AID Flashcards

Question

What is the deleterious aspect of Strehler's concepts?

Answer 1

- should be eventually harmful to the organism | - eg reduced visual acuity, loss of hearing

Answer 2

AGEING - universal - intrinsic - progressive - deleterious DISEASE - individual - intrinsic or extrinsic - progressive but may be halted or reversed - deleterious but may be arrested or cured

Answer 3

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

Answer 4

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

Answer 5

- health promotion - illness prevention - appropriate use of existing technologies - technologies around the corner

Answer 6

- 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

Answer 7

- 10% on contraindicated drugs | - 6% acute admissions due to inappropriate prescriptions

Answer 8

- 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

Answer 9

- 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

Answer 10

- wear and tear - adaptive evolutionary - non-adaptive evolutionary

Answer 11

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.

Answer 12

- 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)

Answer 13

2 theories: - Mutation accumulation - Antagonistic pleiotropic gene + disposable soma theory

Answer 14

- 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

Answer 15

- 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

Answer 16

* 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

Answer 17

- 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

Answer 18

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

Answer 19

- System level theories - Cellular/molecular level theories - Genetic theories - Genomic stability

Answer 20

- 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

Answer 21

- Some aspects of ageing look like wear and tear - Higher basal metabolic rate shorter lifespan - Accumulation of damage may be important

Answer 22

- 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

Answer 23

- 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

Answer 24

- 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

Answer 25

- 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

Answer 26

- 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

Answer 27

* 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

Answer 28

- 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

Answer 29

- 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

Answer 30

- 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

Answer 31

- 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

Answer 32

* 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

Answer 33

- 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

Answer 34

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.

Answer 35

- 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

Answer 36

- Moderate exercise = positive effect (live longer) - Sexual activity = positive effect (live longer) - Overcrowding = negative effect (live shorter)

Answer 37

* Cortical (compact) bone * Trabecular (spongy, cancellous) bone These two types of bone give bone its combination of strength and light weight properties

Answer 38

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

Answer 39

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

Answer 40

• 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

Answer 41

• 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

Answer 42

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.

Answer 43

- 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.

Answer 44

Factors favouring resorption - Unloading (bed rest, zero-gravity, etc) – anything removing mechanical loading Factors favouring formation - Load-bearing exercise

Answer 45

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

Answer 46

* 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

Answer 47

* Increases Ca absorption from gut * Promotes differentiation of osteoclast and osteoblast lineages * Inhibits PTH release * Inhibits 1-alpha hydroxylase

Answer 48

* 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.

Answer 49

* 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

Answer 50

* 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

Answer 51

``` 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

Answer 52

* Hypogonadism – notably any cause of oestrogen deficiency, particularly in post menopausal women * Excess glucocorticoids - endogenous or exogenous * Hyperparathyroidism * Hyperthyroidism

Answer 53

DEXA scan to measure BMD

Answer 54

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:

Answer 55

* 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

Answer 56

- 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

Answer 57

* 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

Answer 58

- the media approach… (failure to understand concept of relative risk) - overall risk when benefits versus risk factors have been taken into account