1. MCB 135K Discussion Monday, January 30, 2006 GSI: Laura Epstein

2. Information GSI: Laura Epstein E-Mail: Laura_Epstein@berkeley.edu Review sessions will be held prior to each exam –Time and locations TBA Course is graded on a straight scale unless your performance dictates a curve

3. Discussion Material 1.Course Introduction 2.Demography 3.Comparative and Differential Aging/Assessment of Aging 4.Cellular Senescence

4. Course Introduction Age Related Terminology –Aging –Geriatrics –Gerontology –Senescence –Biomarkers –Life-Span –Average Life Span –Life Expectancy –Active Life Expectancy –Longevity –Maximum Life Span 1.Increased length of lifespan & increased number of the elderly in the human population 2.Increased proportion of persons aged 65+ in the population as compared to those aged 14-19 3.This change in the human population is acknowledged by the industries and professions 4.Need to better educate the population in healthy habits 5.Need to support research in biomedicine 6.Points 4 and 5 must take into consideration the entire life cycle as our health today depends on our health yesterday and will influence our health tomorrow

5. Divisions of the Lifespan Prenatal Life Ovum: Fertilization - end 1st week Embryo: 2nd-8th week Fetus: 3rd-10 lunar month Neonatal Period Newborn: end of 2nd week Infancy: 3rd week-1st year Childhood: 2-15 years Adolescence: 6 yrs after puberty Postnatal Life Adulthood Prime & transition (20-65 yrs) Old age & senescence (65 yrs+)

6. Life expectancy and infant mortality throughout human history Life expectancy Infant mortality rate at birth (years) (per 1000 live births) Prehistoric20-35200-300 Sweden, 1750s37210 India, 1880s25230 U. S., 190048133 France, 19506652 Japan, 1996804

7. Questions Lecture 1 - The Journey of Life  What is the primary reason that life span has doubled since ~1900?  What was the average life span in prehistoric times, ~1900, now?  When does the process of aging begin?  Why doesn’t the degree of pathophysiology correlate directly with age?  What is the reason for the increase in average life span from ~1880 - 1960? From 1960 - present?

8. Demography Statistical study of human populations: –Size and density distribution Vital Statistics: –epidemiology: Births, deaths, diseases

9. Life expectancy at birth by sex, France 1806-1997

10. Proportion of population aged 0-14 versus 65+(In Italy)

12. Centenarians Generally good health –Escapers –Late onset of disease –Early disease that was overcome SSC (Semi-Super) –105+ SC (Super) –110+ Possible role of IGF-1 Receptor Oldest Female –122 years –Jeanne Calment Oldest Male –115 years –Christian Mortensen

13. Questions Lecture 2 - Demography of Aging  What is epidemiology?  What is the epidemiologic transition?  What is the mortality transition?  How long was the longest recorded human life span, male and female?  What are some probable causes that favor longevity in women?

14. Comparative and Differential Aging Aging amongst different animal species Aging differences between people of the same species Chronological vs. Physiological Age

15. Figure 3.1: Comparative Maximum Life Spans **Detailed discussion of figure in the legend, pg. 26

17. Geriatric Assessment Involves a multi-dimensional diagnostic process designed to qualify an elderly individual in terms of: Functional capabilities Disabilities Medical & Psychological characteristics A list of typical assessments is summarized in Table 3.3 For our discussion, we will consider particularly: Activities of Daily Living (ADL) Instrumental Activities of Daily Living (IADL) **See Table 3.4**

18. Assessment of Physiological Age in Humans Physiological age depends on Physiologic competence: good to optimal function of all body systems & Health status: absence of disease Physiological age may or may not coincide with chronological age

19. Functional Assessment 1.Tests examining general physical health 2.Tests measuring ability to perform basic self care (ADLs) 3.Tests measuring ability to perform more complex activities (IADLs), reflecting the ability to live independently in the community The severity of the disability may be measured in terms of whether a person : Does not perform the activity at all Can only perform the activity with the help of another person Can perform the activity with the help of special equipment

21. A theory of “compression” of morbidity (rectangularization of survivorship) curve

22. Question Comparative and Differential Aging  How well does chronological age correlate with physiological age? In young versus old individuals?  What parameters do you use to define "healthy" aging?  What sorts of behavior favor a long life span?  What are the mechanisms or traits associated with "successful" aging?  What is aging vs. usual aging vs. successful aging?

23. Questions Continued 1.What are the components of Geriatric Assessment? 2.What are the categories of these assessment programs 3.What are the differences between ADL’s and IADL’s? Provide some examples 4.Discuss the idea that women have more disability than men.

24. Senescence Replicative Senescence Cellular Senescence Senescent Phenotype Cellular Senescence and Cancer Senescence and Aging Antagonistic Pleiotropy

25. Cellular Senescence What is it? Response of normal cells to potentially cancer-causing events

26. First description: the Hayflick limit Proliferative capacity Number of cell divisions Finite Replicative Life Span "Mortal" Infinite Replicative Life Span "Immortal" EXCEPTIONS Germ line Early embryonic cells (stem cells) Many tumor cells What happens when cells exhaust their replicative life span

27. REPLICATIVE SENESCENCE Irreversible arrest of cell proliferation (universal) Resistance to apoptosis (stem cells) Altered function (universal but cell type specific) SENESCENT PHENOTYPE

28. Cellular Senescence What causes it? (what causes the senescent phenotype?) Cell proliferation (replicative senescence) = TELOMERE SHORTENING DNA damage Oncogene expression Supermitogenic signals What do inducers of the senescent phenotype have in common?

29. Inducers of cellular senescence Cell proliferation (short telomeres) DNA damage Oncogenes Strong mitogens Potentially Cancer Causing Normal cells (mortal) Immortal cells (precancerous) Inducers of senescence Cell senescence TransformationApoptosis Tumor suppressor mechanisms

30. Cellular Senescence An important tumor suppressor mechanism Induced by potentially oncogenic events Most tumor cells are immortal Many oncogenes act by allowing cells to bypass the senescence response Senescence is controlled by the two most important tumor suppressor genes -- p53 and pRB Mice with cells that do not senesce die young of cancer

31. Cellular Senescence An important tumor suppressor mechanism What does cellular senescence have to do with aging? The senescent phenotype entails changes in cell function Aging is a consequence of the declining force of natural selection with age

32. Aging before cell phones …… 100% Survivors AGE Natural environment: predators, infections, external hazards, etc Most of human evolution Modern, protected environment (very VERY recent) Antagonistic pleiotropy: Some traits selected to optimize fitness in young organisms can have unselected deleterious effects in old organisms (what's good for you when you're young may be bad for you when you're old)

33. Questions 1.What causes cellular senescence, what are the inducers and what do they have in common? 2.What is replicative senescence? 3.List 3 characteristics of the senescent phenotype. 4.What is the relationship between carcinogenesis, aging, and senescence? 5.Explain antagonistic pleiotropy.

34. Questions continued What are the 2 categories of risks for developing cancer? What are the 2 things necessary for developing cancer? What is the Hayflick limit? What are the exceptions to this idea? Explain the significance of telomeres. How is senescence both “good” and “bad”.