will we have a treatment for aging?heritability h=1 genes only h=0 environment only trait...
TRANSCRIPT
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Will we have a treatment for
aging?
Toren Finkel Aging Institute of UPMC/Univ. of
Pittsburgh
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Why should we study aging?
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Relative Risk for Cardiovascular Disease!
Modifiable Risk Factors
Modifiable?
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Age-related incidence of major diseases
Finkel, Nat. Rev. Mol. Cell Biol. (2005)!!
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How long can we live?
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The world’s oldest person: Jeanne Calment
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The secret to her longevity?
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Is aging genetic?
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Heritability
H=1 Genes only H=0 Environment
only
Trait Heritability Clubfoot 0.8 Height 0.8 Blood pressure 0.6 Body mass 0.5 Verbal aptitude 0.7 Math aptitude 0.3 Spelling aptitude 0.5 Fingerprint ridge count 0.9
Intelligence 0.5-0.8 Total serum cholesterol
0.6
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Genetic Heritability of Human Lifespan
Cournil & Kirkwood 2001
Twin Studies • McGue et al (1993) 0.22 • Herskind et al (1996) 0.25 • Ljungquist et al (1998) <0.33 Traditional Family Studies • Philippe (1978) 0-0.24 • Bocquet-Appel & Jakobi (1990) 0.10-0.30 • Mayer (1990) 0.10-0.33 • Gavrilova et al (1998) 0.18-0.58 • Cournil et al (2000) 0.27
Genes account for 25% of what determines longevity
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Is there something we can do to live longer?
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Calorie restriction extends lifespan universally
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Dietary restriction prevents age-related diseases in primates
Colman et al., Science (2009)
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Two pathways that link CR and lifespan
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The mTOR pathway links nutrients to lifespan
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Mouse model to reduce mTOR expression (mTORΔ/Δ)
14 15 13 14
13 15 LoxP
Neo 12 13 11
11 12 mTOR+/+
mTORΔ/Δ
A
B. Mock (NCI)
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mTORΔ/Δ mice have markedly increased life span
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mTORΔ/Δ mice have preserved age-dependent memory and learning
function
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Can we use drugs to inhibit the mTOR pathway?
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A pill to live longer?
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Why does inhibiting mTOR make you live longer/healthier?
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Autophagy as an intracellular recycling system !
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m-Keima: A fluorescence based assay for mitophagy!
Adapted from Miyawaki and collaborators!
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Age-Dependent Decline in Mitophagy
Young Old!
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Is there a universal theory that can explain aging?
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Energy Partition Theory of Aging
Finkel, T (2015) Nature Medicine
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The anti-diabetic drug metformin has a wide effect on metabolism and energy
balance
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Metformin extends survival in model organisms
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The diabetic drug metformin appears to reduce human cancer incidence
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Pittsburgh Metformin Study
Hypothesis:
Can risks and complications to elderly patients be modified by giving them
something prior to elective surgery that targets the fundamental processes of
aging?
Dr. M. Neal-Dept. of Surgery UPMC
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Patient characteristics
Dr. Oscar Marroquin
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Dr. Oscar Marroquin
Patient characteristics
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Pittsburgh Metformin Study
Retrospective review of UPMC surgical
patients on metformin
Prospective clinical trial in metformin naïve
surgical patients
Inform design
Dr. M. Neal-Dept. of Surgery UPMC
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Can we cure aging?
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Thank you!