Advances in Biogerontology: Clinical Promise and Ethical...
Transcript of Advances in Biogerontology: Clinical Promise and Ethical...
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Advances in Biogerontology:
Clinical Promise and Ethical Pitfalls
John Newman, MD, PhD
Geriatric Medicine
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San Francisco, USA
Geroscientist at Buck Institute:
Geriatrician at UCSF:
Metabolic signals that regulate aging
Hospital Medicine and Geriatrics
Who Am I?
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Additional materials and
questions live on Twitter
@GeriSciDoc
#BiogerCUHK
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Part 1: Aging Biology
Part 2: Clinical Trials
Part 3: Questions
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Part 1: Aging Biology
Part 2: Clinical Trials
Part 3: Questions
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The Longevity
Revolution:
An old story!
Since 1850,
life expectancy has advanced
by one year for every four
(“Christensen’s Law”?)
Christensen et al.,
Lancet 2009
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Mortality is falling throughout life,
even among the very oldest
Christensen et al.,
Lancet 2009
1950 20001975
Chance of dying
while age 80
The Longevity
Revolution:
An old story!
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Healthspan
Healthy life Illness and disability
Extend lifespan
Extend healthspan
Extend both
Geroscience Hypothesis:
Therapies that target mechanisms of aging
can prevent, delay, or treat a wide range of
age-related diseases and conditions
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How to study “Aging”
1. Describe it
2. Define it
3. Operationalize it for studies
Gradual, progressive, universal loss of function
beginning after maturation
Susceptibility to disease
Increasing probability of death
Loss of resilience to stressors
Loss of reproduction capacity
Cell divisions
Lifespan
Multimorbidity
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Aging: Just another biological process
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Hallmarks
Of Aging…
Lopez-Otin, Cell 2013
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Damage Consequences
DNA damage
Protein damage and misfolding
Epigenetic damage
Telomere damage
Senescent cells
Stem cell exhaustion
Mitochondrial dysfunction
Chronic inflammation
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Damage Consequences
Repair
Damage
Stop
Consequences
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Metabolic signals and stress response
Less
Nutrients
Metabolic
Signals
Stress
Response
Dietary Restriction
Fasting
Protein Restriction
Methionine Restriction
NAD
Insulin/IGF
AMPK
TOR
Ketone bodies
FOXO3
Sirtuins
Autophagy
Mitophagy
DRUGS:
Metformin
Rapamycin
…
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Senescent cells and senolytics
Damage Inflammation
DNA damage
Short telomeres
Senescence
Stop dividing =
no cancer
“Zombie cell”Damage nearby cells
Promote cancer
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Senescent cells and senolytics
Damage Inflammation
DNA damage
Short telomeres
Senescence
Senolytics(DRUGS)
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Senescent cells and senolytics
Stem Cell
Exhaustion
New stem cells?
Muscles
Wound healing
Immune system
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Potential Interventions
Metabolic therapies
Metformin
Rapamycin
Acarbose
NAD supplements (NR, NMN)
Sirtuin activators (SRT2104,
SRT1720)
Novel TOR inhibitors
CD38 inhibitors
Ketone esters
Other drugs
Aspirin
17a-estradiol
NDGA
ACEI/ARBs
Dietary
Caloric restriction
Protein restriction
Methionine restriction
Senolytics
Navitoclax
Dasatanib
Quercetin
HSP90 inhibitors (17-AAG,
17-DMAG)
Other BCL-activators
Procedures
Young mesenchymal stem
cell infusion
Young plasma infusion
Blood factors
Myostatin inhibitors
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Part 1: Aging Biology
Part 2: Clinical Trials
Part 3: Questions
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Studies in laboratory animals:
Rapamycin was the first aging therapy
US National Institute on Aging
Interventions Testing Program
Multicenter ”Clinical Trial” for miceHarrison, Nature 2009
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How to test aging interventions in humans?
Healthy life Illness and disability
Extend lifespan
Extend healthspan
Extend both
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How to measure aging in humans?
Healthy life Illness and disability
Extend healthspan
Multimorbidity: chronic diseases
Geriatric Syndromes
- Frailty
- Falls
- Functional Decline
- Delirium
Loss of resilience to acute stress
“Age” is not a number:
Calendar age
versus
Physiological age
(If you’ve seen one 80 year old
you’ve seen one 80 year old)
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Designing Clinical Trials for Aging
Functional Reserve
or “Resilience”
“Healthspan”:
Multimorbidity or
geriatric syndromes
Newman, J Geron 2016
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Designing Clinical Trials for Aging
Geriatric specialty
hospital wards
Exercise for
improving frailty
Newman, J Geron 2016
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Health stress or hospitalization
Rapamycin plus cardiac
rehabilitation in the elderly
(Mayo Clinic)
Rapamycin improves influenza
vaccine effect
(Novartis, Science Trans Med 2014)
Functional Reserve
or “Resilience”
Metformin with resistance
exercise training in the elderly
(U. Kentucky, U. Alabama)
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Multimorbidity or Geriatric Syndromes
“Healthspan”:
Multimorbidity, function,
or geriatric syndromes
Metformin to delay the onset of
multiple chronic diseases
(“TAME: Targeting Aging with
Metformin”, public consortium)
Rapamycin for preventing
respiratory infections in frail elderly
(PureTech/resTORbio)
Young mesenchymal stem cell
infusion to treat frailty
(Longeveron, U. Miami)
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Time
Health First chronic disease:
Delay other chronic disease
Biomarkers of risk:
Preventative therapy
Cardiac valve surgery:
Pre-habilitation
Severe influenza:
Prevent hospital disability
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Part 1: Aging Biology
Part 2: Clinical Trials
Part 3: Questions
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Aging is universal
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Is ”Aging” a disease?
It happens to everyone!
If not, what does a drug company or
regulatory agency do?
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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!
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Who will get these treatments?
Everyone, right? Right?
What if it’s expensive?
What if it’s rare?
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Expensive Treatments
Expensive by choice:
Expensive by design:
Expensive by technology:
Expensive by scarcity:
Hepatitis C cures
Antibody-based drugs
CAR-T, Dialysis
Transfusion, organ transplant
Novel senolytics
Aging-factor blocking antibodies
Autologous organoids or stem cells
Young blood/cell infusion
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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?
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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?
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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
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Therapies for “aging” are on the way
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Thank you!
Buck Institute
National Institute on Aging
American Federation for Aging Research
UCSF Division of Geriatrics
US Veterans Health Administration
@GeriSciDoc
Graphics from openclipart.org and wikimedia
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Geriatrics: Care for older adults
Big-picture goals,
Whole-person
Complexity:
“Everything affects
everything else”
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Delirium
Unable to
use
assistive
device
Muscle
weaknessPain
DehydrationIschemia
Lost hearing aids
Sleep-wake
disruption
Macular
degeneration
Cognitive
impairment
Medications
Environment
Caregivers
…
Neuroinflammation
Systemic
infection from
wound
Why do we get delirium?
Geriatric syndrome:
Multifactorial
Multisystem
Age-related
Integrative outcome
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Geriatrics = Systems Biology of Medicine
Geriatric
syndrome
Multicomponent interventions
Comprehensive assessment
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Risk 1
Risk 2
Risk 3
Risk 4
Risk 5
Risk 6
Therapy 1
Therapy 2
Therapy 4
Therapy 6
Comprehensive
Individualized
Assessment
Risk-Tailored
Multicomponent
Therapy
Treating Geriatric syndromes
50% of delirium prevented
with this approach
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Right care
Right patient
Right time
Goals
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Aging
Healthy/
normalDisease
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Hypertension Smoking Cholesterol Diabetes
Perc
ent In
cre
ase
0
20
40
60
80
100
Heart disease risk factors
Steve Austad, University of Alabama
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Steve Austad, University of Alabama
HypertensionSmoking Cholesterol Diabetes Aging
Pe
rce
nt
Incre
ase
0
2000
4000
6000
Heart disease risk factors