Failure of Asymmetric Cell Division Mechanisms May Contribute to Stem Cell Aging

Researchers have recently proposed that at least some stem cell populations make more subtle use of asymmetric division than thought, and that the mechanisms necessary to this process fail with age. Asymmetric cellular division has its origins deep in the evolutionary past, and it is entwined with the origins of aging. It is best cataloged in bacteria, a form of cellular replication in which the lineage maintains itself by segregating more of its waste and damaged components into one of the daughter cells with each division, leaving the other comparatively pristine. In this way bacteria can continually dilute the accumulation of damage that causes dysfunction and maintain a self-replicating lineage indefinitely, using division and one daughter cell as a form of disposal mechanism.

The situation is considerably more complex in multicellular organisms consisting of many specialized cell types with different replacement rates, but still much the same at the root of it all. Tissues lose cells constantly: old cells die and are replaced by new cells created by a population of stem cells dedicated to maintaining that tissue. The stem cells must maintain themselves in good condition, and asymmetric division appears to play a part in this self-renewal. It isn't just a way to ensure that when a stem cell divides the resulting pair consists of one new stem cell and one other type of cell destined to fill out nearby tissue, but it is also waste disposal for stem cells. It has been established that stem cells offload damaged mitochondria into the non-stem daughter cell when they divide, for example. The research linked below is more of the same, but looks at the partitioning of damaged proteins between the two daughter cells:

A barrier against brain stem cell aging

Neural stem cells generate new neurons throughout life in the mammalian brain. However, with advancing age the potential for regeneration in the brain dramatically declines. Researchers have shown that the stem cells of the adult mouse brain asymmetrically segregate aging factors between the mother and the daughter cells. Responsible for this is a diffusion barrier in the endoplasmic reticulum (a channel system within the cell that is for example important for protein synthesis and transport). The barrier prevents retention of damaged proteins in the stem cell daughter cell keeping the stem cells relatively clean. "Neural stem cell divisions appear to be much more asymmetric than we had previously anticipated."

In addition, researchers found that the strength of the barrier weakens with advancing age. This leads to reduced asymmetry of damaged protein segregation with increasing age of the stem cell. This could be one of the mechanisms responsible for the reduced regeneration capacity in the aged brain as stem cells that retain larger amounts of damaged proteins require longer for the next cell division. "This is an exciting new mechanism involved in stem cell division and aging. But as of now we are only just beginning to understand the molecular constituents and the true meaning of the barrier for stem cell division in the brain." One key question to be answered is whether the barrier is established in all somatic stem cells of the body. The answer to this question may open new routes to target age-dependent alterations of stem cell activity in human disease.

A mechanism for the segregation of age in mammalian neural stem cells

Throughout life, neural stem cells (NSCs) generate neurons in the mammalian brain. Using photobleaching experiments, we found that during cell division in vitro and within the developing mouse forebrain, NSCs generate a lateral diffusion barrier in the membrane of the endoplasmic reticulum, thereby promoting asymmetric segregation of cellular components. The diffusion barrier weakens with age and in response to impairment of lamin-associated nuclear envelope constituents. Weakening of the diffusion barrier disrupts asymmetric segregation of damaged proteins, a product of aging. Damaged proteins are asymmetrically inherited by the nonstem daughter cell in embryonic and young adult NSC divisions, whereas in the older adult brain, damaged proteins are more symmetrically distributed between progeny. Thus, these data identify a mechanism of how damage that accumulates with age is asymmetrically distributed during somatic stem cell division.

The endoplasmic reticulum is a complex structure with many roles, and if you look back in the Fight Aging! archives you'll find more information on other lines of research linking it to aging. Why does its behavior change? There is a question. It might be a consequence of fundamental cellular damage that causes aging, or it might be a direct or indirect reaction to that damage. As for so much of aging the lines of cause and consequence are yet to be filled in. The fastest path to drawing those lines is to work on repairing specific forms of damage known to contribute to aging and then see what happens as a result. That is also a path more likely to result in near-future treatments for degenerative aging than the approach of carefully cataloging everything, working backwards from the chaotic end stages of disease.


How do the stem cells determine the damaged mitochondria when they are dividing, yet fail to identify these mitochondria in cases of gene deletions? Or are these two separate types of damage - gene/non damaged surface and damaged surface?

Is there any evidence that mitochondrial gene deletions contribute to stem cell aging?

Posted by: Jim at September 17th, 2015 7:26 PM

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