In a new study , researchers have identified the reason why cells become defective when they grow too large and why protein creation fails when cells grow larger than their original healthy size, as is typically seen in aged and senescent cells.
They demonstrate that in enlarged yeast and human cells, RNA and protein biosynthesis does not scale in proportion to the additional cell size, which then leads to a dilution of the cytoplasm. This phenomenon is also present in senescent cells, which display similar traits to those of large cells.
The research team concludes that the maintenance of a cell type-specific DNA-to-cytoplasm ratio is essential for the majority of cellular functions, and when cellular growth changes this ratio, it encourages cells to become senescent.
In multicellular organisms, cell size ranges over several orders of magnitude. This is most extreme in gametes and polyploid cells but is also seen in diploid somatic cells and unicellular organisms. While cell size varies greatly between cell types, size is narrowly constrained for a given cell type and growth condition, suggesting that a specific size is important for cell function. Indeed, changes in cell size are often observed in pathological conditions such as cancer, with tumor cells frequently being smaller and heterogeneous in size (Ginzberg et al., 2015, Lloyd, 2013). Cellular senescence in human cell lines and budding yeast cells is also associated with a dramatic alteration in size. Senescing cells becoming exceedingly large (Hayflick and Moorhead, 1961, Mortimer and Johnston, 1959).
Cell size control has been studied extensively in a number of different model organisms. In budding yeast, cells pass from G1 into S phase, a cell-cycle transition also known as START, at a well-defined cell size that depends on genotype and growth conditions (Turner et al., 2012). Cell growth and division are, however, only loosely entrained. When cell-cycle progression is blocked either by chemical or genetic perturbations cells continue to increase in size (Demidenko and Blagosklonny, 2008, Johnston et al., 1977). During prolonged physiological cell-cycle arrest mechanisms appear to be in place that ensure that they do not grow too large. In budding yeast, for example, mating requires that cells arrest in G1. Cell growth is significantly attenuated during this prolonged arrest by actin polarization-dependent downregulation of the TOR pathway (Goranov et al., 2013). This observation suggests that preventing excessive cell growth is important. Why cell size may need to be tightly regulated is not known.
Several considerations argue that altering cell size is likely to have a significant impact on cell physiology. Changes in cell size affect intracellular distances, surface to volume ratio and DNA:cytoplasm ratio. It appears that cells adapt to changes in cell size, at least to a certain extent. During the early embryonic divisions in C. elegans, as cell size decreases rapidly, spindle size shrinks accordingly (Hara and Kimura, 2009). Other cellular structures such as mitotic chromosomes, the nucleus and mitochondria have also been observed to scale with size in various organisms (Levy and Heald, 2012, Neurohr et al., 2011). Similarly, gene expression scales with cell size in human cell lines as well as in yeast (Marguerat et al., 2012, Padovan-Merhar et al., 2015, Zhurinsky et al., 2010).
However, not all cellular pathways can adapt to changes in cell size. For example, signaling through the spindle assembly checkpoint, a surveillance mechanism that ensures that cells enter anaphase only after all chromosomes have attached to the mitotic spindle, is less efficient in large cells in C. elegans embryos (Galli and Morgan, 2016). In human cell lines, maximal mitochondrial activity is only achieved at an optimal cell size (Miettinen and Björklund, 2016). Finally, large cell size has been shown to impair cell proliferation in budding yeast and human cell lines (Demidenko and Blagosklonny, 2008, Goranov et al., 2013).
Here we identify the molecular basis of the defects observed in cells that have grown too big. We show that in large yeast and human cells, RNA and protein biosynthesis does not scale in accordance with cell volume, effectively leading to dilution of the cytoplasm. This lack of scaling is due to DNA becoming rate-limiting. We further show that senescent cells, which are large, exhibit many of the phenotypes of large cells. We conclude that maintenance of a cell type-specific DNA:cytoplasm ratio is essential for many, perhaps all, cellular processes and that growth beyond this cell type-specific ratio contributes to senescence.
This may also tie in with the enlargement of specific cellular components, such as the nucleolus. The nucleolus is a distinct structure within the nucleus of the cell and is composed of filamentous and granular material. This is the where the ribosomes, the tiny cellular machines that build proteins, are created. A significant part of the nucleolus is taken up by the ribosomal DNA (rDNA), which encodes the RNA in ribosomes.
The nucleoli of old, senescent, and progeric cells also tend to be larger; smaller, more compact, nucleoli are a possible indicator of longevity and the basis of the ribosomal clock [2-4]. Larger cell components, such as enlarged nucleoli, may be contributing to the larger overall sizes of senescent cells.
Finally, enlarged cells may be a useful indicator of senescence or pre-senescence, as it would suggest the disrupted DNA-to-cytoplasm ratio that is typical of aging. If an accurate way of measuring varied cell sizes in tissues could be found, it may also prove to be a useful aging biomarker.
 Neurohr, G. E., Terry, R. L., Lengefeld, J., Bonney, M., Brittingham, G. P., Moretto, F., … & Harper, J. W. (2019). Excessive Cell Growth Causes Cytoplasm Dilution And Contributes to Senescence. Cell.
 Tiku, V., Jain, C., Raz, Y., Nakamura, S., Heestand, B., Liu, W., … & Partridge, L. (2017). Small nucleoli are a cellular hallmark of longevity. Nature Communications, 8, 16083.
 Buchwalter, A., & Hetzer, M. W. (2017). Nucleolar expansion and elevated protein translation in premature aging. Nature Communications, 8(1), 328.
 Ribosomal DNA harbors an evolutionarily conserved clock of biological aging,” Meng Wang, Bernardo Lemos, Genome Research, online February 14, 2019, DOI: 10.1101/gr.241745.118