sign in sign up
<<
Home , Biogerontology, Senescence

Advances in : Clinical Promise and Ethical Pitfalls

John Newman, MD, PhD Geriatric Medicine

Who Am I?

Geroscientist at Buck Institute: Metabolic signals that regulate aging

Geriatrician at UCSF: Inpatient Medicine and [email protected] @GeriSciDoc Part 1: Aging Biology

Part 2: Clinical Trials

Part 3: Questions Part 1: Aging Biology

Part 2: Clinical Trials

Part 3: Questions The Revolution: An old story!

Since 1850, expectancy has advanced by one year for every four (“Christensen’s Law”?) Christensen et al., Lancet 2009 The Longevity Revolution: An old story!

Chance of dying while age 80

1950 1975 2000

Mortality is falling throughout life, Christensen et al., even among the very oldest Lancet 2009 Healthspan Healthy life Illness and disability Geroscience Hypothesis: Therapies that target mechanisms of aging can prevent, delay, or treat a wide range of age-related and conditions Extend lifespan

Extend healthspan

Extend both How to study “Aging”

1. Describe it Gradual, progressive, universal loss of beginning after maturation 2. Define it Susceptibility to Increasing probability of Loss of resilience to stressors Loss of reproduction capacity

3. Operationalize it for studies

Cell divisions Lifespan Multimorbidity Aging: Just another biological process Worms and aging genes

1. Describe it Gradual, progressive, universal loss of function beginning after maturation 2. Define it Susceptibility to disease Increasing probability of death Loss of resilience to stressors Loss of reproduction capacity

3. Operationalize it for studies

Cell divisions Lifespan of a laboratory worm Multimorbidity

Mair Lab, Harvard Genetic screens

?

Normal, Create Worms with “Assay”: identical random genetic lifespan worms differences Worms and aging genes

Mutation in the worm version of insulin and growth pathway = longer life

Mapping entire “aging pathways” by seeing how different mutations , interact with each other UCSF “High throughput” aging science

Scanner-based C. elegans Microfluidic chip and “lifespan machine” with microscopy-based automated data processing replicative aging assay Hallmarks Of Aging…

Lopez-Otin, Cell 2013 Damage Consequences

DNA damage Senescent cells damage and misfolding exhaustion Epigenetic damage Mitochondrial dysfunction damage Chronic inflammation Damage Consequences

Repair Stop Damage Consequences Metabolic signals and stress response

Less Metabolic Stress Nutrients/ Signals Response Growth Dietary Restriction NAD FOXO3 Fasting Insulin/IGF Sirtuins Protein Restriction AMPK Autophagy Methionine Restriction TOR Mitophagy Ketone bodies DRUGS: Metformin Rapamycin … Senescent cells and

Damage Inflammation

DNA damage Short

Stop dividing = no “Zombie cell” Damage nearby cells Promote cancer Senescent cells and senolytics

Damage Senescence Inflammation

DNA damage Short telomeres

Senolytics (DRUGS) Senescent cells and senolytics

Stem Cell Muscles Exhaustion Wound healing

New stem cells? Potential Interventions

Metabolic therapies Senolytics Other drugs Metformin Navitoclax Aspirin Rapamycin Dasatanib 17α-estradiol Acarbose Quercetin NDGA NAD supplements (NR, NMN) HSP90 inhibitors (17-AAG, ACEI/ARBs Sirtuin activators (SRT2104, 17-DMAG) SRT1720) Other BCL-activators Novel TOR inhibitors CD38 inhibitors Ketone esters

Blood factors Dietary Procedures Myostatin inhibitors Caloric restriction Young mesenchymal stem Protein restriction cell infusion Methionine restriction Young plasma infusion Part 1: Aging Biology

Part 2: Clinical Trials

Part 3: Questions How to study “Aging”

1. Describe it Gradual, progressive, universal loss of function beginning after maturation 2. Define it Susceptibility to disease Increasing probability of death Loss of resilience to stressors Loss of reproduction capacity

3. Operationalize it for studies

Cell divisions Lifespan Multimorbidity “Pre-clinical trials” of lifespan in laboratory

US National Institute on Aging >30 compounds tested/testing Interventions Testing Program ~7 “hits” so far Multicenter ”Clinical Trial” for mice

Harrison, 2009 How to test aging interventions in ? Healthy life Illness and disability

Extend lifespan

Extend healthspan

Extend both How to measure aging in humans? Healthy life Illness and disability

Extend healthspan

Multimorbidity: chronic diseases

Geriatric Syndromes “Age” is not a number: - Frailty Calendar age - Falls versus - Functional Decline Physiological age - Delirium

(If you’ve seen one 80 year old you’ve seen one 80 year old) Loss of resilience to acute stress Geriatric syndromes

Frailty Geriatric syndrome: Falls Multifactorial Cognitive decline Multisystem FALL Mobility decline Age-related Delirium Integrative outcome Chronic wounds Etc etc… Heart disease risk factors 100

80

60

40

Percent Increase 20

0 Smoking Cholesterol

Steve Austad, University of Alabama Heart disease risk factors

6000

4000

2000 Percent Increase

0 HypertensionSmoking Cholesterol Diabetes Aging

Steve Austad, University of Alabama Multimorbidity

Age is a risk for most chronic diseases…

So most chronic diseases don’t happen alone

Rochester Epidemiology Project Designing Clinical Trials for “Aging”

Functional Reserve “Healthspan”: A. Enhancingor “Resilience” Resilience B. ProlongingMultimorbidity Healthspan or geriatric syndromes Acute Natural Course Stressor Intervention Baseline Recovery

Disability & Disability & Dependence Dependence Function Function Time Time

Newman, J Geron 2016 Designing Clinical Trials for “Aging”

Geriatric specialty for A. Enhancinghospital Resilience wards B. Prolongingimproving Healthspan frailty

Acute Natural Course Stressor Intervention Baseline Recovery

Disability & Disability & Dependence Dependence Function Function Time Time

Newman, J Geron 2016 Multimorbidity or Geriatric Syndromes

Rapamycin for preventing respiratory infections in frail elderly “Healthspan”: (PureTechA. Enhancing/resTORbio Resilience) B.Multimorbidity, Prolonging Healthspan function, or geriatric syndromes Acute Natural Course Metformin to delayStressor the onset of Intervention Baseline Recovery multiple chronic diseases (“TAME: Targeting Aging with Metformin”, public consortium)

Disability & Disability & Young mesenchymal stem Dependencecell Dependence Function infusionFunction to treat frailty (LongeveronTime , U. Miami) Time Health stress or hospitalization

Functional Reserve Rapamycin improves influenza A. Enhancingor “Resilience” Resilience B. Prolonging Healthspanvaccine effect (Novartis, Science Trans Med 2014) Acute Natural Course Stressor Intervention Baseline Recovery Rapamycin plus cardiac rehabilitation in the elderly (Mayo Clinic)

Disability & Disability & Dependence DependenceMetformin with resistance exercise training in the elderly Function Function (U. Kentucky, U. Alabama) Time Time of risk: Preventative therapy Cardiac valve surgery: Pre-habilitation

Health First chronic disease: Delay other chronic disease

Severe influenza: Prevent hospital disability

Time Part 1: Aging Biology

Part 2: Clinical Trials

Part 3: Questions Aging is universal Is ”Aging” a disease?

It happens to everyone!

If not, what does a drug company or regulatory agency do? What aspect of aging will clinical trials target?

Do researchers and doctors decide?

Should the broad community have a say?

What do older think is important to them? Large clinical trials of frail, vulnerable, elderly people?

First to harm, last to help…

We test cancer drugs in patients with cancer…

We need more clinical trials in the elderly anyway! Who will get these treatments?

Everyone, right? Right?

What if it’s expensive?

What if it’s rare? Expensive Treatments

Expensive by choice: Novel senolytics Hepatitis C cures

Expensive by design: Aging-factor blocking antibodies Antibody-based drugs

Expensive by technology: Autologous organoids or stem cells CAR-T, Dialysis Expensive by scarcity: Young blood/cell infusion Transfusion, organ transplant Aside: Frankenstein medicine

“Replacement parts” approach to medicine does not work

Transplants, dialysis, LVADs, etc etc – it’s never just one thing. The whole person is old and frail.

What if aging therapies change that? Who will benefit?

Everyone, right? Right?

Fancy heath care can exacerbate disparities

But it’s easier to fix what’s broken – who is most affected by aging now? Will aging therapies exacerbate or reduce health disparities?

Rich already live longer – less room to improve

Poor and disadvantaged have vicious cycle of health problems, accelerated aging, and geriatric syndromes Aging biology is here

Clinical trials are happening

What do we do from here? Optimizing Aging Collaborative at UCSF

For more information, visit us online at OptimizingAging.com or email us at [email protected].

The Optimizing Aging Collaborative at UCSF is supported by the UCSF Geriatrics Workforce Enhancement Program: Health Resources and Services Administration (HRSA) Grant Number U1QHP28727.