Destruction of Senescent Cells May Not Be Sufficient

Senescent cells build up in our tissues with age. These cells have become damaged or passed the Hayflick limit and thus fallen out of the normal cell cycle of division. They should either self-destruct or be destroyed by the immune system, and until that happens they secrete all sorts of undesirable signaling compounds that tend to harm surrounding tissues. The more senescent cells you have, the more harm they cause - and the growth in their numbers with passing years is one of the root contributing causes of aging.

Given this outline, plans for dealing with the problem tend to involve identifying and destroying senescent cells - removing the cells from the picture is fairly clearly the way to go. The destroying part is pretty easy (there is no shortage of methods to kill cells) but the identification part is still a challenge, despite considerable progress from the cancer research community in building ways to target specific cell populations via aspects of their surface chemistry or other characteristics. At this point the state of the art demonstration of improved health in mice through destruction of senescent cells requires a combination approach of gene engineering and a targeted therapy, which isn't terribly practical as the basis for a human therapy.

Progress will be made nonetheless, and a near-future brace of therapies that remove the contribution of senescent cells to aging seems to be very plausible at this point. Yet this all assumes that senescent cells can be wiped out on an ongoing basis without consequence: a fair enough assumption for most tissues, made up of cells that are replaced and replenished on an ongoing basis. Recent research suggests, however, that cells that are far less readily replaced or are normally not replaced at all in the life span of an individual also turn senescent with age - such as those in the brain.

Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response:

In senescent cells, a DNA damage response drives not only irreversible loss of replicative capacity but also production and secretion of reactive oxygen species (ROS) and bioactive peptides including pro-inflammatory cytokines. This makes senescent cells a potential cause of tissue functional decline in aging.

To our knowledge, we show here for the first time evidence suggesting that DNA damage induces a senescence-like state in mature postmitotic neurons in vivo. About 40-80% of Purkinje neurons and 20-40% of cortical, hippocampal and peripheral neurons in the myenteric plexus from old [mice showed inceasing senescence-like characteristics] with age.


We conclude that a senescence-like phenotype is possibly not restricted to proliferation-competent cells. Rather, dysfunctional telomeres and/or accumulated DNA damage can induce a DNA damage response leading to a phenotype in postmitotic neurons that resembles cell senescence in multiple features. Senescence-like neurons might be a source of oxidative and inflammatory stress and a contributor to brain aging.

So if this research holds up we can't just rampage through the body and destroy everything that looks like a senescent cell. More discrimination is needed, which in turn means more complex therapies and a greater understanding of differences in biochemistry between the cell populations of interest. More to the point, we will also need some method of reversing this senescence-like state in the brain and nervous system cells that we want to keep around. Will a general repair of all of the known forms of cellular damage be sufficient for that? Is neural dysfunction absolutely a consequence of the damage modes described by the Strategies for Engineered Negligible Senescence? It seems unlikely that we'll get a solid answer to that question until SENS version 1.0 is implemented in mice, but the initial expectation would be that yes, it is.

And what about the mice that were treated with a method to destroy senescent cells? They didn't appear to have their brain function markedly impacted, or the researchers would have noted as much. However: (a) it was a study using mice engineered to age rapidly, and thus may not have lasted long enough to uncover issues of that sort, and (b) the method used to destroy senescent cells was very narrow and specific in its targeting, and may or may not have reached these neurons that fall into a senescence-like state.


Is it possible that some DNA "damage" is a self-regulated differentiation/developmental program? e.g., an excerpt from -

"Regulation of cell differentiation by the DNA damage response"

"Three established outcomes of the DDR include transient cell cycle arrest coupled with DNA repair, apoptosis, or senescence. However, recent studies in normal and cancer precursor or stem cells suggest that a fourth potential outcome, cell differentiation, is under the influence of DDR programs. Here we review and discuss the emerging evidence that supports the linkage of signaling from DSBs to the regulation of differentiation, including some of the molecular mechanisms driving this under-appreciated DDR outcome."

How does rate of DNA "damage" vs. rate of DNA "repair" compare in long vs. short lived individuals and species?

Posted by: Lou Pagnucco at September 15th, 2012 8:08 PM
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