Diapositiva 1

1
Phylogeny of age-related fitness decline
function Libertini G. (M.D., Independent
Researcher)
An age-related fitness decline in the wild is
documented for many species 1,2 (Fig. 1) and
there is empirical evidence for an adaptive
meaning of this phenomenon 3, which in its more
advanced expressions, common in protected
conditions, is usually called ageing. A theory
explains this fitness decline as evolutionarily
advantageous by a mechanism of kin selection
that, in consequence of a quicker generation
turnover, allows a faster spreading of
advantageous mutations. According to this theory,
the advantage exists in conditions of K-selection
(species divided in demes, populated by kin
individuals, and in saturated habitats where only
the death of an individual gives space to a new
individual) 4-6. A plausible mechanism of the
fitness decline is the progressive slowdown of
cell turnover, namely a progressive prevalence of
programmed cell death (by apoptosis or other
means) on cell substitution by duplication of
stem cells. Limits in cell duplication and the
related cell senescence (progressive decline of
cell functions in relation to the number of
previous cell duplications) are determined by
telomere-telomerase system and its
species-specific regulation 6,7 (Fig. 2). In
some species, as Rockfish and lobsters,
telomere-telomerase regulation and mortality rate
result unvaried with the age 8,9. Telomere-telom
erase system and apoptosis are ubiquitarian in
eukaryote species 10-13 (Fig. 3). In yeast,
Saccharomyces cerevisiae, telomere-telomerase
system does not allow further replications after
2535 duplications and the cell dies by apoptosis
10, which is also triggered by a) unsuccessful
mating b) particular stresses, as dwindling
nutrients in older cells c) cell senescence 14
(Fig. 4). Apoptosis in S. cerevisiae, as in all
eukaryote species, is a sophisticated function
that kills the cell in a well defined pattern
15, optimal for an useful phagocytosis of cell
fragments by other cells that are able to
survive longer with substances released by dying
cells16. Apoptotic patterns in S. cerevisiae
have been interpreted as adaptive, because useful
to the survival of the clone, which is likely
composed by kin individuals 13,16-20. Moreover,
ecological life conditions of yeast, being of
K-selection type, suggest that limits in cell
duplications and the related phenomenon of cell
senescence are adaptive and explainable with the
same evolutionary mechanisms proposed for
multicellular species subject to K-selection
4-6. These considerations induce to a
phylogenetic correlation between phenomena
observed in colonies of kin yeast cells and
analogous phenomena in multicellular organisms,
that is the formulation of a phylogenetic
hypothesis of ageing. In particular (Table I
and fig. 5) a) apoptosis in yeast is triggered
by starvation, damaged conditions of the cell,
unsuccessful mating, etc., and in these cases it
is favoured by kin selection because increases
survival probability of kin cells 16. In
multicellular species, considering each
individual as a clone having all cells with the
same genes (coefficient of relationship r equal
to 1) although having differentiated functions,
apoptosis of less fit cells is favoured by
analogous mechanisms of kin selection b) in
multicellular organisms, apoptosis as part of
morphogenetic mechanisms and of lymphocyte
selection is clearly a derived function, being
impossible in monocellular organisms c) in
yeast, replicative senescence and cell
senescence, caused by telomere-telomerase system,
and apoptosis limit longevity that would
maintain ancient genetic variants within the
population and, therefore, favor genetic
conservatism 14, which means, in other words,
that these phenomena are favoured by kin
selection 4-6. In multicellular organisms,
replicative senescence, cell senescence and
apoptosis cause age-related limits in cell
turnover with consequent age-related fitness
decline 6,7 (senile state in its more
advanced expressions 6), and this is favoured
by kin selection in conditions of K-selection
4-6. In shorts, ageing mechanisms in yeast
and multicellular eukaryote species, divided by
about 600 millions of distinct evolution, are
incredibly similar in their basic physiological
components and selective explanations.
Fig. 1 Life table of Panthera leo survivors,
extrinsic mortality (me, mortality caused by
external causes, i.e., predation, accidents,
infections, etc.) and intrinsic mortality (mi,
mortality caused by internal causes, i.e.,
aging). Data are from Ricklefs 2.
Fig. 2 Telomere progressive shortening
increases the probability of replicative
senescence and impairs the expression of many
genes (cell senescence). It is likely the
existence near to the telomere of a tract of DNA
regulating overall cell functionality with
telomere shortening the proteinic hood capping
telomere slides down and alters this regulation
7.
Fig. 3 Scheme of trigger mechanisms for
apoptosis in various eukaryote phyla. Figure
redrawn from 13 and with a correction (in red)
apoptosis is a very ancient mechanism clearly in
correlation with ageing, but in the original
scheme this is doubtful only for humans!
Aging in yeast is considered adaptive while for
multicellular eukaryotes this idea is excluded by
current gerontological paradigm, in clear
contrast with theoretical arguments and empirical
evidence
Fig. 4 Apoptosis, that is a programmed form of
death, is triggered in wild yeast by various
conditions, as a) dwindling nutrients trigger
the altruistic death of older cells, b) when
mating is not successful c) replicative
senescence that is genetically determined by
telomere-telomerase system, for which is
considered adaptive 14. For condition c
apoptosis coupled to chronological and
replicative aging limits longevity that would
maintain ancient genetic variants within the
population and, therefore, favor genetic
conservatism 14. The figure is from 14.
Fig. 5 Analogous functions of apoptosis,
replicative senescence and cell senescence in
species separated by about 600 millions of years
of distinct evolution.
Table I
Phenomenon Description Function in yeast (and other monocellular eukaryotes) Function in multicellular eukaryotes
Apoptosis Ordinate process of self-destruction with modalities allowing the use of cell components by other cells Activated when nutrients are scarce, mating is not successful and in old individuals (Note 1) Eliminates damaged cells (Note 2) Essential for morphogenesis (Note 2) Essential to determine cell turnover whoseprogressive impairment contribute to age-related fitness decline (Note 1)
Cell senescence In relation to the number of replications, progressive impairment of cell functions determined by the repression of subtelomeric DNA Cause a quicker generation turnover (Note 1) Contribute to slacken cell turnover determining age-related fitness decline (defined senile state in its more advanced expressions) and, therefore, a quicker generation turnover of multicellular individuals (Note 1)
Replicative senescence In relation to the number of replications, progressive increase of the probability to lose duplication capacity Cause a quicker generation turnover (Note 1) Contribute to slacken cell turnover determining age-related fitness decline (defined senile state in its more advanced expressions) and, therefore, a quicker generation turnover of multicellular individuals (Note 1)
Note 1 altruistic behaviour(s) favoured by kin selection in conditions of K-selection Note 2 altruistic behaviour considering the multicellular individual as a clone Note 1 altruistic behaviour(s) favoured by kin selection in conditions of K-selection Note 2 altruistic behaviour considering the multicellular individual as a clone Note 1 altruistic behaviour(s) favoured by kin selection in conditions of K-selection Note 2 altruistic behaviour considering the multicellular individual as a clone Note 1 altruistic behaviour(s) favoured by kin selection in conditions of K-selection Note 2 altruistic behaviour considering the multicellular individual as a clone
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