2014.03.06 aging lectureclasses.biology.ucsd.edu/bild10.WI14/BILD10...14 Mutations in the same gene...
Transcript of 2014.03.06 aging lectureclasses.biology.ucsd.edu/bild10.WI14/BILD10...14 Mutations in the same gene...
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Understanding Aging: Degeneration, regeneration, and the scientific search for the fountain of youth
Aging
Aging is a conserved physiological process associated with specific health risks and
sociological changes
Muscle atrophy
Neurodegeneration Immune deficiency
Increased rate of cancer
Bone fragility
Cardiac dysfunction
Blood vessel disease
Cancer rates increase with age!
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Bone density decreases with age Cardiovascular disease incidence increases with age
Driver et al. (2008). BMJ.
Why study aging?
• Aging is a conserved physiological process that is regulated genetically, epigenetically and environmentally.
• Aging represents an immediate and growing health concern in the human population.
Why???
The past decade has seen an explosion in aging-related research
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The past decade has seen an explosion in aging-related research
1. Recognition that aging is under genetic regulation
2. Increase in the world’s elderly population has made age-related disability and disease a more prominent global health and medical research issue
Our aging population World-wide changes in population demographics
Population division, DESA, United Nations
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Disability in the aged • 39.6 million Americans
aged 65 or older in 2009 (13% of popula=on).
• Projec=on for 2030 = 72.1 million (19%)
• 20 (2009) – 36 (2030) million Americans with at least one disability (7-‐10% of popula=on).
• 10-‐18 million with 2 disabili=es.
Mitochondria produce free radicals as a by-product of cellular
respiration Oxidative stress theory of aging
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Cellular senescence - when cells stop going through the cell cycle
Telomeres
• https://www.youtube.com/watch?v=8_bNfQd7Smc
Telomeres shorten with each cell division
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Cellular senescence and telomerase
WHAT COULD BE A NEGATIVE CONSEQUENCE OF ACTIVATING TELOMERASE?
POLL:
Aging is an evolutionarily conserved process
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Maximal lifespan of common model organisms for studying aging
14 days 47days
108 days 4 years
Maximal lifespan of common model organisms for studying aging
14 days 47days
108 days 4 years
123years
25-30 years
WOULD YOU STARVE YOURSELF TO LIVE LONGER?
POLL QUESTION
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Pathways that influence lifespan extension in response to chronic dietary restriction
Cynthia J. Kenyon (2010). Nature.
Caloric restriction
Is AGING the same thing as LONGEVITY?
How do we define these?
Longevity & Aging
• Longevity – duration of life • Aging – accumulation of
physiological changes occurring over the life of an organism, which generally decrease the likelihood of survival
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Aging = Longevity
Longevity & Aging
When does aging begin?
Control of Aging/Longevity • Genetic
– Interspecies differences in lifespan
14 days 47 days
108 days 4 years
Control of Aging/Longevity • Genetic
– Interspecies differences in lifespan – Sex differences in lifespan
Control of Aging/Longevity • Genetic
– Interspecies differences in lifespan – Sex differences in lifespan – Cloning of genes that extend or reduce
lifespan
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Aging in the nematode C. elegans
Identification of genes that altered lifespan of C.elegans (Klass, 1983) age-1: first suggestion that aging can be genetically controlled AND that gene LOF could EXTEND lifespan
AGE-1
Control of Aging/Longevity • Genetic • Epigenetic
Epigenetics
• The study of heritable changes in gene function that occur without a change in the DNA sequence
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Control of Aging/Longevity • Genetic • Epigenetic
6 weeks
6 months
Control of Aging/Longevity • Genetic
– Interspecies differences in lifespan • Epigenetic • Reproduction • Environmental
– Twin studies (~25-30% of lifespan variation is heritable
– Diet – Stress (hormesis) – Stochastic events
GENETIC CONTROL OF AGING
Premature aging syndromes • Progeroid syndrome
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Progeroid syndrome Premature aging syndromes
• Werner syndrome
Werner syndrome Lifespan extension in model organisms
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Experiments can compare the lifespan of different populations
Mutations in a single gene can dramatically affect life span
Males that lack the insulin receptor
Hermaphrodites that lack the InR
Tradeoff between growth and development and stress resistance
Insulin receptor
Transcription factor
Mutations in the same gene affect lifespan in other organisms
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Mutations in the same gene affect lifespan in other organisms
Stress responsiveness and longevity in worms (Rea et al., 2005)
+ HSP-GFP
GFP
high median
low
1. How long does each class of worm live?
How long does each class of worm live?
Result: The ability of worms to respond to stress on their first day of adult life has a large stochastic (random) component and is a good predictor of their subsequent longevity.
Implications:
Genetic (and environmental) factors
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EPIGENETIC CONTROL OF AGING
DNA methylation
• Studies compared the DNA methylomes of newborns versus centenarians and found that there are differences between these two extreme stages of life
• Changes in methylation can lead to changes in gene expression
• Increase in cellular heterogeneity • Aging phenotype
ENVIRONMENTAL CONTROL OF AGING
Environmental factors influence aging
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Sun damage
Gordon JR, Brieva JC. N Engl J Med 2012;366:e25.
Smoke damage
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Internet is full of aging information (and hype and misinformation)
• http://www.longevitycentres.com/tools-agecalculator.html
• http://singularityhub.com/2010/09/21/did-a-russian-scientist-really-cure-aging-or-is-it-just-a-fluke-video/
• Telomerase pills or snake oil?
Aging simulators
Summary
• Aging is a conserved physiological process controlled by genetic, epigenetic, and environmental factors that can be studied in a variety of model organisms (including humans!).
• The past decade has seen an explosion in aging-related research…
Questions??
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In this class • Explore the biological process of aging, its
impact on global health, and contemporary strategies to delay, reverse, or mitigate its effects.
• Develop your own definition of “aging” and identify key challenges and opportunities for aging research, therapeutics, and policy over the next 5-10 years.
Major topics (aging and rejuvenation) • Aging research using model organisms and human populations • Evolutionary theories of aging / tradeoffs for extended longevity
• Aging and diet / metabolism
• Age-related damage to cellular macromolecules
• Molecular mediators of aging – Sirtuins, cell cycle proteins, GH/IGF, TOR
• Age-related disease – Sarcopenia, neurodegeneration, cancer, immune deficiency,
cardiovascular disease, diabetes
• Intervention strategies – Stem cells, small molecules, anti-oxidants, anti-inflammatories, calorie
restriction
– Focus on the development of novel therapeutics
Cellular senescence and telomerase
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• https://www.youtube.com/watch?v=AJNoTmWsE0s
• https://www.youtube.com/watch?v=BkcXbx5rSzw
• https://www.youtube.com/watch?v=8_bNfQd7Smc