A Demonstration of the Merits of ApoptoSENS

At any given time a whole bunch of cells in your body need to be destroyed before they cause harm - cells that are past the productive stage of their life cycle and have become senescent, cells that are damaged and malfunctioning, and so forth. The majority of these cells are indeed destroyed, either by the immune system or through self-destruction mechanisms that evolved to trigger when vital cellular processes begin to run ragged. But this protective culling fails with age, and the accumulation of cells that should have been destroyed but were not is one of the driving forces of degenerative aging.

This fact is reflected in the proposed apoptoSENS research program, one of the seven branches of the Strategies for Engineered Negligible Senescence. Where the body isn't keeping up with cells that should be destroyed, appropriate forms of biotechnology can could be developed to perform this necessary work - and thereby remove and reverse this contribution to aging. The first array of therapies will probably look much like the targeted cell killing strategies under development in the cancer research community: using bacteria, viruses, nanoparticles, or the patient's own immune system to selectively seek out and destroy cells based on their surface markers.

I see that recent research adds weight to proposals for therapies that will eliminate senescent cells:

Scientists at the Mayo Clinic, in the US, devised a way to kill all senescent cells in [mice genetically engineered to age more rapidly than normal, and therefore accumulate senescent cells more rapidly than normal]. ... when they were given a drug, the senescent cells would die. The researchers looked at three symptoms of old age: formation of cataracts in the eye; the wasting away of muscle tissue; and the loss of fat deposits under the skin, which keep it smooth. Researchers said the onset of these symptoms was "dramatically delayed" when the animals were treated with the drug. When it was given after the mice had been allowed to age, there was an improvement in muscle function.

[The study] suggests if you get rid of senescent cells you can improve [physical traits] associated with ageing and improve quality of life in aged humans.

The caveat here is that these are not normal mice. Animals that suffer accelerated aging are used for the standard cost effectiveness reasons: the researchers were already working with the breed, effects will be easier to find, and can be found in a shorter period of time. Now that the researchers have an effect and a mechanism by which they can reliably destroy senescent cells, the next step is to repeat the study in ordinary mice and see what happens - which will of course take a few years if they want to evaluate the effects on life span as well as health, risk of age-related disease, and so forth.

Here's a link to the research paper and a little detail on how the authors are clearing out senescent cells:

Senescent cells accumulate in various tissues and organs with ageing and have been hypothesized to disrupt tissue structure and function because of the components they secrete. However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, p16Ink4a, to design a novel transgene, INK-ATTAC, for inducible elimination of p16Ink4a-positive senescent cells upon administration of a drug.

The mice used were BubR1 mutants, and you can find an interesting article on that topic at the laboratory website.

Comments

For at least a while, the full text is available at URL:
http://extremelongevity.net/wp-content/uploads/senescent-aging.pdf

I would like to know whether mTOR inhibitors, like rapamycin, caffeine, curcumin, ..., which increase apoptosis also accelerate clearance of senescent cells.

Posted by: Lou Pagnucco at November 3rd, 2011 10:00 AM

Maybe it's also relevant that removing senescent cells in elderly skin (more concentrated in outer tissue layers) via dermabrasion appears to rejuvenate it. See -
"Reversing the aging stromal phenotype prevents carcinoma initiation"
http://www.impactaging.com/papers/v3/n4/full/100318.html
So this approach may work in humans as well.

Posted by: Lou Pagnucco at November 3rd, 2011 3:10 PM

It's amazing how people are getting this story wrong. For example,

"The caveat here is that these are not normal mice. Animals that suffer accelerated aging are used for the standard cost effectiveness reasons: the researchers were already working with the breed, effects will be easier to find, and can be found in a shorter period of time. Now that the researchers have an effect and a mechanism by which they can reliably destroy senescent cells,"

Yes, the caveat is that these are not normal mice and no, that has nothing to do with them being accelerated aging mice. These are synthetic mice created with a specific genetic marker implanted into their senescent cells that enables a routine compound to kill those senescent cells. The method will not work on "normal" mice.

The primary science in this report was figuring out how senescent cells, and only senescent cells, could be killed. The researchers solved that puzzle by creating a line of synthetic mice with altered genome that makes their senescent cells, and only their senescent cells vulnerable to a specific, off the shelf, cell killing compound.

The technique is a research demonstration that senescent cells cause pathologies of aging, but other than confirming what many suspected the technique offers no "real world" benefits, other than for those people, for example, who just happened to have been genetically engineered by their parents so many years ago to have specific genetic trap doors engineered into their DNA for expression by senescent, and only by senescent, cells. That is, it has zero "real world" applicability.

Is it possible that some technique, other than genetically engineering an artificial animal, could be found that would allow killing senescent, and only senescent cells? Sure, perhaps, but as hundreds of billions of dollars spent on trying to kill cancerous, and only cancerous, cells has shown, that's not so easy to do if the animal was not artificially created to have a convenient "please kill me" sign on the targeted cells.

Posted by: Spike Africa at November 3rd, 2011 9:16 PM

@Spike Africa: By repeat the study in normal mice, I mean that they should repeat the genetic engineering that marked the senescence cells, but in something other than the BubR1 mutants.

As to practical uses, I would like to see an explanation as to whether it is feasible to target the p16Ink4a biomarker successfully and safely with targeted cell killing therapies such as those used to attack cancer cells by surface chemistry. i.e. is it really distinctive enough on its own.

Posted by: Reason at November 3rd, 2011 9:35 PM

To Spike -
This is strictly lab science for now, but the study's take-away message is summed up in the closing remark:

"There were no overt side effects of senescent cell clearance in our
model, even though it has been postulated that senescent cells enhance
certain types of tissue repair. Our proof-of-principle experiments
demonstrate that therapeutic interventions to clear senescent cells or
block their effects may represent an avenue for treating or delaying
age-related diseases and improving healthy human lifespan."

Posted by: Lou Pagnucco at November 4th, 2011 10:07 AM

I always found counter intuitive the whole notion that old cells in your tissues is a good thing, that somehow it aids in the repair of tissue. Young humans seem to repair their tissues just fine without the "aid" of senescent cells. It does not surprise me at all that clearing all senescent cells has no "side effects". Why scientists would have been on the fence about this is puzzling

Posted by: Daniel Ullfig at November 4th, 2012 3:38 PM

"As to practical uses, I would like to see an explanation as to whether it is feasible to target the p16Ink4a biomarker successfully and safely with targeted cell killing therapies such as those used to attack cancer cells by surface chemistry. i.e. is it really distinctive enough on its own."

I really hope that some lab somewhere is working on this. At least there are a lot of funds going towards cell ablation on the cancer side of things, and if any of those are highly successful the technology may be applicable against senescent cells.

Posted by: Jim at November 27th, 2013 1:06 AM

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