Arguments against age-related telomere-telomerase limitations

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.liberated/). 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. 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