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Pathophysiology of Ageing

Pathophysiology of Ageing. Mikl ós Molnár 6357 Semmelweis University Inst. of Pathophysiology. Aging as a global phenomenom. Cumulatív % of Increase. Years. Introduction to Human Aging. Number and percentage of the elderly. In the US, more persons over 65 than under 25 years of age

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Pathophysiology of Ageing

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  1. Pathophysiology of Ageing Miklós Molnár 6357 Semmelweis University Inst. of Pathophysiology

  2. Aging as a global phenomenom Cumulatív % of Increase Years

  3. Introduction to Human Aging • Number and percentage of the elderly • In the US, more persons over 65 than under 25 years of age • Median age was ~32 in 1995; was 36 in 2000, and will be ~42 by 2040

  4. Estimates/projections of total U.S. population and percentage of elderly yearpop.number > 65% 1900 75.6 mil 3.1 mil 4.1 1940 132.3 mil 9.0 mil 6.8 1960 181.0 mil 16.6 mil 9.2 1980 228.0 mil 25.6 mil 11.2 1990 250.0 mil 31.2 mil 12.5 2000* 268.5 mil 34.9 mil 13.0 2030* 304.7 mil 64.6 mil 21.2

  5. Percentage of elderly by age group

  6. Problems for the younger members of our society • 30% of health care resources used by persons >65 years (will increase to 50% by 2030) • Older persons require more social services and specialized recreational facilities; these require money (increased taxes) • The burden of support falls now and will fall more heavily on the younger generations.

  7. Ages • Chronologic age • Biologic age • mitochondrial DNAdamage • β-galactosidase (fro skin biopsy) • Glycolysation products • presbyopia • Rate of DNAunrounding • vitalcapacity • etc.

  8. WHO Classification of age groups • Middle-aged (45-59 years) • Elderly (60-74 years) • Old (75-90 years) • Very old (90- )

  9. Introduction to Human Aging • General effects of aging • Aging is a continuing, normal process. • Begins at maturity, ends with death • Effects of aging increase at age 40. • Aging is influenced by interactions of genetics and environmental factors.

  10. Biologic Changes Occuring by Age • Universal, in every species • Progressively on going process • Internal causes • Viability of the body is decreasing

  11. So what is normal biological ageing? Ageing is characterised primarily by a reduc-tion in the capability to adapt to changes in the environment. This adaptation includes an ability to recognise the abnormal substances which we come into contact with in daily life. Hence if this capacity is reduced then the organism becomes ever greatly prone to disease and damage.

  12. Estimated declines in some human functions with age (age 30 = 100%) % at 60% at 80 nerve conduction velocity 96 88 basal metabolic rate 96 84 cardiac index 82 70 kidney function 96 61 renal plasma flow 89 51 vital capacity 80 58 maximal breathing capacity 80 42

  13. The Deficits of Aging Basic physiologic changes: • less water, more fat • decreased circulation • Immune system failure • neuronal loss, myofibril loss,cartilage loss • Limited fibroblast replication lifetime limit = 50 replications

  14. Deficits of Aging: Sensory Hearing • Tinnitus (ringing): blocking frequencies • Presbycusis: limited ability to pick out speech in a noisy environment Visual • Macular degeneration, cataracts

  15. Deficits of Aging: Sensory • Taste > Loss of most taste buds except sugar and salt • Smell > Loss of olfactory stimulation > Stimulation helps preserve what’s lost

  16. Deficits of Aging: Anatomic • Bones > 1-2% mineral loss of bone matrix after age 65 > Exercise > Medication • Muscles > 1-2% loss of myofibrils per year after 65 > If you can increase strength by 25% through exercise, you can add a decade of function, compensated by increasing myofibril size

  17. Deficits of Aging: Functional • Reflexes > Slowed with age • Balance > Loss of proprioceptive neurons from feet and neck receptors Result = FALLS (40% of >70y will fall) > Compensate with exercise and balance drills

  18. Deficits of Aging: Functional • Cognition > Decrease in short term memory > Can recall, but need more time for recall > Affected by diabetes, HTN • Learning > Visuospatial is diminished but auditory is well preserved > Learn slowly, but better able to put it to wider use

  19. Deficits of Aging: Psychiatric • Depression • Dementia > Often with depression, frequently medication related > Incidence rises with survival - Age 65-74, 2-3% - Age 75-84, 22% - Age >85, 50%

  20. Pathology of elderly

  21. Normal Brain surface:

  22. Atrophy – Senile / Alzheimer's

  23. Ageing: “Progressive time related loss of structural and functional capacity of cells leading to death” • Senescence, Senility, Senile changes. • Ageing of a person is intimately related to cellular ageing. • Blood vessel damage precedes ageing.

  24. Plasma Membrane: Structural Changes lead to Changes in permeability Less Fluid due to increase in saturated fatty acids

  25. Nuclear Changes Chromatin becomes more condensed (increase cross-links) (disulfide bonds between histones) Implication: Damage to DNA less likely repaired Lymphocytes in culture, add reducing agents to medium (break disulfide bonds) senescent cells divide again

  26. Cytoplasmaic Changes Increase volume with age Lipofuscin- (age pigment) found in non-dividing cells e.g. nerve and muscle Lipofuscin granules

  27. Ribosomal Changes rRNA decreases with age general decline in protein synthesis

  28. Mitochondrial Changes Decrease number of folds (cristae) Decrease in number of mitochondria

  29. Lysosomal Changes Decrease in activity leads to accumulation of cellular garbage e.g. lipofuscins Release of enzymes leads to cell death

  30. Pre-programmed Cell Death (apoptosis) Apoptosis vs. Necrosis Necrosis - external cause (trauma) random breaks in DNA Apoptosis- internal cause (cellular suicide) non-random 180 base fragments Apoptosis - natural developmental process e.g. interdigital tissue (webbing) neurons

  31. Factors affecting Ageing: • Genetic 60% & Environmental 40% • Clock genes, (fibroblast culture) • Werner’s syndrome. • Age gene on Chromosome 1. • “Age” is a character from female parent. • Mammalian mitochondria come from ovum.

  32. Progeria

  33. Factors affecting Ageing: • Environmental factors (40%) • Trauma • Diseases – Atherosclerosis, diabetes • Diet – malnutrition, obesity etc. • Psychological & Social health – stress.

  34. Theories of Aging Possible Mechanisms (How ?)

  35. 3 Criteria of Aging Theories 1. Must occur in all individuals of the population 2. Produce Changes in function/ structure 3. Changes increase with age (progressive)

  36. 3 Catagories of Theories 1. Wear and Tear (Damage) Theory 2. Physical/ Chemical Changes 3. Genetically Programmed

  37. Why Do We Age? Why do not we die aerlier?

  38. Wear and Tear Theories Weismann (1891) Ordinary insults and injuries of daily living accumulate and decrease function to some sub-vital level e.g. loss of teeth  starvation molecular level: enzymes accumulation of harmful metabolites (cell garbage theory) e.g. aldehydes, free radicals, lipofuscins interfere with cell function

  39. Wear and Tear Theories (cont.) • animals with high metabolic rates have shorter life spans • rats on calorie restrictive diets live longer finite energy theories

  40. Wear and Tear Theories Refuted • Animals in protected environments have no change in maximum life span. • Time-dependent changes cannot initiate aging • Cellular/ Genetic evidence Reformulated as Failure to Repair Theories

  41. Physical/ Chemical Changes • Cross Linkage Theory (Post-translational modification) • macromolecules cross linked (denatured) leading to a decline in function e.g. proteins- collagen, elastin How ? Disulfide bonds Advanced Glycation End-Products (AGEs) accelerated in diabetics DNA cross-linkage occurs also

  42. Physical/ Chemical Changes • Altered Protein Theory • protein folding no change in primary structure decline in catalytic activity with age e.g. enolase in nematodes denature/renature experiments • increased carbonyl content (ketones, aldehydes) of proteins (oxidative)

  43. Physical/ Chemical Changes • Free Radical Theory (Oxidative Damage) • Free Radicals: contain unpaired electrons making them highly reactive therefore only exist for a short time. e.g. Super oxide, hydroxyl , peroxide • Lipid peroxidation- damage to cell membranes Protein cross linkage DNA damage Antioxidants - Vitamins A, C, E, Cellular Defenses- Catalase, Superoxide Dismutase

  44. Free Radical Theory

  45. Aging By Program Assumptions: Biological Clock Molecular Clock- the Telomere ? Life Span Inheritable Twin Studies Biological Clock: Hypothalamus Decline in Signal Decreased Sensitivity to Feedback Programmed senescence does not require central control - cell culture evidence

  46. Telomerase in ageing: Germ Cells Somatic Cells

  47. A telomer hypothesis

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