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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