what is ageing? Decrease in functional capacity - molecular to organ level genetic factors

4. what is ageing? • Decrease in functional capacity - molecular to organ level • genetic factors • environmental factors • ageing disease /disablement • wear & tear

5. Theories genetics - ‘biological clock’ • Environmental factors • radiation - induced mutation • chemical - induced mutation • free radical damage • physical damage - joints • Evidence • Genetic - ‘biological clock’ • Hayflick number • human fetal cells 50X doubling • 80 yr old 20-30X • ‘memory’ retained

6. Disease states eg. Progeria and Werners Syndrome premature ageing Werners Syndrome mutation located on chromosome 8 codes for ‘helicase’ enzyme - mutation leads to DNA damage

7. Extracellular and intracellular factors • UV and radiation • heat • free radicals • exogenous microorgansims • Cellular defence mechanisms • DNA repair enzymes • anti-oxidants • heat shock / stress proteins • apoptosis

8. Are telomeres involved? Telomeres are additional ‘nonsense’ repeats at the end of all chromosomes which shorten every time the cell replicates

9. Telomeres are additional ‘nonsense’ repeats at the end of all chromosomes which shorten every time the cell replicates The Nobel Prize in Physiology or Medicine 2009 was awarded jointly to Elizabeth H. Blackburn, Carol W. Greider and Jack W. Szostak"for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase".

10. When the telomere has been removed then the cell moves to a ‘replicative senescence’ stage Not functioning apoptosis • Some cells prevent this by having a telomerase enzyme which adds back bits of the telomere • Useful for highly proliferating cells eg immune cells • Used by cancer cells to become immortal

11. Taken from: Samassekou et al (2010)

12. What causes the ageing of cells? Reactive Oxygen Species - affect mitochondrial function - may cause apoptosis

13. Taken from: Chung et al. (2009) Ageing Research Reviews

14. Anti-oxidants derived through diet and intracellularly prevent the damaging effects of free-radicals With age your ability to generate anti-oxidants is reduced thus changing the balance towards the damaging effects of free-radicals

15. Biochemical and physical changes changes associated with ageing modified by lifestyle / diet / smoking / alcohol • Skin • decrease elasticity of collagen / elastinfibres • affected by UV radiation • loss of pigment in hair follicles • decrease in wound healing

16. Liver • 60-90years old liver shrinks • decreases capacity to metabolise drugs and hormones • decreases alcohol tolerance • Bone • decrease in bone loss • linked with oestrogen / tostesterone • most severe bone loss seen in females

17. Balance between osteoblasts and osteoclasts is affected with loss of oestrogen and leads to less bone formation

18. Brain • 20 years old 1.4Kg • 60 years old 1.3Kg • changes in brain composition • nerves lost • Amyloid deposits associated with blood vessels • decreased reaction times

19. Corticocortical systems show age-related changes in morphology Hof et al (2004) Trends in Neurosciences Recent research shows that oestrogen can reverse some of these changes

20. Ageing and disease • atherosclerosis • arthritis • osteoporosis • cataract • chronic renal failure • diabetes • senile dementia • cancer due to; - physical / biochemical changes in normal ageing - cumulative exposure to harmful agents - increased sensitivity to agents / environment with age

21. Cancer > 65 years old 50% of all cancers incidence increases with age children/young adults - leukaemia and sarcoma older adults - carcinoma and lymphomas childhood - increased proliferative capacity of cells may lead to increased susceptibility to carcinogenic agents

22. SO why increased frequency in older adults? Hypothesis; - age-related accumulation of carcinogens - senescence changes lead to increased sensitivity eg. Immune system nutrition metabolism endocrine system • all affect intracellular functioning • detoxification of mutagenic agents • DNA repair • response to oncogenic activation

23. Dementia deterioration of intellectual and cognitive functions 1% 65-75years dementia 10% > 75 years 20% > 85 years • Alzheimer’s • multiple infarcts of the brain • accumulation of amyloidb and tau proteins in the brain • may be due to reduced immune function to ‘clear up’ accumulated proteins

24. Gradual build up of Ab and tau proteins causing neuro-fibrillary tangles (NFT) Leading to – mild cognitive impairment (MCI) and then Alzheimer’s disease (AD) Taken from: Jaworski et al (2010) Biochimicaet BiophysicaActa

25. IMMUNOSCENESCENCE deterioration of immune function seen in elderly increased susceptibility to; - infection - cancer - autoimmune diseases

27. Thymus atropy Leads to a reduction in numbers of naive T cells Research suggests that IL-7 can reverse this process

28. Balance of naive T cells to memory/activated T cells changes with age – so less able to fight off new pathogens eg influenza

29. CD28 T cell activation How do T cells in the elderly function? T cells need co-stimulation from CD28 to function antigen TCR

30. These cells have reduced proliferative capacity and short telomeres indicates replicative senescence But remaining T cells show adequate co-stimulation In the elderly 50% of T cells lack CD28 and therefore are unable to respond to antigens

31. Thus although the immune system itself ages leading to poor overall effective protection to pathogens it also impacts on other key age-related diseases; • Cancer • autoimmune diseases eg rheumatoid arthritis • Alzheimer's disease

32. Can we increase longevity? Do we want to increase longevity? • Evidence suggests that ageing can be ‘slowed’ by; • Moderate exercise • caloric restriction • Moderate exercise has been shown to increase health overall; • muscle mass, • cardiovascular, • bone mass, • immune function • prevent the reduction in anti-oxidants But longevity is not affected

33. Caloric Restriction CR is when 30-40% less than adlibertum food intake is taken Animal trials have shown increase health and longevity

34. Some evidence that affects human similarly (Eur J Clin Invest. (2010) 5:440) Volunteers in Biosphere 2 also showed expected beneficial effects ‘normal’ diet CR diet