Comparing Senescent Cells and Cells From Progeria Patients

The path of the life sciences is to learn all there is to know about human biochemistry, regardless of use or application. The path of medicine, like the path of engineering, is to take what is known today and build the best and most useful technologies possible in that environment of incomplete knowledge. In the case of senescent cells there is certainly a lot left to learn, as is the case for all cellular biology: the massed data that the research community possesses at present is only an outline in comparison to the vast forest of low-level details and interactions yet to be uncovered.

Senescent cells are those that permanently exit the cell cycle and cease replication in response to damage or circumstances such as the presence of toxins that indicates a strong possibility of damage. This serves at least initially as a defense against cancer: some portion of those cells most likely to become cancerous are removed from the picture via senescence. Unfortunately senescent cells can linger, and they behave in ways that cause harm to surrounding tissue structures. The more senescent cells there are then the worse the resulting damage. Many of these cells are destroyed by the immune system or by their own programmed cell death mechanisms, but nonetheless a sizable fraction of many tissues consist of senescent cells by the time late life rolls around. This is a material contribution to many of the dysfunctions and frailties of degenerative aging.

For all that I can repeat the summary above, scientific institutions still have a long way to go in deciphering every last aspect of cellular senescence. But in the medical world there is a very clear path to producing meaningful treatments in the very near future, which is to simply destroy these cells on an ongoing basis. This has been demonstrated in mice engineered to suffer accelerated aging, and better studies on more normal mice are presently underway. A few research groups are working on a variety of ways to clear senescent cells from tissues, but are still quite early in the process of moving from laboratory to clinical applications of research. Nonetheless, this is a very viable way to circumvent present lack of knowledge: if researchers can selectively destroy senescent cells and show benefits as a result, then for this purpose the fine details of how senescence progresses and causes harm don't really matter.

Back to the science, here is an example of ongoing investigation of some of those fine details. Here researchers compare ordinary cellular senescence with the dysfunctional state of cells obtained from Hutchinson-Gilford progeria syndrome patients. This condition has many of the appearances of accelerated aging, though it is not that, and there is some interest in understanding whether any of the mechanisms involved in progeria have relevance to normal aging:

Understanding cellular ageing

Researchers have mapped the physical structure of the nuclear landscape in unprecedented detail to understand changes in genomic interactions occurring in cell senescence and ageing. Their findings have allowed them to reconcile the contradictory observations of two current models of ageing: cellular senescence of connective tissue cells called fibroblasts and cellular models of an accelerated ageing syndrome.

In the first model, cellular senescence triggers large-scale spatial rearrangements of chromatin and the formation of dense nuclear domains called SAHF (senescence associated heterochromatic foci). Chromatin is the complex of DNA and proteins that forms the chromosomes in the nucleus. The second model uses fibroblast cells from people with a syndrome causing accelerated ageing (Hutchinson-Gilford progeria syndrome, HGPS) and these cells show reduced compaction of chromatin and do not show the creation of SAHF domains.

Unexpectedly, the researchers found that SAHF regions, thought to be highly condensed and structured, show a dramatic loss of local interconnectivity and internal structure in senescence chromatin and that this effect was also seen in the genomes from HGPS cells. "The seemingly opposite changes in chromatin behaviour between cell senescence and cells from HGPS patients have been an obstacle to understanding their contribution to ageing. Using physical interaction mapping, a direct measure of the genome architecture, our study suggests that the chromatin does initially change in a similar way in cell senescence and HGPS. We can now focus our studies on these early events common to both model systems."

Global Reorganization of the Nuclear Landscape in Senescent Cells

Cellular senescence has been implicated in tumor suppression, development, and aging and is accompanied by large-scale chromatin rearrangements, forming senescence-associated heterochromatic foci (SAHF). However, how the chromatin is reorganized during SAHF formation is poorly understood. Furthermore, heterochromatin formation in senescence appears to contrast with loss of heterochromatin in Hutchinson-Gilford progeria.

We mapped architectural changes in genome organization in cellular senescence using Hi-C. Unexpectedly, we find a dramatic sequence- and lamin-dependent loss of local interactions in heterochromatin. This change in local connectivity resolves the paradox of opposing chromatin changes in senescence and progeria. Comparison of embryonic stem cells (ESCs), somatic cells, and senescent cells shows a unidirectional loss in local chromatin connectivity, suggesting that senescence is an endpoint of the continuous nuclear remodelling process during differentiation.

That last point ties in nicely with the concept of cellular senescence as a tool initially evolved to steer embryonic development, and only later emerging as a system to reduce cancer incidence in damaged tissues.

Comments

Reason, you say some research groups are working on a system to remove Senescent cells which ones?

I definately agree removing them would be a huge step in reducing aging damage and combined with Stem cell replenishment for example could be useful in rejuvenation.

Posted by: Steve H at January 30th, 2015 6:58 AM

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.