Advancing the Health of an Aging Population

Friends of the NIA Senate Briefing

Richard J. Hodes, M.D., DirectorMarie A. Bernard, M.D., Deputy Director

National Institute on Aging

June 30, 2016

Advances at the NIA: From Bench toBedside to Real-World Practice

World’s Older Population is Growing

He et al. U.S. Census Bureau, International Population Reports, P95/16-1,An Aging World: 2015,

• America’s 65-and-over population is projected to nearly double, from 48 mill to 88 mill by 2050

• Global life expectancy is projected to increase by almost eight years, from 68.6 years in 2015 to 76.2 years in 2050

• The global population of people aged 80 and older is expected to more than triple, growing from 126.5 mill to 446.6 mill by 2050

$200M for PMI

$85M for BRAIN

$350M for AD

• $1.6B for the NIA • 4 percent increases across

all ICs (not counting the $$ above) – 4.2% for the NIA

• All divisions will benefit DBSR DGCG

DAB DN

$32 Billion for the NIH

Difference from FY2006

In Current Dollars: $561.6M Increase

In Constant Dollars: $62.7M Increase

6.3% increaseFY06-FY17

NIA Appropriations FY 2005-2017 PBCurrent versus Constant, FY05 Base Year

06 07 08 09 10 11 12 13 14 15 16 17

Actual 1,036.6 1,045.5 1,051.0 1,079.0 1,108.2 1,100.4 1,121.3 1,040.6 1,171.7 1,197.5 1,598.2 1,598.2

Constant 988.9 957.7 913.3 906.4 897.6 859.4 861.2 779.4 851.8 844.2 1,090.0 1,051.6

700

750

800

850

900

950

1,000

1,050

1,100

1,150

1,200

1,250

1,300

1,350

1,400

1,450

1,500

1,550

1,600

1,650D

olla

rs,

in M

illio

ns

$0.000

$0.200

$0.400

$0.600

$0.800

$1.000

$1.200

$1.400

$1.600

$1.800

2013 2014 2015 2016 2017

Do

llars

(in

bill

ion

s)

Fiscal Year

NIA Appropriations

AD funds

Bench

Bedside

Real world

Bench

Bedside

Real world

St. Sauver, JL et al. (2015) BMJ Open Feb 3;5(2):e006413.

Chronic Kidney Disease

Stroke OsteoporosisCong. Heart

Failure

COPD

Hyperlipid. HTN Depression Diabetes

Arthritis CancerCardiac

ArrhythmiasCAD

Disease Prevalence as a Function of Age

Schizophrenia

Epigenetics

MetabolismInflammation

Damage(Repair)

Stress(Adaptation)

Genetics

StemCells

Immunity

Proteostasis

Arthritis

SarcopeniaCKD

COPD Heart Disease

Immunity

VascularDiseaseNeurological

Disease

Cancer

MacularDegeneration

HearingBiologyof

Disease

Biologyof

Aging

Proteostasis

Epigenetics

MacromolecularDamage

Inflammation

OtherBiology

Metabolism

StemCells

StressResponse

Burch, JB et al. (2014) J Gerontol A Biol Sci Med Sci Jun; 69 Suppl 1:S1-3;Kennedy, BK et al. (2014) Cell 159(4): 709–713.

“Geroscience” is the Convergence of Two Fields of Study

Rapamycin -- ITP

Aspirin – ITP Acarbose – ITP

17-a estradiol -- ITP

Lifespan is Plastic

Ad LibitumRestricted

Calorie Restriction

Intermittent Fasting: A Promising Lead

Brandhorst, S et al. (2015) Cell Metabolism 22, 22(1):86-99.

Intermittent Fasting: A Promising Lead

Brandhorst, S et al. (2015) Cell Metabolism 22, 22(1):86-99.

Stay tuned…more to come on calorie restriction later in the talk

Baker DJ et al. (2011) Nature 479:232

Deleting senescent cells delays age-associated disorders

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

14

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

Number of genes or loci

1990 1995 2000 2005 2010 2015

30

25

20

15

10

5

0

Early Onset genes

Innate immune/Brain inflammatory response

Endocytosis and cellular protein trafficking, including APP trafficking and Aββ processing

Lipid transport/metabolism

Synaptic transmission

Cytoskeletal function, including tau

APPPS 1

PS2APOE

CLU

PICALM

SORL1

BIN1

CD2AP

EPHA

MS4A4A

ABCA7

HLA-DRB5

PTK2B

CASS4

CD33

MEF2cC

NME8

CELF1

TREM2

Genetic Regions of Interest in Alzheimer’s Disease

By Year of Discovery

Confirmed loci with no assigned function:IMPP5D, SLC24A4/RIN5

FERM T2

TRIP 4

MAPT

CRI

Bench

Bedside

Real world

Biomarkers Inform Our Understanding of Alzheimer’s Progression

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

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

Bateman RJ et al. (2012) N Engl J Med; Aug 30; 367:795-804

Aβ Deposition in Autosomal Dominant ADYears before Expected Clinical Symptoms

Bateman RJ et al. (2012) N Engl J Med; Aug 30; 367:795-804

For example, a family in Colombia that develops AD early is generously working with researchers

Early Intervention is One Goal of NIA’s Alzheimer’s Trials

Fleisher, AS et al. (2012) Lancet Neurology 11(12):1057-65.

Gene Carriers, late 30’s

Beta-amyloid, late 20’s

Dementia onset is in late 40’s

Non-Carriers, late 30’s

NIA’s Alzheimer’s-related Trials Explore Many Different Disease Pathways

• Anti-amyloid trials API-ADAD (Colombia families) DIAN-TU API-APOE4 A4

Adds tau imaging and novel fluid biomarkers to these trials - for tracking

responsiveness to treatment and/or disease

progression

NIA’s Alzheimer’s-related Trials Explore Many Different Disease Pathways

• Anti-amyloid trials API-ADAD (Colombia families) DIAN-TU API-APOE4 A4

NIA’s Alzheimer’s-related Trials Explore Many Different Disease Pathways

• In addition to anti-amyloid therapies, NIA-funded clinical researchers are also studying:

o Compounds that

Prevent loss of nerve connections

Restore function of damaged synapses

Promote new neuron growth

o Dietary and physical activity interventions

o Blood pressure control

o Repurposing of drugs that were not successful for their original indications

In the news…

The company NeurotrophiX is planning a test of a growth factor called LM11A-31

The drug may prevent the activation of degenerative processes and protect nerve cells and their connections

February, 2016

The initial Federal investment…

Successful pre-IND studies supported in large part by the NIA/NIH made possible FDA approval for phase I and IIa human testing• AD Translational

Program • IND (Investigational

New Drug) Toxicology Program

February, 2016

NIA Aging-related Clinical Trials in Process

• Examples include:

–Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE)

–Aspirin in Reducing Events in Elderly (ASPREE)

–Enabling Reduction of Low-Grade Inflammation in Seniors (ENRGISE)-Pilot Study

–Study To Understand Fall Reduction and Vitamin D in You (STURDY)

26

Bench

Bedside

Real world

Randomized Trial of Financial-Incentive Programs for Smoking Cessation

Halpern, SD et al. (2015)NEJM 372(22):2108-17.

“Reward” and “Commitment” participants quit more often than treatment as usual

Systolic Blood Pressure Intervention Trial Primary Outcome

The SPRINT Research Group (2015) NEJM 373(22):2103-16.

SPRINT Study

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

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

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

Remember Calorie Restriction?

First human trial of long-term CR on effects on aging-related outcomes

Tested feasibility and safety of two-year CR, and its mechanisms

Comprehensive Assessment of Long-

term Effects of Reducing Intake of

Energy

CALERIE Results

Ravussin, E et al. J Gerontol A Biol Sci Med Sci 2015 Sep;70(9):1097-104.

Participation in Research is Essential!

• NIA, CDC, and ACL collaboration -- Recruiting Older Adults into Research (ROAR)

• Encourages older adults, family caregivers to join studies

• First focus is Alzheimer’s; a toolkit is available at https://www.nia.nih.gov/health/publication/roar-toolkit

• Encourages sedentary older adults to be active every day

• Based on the science

• Includes

– people with chronic health conditions and

– older people who traditionally have not embraced exercise and shows them how to do so safely

-- Putting Research in Action

• Examined the affordability and accessibility of hearing –related services to consumers

• Recommended the expansion of options available with the creation of over-the-counter wearable hearing devices

• Recommended clear guidance and regulatory oversight by the FDA

Hearing Health Care for Adults

National Academies of Sciences, Engineering, and Medicine, 2016.

Sponsors included: CDC, DOD, VA, FDA, Hearing Loss Association of America, NIA, NIDCD

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