Answering age-old questions

09 March 2015
By Tamir Chandra and Philip Ewels

What is cellular senescence? Credit: Designed by Freepik

What is cellular senescence? Credit: Icons from Freepik.com

The reason for mankind’s ageing has fascinated scientists for generations and, over the years, many theories have emerged in an effort to explain it. A central question within these studies is the nature of ageing; is it unavoidable programming in our body or simply an effect of wear and tear?

Short-lived vertebrates such as the turquoise killifish, whose average life-span is six months, seem to suggest that ageing may be partly predefined by a programme written into our DNA.

One theory of cellular ageing predicts that as mammals mature we accumulate increasing numbers of ageing cells, known as senescent cells, within our organs. These cells stop dividing and no longer perform their original function; as their number increases, the ability of that organ system to do its job is restricted.

The same mechanism might also affect stem-cell populations, decreasing our regenerative potential as we exhaust our stem-cell pool. It’s thought that this could be one of several cellular ageing mechanisms that contribute to the effects of ageing we observe.

People have approached the phenomenon of cellular ageing in a variety of contexts. Some studies use isolated cells from older individuals or children suffering premature ageing syndromes as a model. Other groups have observed that cells isolated from healthy young individuals stop dividing after a certain number of cell divisions (replicative senescence) or after exposing the cells to certain cellular stresses (oncogenic stimulus and stress-induced senescence).

While these models agree on a number of details, there are also areas where they contradict one another. One particular point of dispute is the qualitative change of heterochromatin, the most condensed part of the genome.

The tightly packed DNA that forms heterochromatin seems to open up in cellular models of the premature ageing disorder Hutchinson-Gilford Progeria Syndrome. However, heterochromatin appears to tighten up in stress-induced senescence, culminating in a chromatin structure called senescence associated heterochromatic foci.

We initiated our study to understand senescence associated heterochromatic foci function, a phenomenon that has been observed in different forms of stress-induced senescence and to a lesser extent in replicative senescence. Senescence associated heterochromatic foci can be easily detected using a DNA stain and a microscope and the prominence of these foci suggests a change in the nuclear architecture in senescent cells.

Before our project, there had been a lack of functional understanding of this phenomenon and we used a recently developed method to map the architecture of the genome, hoping that a structural understanding of senescence associated heterochromatic foci would suggest possible functions of this process.

Initially, we were disappointed; the general changes we observed did not fit in with what we previously thought about stress-induced senescent chromatin and senescence associated heterochromatic foci formation. We expected a tightening or increase of heterochromatic domains; instead, we found a relaxation of these domains.

Stepping back from our initial research question, we realised that our findings might provide an explanation of the perceived difference between Hutchinson-Gilford Progeria Syndrome and stress-induced models of cellular ageing: the role of heterochromatin. This was made possible through directly mapping the physical contacts, regions of DNA that are touching because the chromatin structures are folded or coiled over one another.

Now, our data indicated that we may be able to align the behaviour of these domains in both conditions, suggesting a common mechanism for both models of cellular ageing. Finally, our findings may suggest that we should focus our future efforts on understanding the early events of cellular senescence chromatin changes.

Tamir Chandra is a Postdoctoral Fellow at the Wellcome Trust Sanger Institute. He works with Wolf Reik at the Babraham and Sanger Institutes on the nuclear biology of cellular ageing, with implications for cancer and ageing. Tamir has a long standing interest in senescence biology and did his PhD at the Cancer Research UK Institute in Cambridge with Masashi Narita on chromatin dynamics in senescent cells.

Philip Ewels is a bioinformatician at National Genomics Infrastructure at the Science for Life Laboratory in Stockholm, Sweden. Previously he worked with Wolf Reik at the Babraham Institute in Cambridge. His core interests are in the field of epigenetics, with particular emphasis on bisulfite sequencing, HiC data analysis and systems approaches to data analysis. You can find out more at his site: http://phil.ewels.co.uk/

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