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bio 310 > lecture 4 rodent models > Flashcards

lecture 4 rodent models Flashcards

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Biology 101 flashcards
1
Q

projected growth in population by age group

A

85+ will be the largest group looking at the increase over 1980-
2050

85+ demographic is the fastest growing segment in the western world

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2
Q

child mortality

A

from 1900-1925 there was a rise in life expectancy at birth in industrialized countries
-this rise was attributable to reductions in child mortality

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3
Q

oldest adults

A

future gains will depend on beating the biggest age-related killers

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4
Q

immune system changes with normal aging?

A

increased natural killer cell activity, increased susceptibility to infection

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5
Q

Cardiovascular system changes with normal aging?

A

increase in size and wt of heart, increased collagen in blood vessels–> strokes, altered homeostasis of blood pressure

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6
Q

Respiratory system changes with normal aging?

A

decreased vital activity

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7
Q

Musculoskeletal system changes with normal aging?

A

reduction in muscle mass and muscle strength, loss of bone matrix

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8
Q

gastrointestinal changes with normal aging?

A

decreased blood flow to the gut and liver, altered absorption from the GI tract

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9
Q

Integument changes with normal aging?

A

graying of hair, wrinkling of skin, decrease in melanin

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10
Q

special senses changes with normal aging?

A

reduced peripheral vision, thickening of the optic lens, reduced acuity of taste, smell, and touch

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11
Q

age-related changes in the endocrine system

A

during aging
menopause: E2 goes down

andropause: Testosterone decreases

adrenopause: DHEA goes down

somatopause: GH/IGF-I goes down

has huge involvement

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12
Q

age-related changes in the central nervous system

A
  1. gross brain atrophy
  2. ventricular enlargement
  3. selective, regional neuronal loss
  4. selective deterioration of axons and dendrites
  5. appearance of senile plaques and neurofibrillary tangles
  6. selective regional decrease in neurotransmitters/modulators
  7. regional decline in cerebral blood flow
  8. regional decline in cerebral metabolic rate
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13
Q

using humans as subjects is not common because of what 4 things?

A
  1. ethical issues
  2. the long natural lifespan
  3. environmental /social influence
  4. lack of appropriate controls
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14
Q

using non-human primates is also not feasible due to what reasons?

A
  1. ethical issues
  2. long natural lifespan
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15
Q

lower organisms such as budding yeast or worms and flys have been used extensively because?

A
  1. they have short life cycles
  2. accommodating genetics
  3. inexpensive and easy to be manipulated in a normal laboratory setup

** however lower organisms are far from human and do not represent a good model of human physiology

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16
Q

why rodents are a good animal model

A
  1. relatively shorter lifespan
  2. closer to humans on the evolutionary scale
  3. quite similar in physiology, cellular function, and anatomy to humans
  4. housing, diets, health, and genetic background can be manipulated easily

**24 months to a mouse is equivalent to 70 years in a human

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17
Q

important factors for rodent models of aging

A

age: Young animals should be fully mature and not sexually mature. aged animals should be around the age where 50% of the population die

genetic background: inbred strains provide genetic uniformity, facilitate interpretation of results and allow us to use small sample size, but are subject to strain-specific pathologies, and the results may not hold for other strains

-hybrid strains are more robust than inbred strains and have lower levels of strain-specific pathologies (especially f1 hybrids)
-outbred rodents have extreme variability so they require a large sample size and are not the most suitable for studying genetic origins of normal changes

choice of strains: strain-specific characteristics relevant to the study have to be considered

environmental influences: husbandry and environmental conditions can influence health and behavior –> affect experimental outcomes

genomic manipulations: many manipulations can be done on rodents to provide info about the genetic basis of normal aging and age-related diseases

resources: strain-specific characteristics relevant to the study must be considered –> can use the rat and mouse online databases to choose

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18
Q

genetic models include

A

spontaneous and induced mutations, transgenic, knockout and knock-in

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19
Q

What is the most widely accepted marker of aging?

A

lifespan i.e. maximum lifespan

other biomarkers could be products of oxidative stress, protein glycation, inflammation, and hormones must be used simultaneously

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20
Q

what are some new generations of biomarkers of aging?

A
  1. DNA methylation level which can predict the chronological age
  2. microbiomic clock capable of predicting age based on microbiotic profile
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21
Q

interventions/pharmacological treatments

A

important for 2 reasons:
1. delay aging and gain insight into the factors regulating the aging rate

  1. to serve as a step in developing drugs that can slow aging
22
Q

Caloric restriction

A

restricting food intake without malnutrition has been shown to increase lifespan in different rat and mouse models and in other species

-delays onset and or slows the progression of most age-associated diseases like neoplastic, degenerative, and immune disorders

-studies have shown that this shortens lifespan in some strains, while increasing it in other strains –> suggests it depends on the strain

-can increase average and maximum

23
Q

Methionine restriction

A

can extend lifespan in several strains of rodents, it slows age-related T-cell subsets, cataracts, insulin, and IGF-1

-The mediterranean diet is a good example of a diet with low methionine

-it is said that vegetal based diets could increase life expectancy by up to 10 years compared to typical western diets

24
Q

Pharmacological/biological compounds

A

Resveratrol is a molecule produced by plants in response to stress has been shown to extend lifespan in lower organisms such as yeast, flies, and worms, and fish but NOT mice

-resveratrol is in red wine, is an antioxidant

-inhibition of rapamycin signaling pathway by rapamycin can delay aging and extend lifespan in mice

25
Q

Snell dwarf mutant mice

A

-have naturally occurring spontaneous mutations affecting the somatotropic axis

-Snell dwarf mouse has a recessive mutation in the pit-1 (pituitary-specific transcriptional factor-1) gene

-these dwarf mice have phenotypes with lower levels of pituitary hormones ( GH. PRL, TSH and circulating IGF-I levels

-these mutants mice life 26-28% longer than wild-type control mice

26
Q

what are the shortcomings of rodent models?

A

-there are important age-related differences between rodents and human that highlights the shortcomings of rodent as a model for human aging studies

-mice in contrast to humans have long long telomeres and high telomerase activity in many organs

-Vitamin C can influence certain aging processes and is known to be synthesized in mice but not in humans

-aging mice do NOT demonstrate all the typical age-related diseases seen in humans (e.g. Alzheimer’s disease and cardiovascular disease)

27
Q

which animal is more appropriate as a model for aging studies, a rat or mouse?

A

rats are appropriate models because they are closer to humans

-> unlike transgenic mice, there have been hurdles to develop transgenic rats

  • some interventions that are successful in mice are NOT successful in rats e.g. metformin treatment is good in mic, but not in F344 rats
28
Q

why are naked mole rats interesting to study?

A

because after 24 years they exhibit signs of aging consistent with humans such as retinal degeneration and osteoarthritis

also ** mating nmr’s live longer, and NMR’s colonize in groups (complex systems)

29
Q

what are the underlying causes of longevity in naked mole rats?

A

-enhanced antioxidant defense and resistance to experimental tumorigenesis

-lower levels of insulin and IGF-1

-higher levels of basal autophagy and production of fewer aberrant proteins

-active proteasome system leading to enhanced protein stability under stressful conditions

-mitochondrial genes are not altered with age

-telomerase reverse transcriptase showed stable expression regardless of age

30
Q

longevity assurance genes
- Werner syndrome

A

human inheritable disease termed segmental progeroid syndrome - displays few but not all signs of aging, this is caused by a gene mutation

Werner syndrome: similar to normal aging is caused by a defect in WS gene, it encodes a DNA helicase (RecQ) that regulates genome stability

-mutation of this gene leads to impaired DNA replication, DNA repair, and in resolving DNA secondary structures

autosomal recessive, defect is double-strand break repair

31
Q

other human segmental progeroid syndromes

A

Hutchinson-Gilford: inheritance is De novo, genes affected are LMNA and the defect is nuclear stability and transcription.

cockayne: autosomal recessive, different genes like CSA, ERCC6, etc. The defect is in transcription-coupled excision repair

Ataxia telangiectasia: autosomal recessive, affects ATM gene and the defect is in response to dna damage

down: de novo, genes affected are DCR and the defect is in antioxidant defense

32
Q

genetic modulation slide in notes: short-lived mice

A

Ku80 knockout: decrease in lifespan, increase in genomic instability. increase in cancer, early kyphosis, skin atrophy, decrease in resistance to genotoxins

klotho knockout: mutation; transgene insertion, decreased lifespan, increase in genomic instability. early kyphosis, skin atrophy, osteoporosis, reactive immune response

LMNA knockout: decrease in lifespan, increase in genomic instability, early kyphosis, skin atrophy

Brca1, Trp53+/-: mutation: subtle, heterozygous. decrease in lifespan and increase in genomic instability. early atrophy, decreased cell lifespan, resistance to genotoxin

kyphosis: spinal disorder, excessive curving of the spine results in abnormal rounding of the back. hunchback

33
Q

genetic modulation long-lived mice strain: klotho transgenic

A

The gene involved is klotho, genetic mutation: gene targeting. inhibition of insulin and IF-1 signals reduced fecundity and suppression of aging.

-lifespan extension 20% males, 19% females

34
Q

long lived mice strain: p66she-/- knockout

A

gene: p66she (66kD) isoform of the protooncogene She)

mutation: gene targeting

lifespan extension: 30% both sexes

comments: resistance to oxidative stress

35
Q

long lived mice strain: PAPPA -/-

A

gene: PAPPA (pregnancy-associated plasma protein A)

mutations: gene targeting

lifespan: 33% for male and 41% for female

comments: dwarfism, reduced local availability of IGF-1, resistance to thymic atrophy

36
Q

insulin signalling pathway

FIRKO

A

gene: Ir (insulin receptor)

mutation: fat-specific insulin receptor knockout

lifespan extension: 18% for both sexes

comments: reduced fat mass, protected against age-related obesity

37
Q

Insulin signaling pathway

irs-1-/- knockout

A

gene: irs-1 (insulin receptor substrate-1)

mutation: gene targeting

lifespan extension: same in males, 32% in females

comments: insulin resistance and growth retardation

38
Q

antioxidant enzymes

MCAT transgenic

A

gene: human catalase overexpression

mutation: mitochondrial targeting of catalase overexpression

lifespan extension: 17% for both sexes

comments: attenuates cardiac aging and oxidative damage, delayed cataract development

39
Q

antioxidant enzymes

strain: metallothionein transgenic

A

gene: human metallothionein-IIa

mutation: cardiac-specific overexpression

lifespan extension: 14% in males, ND in females

comments: age-induced cardiac contractile defects were attenuated

40
Q

first genetic modulation slide of long-lived mice is not in this deck, study from the notes*** too much writing

A
41
Q

which factor is the most important in selecting a model for a study?

A

genetic background

42
Q

random animals facts said

A

rats and mice live approx 2-3 years

primates –> are the most evolutionarily similar to humans

budding yeast are very easy to make manipulations to

43
Q

what is the best way to measure aging?

A

average or maximum lifespan

44
Q

igf growth hormone goes _____ with age?

A

down, and plays a critical role in longevity

45
Q

where do the longest living humans live?

A

in Japan
-> Lifestyle is completely different there
-> genes, environment, diet and social activity

46
Q

autophagy

A
  • eliminate long-lived proteins

-this process lessens as we age so things begin to accumulate

47
Q

diseases that mice do not show naturally?

A

atherosclerosis does not happen in mice, naturally don’t show Alzheimer’s or Parkinson’s, Huntington’s or ALS

48
Q

mouse strains engaging in violence

A
  • some strains engage in violence and aggression

e.g. BALB, C3 strains

-if you remove the dominant male another one will just take its place. There is no way to remove this aggressive territorial behavior

49
Q

environmental enrichment for mice

A

-toys, exercise wheel

-positive impact on brain aging and plasticity

50
Q

E2

A

has been seen to increase lifespan

51
Q

what is the inevitable consequence for multicellular organisms?

A

age-related decline, death

52
Q

in the 1890’s in Europe the ave. lifespan was?

A

approx. 50 years old

in 1993 up to 75 years old

bio 310 (8 decks)

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