 90% confidence intervals

Each incremental unit in midlife BMI is associated with an earlier age-of-onset of AD by an average of 6.7 months

Chuang, Y (2015) Mol Psychiatry 21(7):910-5.

Three new risk loci for myasthenia gravis

Renton, A et al. (2015) JAMA Neurology 72(4):396-404.

Chuang Y. F. 2015 Mol Psychiatry 21(7):910-5

Translating genetic findings to help patients with myasthenia gravis

Clinical trial of Abatacept in myasthenia gravis patients to start at Johns Hopkins in late 2016/early 2017

Renton, A et al. (2015) JAMA Neurology 72(4):396-404.

Division of Aging Biology• Nathan Shock Centers of

Excellence • Genetics and Cell Biology

• Genetics• Cell Biology• Metabolic Regulation

• Aging Physiology• Cardiovascular Biology• Immunology• Endocrinology• Musculoskeletal Biology• Stem Cell Biology• Tissue Physiology

• Biological Resources• Animal Models• Biological Resources

Director: Felipe Sierra, Ph.D. sierraf@nia.nih.govDeputy Director: Ron Kohanski, Ph.D. kohanskir@nia.nih.gov

Naked Mole Rats

Appearance of all diseases in relationship to ageNECS-New England Centenarian Study (Perls)LGP-longevity Genes Project (Einstein)F-females

M-malesC-controlP-proband (centenarians)

Ismail, K et al (2016) J Am Geriatr Soc (8):1583-91.

Xu, M. et al. (2015) PNAS 17;112(46):E6301-10

JAK inhibition alleviates inflammation

Senescent Cells have Beneficial Functions

De Maria, M et al. (2014) Dev Cell 31(6):722-33.

Menopause accelerates the epigenetic clock

Levine, ME et al. (2016) PNAS 113(33):9327-32.

DNA Methylation and health disparities

Horvath, S et al. (2016) Genome Biol 17(1):171.

Ethnicity Gender

Trans-NIH organization of 21 Institutes initiated by NIA to: • Raise awareness of the relevant

role played by aging biology in the development of diseases and disabilities.

• Promote discussion and co-funding of initiatives across the NIH, based on the above.

• Gero I – 2013 Summit

• Gero II - Disease Drivers of Aging: 2016 Advances in Geroscience Summit- focused on how diseases and associated therapies can accelerate the onset of age-related changes

NIH GeroScience Interest Group (GSIG)

Division of Neuroscience

• Basic Neurobiology• Alzheimer’s Disease• Sensory Processes• Learning and Memory• Sleep• Cognitive Health

Director: Eliezer Masliah, M.D.Deputy Director: Creighton Phelps, Ph.D.phelpsc@nia.nih.gov

The Busier the Better?

An observed association: Increases in busyness are associated with improved cognition

Festini, SB et al. (2016) Front Aging Neurosci 17;8:98

● APP

● APOE

●●●●●●

Early-onset genes

Innate immune/brain inflammatory response genesEndocytosis and cellular protein trafficking, including APP trafficking and Aβ processing

Lipid transport/metabolism

Synaptic transmissionCytoskeletal function, including tau

No assigned mechanism of action

● PS1

● PS2●● CR1

●● CLU● PICALM

● BIN1

● CD33

● TREM2

●● ABCA7

● HLA-RB5 ● TRIP4

● MAPT

KEY

● SORL1

● CD2AP

● MS4A4/MS4A6E

● EPHA1

Genetic Regions of Interest in Alzheimer’s DiseaseBy year of discoveryNOTE: Color indicates mechanism of action in the body. See key below.

● MEF2cC

● PTK2B

● FERM T2

● CASS4

● NME8

● CELF1

SLC24A4/RIN5

IMPP5D

Biomarkers Inform Our Understanding of Alzheimer’s Progression

Jack, C et al. (2013) Lancet Neurol 12(2):207-16.

Clinical, Cognitive, Structural, Metabolic, and Biochemical Changes years Before AD Symptom Onset

Bateman, R et al. (2012) N Engl J Med 367 (9):795-804.

Courtesy of Tammie Benzinger; Bateman, R et al. (2012) N Engl J Med 367(9):795-804.

Aβ Deposition in Autosomal Dominant Alzheimer's Disease Years before Expected Clinical Symptoms.

Decreased smell identifies risk for Alzheimer’s Disease

Almost 25% of patients with low University of Pennsylvania Smell Identification Test (UPSIT) scores transitioned to AD compared to less than 5%of patients who scored the highest

Devanand, D et al. (2015) Neurology 84(2):182-189.

Relationship between sleep and amyloid load

Mean PET PiBimages show increased amyloid burden in those subjects who report sleeping less than 6 hours nightly

Spira, A et al. (2013) JAMA Neurology 70(12): 1537-1543.

≤ 6 h> 6 h to ≤ 7 h>7 h

Basic & Translational Projects in the AD Pipeline

• A consortium to look at how vascular risk factors influence AD – focused on molecular mechanisms

• New translational centers to develop – and share – the next generation of animal models of AD

• A biomarkers consortium to study AD in individuals with Down syndrome

• Discovery and development of novel therapeutics for AD against a wide range of targets –Facilitated by AMP

25

Target Discovery and Preclinical Validation • Shortens the time between discovery of targets to

development of new drugs • Integrates analysis of large-scale molecular data from

human brain samples with network modeling approaches and experimental validation

Middeldorp, J et al. (2016) JAMA Neurology Epub ahead of print.

Young Blood Plasma Affects Memory in Amyloid Precursor Protein (APP) Mice

Circulating factors within young blood were sufficient to restore abnormal gene and protein expression in APP mice

Division of Behavioral and Social Research

• Reversibility of early-established risk factors

• Regional and int’l differences in health and longevity

• Social neuroscience of aging• Longitudinal Studies• Centers programs• Interventions

c/o Gerontology Society of Iowa

Director: John Haaga HaagaJ@mail.nih.govActing Deputy Director: Georgeanne Patmios patmiosg@nia.nih.gov

Park, D et al. (2013) Psychological Science 25 (1):103-112.

Episodic Memory in Older Adults Enhanced by Productive Engagement

Episodic memory was enhanced in these productive-engagement conditions relative to receptive-engagement conditions.

Stan

dard

ized

Gai

n Sc

ore

Condition

Episodic Memory

• Biomarkers for AD include: decreased hippocampal volume, amyloid plaques, and neurofibrillary tangles

• The hippocampus is a critical brain region for maintenance of intact memory

• People who held negative stereotypes about aging 20 years prior to brain assessments showed steeper declines of hippocampal volume than people holding positive aging stereotypes

Levy, B et al. (2016) Psychol Aging 31(1): 82-88.

Negative Stereotypes about Aging Predict AD Biomarkers

• Biomarkers for AD include: decreased hippocampal volume, amyloid plaques, and neurofibrillary tangles

• The hippocampus is a critical brain region for maintenance of intact memory

• People with negative age stereotypes - measured 20 years prior to brain assessments - had greater accumulations of amyloid plaque and neurofibrillary tangles

Levy, B et al. (2016) Psychol Aging 31(1): 82-88.

Negative Stereotypes about Aging Predict AD Biomarkers

Improving Inappropriate Antibiotic Prescribing

Both behavioral interventions resulted in lower rates of inappropriate antibiotic prescribing

Meeker, D et al. (2016) JAMA 315(6):562-570.

Accountable justification Peer comparison

Division of Geriatrics and Clinical Gerontology

• Older Americans Independence Centers

• Menopause

• Cardiovascular Disorders

• Cancer and Aging

• Exercise and Physical Activity

• Osteoporosis/Musculoskeletal Disorders

Director: Dr. Evan Hadley, M.D.hadleye@nia.nih.govDeputy Director: Winnie Rossi, M.A.rossiw@nia.nih.gov

Diet and/or Exercise to Treat Heart Failure With Preserved Ejection Fraction

Kitzman, D et al. (2016) JAMA 315(1):36-46.

Early versus Late Postmenopausal Treatment with Estradiol (ELITE) Trial

• The study tested the effects of menopausal hormone therapy on atherosclerosis depending on the timing of the initiation of therapy (< 6 years vs. ≥ 10 years post menopause)

• A trial testing effects of hormone therapy on prevention of heart attacks, cardiac death, and stroke is needed to establish clinical significance of these findings

Hodis, H et al. (2016) N Engl J Med 374:1221-1231.

Effects of Testosterone Treatment in Older Men

Snyder, P et al. (2016) NEJM 374(7):611-624.

SPRINT Follow-up in Adults 75 years or Older

Williamson, J et al. (2016) JAMA 315(24):2673-82.

• Cumulative hazard was reduced in participants, even those less fit and frail

• Incident cardiovascular disease was reduced by 33% and mortality (from any cause) was reduced by 32%

• The rate of serious adverse events was not statically different across treatment groups, including among the most frail participants

STrategies to Reduce Injuries and Develop Confidence in Elders (STRIDE)

• A trial of a multifactorial, evidence-based, patient-centered fall injury prevention strategy

• 6000 community-living adults aged ≥ 75 years who are at increased risk for serious fall injuries will be enrolled and followed for up to 36 months

• The project is a collaboration of researchers from 14 Claude D. Pepper Older Americans Independence Centers, practitioners from 10 healthcare delivery systems and patient representatives- funded by NIA and PCORI

• It is expected to be completed in 2019

What’s on the horizon?

Division of Aging Biology• Comparative Biology of Neurodegeneration• Dynamic interactions between Peripheral Systems and the Brain in

Aging and in Alzheimer’s Disease• Systems biology approaches to Alzheimer’s Disease using Non-

Mammalian Models• The role of aging metabolic changes in Alzheimer’s disease (AD)• The Role of Peripheral Proteostasis on Brain Aging and on

Alzheimer’s Disease

Division of Behavioral and Social Research• Improving Quality of Care and Quality of Life for Persons with

Alzheimer’s Disease and Related Dementia at the End of Life• Leveraging Existing Cohort Studies to Clarify Risk and Protective

Factors for Alzheimer’s disease and related dementias

New Alzheimer’s Concepts

Division of Neuroscience• Brain lymphatic system in aging and Alzheimer’s disease

• Commonalities, and Interactions Between Neurodegenerative Diseases

• Human Cell Reprogramming for Functional Genetics of Alzheimer’s Disease

• Mechanisms of Selective Neuronal Vulnerability in Alzheimer’s Disease

• NIA Small Business Opportunities to Advance Alzheimer’s Disease Research

• Revision Applications to Enhance the Target and Biomarker Discovery Efforts of the AMP-AD and M2OVE-AD Consortia

• Role of Exosomes in Alzheimer’s Disease

• Validation of NIH Toolbox Instruments for Tracking and Diagnosis of MCI and early AD, and for Extension of Assessment in the Oldest Old

• Understanding the Impact of Sex Differences on the Phenotypes of AD Risk and Responsiveness to Therapy

• Complex Biology of Resilience from Alzheimer’s

New Alzheimer’s Concepts

Division of Geriatrics and Clinical Gerontology• Clarifying the relationship between delirium and Alzheimer’s

disease and related dementias• Development of Socially Assistive Robots to Engage Persons with

ADRD and their Caregivers • Multimorbidity in Alzheimer’s Disease Impacts Choice of Ancillary

Treatments • Pragmatic Trials for Dementia Care in Long Term Services and

Support (LTSS) Settings• Tools for Clinical Care and Management of Alzheimer’s disease

and its comorbidities• Understanding the Effects of APOE2 on the Interaction between

Aging and Alzheimer’s Disease.

New Alzheimer’s Concepts

Division of Extramural Activities• Alzheimer’s Disease Research Revision Awards to

Institutional Training Grants • Institutional Training Programs to Advance Translational

Research for Alzheimer’s Disease and AD Related Dementias

• Research Career Enhancement Award to Advance Therapy Development for AD and Related Dementias

New Alzheimer’s Concepts