On the Potential Treatment of Cellular Senescence in Aging

With advancing age ever more cells in any given tissue in the body are found to be in a senescent state. These cells have permanently exited the cell cycle in response to damage or stress, most likely in order to suppress cancer risk, but their accumulation causes progressive harm to tissue structure. One promising approach to removing this contribution to degenerative aging is the use of targeted cell destruction therapies, such as those under development in the cancer research community. Periodic clearance of senescent cells would prevent the dysfunction they cause, and while this research is poorly funded in comparison to its potential, a few groups are working on it.

Cellular senescence is a process in which cells at risk of becoming cancerous adopt a state of permanent growth arrest. While this process prevents tumor formation (a cell that does not divide cannot become a tumor), senescent cells may also cause or contribute to aging and age-related conditions. The senescent phenotype is complex, and consists of many changes to the nature of the cell: permanent arrest of cell division; morphological changes; beta galactosidase expression and other epigenetic changes including the senescence-associated secretory phenotype in which senescent cells secrete a myriad of factors with potent biological activities. This senescence-associated secretory phenotype, or SASP, is the most potentially damaging effect of senescent cells. While senescent cells account for less than 10% of total cells in aged tissues, the SASP allows these cells to play a much larger role than their relatively small numbers would otherwise suggest. It is hypothesized that this aspect of senescent cells is what drives aging or age-related conditions.

Senescence as a therapeutic target for aging. If senescent cells are so bad, why not get rid of the genes that cause the formation of senescent cells in the first place? Evidence from humans and animals indicates this is not an effective strategy. For example, mutations in the retinoblastoma or P53 genes, the two most essential pathways for senescence, result in strong predisposition to cancer. Therefore, the loss of the cells' ability to undergo senescence would cause a person to die of cancer long before they would grow old enough to worry about the effects of senescent cells.

What about killing the senescent cells that have already formed in the body? This could allow cells to senesce and prevent cancer, but could then eliminate them from the body before they produce harmful effects. In 2011, a group of researchers decided to test this idea using a mouse engineered to kill senescent cells when the mice were given a drug. The results were astonishing: the mice were prevented from developing a host of issues including cataracts and loss of fat, hair, and muscle. They proved to be healthier in most ways than untreated mice. This new therapeutic option, termed "senolysis" (lysis or breaking down of senescent cells), is currently being tested by several aging researchers for its effectiveness in treating the conditions of old age.

Now that senescent cells have been demonstrated to cause many of the conditions of old age, the field of senescence research is primed for a renaissance that could result in a host of new strategies for the therapeutic treatment of aging.

Link: http://sage.buckinstitute.org/aging-fundamentals-cellular-senescence/

Comments

ApoptoSENS in the making! I wonder if all three types of senescent cells can be tackled this way?

Coupled with restoration of Telemores though rDNA (or other delivery methods)or replacing lost Stem Cells along with this could considerably extend lifespan.

It is very interesting too that the inflamation and other effects caused by senescent cells if removed could mean the tissues remain at a younger Phenotype.

Posted by: Steve H at February 9th, 2015 8:42 AM

Steve H - Like they say in the article, decreasing senescence incidence, as with lengthening of telomeres, seems to increase the cancer rate too much. I've suspected that the positive effects that have been observed from telomere lengthening are related to decreased incidence of senescent phenotype anyway (I haven't been following closely, but does anyone know if there are any researches who have similarly speculated?). If that's right, then selective periodic destruction of senescent cells would have all of the positive effects of telomere lengthening (more actually, since senescence can be induced by other factors, as they say in the article), without increasing the cancer rate (unless SASP somehow decreases the chance of cells from becoming cancerous in nearby tissue, but I believe that there is evidence that SASP actually does the opposite, i.e. increases cancer incidence). The more I read about the biological role of senescent cells in aging the more hopeful I become in (what seems to me) near-future therapies designed to eliminate these cells. This is a very exciting time!

Posted by: gheme at February 9th, 2015 10:58 AM

What I am suggesting is removal of Senescent cells that is then followed by rejuvenation of the remaining cells to lengthen Telomeres again to a more youthful state. In other words sweep out the bad cells then restore the length of Telomeres in the good cells left to restore a more youthful phenotype.This could also help maintain the Stem cells in tissue allowing it to divide for longer and keep a youthful function.

The lengthening of Telomeres has in some studies offered protection against cancer incidence rather than promoting it too. I also agree with you that Senescent cells influence nearby tissue too and there is evidence that they cause nearby cells to fail too. Clearing out these cells is a very good idea provided the loses can be replaced.

Posted by: Steve H at February 9th, 2015 1:26 PM

My question is, how do you get rid of all the senescent cells in an adult body? And second, how do you lengthen the telomeres in all of the cells in the body?

Posted by: APersonOnline at February 9th, 2015 7:20 PM

Steve H - I'm aware of research that indicates lengthening telomeres decreases cancer incidence, and it's pretty interesting. I suppose for me it's an open question whether the positive effects of telomere lengthening, including less chance of cancer, are due to that lengthening or due to fewer senescent-phenotype cells being produced. Part of this worry is based on the experiments mutating P53 mentioned in the article, and that perhaps in the long run for long-lived species telomere extension would be overall harmful. But again, all subject to ongoing and exciting investigation.
APersonOnline - Not sure about a therapy that would lengthen all somatic cells' telomeres in situ, but there are many groups working on that. For selective clearance of senescent cells, either a targeted immune-therapy or something like this: http://www.sciencedaily.com/releases/2012/10/121003082728.htm

Posted by: gheme at February 9th, 2015 10:28 PM

On a related note SENS was working on a senescent cell scrubber that filtered blood and removed Senescent cells. That was back in 2010 but little has been heard about the technique despite promising initial tests. I heard it is currently shelved which is a shame as it could be a very powerful therapy.

Posted by: Steve H at February 10th, 2015 2:52 AM

APersonOnline- A few techniques have been demonstrated that restore telomere length in targetted tissues. The CNIO with M.Blasco have demonstrated a number of possitive benefits to restoring Telomeres and its abilty to repair damage somewhat using a modified vector. The technique is transient which means it doesnt hang around in the system long promoting cancer.

More recently Stanford discovered a way to lengthen Telomeres with a transient technique in Human cells. Again the RNA is transient so does not hang around in the system long. They are investigating how the technique could be applied to a broader range of cell types.

http://med.stanford.edu/news/all-news/2015/01/telomere-extension-turns-back-aging-clock-in-cultured-cells.html

Regards removal of system wide Senescent cells the artical says a number of reasearchers are investigating further so hopefully a strategy for system wide therapy will be forthcoming.

Posted by: Steve H at February 10th, 2015 4:24 AM

That's amazing. It could be such a simple and powerful therapy!

My big question is if this therapy drastically reduced ageing -related maladies, what did the nice die of? Vivisection?:) and if so, how would this therapy affect life spam? And what sort of things WOULD the mice die of if given this therapy?

Posted by: Cam at February 10th, 2015 8:27 AM

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