1. MCB 135K Discussion February 2, 2005

2. Topics Functional Assessment of the Elderly Biomarkers of Aging Cellular Senescence –Lecture PowerPoint to be posted on website

3. 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**

4. 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

6. Figure 3. 6: % of persons 70 years & older having difficulty/inability to perform ADLs & IADLs With advancing age, 1) disability intensity increases in men & women; 2) disability intensity is higher in women than in men at the same age (esp. at later ages); 3) females live a longer average life span but live longer with disability

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

9. Questions 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 5.Explain compression of morbidity

10. How genetic susceptibility may influence a disease: By itself By making the carrier more susceptible to disease By increasing the expression of a risk factor, or the risk factor may increase the genetic effects

11. Disease as a tool for the study of aging Sporadic cases of syndromes having multiple characteristics of premature (early onset, 20-30 years of age) or accelerated (rapid progression) aging occur in humans These conditions are grouped under the name of progeria. Examples of progeria syndromes are Werner’s syndrome (WS) and Hutchinson-Guildford syndrome

12. Differences between WS & Aging WS Rare NO hypertension NO dementia Tissue calcifications Aging Universal Hypertension Dementia NO tissue calcifications

13. Questions 1.What are three ways that genetic susceptibility influences disease? 2.What is progeria? 3.What is a biomarker and how can progeria be used as one? 4.What are some characteristics of WS? 5.List the differences between diseases and aging

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

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

16. 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

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

18. 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?

19. 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

20. 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

21. 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

22. 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)

23. 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