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- Mating strategy and production of gametes determines rate of ageing.
- species producing large numbers of gametes in a single mating season, or having multiple mating seasons in a single year have short life spans
- species having typically single offspring in which extensive parental care is invested have long life spans

Glomeruler Filtration rate (GFR) decreases from the age of 20, by 75 it has decreased by 50%.
N.B creatinine is not a good indicator, because of reduced muscle mass.

The effect on drug choice in the elderly:
- avoid drugs which are nephrotoxic or unsafe in renal impairment
- reduce dose of other renally excreted drugs

- difficulty collecng prescription
- lack of understanding
-ADRs
- memory failure
- hoarding
- complicated regime
- inability to read labels
- physical difficulties

Good reasons
- co-morbidity
-guidelines

bad reasons
- failure of review
- failure to use non-drug treatment
-cascade of prescribing

- adverse drug reactions
-drug interactions increase
Problem drugs = anticoagulants, anticonvulsents, antihypertensives, oral hypoglycaemics, digoxin, theophylline
- non- compliance
  1 drug - 15%
  2 or 3- 25%
  4 or more --> 35%

- decreased iron absorption
- reduced intestinal blood flow

- reduced GFR
  (increased concentration due to reduced excretion)
- reduced lean body mass (Vd decreases)
  increased concdntration due to reduced Vd
- reduced body water
  increased concentration due to reduced Vd
- decreased albumin
  increased free(active) concentration

Benzodiazepines accumulate due to
- reduced hepatic metabolism
- increased Vd
- reduced albumin bindings

ADRs
- hypothermia, increased dependence, increased sedation, hangover effects, confusion, ataxia, memory problems, unsteady gait and balance problems

-temazepam
-shorter half life
-hangover effects and dependence can still occur
- sedation still a problem

glibenclamide is long acting, causes hypoglycaemia

gliclazide shorter acting so safer

- hypothermia
- reduction in homeosatic control
- also a problem for some drugs (e.g. halperidol and prochlorperazine)

- setraline - SSRI- safer
- amitrityline -- tricyclic
      anti- muscarinic SEs: Constipation, urinary retention, dry     mouth, glaucoma, drowsiness, dizziness, syncope, confusion, postural hypotension, hyponatraemia, hypothermia and cardiac arrhythmias.

- low dose with caution
  interactions may also be problematic (e.g. with antiarrhythmics and antiepilectics)

glucocorticoids
heparin
phenytoin
rifampicin

- superiro peduncle mainly carries fibres from the dentate nucleus to the contralateral red nucleus
- the middle carries fibres from teh contralateral pointine culcei to the cortex,
- the inferior peduncle carries mainly fibres from the spino-cerebellar tracts and from the olivary nuclei to the cortex

the fastigial nucleus sends fribres to the vestibular nuclei and reticular formation

- purkinje cells > output of cortex

input
- climbing fibres > from the olivary nuclei, for multiple synaptic contacts on a single purkinje cells
- mossy fibres--> form synaptic contact with granule cell; originate from pons and spinal cord

Cerebrocerebellum > thalamus and cerebral cortex
spinocerebellum> spinal cord
vestibulocerebellum--> vestibular nuclei

- they are composed of axons of neurons in the nucleus dorsalis and in the accessoory cuneate nucleus.
- enter cerebellum ipsilaterally via the inferior cerebellar peduncle
- input is provided by collateral branches of a variety primary afferent neurons, including those from muscle spindles, tendon organs, joint and cutenous mechanoreceptors.

- composed of axons of large neurons located between the dorsal and ventral grey columns of the spinal cord.
- the axons cross the midline in their segment of orgion, ascend thorugh the inferior peduncle, before entering the cerebellum via the contalateral superior pedunce.
they therefore cross the midline twice and so return ipsilateral to their side of origin on entering the cerebellum.
- get sensory input from various types of large receptive field afferents, including those of flexor reflex system,
- also receive input from all desceding tracts (corticospinal, reticulospinal and vestibulospinal)

1. Body water
- decreases by up to 15%
- Vd of polar (water soluble drugs decreases
- plasma concentratoin goes up (digoxin, cimetidine)

N.B diuretics exacerbate this

2. Body fat
- increases as a proportion of body mass
- Vd of fat soluble drugs increases
- accumulation of drugs ( e.g benzodiazepines)


3. Lean body mass
- decreases
- Vd of highly protein bound drugs decreases
- increased plasma concentration (e.g. digoxin)
- use lean body weight for doese calculations

- phase 1 is most affected
- microsomal mixed function oxidase
- metabolising capacity decreases by up to 60%

Drugs metabolised by phase 1 are:
- diazepam, warfarin, phenytoin, analgesics, theophylline.

pre frontal cortex

basal ganglia and procedural memory

learning > hippocampus
semantic > cortex

medial temporal lobe (para/hippocampal region - including entorhinal coretx, CA1 field, amygdala) medial diencephalon, pre-frontal cortex, neocortex

pre-frontal cortex

basal ganglia and cerebellum

- memory difficulties
- associated cogntive decline e.g language, visuspatioal function, planning and judgement
- functional impairment i.e not normal ageing or "mild cognitive impairment"
- preserved awareness i.e not delirium
- porgressive decline

features are
- memory complaint
- normal activities of daily living
- normal general cognitive function
- abnormal memory for age


mild cognitive impairment is often considered the middles tage between ageing and dementia. People with MCI can however function normally.

- Alzheimer's disease
- Vascular dementia
- mixed AD/ VaD
- Lewy Body disease
- Fronto-temporal

others are
- alcohol associated problems
- Hntington's
- CJD,
- subdural haematoma

Alzheimer's disease is commonest with 50 % of all dementia patients having it. It is more common in women

Vascular dementia is second commonest with 25 %; more men than women have it

Dementia with lewy bodies may be 10 %

1.  Behavior
   - inability to make decisions
  - loss of interest and initative
  - social withdrawal
2. Thinking
   - reduced concentration
   - preservation ( getting fixed on one object or topic)
  - less flexible
  - confabulation (fill in gabs in ones memory with fabricatiosn that one beleives to be facts
3. Speech
  - difficulty with names
  - less complex
  - more disorganised
4. Memory
- difficulty with new learning
- recent > remote (but both affected)
- disruption of temporal sequences
5. Insigt
- may be present early on, later generally lost

- insidious onset
- gradual progression
- often starts with recent memory impairment
- other fatures like langauge, visuospatial impairment come later
- no focal neruological signs
- no evidence for other disease process

- protein error and turnover
- DNA damage and repair
- oxidative stress
- Mitochondrial damage

random accumulation of damage may occur through four principle synergistic cellular mechanisms mentioned above

- osteoporosis
- Athlerosclerosis
- cancer

- rare genetic disease in which individuals display accelerated ageing
- genes mutated in progeria are likely to be required for maintaining or repairing cells/tissue

1. unimodal progeroid syndrome - only a single tissue is affected e.g alzheimers disease
2. Segmental progeroid syndromes - multiple tissues affected but some features of ageing not observed

- adult progeria (related to or sometimes known as werner's syndrome)
- werner's syndrome
- cockayne's syndrome
- blooms syndrome
- xeroderma pigmentosa

- death in third or forth decade

- short stature
- graying and/or loss of hair
- osteoporosis
- skin ageing
- cataract
- diabetes
-mental retardation
- predisposition to cancer

defective RecQ helicase (also mutated in Bloom's syndrome)

result in failure of DNA excision repair mechanisms, genome Instability and replicative senescence

Hutchinson- Gilford syndrome -
LMNA defect ( a a member of the intermediate filament super gene family and forms part of the nuclear lamina/nucleoskeleton. The lamia protects the nucleus fromphysical damage, acts as a sensor foroxidative stress and controls the differentiation of adult stem cells)

clincial features for HGPS are: short stature, atrophy of sub cutaneous fat, alopecia, musculoskeletal abnormalities, osteolysis, premature atherosclerosis,

Widermann- Rautenstrauch syndrome - genes unkown

mutations of genes lead to replicative senescence and genome instability including telomere shortening and aneuploidy

clincal features general:
failure to thrive-
short stature
alopecia,
manibular dysplasia
hyperlipidemia,
type 2 diabets,
atherosclerosis
osteolysis
death before second decade from coronary artery disease or stroke