Transcript Diapositiva 1 - r

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-telomerase 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 25±35 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 cells”[16]. 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].
Phenomenon
Apoptosis
Cell senescence
Description
Ordinate process of self-destruction with modalities
allowing the use of cell components by other cells
In relation to the number of replications, progressive
impairment of cell functions determined by the
repression of subtelomeric DNA
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
Function in yeast
(and other monocellular eukaryotes)
Function in multicellular eukaryotes
Eliminates damaged cells (Note 2)
Activated when nutrients are scarce, mating is
Essential for morphogenesis (Note 2)
not successful and in old individuals (Note 1)
Essential to determine cell turnover whoseprogressive
impairment contribute to age-related fitness decline (Note 1)
Contribute to slacken cell turnover determining age-related
fitness decline (defined senile state in its more advanced
Cause a quicker generation turnover (Note 1)
expressions) and, therefore, a quicker generation turnover of
multicellular individuals (Note 1)
Replicative
In relation to the number of replications, progressive
senescence
increase of the probability to lose duplication capacity
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
REFERENCES: [1] Finch CE (1990) Longevity, Senescence, and the Genome, Univ. Chicago Press; [2] Ricklefs RE (1998) Am. Nat. 152,24-44; [3] Libertini G (2008) TheScientificWorldJOURNAL 8,182-93; [4] Id.
(1983) Ragionamenti evoluzionistici, SEN; [5] Id. (1988) J. Theor. Biol. 132,145-62; [6] Id. (2006) TheScientificWorldJOURNAL 6,1086-108; [7] Fossel MB (2004) Cells, Aging and Human Disease, Oxford Univ. Press;
[8] Klapper W, Heidorn H et al. (1998) FEBS Letters 434,409-12; [9] Klapper W, Kühne K et al. (1998) FEBS Letters 439,143-6; [10] Jazwinski SM (1993) Genetica 91,35-51; [11] Fabrizio P & Longo VD (2007)
Methods Mol. Biol. 371,89-95; [12] Laun P. et al. (2007) Nucleic Acids Res. 35,7514-26; [13] Longo VD et al. (2005) Nat. Rev. Genet. 6,866-72; [14] Büttner S et al. (2006) J. Cell Biol. 175,521–5; [15] Kerr JFR et al.
(1972) Br. J. Cancer 26,239-57; [16] Herker E et al. (2004) J. Cell Biol. 164,501-7; [17] Skulachev VP (2002) FEBS Lett. 528,23-6; [18] Skulachev VP (2003) Aging and the programmed death phenomena. In: Topics in
Current Genetics, Vol. 3, Nyström T & Osiewacz HD (eds) Model Systems in Aging, Springer-Verlag; [19] Skulachev VP & Longo VD (2005) Ann. N. Y. Acad. Sci. 1057,145-64; [20] Mitteldorf J (2006) Rejuvenation
Res. 9,346-50.