Longevity Stress Response and Cancer in Aging Telomerase-Deficient Mice

2015-01-13

paper 
survival curve g1 g2 g3 g4 tert deficient mice
lifespan of g1, g2, g3, and g4 tert deficient mice

Some notes
-some notes from Christian Bar: "this study is looking at the Terc ko not Tert! In theory both deletion -strains should behave more or less the same! Another important thing to consider is the genetic background of the mice. In the paper you send me they are using a mixed genetic background in which even G6 is possible. I dont think that is possible in our pure C57/bl6 background!"
--me: So do you know of a paper (off the top of your head) that compares G1 TERT-/- mice rather than G1 TERC-/- mice?
---answer: Distinct dosage requirements for the maintenance of long and short telomeres in mTert heterozygous mice; also more from Christian: "They also refer to a paper in which they describe the generation of the mouse. U might find more information there…"

1999 Cell paper
Blasco, Greider, DePinho (Dana Farber Cancer Institute) were authors

wow one of the institutions was "Center of Molecular Medicine Samsung Biomedical Research Institute"

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Telomere maintenance is thought to play a role in signaling cellular senescence; however, a link with organismal aging processes has not been established.

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Loss of telomere function did not elicit a full spectrum of classical pathophysiological symptoms of aging

there was a shortened life span. . 
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as well as a reduced capacity to respond to stresses such as wound healing and hematopoietic ablation

there were more spontaneous malignancies

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implying that telomere shortening is not a cause of aging in yeast

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One might antici-pate that high turnover organs such as the skin, lym-phoid, and gastrointestinal tract would be more ad-versely affected due to an accelerated loss of telomere repeats

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Third generation mTR
2 / 2
mice (G3) possess shortened telo-meres early in life but, at this point, appear to be pheno-typically normal in every respect

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The current study focused primarily on the physiological consequences in an aging population of G3 mice and compared these results to first and sixth generation mTR
2 / 2
mice (G1 and G6, respectively) to dissect the contribution of telomere dysfunction to the pathophysio-logical processes and events associated with aging.

hair loss and hair graying occurred earlier
 
 telomere length decreases at a rate of 4-5 kb/generation in mTR null mice
 
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 animals with shorter telomeres are more likely to display a disease phenotype in the skin
 
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 analysis of the cardiovascular system, liver, kidneys, and brain showed no pathological changes typical of aging organisms
 
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 while telomere shortening with age directly affected the skin, mTR-/- mice did not display other phenotypes classically associated with aging
 
 
 Various health parameters that can be measured
 -body weight
 -insulin sensitivity (diabetes)
 -osteoporosis
 -artherosclerosis
 -peripheral RBC and WBC counts
 -Blood chemistry
 -cataracts
 -fecundity
 -hair graying and alopecia
 -wound healing
 -cancer incidence
 -lifespan (50% mortality mark)
 
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 loss of telomere ends correlates with a shortened life span
 
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 It is interesting to note that, despite comparably short telomeres in old G3 and young G6 mice, impaired wound healing is observed only in aged mTR-/0 possessing critically short telomeres and accompanying telomere dysfunction (e.g. chromosomal fusions)
 
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 elay in renewal was observed in old G3 and G6
 
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  Genomic Instability and an Increased
Incidence of Spontaneous Cancer in Aging
mTR
2 / 2
Mice

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There was a 4- to 6-fold increase in the incidence of spontaneous cancers in mTR-/- animals

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At face value, the increased tumor incidence seems to contradict the decrease in tumor formation expected from the loss of cell viability associated with telomere dysfunction.

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