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LETTER TO THE EDITOR Hypertrophy, replicative ageing and the ageing process YEAST RESEARCH DOI: 10.1111/j.1567-1364.2012.00843.x Final version published online 14 September 2012. Two Letters to the Editor (Ganley et al., 2012; Kaeberlein, 2012) have been published as a reaction to our commentary entitled ‘Hypertrophy hypothesis as an alternative explanation of the phenomenon of replicative ageing of yeast’ (Bilinski et al., 2012). Our response to those letters, because of its limited length will concentrate only on the most important issues raised. The main experimental argument against the hypertrophy hypothesis was that ‘yeast mothers stop replicating with a range of sizes: enlarged, but not uniformly so’. This statement confirms that hypertrophy (enlargement) is observed also in other strains. Uniformity is rather rare in biology. The heterogeneity of the volume at which replication stops is a simple consequence of the molecular noise, important especially at the level of regulatory molecules whose copy number in a cell is very low (Di Talia et al., 2007; Frigola et al., 2012). The critical events in cell division are regulated by such molecules. The main point of controversy is not hypertrophy itself, but its origin. In one of the replies, it was stated ‘there is an implicit (and as yet untested) assumption: hypertrophy results from increasing cell cycle arrest’ (Ganley et al., 2012). However, even if cells are not arrested, they also stop reproduction after attaining the same maximal volume, like those arrested. Unfortunately, these authors did not explain why they consider increasing cell cycle arrest as an element of the ageing process. In the other reply, we find ‘one obvious hypothesis is that one or more of these senescence factors cause hypertrophy (Kaeberlein, 2012), but no mechanism leading to hypertrophy was suggested’. However, we have postulated that the existence of reproduction limit in the budding yeast cells is a consequence of hypertrophy. The reason for hypertrophy is obvious and results from the choice of budding as a mechanism of reproduction. Our reasoning is as follows: Budding yeast cells increase their size during each cell cycle (Mortimer & Johnston, 1959; Zadrag et al., 2005; Zadrag-Tecza et al., 2009). The G1 phase, during which the growth of the mother cell mainly takes place (Hartwell & Unger, 1977), cannot be omitted because of its multiple regulatory roles. Equally important is that there is no reduction in cell volume during reproduction by budding. In contrast, cells which reproduce by binary fission reduce their volume during each cell division. FEMS Yeast Res 12 (2012) 739–740 Therefore, hypertrophy is a direct and unavoidable consequence of budding and as such, is a primary phenomenon, not secondary to ageing. Thus, in our opinion, there is no need for search of the molecular mechanisms of hypertrophy, while it is necessary to elucidate molecular mechanisms by which hypertrophy arrests cell cycle. It was argued (Kaeberlein, 2012) that ‘if cell size is sole limiting factor for yeast replicative life span (RLS), then the mutations that increase RLS should always be accompanied by either a reduced mother cell size or altered kinetics of enlargement during replicative ageing’. Our hypothesis assumes that RLS depends on three, instead of two independent factors mentioned: threshold size to enter the S phase (which is most probably independent of the initial mother cell size), maximal size and the rate of volume increase per generation. RLS; therefore, is a resultant of three factors, each of which can be changed by mutations. Hypertrophy hypothesis explains differences in reproductive capacity of all tested strains, irrespective of their origin and character. For example, cells of the mutant rad 52 stop reproducing after much smaller number of buddings than cells of the parent strain (Kaeberlein, 2012), but both strains stop reproduction after attaining the same maximal volume (R. Zadrag-Tecza, A. Skoneczna, M. Skoneczny, in preparation). The ad hoc hypothesis on two independent mechanisms ‘of ageing for short-lived and wild-type individuals’ (Delaney et al., 2011; Kaeberlein, 2012) is thus fully redundant. It was stated that our model is purely correlative. In no case, the content of the presumable senescence factor was measured in cells that have already stopped reproduction. In contrast, we are recording changes in volume during each cell’s entire life, and measure it in arrested cells, to establish their final volume. The next argument against our hypothesis is that our ‘model lacks mechanistic insight into the molecular processes that cause replicative ageing’ (Kaeberlein, 2012), or ‘it is not biochemically tractable’ (Ganley et al., 2012). We have already mentioned that the mechanism by which hypertrophy influences reproductive capacity of cells is so far unknown. Its nature could be either physical or molecular. Our articles (Bilinski & Bartosz, 2006; Zadragª 2012 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved 740 Tecza et al., 2009) inspired another group to postulate that ageing is a consequence of ‘increased intracellular water volume and density’ (Bonatto et al., 2011). It suggests new biophysical mechanism of the phenomenon. We believe, however, that up to 10-fold increase of the cellular volume raises demand for cell maintenance processes, including protein turnover. In our opinion, it is possible that hypertrophy lowers the effective concentration of some crucial regulatory protein molecules, whose number and stability are very low. Simultaneously, their diffusion to and from the nucleus could be less effective in oversized cells. Therefore, we postulate that the limit of reproductive capacity is caused by a deficiency of some factor(s) in hypertrophic cells. Our postulate is thus biochemically tractable. We do not question any accumulation of some metabolic byproducts within the mother cell, but only the effects of this accumulation. Ganley et al. (2012) declare ‘We believe that yeast is a valuable model system for ageing and will continue to contribute to our understanding of ageing generally’. We think that this (as any) belief should be treated with caution, according to the basic principles of the methodology of science. If the ageing of Saccharomyces cerevisiae is because of a private rather than public mechanism of ageing (as we postulate), its studies may broaden our understanding of the biology of ageing but may have limited relevance to ageing of higher eukaryotes. Our hypothesis provides a new explanation why yeast cells have limited reproductive potential. Further studies are indeed necessary to clarify whether this potential is causally connected with the ageing process. Letter to the Editor Bilinski T, Zadrag-Tecza R & Bartosz G (2012) Hypertrophy hypothesis as an alternative explanation of the phenomenon of replicative aging of yeast. FEMS Yeast Res 12: 97–101. Bonatto D, Feltes BC & Poloni JdF (2011) Aging as a consequence of intracellular water volume and density. Med Hypotheses 77: 982–984. Delaney JR, Sutphin GL, Dulken B et al. (2011) Sir2 deletion prevents lifespan extension in 32 long-lived mutants. Aging Cell 10: 1089–1091. Di Talia S, Skotheim JM, Bean JM, Siggia ED & Cross FR (2007) The effects of molecular noise and size control on variability in the budding yeast cell cycle. Nature 448: 947–951. Frigola D, Casanellas L, Sancho JM & Ibanes M (2012) Asymmetric stochastic switching driven by intrinsic molecular noise. PLoS ONE 7(2): e31407. Ganley ARD, Breitenbach M, Kennedy BK & Kobayashi T (2012) Yeast hypertrophy: cause or consequence of aging? Reply to Bilinski et al. FEMS Yeast Res 12: 267–268. Hartwell LH & Unger MW (1977) Unequal division in saccharomyces-cerevisiae and its implications for control of cell-division. J Cell Biol 75: 422–435. Kaeberlein M (2012) Hypertrophy and senescence factors in yeast aging. A reply to Bilinski et al.. FEMS Yeast Res 12: 269–270. Mortimer RK & Johnston JR (1959) Life span of individual yeast cells. Nature 183: 1751–1752. Zadrag R, Bartosz G & Bilinski T (2005) Replicative aging of the yeast does not require DNA replication. Biochem Biophys Res Commun 333: 138–141. Zadrag-Tecza R, Kwolek-Mirek M, Bartosz G & Bilinski T (2009) Cell volume as a factor limiting the replicative lifespan of the yeast Saccharomyces cerevisiae. Biogerontology 10: 481–488. Acknowledgement The experiments, the conclusions of which were presented, were supported by a Grant No. N N303 376436 from the Polish National Science Center. Tomasz Bilinski Department of Biochemistry and Cell Biology University of Rzeszow Rzeszow, Poland E-mail: [email protected] References Bilinski T & Bartosz G (2006) Hypothesis: cell volume limits cell divisions. Acta Biochim Pol 53: 833–835. ª 2012 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved FEMS Yeast Res 12 (2012) 739–740