Cellular Enlargement in Aging, a Poorly Studied Topic

Some cells are small, others large. Cell size is connected to cell function, and different varieties of cell maintain tight control over their various different sizes. Senescent cells are known to become much larger than their origin cell type, and one effort to detect senescent cells in blood samples made use of this feature. Do non-senescent cells lose control of size in old tissues, however? To what degree is this a feature of aging that produces further downstream issues, versus being a consequence of other problematic changes in cell behavior that occur with age? These are not well-studied questions.

A large body of literature highlights two important findings: 1) Different cell types display different average sizes and 2) cells maintain a uniform size by using several regulatory pathways. This raises the question of why cells invest in maintaining their size. Therefore, understanding what happens when cells fail to regulate their size is important. While the first findings around this topic led to controversial conclusions, budding yeast has been a key model organism to provide the first evidence that cellular enlargement could be directly linked to cellular dysfunction during aging. It is known that budding yeast cells enlarge during aging. Preventing this enlargement with drugs preserves their replicative age. Similarly, preventing cellular enlargement in vitro in primary human cells has been shown to maintain their capacity to enter the cell cycle thereby avoiding cellular senescence.

Our recent publication dissected whether the role of cell size on cell function is based on correlation or causation. An intrinsic challenge was to manipulate cell size without targeting other pathways, and to delineate that the observed changes are causal and not correlative. This hurdle was tackled using hematopoietic stem cells (HSCs) in vivo. Six orthogonal approaches were examined under which HSCs became larger. In each of these conditions, HSC function was also compromised. HSC function was determined as their ability to form a blood system after transplantation into recipient mice. While it could be argued that each single manipulation affected HSC function unrelated to cell size, together these experiments suggest that the dysfunction was not driven by an unaccounted variable. Furthermore, alternate causes were excluded by analyzing other parameters of the hematopoietic system: homing, stem cell identity, differentiation potential and cell cycle state. Therefore, the simplest explanation is that enlargement of HSCs reduces their functionality.

Interestingly, numerous other cell types have also been observed to enlarge during aging. This raises the possibility that cellular enlargement contributes to aging in other cell types. Moving forward, the research community will benefit from further experiments providing critical evidence of whether cellular enlargement is cause or consequence of aging in other stem cell types and differentiating cells.

Link: https://doi.org/10.3389/fcell.2022.1036602


The attention to the cell size aspect as in this paper might one day explain e.g. why RDW has the highest weight in Levine's "Phenotypic Age" biological age estimator. The questions Reason rise are nevertheless very much valid.

Posted by: albedo at December 13th, 2022 12:23 PM
Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. 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.