A Study of Cell Size in the Context of Cellular Senescence

Senescent cells are a major problem in our bodies, in that their growing presence over the years is an important cause of degenerative aging. Unfortunately, the research community can't just prevent cells from ever becoming senescent, even were the capacity to do that in hand today, because transient senescence serves many useful, even necessary purposes in our biochemistry. It is only the lingering senescent cells that are the problem. Periodically removing these unwanted, harmful cells is a very viable way forward, however, and a new biotechnology industry is springing up to do just that.

One very interesting point about senescent cells is that they are notably larger than normal cells. One research group has produced a way of counting senescent immune cells from a blood sample based on sorting by size. Another measured the sizes of cells in old hearts, before and after clearing out senescent cells with a senolytic treatment, showing that the senescent cells were larger. I have to think that there is something useful, potentially even important, that can be done with this feature of senescent cells - the clever implementation just hasn't arrived yet.

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. Cellular senescence in human cell lines and budding yeast cells is also associated with a dramatic alteration in size: senescing cells become exceedingly large. Cell size control has been studied extensively in a number of different model organisms, but 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. Other cellular structures such as mitotic chromosomes, the nucleus and mitochondria have also been observed to scale with size in various organisms. Similarly, gene expression scales with cell size in human cell lines as well as in yeast.

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. In human cell lines, maximal mitochondrial activity is only achieved at an optimal cell size. Finally, large cell size has been shown to impair cell proliferation in budding yeast and human cell lines.

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.

Link: https://doi.org/10.1016/j.cell.2019.01.018

Comments

One application that comes to mind is filleting the blood cells based on size.

Another is a these for senecence.

And we can explain the larger size due to less efficient organelles( need more of them) and garbage accumulation within the cell(pure bloat).

It would be interesting to measure how calorie restriction , fasting and mimetics can influence the cell size....

Posted by: Cuberat at February 19th, 2019 8:16 AM

Interestingly the nucleoli of aged cells (and progeric cells) also tend to be larger and small nucleoli are a suggested hallmark of longevity and the basis of the rDNA aging clock. So larger cell components such as enlarged nucleoli may be contributing to the larger overall cell size in senescent cells.

[1] 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.

[2] Buchwalter, A., & Hetzer, M. W. (2017). Nucleolar expansion and elevated protein translation in premature aging. Nature Communications, 8(1), 328.

[3] 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

Posted by: Steve Hill at February 19th, 2019 8:38 AM

Maybe a graphene or some other metamaterial sieve - at least for the blood and maybe other body fluids.

Posted by: Neal Asher at February 20th, 2019 3:49 AM

@cuberat: The regulation of cell size is actually a rather complicated question when you get into it, since there's no obvious way for the cell to "know" how big it is. There's a professor at my institution who works on that question, and their most recent paper suggested copy number of cell cycle regulators is one such sensing mechanism.

Posted by: Dylan Mah at February 20th, 2019 3:29 PM

Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.