Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice

2015-01-13

Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice
2011 Harvard Nature Letter

There is also
"Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice Supplementary Information"

effects of telomere treatment: neurogenesis, tissue rejuvenation, reduced apoptosis of testes germ cells and intestinal crypt cells, normal spleen size, normal testes, increased fecundity, reverses hypomyelination, increased brain weight, alleviation of olfactory defects
effects of aging: neural cell senescence, tissue atrophy, splenic atropy, intestinal crypt depletin, hypomyelination, brain size defects, hyposmia (reduced ability in odour identification)

" knock-in allele encoding a
4-hydroxytamoxifen (4-OHT)-inducible telomerase reverse tran-
scriptase-oestrogen receptor (TERT-ER) under transcriptional con-
trol of the endogenous TERT promoter."

4-OHT time-release pellets (2.5 mg; Innovative Research of America) were
inserted subcutaneously to reach steady state blood levels of 1 ng ml
21
4-OHT.

However, to our
knowledge, there are no genetic or pharmacological studies showing
somatic reversal of age-related degenerative phenotypes driven by endo-
genous genotoxic stresses in adult mammals.

At the end of 4 weeks of continuous 4-OHT expo-
sure, documentation of telomerase-mediated telomere restoration and
function in G4
TERT-ER
tissues included increased telomere-FISH signal
in primary splenocytes (Fig. 1b, e, f), decreased p53 activation and
expression of p21
CIP1
in liver (Supplementary Fig. 2d, e), and marked
decrease in 53BP1 foci in splenocytes (Fig. 2b, e) and intestinal crypt
cells (Fig. 2c, f).

Moreover, median survival increased in
G4
TERT-ER
mice treated with a 4-week course of 4-OHT (**P , 0.005,
Supplementary Fig. 2f).

In G4
TERT-ER
mice with advanced degenerative phenotypes, short-term telomerase reactivation restored telomere
reserves, quelled DNA damage signalling, and alleviated cellular check-
point responses in several high-turnover organ systems with significant
functionalimpactincluding increased fecundity.

However, it remains possible that more prolonged telomerase reactiva-
tion schedules or applications in later life may provoke carcinogenesis.

me: It doesn't look like anyone has tried continuous telomerase reactivation in this model for longer than 4 weeks.  They don't know whether it would cause more cancer or not.

They didn't carry out the study long enough to determine how much longer the Tert treated mice lived.
TERT treatment (by administering 4-OHT) was started at about 24 weeks and continued to 28 weeks.

Kaplan-Meier plot and analysis
"C:\ativ6_storage\2014\09-23-2014d1038\Kaplan-Meier Plot Analysis 9-23-14.png" (temp link that will change)

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