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what is ageing? Decrease in functional capacity - molecular to organ level genetic factors environmental factors ageing disease /disablement wear & tear . Theories genetics - ‘biological clock’. Environmental factors radiation - induced mutation chemical - induced mutation

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Presentation Transcript
slide4

what is ageing?

  • Decrease in functional capacity - molecular to organ level
  • genetic factors
  • environmental factors
  • ageing disease /disablement
  • wear & tear
slide5

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
slide6

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

slide7

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
slide8

Are telomeres involved?

Telomeres are additional ‘nonsense’ repeats at the end of all chromosomes which shorten every time the cell replicates

slide9

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".

slide10

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
slide12

What causes the ageing of cells?

Reactive Oxygen Species

- affect mitochondrial function

- may cause apoptosis

slide14

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

slide15

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
slide16

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
slide17

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

slide18

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
slide19

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

slide20

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

slide21

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

slide22

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
slide23

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
slide24

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

slide25

IMMUNOSCENESCENCE

deterioration of immune function seen in elderly

increased susceptibility to;

- infection

- cancer

- autoimmune diseases

slide27

Thymus atropy

Leads to a reduction in numbers of naive T cells

Research suggests that IL-7 can reverse this process

slide28

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

slide29

CD28

T cell activation

How do T cells in the elderly function?

T cells need co-stimulation from CD28 to function

antigen

TCR

slide30

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

slide31

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
slide32

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

slide33

Caloric Restriction

CR is when 30-40% less than adlibertum food intake is taken

Animal trials have shown increase health and longevity

slide34

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