MCB 135K Mid-Term I Review

1. MCB 135K Mid-Term IReview February 15, 2005 GSI: Laura Epstein

2. General Information • Mid-Term I – Friday • In Class Exam • 100 Points • 50 Points Multiple Choice and True / False • 50 Points Short Answer / Essay • Be prepared to place all personal belongings in aisle or at front of room before exam begins

3. Exam Material • Intro and Demography • Comparative/Differential Aging • Mitochondrial Decay • Cellular Senescence • Functional Assessment • Epidemiology • Telomeres • Evolutionary Theory of Lifespan • Oxidants, and Anti-Oxidants • Neurodegeneration, Repair, and Plasticity—save for next exam • Yeast as a model for cellular lifespan

4. Demography • Be familiar with: • When does aging begin • Role of genome and environment on aging • What Demography is and how it is useful • How life expectancy has changed in the last 200 years and what has contributed the most to this change • How the population distribution has changed and what impact this might have for the future • Centenarians and aging • What have we learned from these studies • How old was the oldest living documented person of each sex

5. Demography • Statistical study of human populations: • Size and density distribution • Vital Statistics: • Epidemiology: Births, deaths, diseases

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

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

8. 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 Centenarians

9. Women and Longevity • Probable Causes for increased longevity • Genetic • Environmental • Lesser Life Stress • Decreased Smoking • Protective Hormones • Better Protection Against Oxidative Damage

10. Comparative / Differential Aging • Be familiar with: • What are the models for study • What does physiological assessment require • What are the physiological correlates with longevity and how do they correlate

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

12. Mitochondrial Decay • Be familiar with: • Mitochondria function/damage • Acetyl Carnitine (ALCAR) • R-a-Lipoic Acid (LA) • Behavior of old rats fed ALCAR and LA • Micronutrient under-nutrition in Americans

13. Mitochondria • O2® O2-® H2O2®· OH ® H2O, oxidative metabolism • - Reaction intermediates are similar to products formed by radiation exposure. • -We are always making lesions in our DNA and fixing it • -With infection, our immune cells fight the infection and release free radicals • - 1-2% leakage of reactive oxygen species (ROS)

14. Oxidative Damage Products from Base Excision Repair (BER) and Nucleotide Excision Repair (NER) are secreted in the urine. - Frequency of oxidative events increases in older individuals Rat liver cells – Young ~24,000 oxidative lesions/cell Old ~67,000/cell

15. 160 140 120 100 80 60 40 20 0 MDA (pmol/mg protein) MDA is a product of lipid oxidation Young Old * * * * * Brain Liver Heart Kidney Lung 6

16. Mitochondria from old rats compared to those from young rats: 1) Lower Cardiolipin—a lipid used in the mitochondrial membrane 2) Lower Membrane Potential 3) Lower Oxygen Utilization 4) Increased Oxidant Leakage

17. L-Carnitine/Acetyl-L-Carnitine (ALCAR) • Transports long-chain fatty acids into mitochondria • Removes short- and medium-chain fatty acids that accumulate • Feeding ALCAR to aging rats is able to suppress or ameliorate many age-related changes in mitochondrial function and oxidant stress. • restores membrane potential • although oxidant leakage remains • Mediates the ratio of acetyl-CoA/CoA • Decreases with age in plasma and in brain • Improves cognitive function in rats • ALCAR is something beneficial!! And we lose it with age! 12

18. 30 20 Cardiolipin (µg per 10 cells) 10 0 Effect of ALCAR Supplementation on Cardiolipin Levels—ALCAR increased cardiolipin levels. Cardiolipin is basically a marker of mitochondrial health + ALCAR ** Old Young 14

19. R-a -Lipoic Acid (LA) • Potent Anti-oxidant • Lowers oxidants in old rats • Restores ascorbic acid levels (vitamin C) • Restores glutathione levels (another anti-oxidant) • Has been shown to be beneficial to rats in combination with ALCAR

20. Behavior of old rats fed ALCAR and LA • ALCAR/LA can reverse age-associated losses in cognitive function • Increased ambulatory activity

21. * 800 600 400 + LA + ALCAR 200 + LA + ALCAR 0 Young Old Ambulatory Activity before and After Supplementation with Lipoic Acid (LA) + Acetyl-L-Carnitine (ALCAR) vs. young * vs. old # Distance Traveled (cm/hour/day) # *

22. As organisms age… • - mitochondrial potential decreases. • - oxidant leakage increases.

23. Do americans get enough micronutrients? NO • Iron deficiency, results in loss of complex 4 (part of the electron transport chain in the mitochonrial membrane). • Complex 4 loss results in increased oxidative stress. • Iron deficiency mimics neurodegeneration. • Zinc deficiency • Increased DNA damage in zinc deficient cells • Biotin deficiency • Accelerates cell senescence • Magnesium deficiency

24. Other types of oxidative damage increase with age • Protein Carbonylation (Stadtman) • - Lipid oxidation (aldehydes "stuck" to proteins/enzymes) • - age pigment -fluorescent lipid peroxides accumulate with age, can see fluorescence in tissues of older individuals (humans and rats) • Mitochondria may deteriorate with time, old or damaged mitochondria may be destroyed by lysosomes in the cytoplasm.

25. Senescence • Be familiar with: • What senescence is • What the types of senescence are • What causes senescence • Why senescence is important to aging and disease

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

27. Cellular Senescence What causes it? (what causes the senescent phenotype?) Cell proliferation (replicative senescence) = TELOMERE SHORTENING DNA damage Oncogene expression Supermitogenic signals

28. First description: the Hayflick limit Finite Replicative Life Span "Mortal" Infinite Replicative Life Span "Immortal" Proliferative capacity Number of cell divisions EXCEPTIONS Germ line Early embryonic cells (stem cells) Many tumor cells

29. What happens when cells exhaust their replicative life span REPLICATIVE SENESCENCE • Irreversible arrest of cell proliferation • (universal) • Resistance to apoptosis • (stem cells) • Altered function • (universal but cell type specific) SENESCENT PHENOTYPE

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

31. p53 and pRB proteins • Nuclear proteins controlled by complex pathways • (upstream regulators and downstream effectors) • Control expression of other genes • Halt cell cycle progression in response to inducers • of senescence • Crucial for allowing normal cells to sense and respond to senescence signals

32. 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 decling force • of natural selection with age

33. Antagonistic pleiotropy Cellular senescence Functional changes unselected, deleterious Selected for tumor suppression (growth arrest) FUNCTIONAL CHANGES ASSOCIATED WITH CELLULAR SENESCENCE: Secretion of molecules that can be detrimental to tissues if not controlled e.g., senescent fibroblasts secrete proteases, growth factors, inflammatory cytokines

34. Functional Assessment • Be familiar with: • What comprises geriatric assessment • What programs are used to test assessment and what are their parameters • Why do women have more disability • Compare/Contrast aging with physical inactivity • Know some parameters • Aging vs. Disease

35. 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**

36. Assessment Programs include tests that are grouped into three categories: • Tests examining general physical health • Tests measuring ability to perform basic self care (ADLs) • Tests measuring ability to perform more complex activities (IADLs), reflecting the ability to live independently in the community

38. 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

40. Aging is associated with increased incidence of: • Diseases • Accidents • Stress

41. Aging should be differentiated from DiseaseDisease: • is selective; it varies with the species, tissue, organ, cell molecule • may depend on intrinsic & extrinsic factors • is discontinuous (may progress, regress or be arrested) • is occasionally deleterious, damage is often variable/reversible • is often treatable with known cause(s)

42. 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

44. Epidemiology • Be familiar with: • What is epidemiology and why is it useful • Why is it thought that older people are at an elevated risk for disease • What are the major age associated causes of death • Understand why falls are a problem for the elderly

45. EPIDEMIOLOGY OF AGING • THE STUDY OF THE AGE-RELATED DISTRIBUTION AND CAUSES OF DISEASE, DISABILITY, AND MORTALITY IN HUMAN POPULATIONS.

46. EPIDEMIOLOGY OF AGING • ACCUMULATION OF ENVIRONMENTAL/BEHAVIORAL INSULTS. • REDUCED IMMUNOLOGICAL SURVEILLANCE

47. EPIDEMIOLOGY OF AGING • WHY IMPORTANT? • AGING OF THE HUMAN POPULATION • HEALTH AND VITALITY OF AN AGING POPULATION • QUALITY OF LIFE AND COST OF CARE

48. EPIDEMIOLOGY OF AGING • MAJOR AGE-ASSOCIATED CAUSES OF DEATH • CANCER • CARDIOVASCULAR DISEASE • CHRONIC OBSTRUCTIVE PULMONARY DISEASE • DIABETES

49. EPIDEMIOLOGY OF AGING AGE-SPECIFIC COLORECTAL CANCER INCIDENCE RATES (Per 100,000 in population) WM WF BM BF <65 20.4 14.7 25.3 20.4 65+ 408.0 269.3 385.8 286.1

50. EPIDEMIOLOGY OF AGING COGNITIVE FUNCTION Moderate/Severe Memory Impairment Male Female 65-69 5.3 3.8 85+ 37.3 35.0