Diapositiva 1

1
Arguments against age-related telomere-telomerase
limitations on cell turnover as a general
defence against cancer Libertini G. (M.D.,
Independent Researcher)
Telomere-telomerase system, which is genetically
determined and regulated, causes cell senescence
and limits cell replication capacity 1 and
these phenomena are a plausible general mechanism
of senescence 1,2. Non-adaptive aging theories
do not predict the existence of mechanisms
genetically determined and regulated that cause
age-related mortality increment, i.e. fitness
decline. Mechanisms of this type could be
compatible with non-adaptive aging theories only
if an adaptive function is a plausible and
exhaustive evolutionary justification for their
actions. On the contrary, adaptive aging theories
predict and require the existence of mechanisms
genetically determined and regulated causing
age-related mortality increment. Therefore, in
absence of an alternative explanation, the
existence of telomere-telomerase system with its
effects on cell turnover is a strong argument
against non-adaptive aging hypotheses and in
support of adaptive aging hypotheses
3.   Non-adaptive hypotheses try to explain
replicative senescence and cell senescence as a
general defence against malignant neoplasia
4,5, that is a terrible evolutionary trade-off
between ageing and defence against cancer
6. There are strong arguments against this
interpretation   1) It does not justify the
existence of animals that show in the wild no
observable increase in age-specific mortality
rate or decrease in reproduction rate after
sexual maturity and no observable age-related
decline in physiological capacity or disease
resistance 7, alias animals with negligible
senescence" 8 (Fig. 1-2), and the great
differences of duplication limits and of cell
overall functionality decay from species to
species, unless the risk of malignant tumors is
postulated as varying from species to species in
direct correlation with the limits imposed to
cell duplication capacities and to cell overall
functionality by the genetic modulation of
telomere-telomerase system. But, old lobsters and
rainbow trouts, animals with negligible
senescence, have, in the wild, the same levels of
telomerase activity as young individuals 9,10
and increasing problems of carcinogenesis at
older ages are not plausible for them because, as
their definition states, their mortality rates do
not increase with age 3. For these animals,
telomerase action involves no evident oncogenic
risk and, therefore, telomerase hypothesized
oncogenic effect could be explained and
documented in its possible existence only for
other animals. 2) Shortened telomeres increase
vulnerability to cancer because of dysfunctional
telomere-induced instability 11,12 (Fig. 3)
Fig. 3 - A) Healthy liver B) Hepatic cirrhosis
C) Hepatocellular carcinoma. After various years
of chronic cell damage (caused by alcoholism,
hepatitis B and C virus, etc.), which causes a
quickened hepatocyte turnover, liver stem cells
exhaust their duplication capacity. Their
shortened telomeres determine dysfunctional
telomere-induced instability and, so,
hepatocellular carcinoma.
Fig. 2 Rougheye rockfish (Sebastes aleutianus)
are probably among the longest-lived marine
fishes on Earth, living as old as 205 years. For
Yelloweye rockfish (Sebastes ruberrimus, living
as old as 118 years), commercially caught off
Sitka, Alaska, "16 of the fish going to people's
dinner tables were 50 years of age or older, with
several over 100 years old!" (from the site
http//www.agelessanimals.org)
Fig. 1 January 2009 A giant lobster named
George, estimated to be 140 years old, escaped a
dinner-table fate and was released into the
Atlantic Ocean after a New York seafood
restaurant granted him his freedom
(http//www.cnn.com/2009/US/01/10/maine.lobster.li
berated/).
3) The decline of duplication capacities and of
overall cell functionality weakens immune system
efficiency 1, which has, for a long time, been
known to be inversely related to cancer incidence
13   4) The role of the telomere in
chromosomal stability (Blagosklonny, 2001
Campisi et al., 2001 Hackett et al., 2001)
argues that telomerase protects against
carcinogenesis (Chang et al., 2001 Gisselsson et
al., 2001), especially early in carcinogenesis
when genetic stability is critical (Elmore and
Holt, 2000 Kim and Hruszkewycz, 2001 Rudolph et
al., 2001), as well as protecting against
aneuploidy and secondary speciation (Pathak et
al., 2002). The role of telomerase depends on the
stage of malignancy as well as cofactors (Oshmura
et al., 2000) expression is late and permissive,
not causal (Seger et al., 2002). 1   5) In
yeast, an eukaryotic species, replicative
senescence and cell senescence, although not
caused by telomere shortening but by another
unknown mechanism related to the number of
duplications (likely, the accumulation of
extrachromosomal ribosomal DNA circles - ERCs -,
which block subtelomeric DNA) 14, is a well
documented phenomenon 15-17, and, being yeast
unicellular, cannot be a consequence of an
impossible cancer risk. (Moreover, these
phenomena and others strictly associated 18,19
observed in yeast have been interpreted as
adaptive 20-25 and are consistent with the
explanation that they determine a greater
evolution rate and are favoured in conditions of
K-selection 2,26.) 6) Dyskeratosis congenita
(DC), an inherited human disease 27, is
characterized by an altered telomerase 28.
Problems tend to occur in tissues in which cells
multiply rapidly skin, nails, hair, gut and
bone marrow with death usually occurring as a
result of bone-marrow failure. 29. DC patients
present defects in these tissues 29 and also
suffer from a higher rate of cancer that can
likewise be explained by the lack of telomerase,
which results in unstable chromosomes
30,31. But 7) In rodents, telomerase activity
is not related to maximum lifespan while is
inversely related to body mass 32. This has
been interpreted as a fact in support of the
defensive role against cancer risk of
telomere-telomerase system, as a greater body
mass presumably increases cancer risk 32. In
short, with the important exception of point (7),
which stimulates further data and discussions,
there are not specific arguments and experimental
tests in support of the hypothesis that
telomere-telomerase age-related limiting actions
on cell turnover is a general defence against
cancer. Therefore, telomere-telomerase
age-related limits on cell turnover are hardly
justifiable as a defence against cancer risk and,
lacking other plausible explanations, only the
adaptive hypotheses of age-related fitness
decline appear a rational cause for their
existence.
Telomere-telomerase age-related limits on cell
turnover require an evolutionary
justification. For adaptive aging theory, these
limitations are essential life span limiting
mechanisms. For non-adaptive aging theory, they
are a general defence against cancer but the
strong arguments against this interpretation
should be falsified
REFERENCES 1 Fossel MB (2004) Cells, Aging and
Human Disease. Oxford Univ. Press, NewYork 2
Libertini G (2006) TheScientificWorldJournal, 6,
1086-1108 DOI 10.1100/tsw.2006.209 3 Libertini
G (2008) TheScientificWorldJournal 8, 182-93 DOI
10.1100/tsw.2008.36 4 Campisi J (1997) Eur.
J. Cancer 33, 703-9 5 Wright WE Shay JW
(2005) J. Am. Geriatr. Soc. 53, S292-4 6
Campisi J (2000) In Vivo 14, 183-8 7 Finch
CE Austad SN (2001) Exp. Gerontol. 36, 593-7
8 Finch, C.E. (1990) Longevity, Senescence, and
the Genome. Univ. of Chicago Press, Chicago 9
Klapper W, Heidorn K et al. (1998) FEBS Letters
434, 409-12 10 Klapper W, Kühne K et al.
(1998) FEBS Letters 439, 143-6 11 DePinho RA
(2000) Nature 408, 248-54 12 Artandi SE
(2002) Trends Mol. Med. 8, 44-7 13 Rosen P
(1985) Med. Hypotheses 18, 157-61 14 Lesur I
Campbell JL (2004) MBC Online 15, 1297-312
15 Jazwinski SM (1993) Genetica 91, 35-51
16 Laun P et al. (2007) Nucleic Acids Res. 35,
7514-26 17 Fabrizio P Longo VD (2007)
Methods Mol. Biol. 371, 89-95 18 Laun P et
al. (2001) Mol. Microbiol. 39, 1166-73 19
Kaeberlein M et al. (2007) PLoS Genet. 3(5) e84
20 Longo VD et al. (2005) Nat. Rev. Genet. 6,
866-72 21 Mitteldorf J (2006) Rejuvenation
Res. 9, 346-50 22 Skulachev VP (2002) FEBS
Lett. 528, 23-6 23 Skulachev VP (2003) Aging
and the programmed death phenomena. In Topics in
Current Genetics, Vol. 3, Model Systems in Aging.
Springer-Verlag, Berlin Heidelberg 24 Herker
E et al. (2004) J. Cell Biol., 164, 501-7 25
Skulachev VP Longo VD (2005) Ann. N. Y. Acad.
Sci. 1057, 145-64 26 Libertini G (1988) J.
Theor. Biol. 132, 145-62 27 Dokal I (2000)
Br. J. Haematol. 110, 768-79 28 Mitchell JR et
al. (1999) Nature 402, 551-5 29 Marciniak R
Guarente L (2001) Nature 413, 370-2 30 de
Lange T Jacks T (1999) Cell 98, 273-5 31
Artandi SE et al. (2000) Nature 406, 641-5 32
Gorbunova V et al. (2008) Age 30, 111-9.