1
Q
What are the demographic trends in the first 30 years of the NHS?
A
infant mortality/1000 live births
Girls: (1948) 39, (1996) 7
Boys: (1948) 30, (1996) 5
With the introduction of the NHS, there have been lots of factors contributing to increasing old age. There is therefore less infant mortality and the dramatic initial change was due to the introduction of the NHS, but it is still decreasing.
proportion of deaths below 65 in England and Wales
(1948) 40%
(1996) 7%
2
Q
Are the increasing numbers of people reaching old age worrying figures?
A
- By 2007 there were more people over 65 than under 18
- The over 85s are the fastest growing segment of the population and are set to double by 2020
- The potential problems with this are that they are the people taking pensions and needing health care, and these things are paid for and supplied by the younger working people, which there may not be enough of, and this can have a huge impact
3
Q
What shape of population pyramid have we reached now?
A
This is how we have now reached. A barrel shape with a bulge in the middle – this is the ‘baby boomers’, those born in 40s/50s after WWII, they are now in their 60s-70s and are the ones who could cause potential problems in the future
4
Q
What are survival curves?
A
graphical representation of population survival with age
5
Q
What are logarithmic scales?
A
haracteristic of populations that do not age or live under such severe conditions that none survive to old age.
This gives some more information about % population at birth and how they decline with time
6
Q
What does it mean to ‘square the rectangle’ of a logarithmic scale?
A
With further improvements in living conditions death is compacted to old age, squaring the rectangle of survival.
This is the ideal situation – we want to ‘square off’ the rectangle
7
Q
What needs to be done to square the rectangle of survival in the UK?
A
- Decreased infant mortality
- Increased standard of living
- Improvements in public health
- Improvements in sanitation
- Improved diet – 1842 abolition of corn laws allowed importation of cheap American Food.
These are what have caused the changes in life expectancy/population
8
Q
What is the future of old age?
A
- meagre increments?
- unenjoyed?
9
Q
What are meagre increments?
A
- Expected length of retirement increased 4-8 fold since 1870
- Nearly all of this due to increased life expectancy rather than early retirement
- Average length of retirement increased by 5 years between 1981 and 2001
10
Q
What is theoretical gloom?
A
- Exponential relationship between age and prevalence of disability
- Exponential relationship between age and chronic disabling diseases
- The older you are, the more likely you are to be disabled
11
Q
What are some chronically disabling diseases that have a steep relationship to age?
A
- stroke
- alzheimers
- parkinsons
- osteoarthritis
12
Q
What are dependency profiles of elderly people by age?
A
Height of column represents the number of people dependent on someone else for that activity
13
Q
What are the 4 scenarios of the future of old age?
A
1 - 1 year of additional woe for every year of life gained
2 - less than 1 year of additional woe for one year of life gained
3 - no additional woe for each year of life gained
4 - less woe despite life gained: Fries’ ‘compression of morbidity’
14
Q
What are the GHS trends from 1980-2001?
A
- no overall change in proportion of elderly people reporting their health as good (37%) fairly good (38%) and not good (25%)
- proportion of people reporting long-standing illness has not changed significantly
The height is the cumulative number of days spent in hospital until you die. This shows that its always the last three years that you spend most time in hospital regardless of what age you die at.
15
Q
What are the days spend in hospital in 3 years prior to death?
A
- median 23 days
- did not rise with age above 45
16
Q
About the predicted numbers of people over 65 in the UK unable to perform activities of daily living…
A
- predictions of people over 65 that are dependent on people for activities
- predictions made at different times
- when re-estimated using best actual data at the time, the more up to date statistical information we had, the lower and lower the estimate was getting
- the figures didn’t project – something is changing!
17
Q
About ‘squaring the circle’…
A
‘ageing to the rescue!’
- progressive generalised impairment of function
- resulting in the loss of adaptive response to stress
- and a growing risk of age related disease
ageing starts at 14 – the eyes being the firs thing to be affected, needing more light to see things.
18
Q
What is frailty?
A
a physiological syndrome characterised by decreased reserve and diminished resistance to stressors, resulting from cumulative decline across multiple physiological systems and causing vulnerability to adverse outcomes.
19
Q
What is physical frailty?
A
the combination of weight loss, fatigue, impaired grip strength, diminished physical activity of a slow gait
20
Q
Ageing vs disease
A
- disease need to be identified as it may respond to treatment or be preventable
- ageing is not reversible but may be compensatable
- all changes should not be put down to age
we cant just assume that something is down to ageing when there might be something more serious going on underneath
21
Q
What are Strehler’s concepts for a true ageing process?
A
- universal
- intrinsic
- progressive
- deleterious
to be a true ageing process all 4 must be fulfilled
22
Q
What is the universal aspect of Strehler’s concepts?
A
- identifiable in all members of a species
- may effect individuals to a different extent
- eg collagen cross links, loss of calcium from bones
23
Q
What is the intrinsic aspect of Strehler’s concepts?
A
- restricted to changes of endogenous origin
- e.g. skin in axilla, hair loss
24
Q
What is the progressive aspect of Strehler’s concepts?
A
- all changes continue progressively with time
- eg greying of hair, loss of muscle power
25
What is the deleterious aspect of Strehler's concepts?
- should be eventually harmful to the organism
| - eg reduced visual acuity, loss of hearing
26
What are the differences between ageing and disease?
AGEING
- universal
- intrinsic
- progressive
- deleterious
DISEASE
- individual
- intrinsic or extrinsic
- progressive but may be halted or reversed
- deleterious but may be arrested or cured
27
What is the geriatrician's profession de foi?
Squaring the circle
By delaying the onset of disabling diseases to alter ages when intrinsic ageing has raised frailty by reducing adaptability, the average duration of disability before death will be shortened. In brief, we will spend a longer time living and a shorter time dying
28
About dependent life before death...
The older the age one attains without becoming disabled the shorter the period of dependency to be expected before death. The suggests that for disability in later life, postponement of age onset would result in preventing suffering
29
What is the untapped potential for postponing disability in old age?
- health promotion
- illness prevention
- appropriate use of existing technologies
- technologies around the corner
30
What is the rule of halves?
- of the population qualifying for lipid lowering treatment
- approximately, half are treated with lipid lowering therapy
- less than half achieve treatment goals
This data precedes the introduction of rosuvastatin and helps explain the need for rosuvastatin. Some of this lack of ideal management may be attributable to the efficacy of drugs and some may be due to compliance issues. However patients who get to their LDL goal at the first dose they use may well be more likely to comply to treatment.
Despite the universally accepted evidence that confirms the benefit of lipid lowering therapy, large observational studies such as EUROASPIRE II have shown that many patients in need of lipid lowering therapy remain untreated. The EUROASPIRE II study was a large survey of lifestyle, risk factor management and drug therapy undertaken in clinical practice and involving over 8000 CHD patients in 15 countries across Europe. The results provide valuable insight into what is actually happening in practice and highlight that many patients - two in every five - in need of lipid lowering therapy remain untreated
31
What is the drug treatment of older people?
- 10% on contraindicated drugs
| - 6% acute admissions due to inappropriate prescriptions
32
What is the effect of older people on finances?
- We cant afford to make or keep old people healthy
- We cant afford healthy old people
We cant afford to make or keep old people healthy
- Prevention is cheaper than cure
- Postponement and compression of morbidity is cheaper than community or institutional care for people with chronic disability
Increases in healthcare expenses in old age
- Availability of new treatments
- Appropriate expectation that older people would benefit from them
- Age specific need for health care is falling
- Expenditure on health care always maximal in the last year, irrespective of age of death
Health expenditure UK
- Smaller increase in per capita costs for older rages compared with younger age groups
- Combined NHS and hospital and community services for 85+ has decreased in real per capita costs between 1985-87 and 1996-99
Affording to keep healthy old people
- Old age is a social construct as well as a biological phenomenon
- Older people can be producers as well as consumers
- Peg median age of compulsory retirement to median age of death
33
What is the secret to healthy old age?
- Lies within our grasp
- Not a contradiction in terms
- Not unaffordable
- Postponement of onset of disease
- Abatement of disease resulting in postponement of progression of severity of disease
- Lesser postponement of death
- Terminal, not unpleasant, frailty
- A human rather than an animal death
- Memorable last words
34
What are the three major views about why we age?
- wear and tear
- adaptive evolutionary
- non-adaptive evolutionary
35
What is the wear and tear theory of ageing?
view an organism as a machine that wears out
eg an elephants teeth – they have 6 sets of 4 teeth. When they have all run out then they go into a poor nutritional state and dies.
BUT
- Not all animals age eg sea anemone – undergo disease and attack but no ageing
- Ability to repair eg germ line – maintaining it in an optimal state at all times
- We can repair whole organs eg salamanders limbs
Therefore wear and tear cannot be the whole answer.
36
What is the adaptive evolutionary theory of ageing?
- Developed through process of evolution and natural selection
- Conforms to popular Darwinian principles
- Ageing selectively advantageous to species
- Prevents old and worn out individuals competing
BUT
- Advantage to population not individual
- Ageing rarely seen in natural populations
- Prevents old and worn out individuals competing (circular argument)
37
What is the non-adaptive evolutionary theory of ageing?
2 theories:
- Mutation accumulation
- Antagonistic pleiotropic gene
+ disposable soma theory
38
What is mutation accumulation?
- Powers of natural selection decline with age
- Early expressed genes effect most of population
- Those expressed after reproduction are lost from evolutionary control
- Ageing due to a miscellaneous collection of late acting deleterious genes
- No experimental support
39
What are antagonistic pleiotropic genes?
- Early food effect therefore retained
- Bad late effect contributing to ageing
- Evidence in drosophila studies
Advantageous gene – hard to do ageing studies in human because we need to do them for many many years and it is hard to get publishing for this. Therefore studies are done on organisms with life spans of only a few days eg fruit flied and nematode worm
40
What are the two ageing experiments that were done on drosophila?
* aa (abnormal abdomen) allele greatly increases early fecundity and pleiotropically reduces longevity
* if breeding prevented until later in life over 15 generations lifespan extended by 1/3 but short winged and flying ability reduced
Very fertile with the aa and so produce lots of offspring but they die young.
If the sexes are separated at a very young age before they have a chance to breed and only reproduce later on in their lifespan when some have already died, and if we do this over 15 generations they get an increased lifespan. However, the resulting beings aren’t very good at flying and so they wouldn’t survive in a wild environment
41
What is the disposable soma theory?
- development of non-adaptive evolutionary views
- theory views organism as machine that transfers free energy into progeny
- success is to ensure survival of genes in most efficient way
- disposable = produced with limited lifespan
- soma = not of germ line
Organisms take in a set amount of energy. The organism needs to decide how its going to use that energy.
The organism can use this energy in a number of ways; food, foraging, maintaining, reproducing, defence. Maintaining and reproducing can potentially be given more or less energy depending on the species and circumstances
42
What are examples of the disposable soma theory?
Survival for mouse is about breeding fast. It is not very necessary for maintaining body as very highly predated. Cats need to live longer and need to teach offspring how to hunt etc.
Cats often lose first litter as learning how to teach offspring and look after them. Cats are less fertile than mice. The mammals which have the longest lives have the least fertility.
* The amount of energy expended on the various possibilities will depend on the ecological niche occupied by that organism
* This will result in species specific longevity
* For some fertility is priority
* Others need to maintain soma for longer
- From the second law of thermodynamics entropy increases
- Ie we age and decay
- We resist this with defensive and repair processes
- Protective mechanisms eventually fail
- Rate of ageing is determined by investment in self maintenance
Ie. We are programmed to survive – not to age
43
What theories are there for how we age?
- System level theories
- Cellular/molecular level theories
- Genetic theories
- Genomic stability
44
What is the neuroendocrine theory of ageing?
- Functional decrease in neurones and associated hormones in central to ageing process
- Hypothalamic, pituitary, adrenal axis controls growth and development so why not ageing
- Decreased pulsatile growth hormone and GnRH in ageing rats
- Hypothesectomy and hormone replacement increases lifespan
- DECO or death hormone proposed but never found
45
What is the relationship between wear and tear and rate of living?
- Some aspects of ageing look like wear and tear
- Higher basal metabolic rate shorter lifespan
- Accumulation of damage may be important
46
What is cross link formation?
- Many biological molecules develop cross linkage or bonds with passage or time, altering physical or chemical properties
- Collagen cross links
- Collagen allows the skin to stretch
47
What are heat shock proteins?
- Produced at time of cell stress
- Disassemble damaged proteins and transport in new
- Reduced production with age
- Decreased ability to cope with stress leads to ageing
48
What is the Hayflick phenomena?
- Fibroblasts grown in culture undergo a set number of divisions then stop
- More divisions if form younger source
- Repeated in other cell types
- Biological clock
- HeLa cell line form Ca breast unlimited divisions
49
What are geronto genes and longevity assurance genes?
- Genes are important: twin studies, long lived families, species specific longevity
- Genes in drosophila, yeast and nematodes identified that shorten and lengthen life
- Mutation in nematode that doubles 3/52 lifespan by increasing superocide dismutase
Geronto Genes: live longer
Longevity assurance genes: age faster
50
About telomeres and ageing...
- Chromosome tail repeated short DNA base sequence
- Stabilise chromosome during cell division
- Shorten with each division
- Critical length at which no further divisions can occur
- Explain hayflick phenomena
- In germ cells and tumour cells telomerase produced
51
About telomerase in mice...
* Possibly important in ageing - 2010 looked at knock out mice
* Couldn’t produce telomerase
* Aged very rapidly
* Quickly forgot mazes
* Characteristics of ageing at very young age
* If gave telomerase back a little bit of the ageing was reversed
52
What is error catastrophe?
- Errors occur at transcription and translation that result in abnormal protein production
- Usually corrected when protein replaced
- If protein important in DNA repair or protein synthesis may lead to a cascade and cell death
- Accumulation of such errors may result in ageing
53
What is somatic mutation and DNA repair?
- Based on irradiation shortens life of mice
- Somatic mutation now considered unimportant because: occurrence rate too low, DNA repair sufficient
- However may fail in combination with other toxic agents eg UV light or O2 radicals: DNA repair more efficient in man than mouse, more efficient in germ cells, declines with ageing (more cancer cells seen)
We don’t age at a constant rate – later ageing happens much faster. The ability to repair is reduced
54
What is free radical theory?
- Highly reactive chemical compounds arise from enzymatic and non-enzymatic reactions
- These damage cellular DNA
- Several enzymes (superoxide dismutase, catalase, glutathione peroxidase) and vitamin e, C, carotene protect cells
- Protection reduces with age
- People believe this is the predominant feature that contributes to ageing
55
What is the mitochondrial theory?
- Ageing due to mitochondrial DNA damage
- High exposure to O2 radicals
- No protein coat to mitochondrial DNA
- Damage and mutation increase with age
- Genetic mitochondrial dysfunction syndromes mimic ageing
56
What is cell senescence?
* Stressors: dysfunctional telomeres, other DND damage, oxidative stress, strong mitogenic signals, chromatin perturbations
* Can push the cell into senescent state
* Doesn’t divide anymore
* Cant get rid of senescent cels they hang around
* Senescent cells increase with age and accumulate in sites where there are disorders associated with ageing
57
What is the relationship between cellular senescence and ageing?
- Senescent cell numbers increase with age and are at the site of age related pathologies eg osteoarthritis and pancreatic dysfunction
- Neurogenesis, haemopoesis and pancreatic function decreases associated with p16 depended senescence
- Altered gene expression
- Up-regulation of genes controlling extracellular matrix degrading enzymes, inflammatory cytokines and growth factors
- Disrupt normal tissue structure and function
- Stimulate growth of pre-malignant cells
58
What controls the balance between ageing and self-maintenance?
There is a balance between ageing and self-maintenance.
Things damaging us that may speed up ageing include: free radicals, UV light, irradiation, protein glycation.
Things protecting us include: DNa repair, heat shock proteins, protective enzymes, free radical scavengers.
There is a balance slightly towards ageing.
Gerontogenes (make us age faster) and longevity assurance genes (make us age slower) also have an effect on the balance.
59
What is calorie restriction?
- Calorie restriction in rats increases lifespan
- But delayed puberty, increased infection and death in pre-puberty
- Some evidence in humans: Okinawa diet
Gives rats a dramatically reduced number of calories and they live longer but at the above stated costs.
The Okinawa diet is from an area of relative poverty in Japan. It is a fishing community with a very restricted calorie intake, these people tend to live longer than the rest of Japan. There are whole studies being conducted on this community by local universities.
There was also another study done in the Arizona desert where they created a biosphere and wanted to see if humans could live in total isolation. They realised that their calculations were wrong, and that all the people would die. Therefore, they took some people out and some people stayed in. They then compared the ageing of those who stayed in with those who came out, and those that had come out had aged faster. This didn’t take into account factor such as smoking and drinking though
60
What else can affect the length of life in rats?
- Moderate exercise = positive effect (live longer)
- Sexual activity = positive effect (live longer)
- Overcrowding = negative effect (live shorter)
61
What is the make up of bone?
* Cortical (compact) bone
* Trabecular (spongy, cancellous) bone
These two types of bone give bone its combination of strength and light weight properties
62
What are the two lineages of bone cells?
Two lineages of bone cells:
• Immune lineage – from haemopoietic stem cells get osteoclasts
- degrade the organic matrix
• Osteoblastic lineage from mesenchymal stem cells
- Differentiate form various precursor stages into osteoblasts
63
What are osteocytes?
Osteoblasts form new bone – lay down osteoid composed mainly of collagen and contribute to the mineralization of bone giving its rigidity.
Osteocyte is the mature bone which becomes entombed within the organic matrix. May live for decades. Bone remodeling balance between osteoblasts and osteoclasts – osteocytes seem almost quiescent but clear that they have an important regulatory role which partly depends on their ability to sense mechanical strains
• Terminally differentiated, post-mitotic osteoblasts
- Entombed” within lacuae in the bone matric
- Communicate with each other and bone surface via cellular processes (dendrites) which run along canaliculi
- Lacunar-canalicular network
• May live for decades
64
What are osteoblasts and their function?
• Differentiate from mesenchymal stem cells
• Bone forming cells
- Lay down organic bone matrix (osteoid)
- Promote mineralization of osteoid
• Life cycle determined by control of differentiation and apoptosis
65
What are osteoclasts and their function?
• Derived from haematopoietic stem ce;ls
• Resorption of bone
- Secrete acid to dissolve and release mineral content of bone
- Enzymes to degrade organic matrix
• Life cycle determined by control of differentiation and apoptosis
66
What is the lacunar-canalicular network?
Allows communication between osteocytes and from osteocytes to surface cells and systemic circulation.
As osteoblasts lay down bone they differentiate into osteocytes. They become surrounded by the bone they had previously created. The cell is within a ‘lacuna’.
The differentiated osteocytes give off cellular processes such as dendrites which pass through canaliculi.
67
What is the function of osteocytes?
- Regulate bone remodeling in response to mechanical and endocrine stimuli
- Function as endocrine cells
In turn the osteocytes are known to function in their own right as endocrine cells.
FGF23 is a protein released by osteocytes which has multiple effects – directly effects kidney in phosphate homeostasis.
68
What controls bone remodelling?
Factors favouring resorption
- Unloading (bed rest, zero-gravity, etc) – anything removing mechanical loading
Factors favouring formation
- Load-bearing exercise
69
How does bone act as a metabolic organ?
Bone turnover serves homeostasis of serum calcium, phosphate, in conjugation with
- Parathyroid hormone
- Vitamin D (1,25-dihydroxy D3)
- Calcitonin
Short term turn over serves calcium homeostasis in partnership with PTH and vitamin D, calcitonin in some species – especially humans
70
What are the actions of PTH?
* Maintains tight (negative feedback) control of serum Ca (2.2 - 2.6 mmol L-1)
* Released in response to decreases in Ca
* Stimulates bone remodelling (both anabolic and catabolic effect)
* Stimulates conversion of active hormonal Vit D in kidney (stimulates 1-alpha hydroxylase) – endocrine function of the kidney, not classic function
* Increases Ca reabsorption in kidney
71
What are the actions of Vitamin D?
* Increases Ca absorption from gut
* Promotes differentiation of osteoclast and osteoblast lineages
* Inhibits PTH release
* Inhibits 1-alpha hydroxylase
72
What are the actions of calcitonin?
* Negative feedback regulation of serum Ca
* Released in response to rises in Ca
* Importance in human Ca homeostasis is doubtful
* Inhibits osteoclast function
This has been used for decades to treat diseases involving bone loss eg osteoporosis.
73
What are the actions of oestrogen?
* Regulates life cycle of osteoblasts and osteoclasts
* Osteoclasts: shorten (promote apoptosis)
* Osteoblasts: lengthen (protect from apoptosis)
* Indirectly inhibit osteoclast differentiation
* May be necessary for new bone formation in response to mechanical stress
Cimplex effects are not fully understood
74
How does RANK ligand introduce osteoclast differentiation?
* RANK (receptor activator of nuclear factor kappa-B): surface receptor on pre-osteoclasts, stimulates osteoclast differentiation
* RANK-ligand: produced by pre-osteoblasts, osteoblasts and osteocytes; binds to RANK and stimulates osteoclast differentiation
* OPG (osteoprotogerin): decoy receptor produced by osteocytes; binds to RANK-L, preventing activation of RANK
Osteocyte regulation of bone remodeling. Osteocytes express RANKL and macrophage-colony stimulating factor (M-CSF) to promote, and OPG and NO to inhibit, osteoclast formation and activity. Osteocytes also regulate bone formation via the secretion of modulators of the Wnt signaling pathway. PGE2, NO, and ATP act to activate Wnt signaling, whereas sclerostin, DKK1, and SFRP1 all inhibit Wnt signaling and subsequent osteoblast activity. Maintenance of this balance between resorption and formation by the osteocyte is essential for bone homeostasis.
Sclerostin acts as a BREAK in bone formation
75
What are the two most common types of metabolic bone disease?
```
Osteoporosis: loss of bone mass
• Endocrine
• Malignancy
• Drug-induced
• Renal disease
• Nutritional
```
Osteomalacia: loss of bone mineralization – soft bones like cartilage
Osteoporosis is the most common form. It is thinning of the cortical bone and eating away of trabecular bone, causing bones to be weaker and more fragile
76
What are the endocrine causes of osteoporosis?
* Hypogonadism – notably any cause of oestrogen deficiency, particularly in post menopausal women
* Excess glucocorticoids - endogenous or exogenous
* Hyperparathyroidism
* Hyperthyroidism
77
What is the diagnosis of osteoporosis?
DEXA scan to measure BMD
78
How is dexascan analysed?
Measurement of bone mineral density (BMD)
Dual-energy X-ray absorptiometry (DEXA or DXA scan)
T score
Number of SDs below average for young adult at peak bone density
Z score
Matched to age and/or group
T scores
Normal: >-1
Osteopenia: -1 to -2.5
Osteoporosis:
79
How does bone density vary between women in different ages?
* Varies between men women ethnicities etc.
* Similar shape for men and women
* Gradual decline form around 30
* In women there is a decline with a slight acceleration of decline during menopause
* Can be variable between women
* Then a continuing decline
* Early menopause is a risk factor for osteoporosis
* Men and women risk factor is failure to achieve a good peak bone mass when young
80
What are the clinical features of menopause?
- Most common early manifestation: vasomotor symptoms (hot flushes)
- Later: accelerated bone loss, osteoporosis
1/3 chance of women over 50 suffering a fracture due to osteoporosis
1/5 chance of men over 50 suffering a fracture due to osteoporosis
81
What are treatment options for osteoporosis?
* ERT/HRT – effects well established but safety of long term treatment is questioned
* Bisphosphonates – inhibit function of osteoclasts: risedronate, alendronate
* PTH analogues
* Denosumab – antibody against RANK ligand
* Ensure adequate calcium and vit D intake, appropriate exercise
82
What is relative risk vs absolute risk?
- the media approach… (failure to understand concept of relative risk)
- overall risk when benefits versus risk factors have been taken into account
Semester 4 Revision
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