Why we age Osher 106962 Instructors: Matt Kaeberlein & Lara Shamieh Meets Tuesdays 1/26, 2/2, 2/9, and 2/16, 10 AM – 11:50 AM, FSH 102 Course web page:

Why we age Osher 106962 Instructors: Matt Kaeberlein & Lara Shamieh Meets Tuesdays 1/26, 2/2, 2/9, and 2/16, 10 AM 11:50 AM, FSH 102 Course web page: http://www.sageweb.org/content/osher http://www.sageweb.org/content/osher Emails: [email protected] (Matt); [email protected] (Lara); [email protected] (class)[email protected] [email protected] [email protected]

Course topics Jan 26. Course introduction. Why we age and what causes aging. Feb 2. Calorie restriction. Does eating less help you live longer? Feb 9. Are there anti-aging drugs on the horizon? The red wine effect Feb 16. The importance of healthy aging. The relationship between aging-related diseases and healthy aging.

Todays topics Introductions and ice breakers Intro to aging-related research Overview of human and cellular physiology Possible molecular causes of aging

Introductions and ice breakers Why do you think aging happens? What are the symptoms and diseases of aging? What kind of things have you heard about that might influence how you age? Would you want to live to be 150 years old? Why or why not?

An (incorrect) definition of aging: The gradual changes in the structure and function of humans and animals that occur with the passage of time, that do not result from disease or other gross accidents, and that eventually lead to the increased probability of death as the person or animal grows older. It does not apply to microorganisms. http://www.biology-online.org/dictionary/Aging Bob Hope (1903- 2003) Introduction to aging-related research

An better definition of aging: The gradual changes in the structure and function of humans and most other organisms that occur with the passage of time, that do not result from gross accidents, and that eventually lead to the increased probability of death as the person or organism grows older. http://www.biology-online.org/dictionary/Aging Bob Hope (1903- 2003) Introduction to aging-related research

Oeppen and Vaupel. Science 296:1029 2006. Average life span has increased recently

ManProfessionYear of Birth (B.C.)Age at Death PittacosKing of Mytilenusc.650~ 80 XenophanesPhilosopher (Pre-Socratic)c.570~ 92 PythagorusMathematicianc.570~ 80 AristidesStatesmen (Military General)c.540~ 72 SophoclesPlaywrite (wrote Electra at the age of 82)c.495~ 90 EuripidesPlaywrite (Tragedy)c.485~ 76 GorgiasPhilosopher (Sophist)c.483 105 or 109 HippocratesPhysician ("Father" of Modern Medicine) 460 90 or 100 DemocritesPhilosopher (Atomic Theory)c.460 90 or 100 AntisthenesPhilosopher (Founder of Cynics School)c.445~ 80 IsocratesLogician (Rhetoric) 436 98 PlatoPhilosopher (The Republic) 429 81 DiogenesPhilosopher (carried lantern)c.410 77 or 91 XenocratesPhilosopher (Platonist)c.400~ 86 AntipatrosKing of Macedoniac.397~ 78 Antigone 1 st Successor to Alexander the Great 382 81 TheophrastesPhilosopher (Aristotelian) 371 84 Ptolemy 1 st Appointed Ruler of Egypt 367 84 PyrrhonPhilosopher (Founder of Skeptics) 365 90 PhilemonPlaywrite (Comedy)c.363+/- 99 Seleucos 1 st King of Syriac.358+/- 78 CleanthePhilosopher (Stoic) 331 99 TimonDisciple of Pyrrhon 320 90 Maximum life span has probably not changed

Extracting information from survival curves Much greater increase in median life span than maximum life span suggests that healthspan has improved but rate of aging has not slowed.

Different people age differently vs.

11/26/1939 12/18/1943 Different people age differently

vs. 11/26/1939 12/18/1943 Aging is influenced by both genetic and environmental components Different people age differently

Hutchinson Gilford Progeria Hutchison Gilford Progeria (Mutations in nuclear structure gene) Werner Syndomes (Mutations in a DNA repair gene) Progeroid diseases aging quickly?

Jeanne Calment aging slowly? http://en.wikipedia.org/wiki/Jeanne_Calment Longest confirmed life span 122 years, 164 days Born Feb 21, 1875 in Arles, France Took up fencing at 85; riding a bicycle at 100 Quit smoking at 117 Ascribed her longevity to olive oil, port wine, and chocolate

Goals of aging-related research Understand the molecular processes that cause aging Identify genetic and environmental interventions that slow aging Develop therapies to delay the onset of age- related diseases and improve healthspan Increase both median and maximum life span

AGING Stroke Arthritis Wrinkles Frailty Heart Disease Type II Diabetes Cancer Neurodegeneration Slowing aging should slow progression of multiple age-associated diseases

What if aging could be slowed? Increase in life expectancy for a 50 year old woman Cure cancer~ 3 years Cure cancer, heart disease, stroke, and kidney-related disease ~8-10 years Slow aging 50% (starting at age 50) ~15-25 years

What if aging could be slowed? Increase in life expectancy for a 50 year old woman Cure cancer~ 3 years Cure cancer, heart disease, stroke, and kidney-related disease ~8-10 years Slow aging 50% (starting at age 50) ~15-25 years Many different ways to do this have been discovered in lab animals!

Dietary restriction slows aging Weindruch and Sohal, 1997 Dietary restriction slows aging in yeast, worms, flies, mice, rats, spiders, fish, and rhesus monkeys (note the change in both median and maximum survival) Delays onset of most (all?) age-associated disease Does it work in humans? Ad lib DR

Rapamycin increases mouse life span Rapamycin NIA Interventions Testing Program Rapamycin encapsulated in food Increase life span when started at 600 days of age (60 year old person) Already clinically approved for use in people Nature July 16, 2009 http://www.nia.nih.gov/ResearchInformation/ScientificResources/InterventionsTestingProgram.htm

Disconnect between funding and payoff

Aging is shared across species Even bacteria and yeast age In general, bigger organisms live longer Some interesting exceptions (e.g. naked mole rat) http://www.senescence.info/comparative.html

Why do organisms age? Idea #1: Aging is programmed Necessary to prevent older generations from competing for resources Idea #2: Aging occurs because theres no evolutionary advantage to not aging Once you produce sufficient offspring youre expendable.

Programmed aging cant explain this If there were a death program in our genetic code, life expectancy couldnt increase so dramatically over so few generations.

Natural selection wont stop aging Natural selection strongest early in life Favors growth and fecundity Effects of aging strongest late in life Primarily post-reproductive What would it cost NOT to age? repair and maintenance = reproduction Growth, fecundity, Aging Repair Longevity

Key ideas so far Aging is a biological process that is under both genetic and environmental control Aging is likely the result of an absence of evolutionary pressure to prevent it. There is no aging program. Average human life span has increased dramatically recently, but maximum life span hasnt = we havent really influenced the rate of aging very much (if at all) Many interventions are known to slow aging in laboratory animals (e.g. dietary restriction) If this can be extended to humans, the impact is much greater than curing any single disease

A brief review of human and cell physiology

Pathologies of Aging AGING Stroke Arthritis Wrinkles Frailty Heart Disease Type II Diabetes Cancer Neurodegeneration

Systems of the Human Body Decline With Age Is there an underlying coordinated decline across systems of the body? skeletal muscular cardiovascular nervous

Age-Related Decline in Individual Organs is Also Observed

Organelles of the Human Cell

Close-Up Schematic of the Human Nucleus Hutchinson-Gilford progeria is caused by a defect in nuclear structure

What Causes Aging?

Possible molecular causes of aging Telomere Shortening Cellular Senescence Advanced Glycation Endproducts DNA Damage Free Radicals / Reactive Oxygen Species Mitochondrial Damage

How do telomeres contribute to aging? Telomeres are TTAGGG nucleotide repeats on the end of chromosomes Telomeres protect the DNA, by functioning as caps Each time the DNA is copied, the telomere gets slightly shorter

Telomeres and Aging Two studies show a direct correlation between telomere length and life expectancy Both are controversial studies One study showed an inverse correlation between telomere length and stress

What Causes Aging? Telomere Shortening Cellular Senescence Advanced Glycation Endproducts DNA Damage Free Radicals / Reactive Oxygen Species Mitochondrial Damage

Cellular Senescence

Advanced Glycation Endproducts (AGEs) AGEs are the result of inappropriate reactions between sugars, proteins, and oxoaldehydes AGEs attack normal long-lived proteins such as collagen and other structural proteins AGEs make bones, tendons, skin, arteries and veins more stiff and less elastic Inflammatory Disease Diabetes Athlosclerosis and Heart Disease Macular Degeneration Osteoarthritis Alzheimers Disease Poor Bone Healing

Role of AGEs in Diabetes

DNA Damage and Aging When damage is not repaired, it results in an increase in mutations that may lead to aging and cancer

Premature Human Aging Diseases and DNA Damage Werners Syndrome is caused by mutations in WRN1, a DNA helicase protein Patients have shorter than normal telomeres Cockayne Syndrome is caused by a defect in DNA repair proteins Xeroderma Pigmentosum is caused by a defect in DNA repair proteins Leads to a marked increase in skin cancers at a young age Little boy with Cockayne Syndrome aged 9

Free Radicals and Reactive Oxygen Species (ROS)

Mitochondria The Powerhouse of the Cell

Free Radicals: A By-Product of the Electron Chain

Mitochondrial Damage and Aging Free radicals produced by mitochondria can come back to damage proteins in the mitochondria This leads to decreased and improper mitochondrial function Recent studies have shown that free radicals attack, DRP-1 (a mitochondrial protein) that leads to mitochondrial fragmentation, damaging synapses and eventually leading to nerve cell death. Mitochondrial Damage and Alzheimers Disease

The Causes of Aging are Interlinked: (It is hard to separate one from the other) Telomere Shortening Cellular Senescence Advanced Glycation Endproducts DNA Damage Free Radicals / Reactive Oxygen Species Mitochondrial Damage

Documents

Why we age Osher 106962 Instructors: Matt Kaeberlein & Lara Shamieh Meets Tuesdays 1/26, 2/2, 2/9, and 2/16, 10 AM – 11:50 AM, FSH 102 Course web page: