Phylogeny of age-related fitness decline function Libertini G. (M.D., Independent Researcher)

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-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]. Fig. 5 – Analogous functions of apoptosis, replicative senescence and cell senescence in species separated by about 600 millions of years of distinct evolution. 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