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Removing Senescent Cells Halts Many Signs of Aging

cellular hacking senescence age immortality proof senescent cells senescent cells

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#61 Arcanyn

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Posted 11 November 2011 - 05:11 AM

Getting rid of senescent cells wouldn't be like getting rid of cancer cells. There's no hurry to get rid of senescent cells, because they accumulate incredibly slowly. Contrast with cancer cells, which multiply quickly, making it necessary to kill them very quickly - if you only kill 1% of cancer cells, you're basically wasting your time, because they'll all be replaced in short order. This makes it necessary to use high doses of cancer killing agents, making it inevitable that large numbers of healthy cells will be affected also. In the case of senescent cells, killing 1% of them in one go will be useful, because it will take a while for them to be replenished, and in the time it takes for this to happen, more senescent cells can be killed. Basically, this means that gradually killing senescent cells over an extended period of time is a viable strategy. Even if a treatment does kill healthy cells as well, by doing it slowly the number of healthy cells that will be killed will likely be so small as to not result in noticable harmful effects.
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#62 Mind

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Posted 11 November 2011 - 10:35 PM

I wonder if it is possible to stimulate senescent cells to endocytotically take up ILGFBP-3? This 2005 study is pertainant, though not in the same vein. I have not located any follow up studies.

http://freepdfhostin.../a5654ce9a8.pdf






The data are consistent with

a model where IGFBP-3 accumulation in conditioned

medium of senescent fibroblasts contributes to growth

arrest of these cells, whereas the failure to endocytose

IGFBP-3 and the absence of nuclear IGFBP-3 may contribute

to the well-established apoptosis resistance of senescent

human fibroblasts.

Key words: Apoptosis; fibroblast; IGFBP-3; senescence.



Does anyone have the expertise to evaluate this proposal. I do not, but I do not want to leave any stone un-turned.

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#63 niner

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Posted 12 November 2011 - 12:26 AM

This isn't quite my area of expertise, but if the senescent cells fail to endocytose IGFBP-3, it would probably be pretty hard to make them do it. It might be easier to try to bypass IGFBP-3 and get apoptosis turned on using a different mechanism, or even use a targeted killing mechanism like the killer antibodies people are using against cancer cells. That would hinge on having a reliable way to recognize a senescent cell.

#64 Mind

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Posted 12 November 2011 - 04:01 PM

I am thinking that recognizing AND targeting senescent cells is a tougher project than we suspect. Senescent cells produce a lot of the same signals as healthy cells, correct? It is just that they typically produce a lot of signalling that is bad in the long term and create chronic stress (for healthy cells). Therefore, it is a matter of quantity not specificity. The trick here seems to be to find unique signalling factors that senescent cells produce (or that healthy cells do not produce) in order to remove them.

Thus, the proposed idea to help this effort out. There must be something we can contribute.

Edited by Mind, 12 November 2011 - 04:05 PM.


#65 revenant

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Posted 13 November 2011 - 07:55 AM

I wonder if it is possible to stimulate senescent cells to endocytotically take up ILGFBP-3? This 2005 study is pertainant, though not in the same vein. I have not located any follow up studies.

http://freepdfhostin.../a5654ce9a8.pdf











The data are consistent with

a model where IGFBP-3 accumulation in conditioned

medium of senescent fibroblasts contributes to growth

arrest of these cells, whereas the failure to endocytose

IGFBP-3 and the absence of nuclear IGFBP-3 may contribute

to the well-established apoptosis resistance of senescent

human fibroblasts.

Key words: Apoptosis; fibroblast; IGFBP-3; senescence.



Does anyone have the expertise to evaluate this proposal. I do not, but I do not want to leave any stone un-turned.


I found these interesting. Is it possibe to upregulate amphiphysi-1, or maybe down-regulate caveolin? Also, I wonder if it possible to pull cells out of senescence rather than induce apoptosis?
http://www.ncbi.nlm....pubmed/11976184
http://www.fasebj.or.../15/9/1625.full

Edited by revenant, 13 November 2011 - 08:52 AM.


#66 Anthony_Loera

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Posted 14 November 2011 - 12:57 AM

More on this, from the GRG, with a thanks to Steve Coles:

"Senescent Cell Clearance in Adult Organisms"
by
Eunice Liu, UCLA Freshman in Chem-19 Gerontology Seminar

Senescent cells, which are cells that have stopped dividing, have until scientists at Mayo Clinic recently conducted a study with mice that proved the elimination of senescent cells in the body would prevent diseases associated with aging and produce health benefits. By identifying the positive p16Ink4abiomarker that is present in senescent cells, scientists administered a drug called AP20187 to remove the senescent cells.

AP20187 is "a synthetic drug that induces dimerization of a membrane-bound myristolated FK506-binding-protein-caspase 8 (FKBP–Casp8) fusion protein expressed specifically in adipocytes via the minimal Fabp4 promoter." For this study, every three days from [weaning to five-months old], 0.2 µg/g body weight of AP20187 was injected into the mice intraperitoneally [1]. Commercially-produced by ARIAD Pharmaceuticals, AP20187 has only been used in mice and in vitro thus far, but it shows promise for use in human patients because it has no immmuosuppressive activity and is non-toxic to cells [2]. Although senescent cells have been assumed to aid certain types of tissue repair, the experimental model conducted by Mayo Clinic detected no side effects of AP20187 [1]. Because this is a synthetic laboratory drug that has not yet been used in human subjects, AP20187 is not listed in the Physician's Desk Reference (PDR), and if used, would only be prescribed "off label," With experimental and scientific advances, however, we may soon see the use of AP20187 to eliminate not only age-induced wrinkles and fat, but diseases associated with senescent inflammation, such as dementia, atherosclerosis, diabetes, and cataracts [3]. Although we may not live forever, the method of senescent cell clearing may slow down the aging process and extend the human health pan.

Refs:

1. Van Deursen, Jan M. "Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders." Nature.com. Nov. 2, 2011. NaturePublishing Group. Nov. 12, 2011 < http://www.nature.com/nature/journal/v479/n7372/full/nature10600.html >.

2. ARGENT Regulated Homodimerization Kit. Sept. 9, 2002. ARIAD Pharmaceuticals. Nov. 12, 2011 < http://www.ariad.com/pdf/Reg_Homodimerization.pdf>.

3. Wang, Shirley S. "Study Suggests Way to Delay Age-Related Changes - WSJ.com." Business News & Financial News - The Wall Street Journal - Wsj.com. November 3, 2011. The Wall Street Journal. Nov. 12, 2011 <http://online.wsj.co...1448483058.html >.



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#67 VidX

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Posted 14 November 2011 - 02:26 AM

Well damn me, but this ^^ is getting interesting (esp. as the drug is readily available, not something "assembled" in the lab for a one-shot experiment. Tho' I'm not sure yet how it works, in regard to targetting the specific cells and whether the actual genetic engineering on mice had any signficance in finding these senescent cells, aside from targetting just specific tissues).

Edited by VidX, 14 November 2011 - 02:34 AM.


#68 niner

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Posted 14 November 2011 - 03:09 AM

I think Ms. Liu is glossing over the part where the animals were genetically modified. Without the genetic hacks, the AP20187 won't do anything.
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#69 Methos000

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Posted 14 November 2011 - 05:04 PM

I think Ms. Liu is glossing over the part where the animals were genetically modified. Without the genetic hacks, the AP20187 won't do anything.


Hmmmmm, such a tiny, wee detail... :)

Edited by Methos000, 14 November 2011 - 05:07 PM.


#70 Mind

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Posted 14 November 2011 - 09:53 PM

So, it still boils down to finding a unique marker of senescent cells in a normal mouse (or humans if we want to move things along faster), correct? If that is not possible, then we would have to target cells that produce an abnormally large amount of signalling factors that create chronic stress for healthy cells. Correct? I am just trying to get the generic, overall layman's view of this potential rejuvenation treatment.

#71 PWAIN

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Posted 14 November 2011 - 10:39 PM

I got an email from TA Sciences this morning and the following is claimed:

TA-65 has also been shown to reduce senescent cells. In a peer-reviewed article published in September 2010, TA-65 was shown to improve the ratio between healthy immune cells and senescent CD28- cells. Not only was the ratio improved, but the absolute number of these senescent CD28- cells was reduced. At Mayo, they killed the non-functioning cells. TA-65's method of action is thought to be restoration of senescent cells to viable functionality. Either way, the result is fewer senescent cells. However, there is a big difference between the Mayo Clinic study and the TA-65 study. The TA-65 results were measured on live humans, not on rodents.

Not sure if this has been covered here, but they certainly seem to be claiming this as a potential mode of action for their product.

#72 Louis

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Posted 14 November 2011 - 11:47 PM

>> TA-65's method of action is thought to be restoration of senescent cells to viable functionality.

Wow, that is a very bold claim.

I agree that TA-65 reduces percentage of short telomeres, and then likely (as a consequence) percentage of senescent cells. But I don't agree at all that the Sept 2010 publication justifies reversal of cells that are already senescent. You should ask them to eleborate: HOW does TA-65 reverse cells that are already senescent?

#73 Mind

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Posted 15 November 2011 - 10:45 PM

Since someone brought up senescent immune cells, I thought I would remind/alert everyone that a long time Imminst/Longecity member/leader has developed a method to remove anergic T-cells from blood. I am not knowledgeable enough to figure out if this has any possible application in generic (stationary) senescent cells, but I thought it was an interesting parallel.

#74 mpe

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Posted 17 November 2011 - 01:53 AM

>> TA-65's method of action is thought to be restoration of senescent cells to viable functionality.

Wow, that is a very bold claim.

I agree that TA-65 reduces percentage of short telomeres, and then likely (as a consequence) percentage of senescent cells. But I don't agree at all that the Sept 2010 publication justifies reversal of cells that are already senescent. You should ask them to eleborate: HOW does TA-65 reverse cells that are already senescent?


Or is it that the immune system being partially restored starts removing senescent cells like it does when you are young. If it has any effect at all

Edited by mpe, 17 November 2011 - 01:57 AM.


#75 Louis

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Posted 17 November 2011 - 07:41 PM

Or is it that the immune system being partially restored starts removing senescent cells like it does when you are young. If it has any effect at all


Very possible. That I would believe.

I noticed that I received the same email from TA Sciences. I wrote them back asking for an explanation of how TA-65 could possibly reverse senescence in a cell. I also pointed out that, contradictory to their claim in the email, their 2010 paper presents no evidence for reversal of a cell once it has already become senescent.

No response so far.

I think the claim is just a lot of marketing mumbo jumbo.

#76 Krell

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Posted 22 November 2011 - 11:01 PM

http://thedianerehms...-aging-research

New Developments in Aging Research

The Diane Rehm Show from WAMU 88.5 in Washington DC broadcast a show today that discussed the research on removing senescent cells and is available on streaming audio Tuesday, November 22, 2011 - 11:06 a.m.

Each day around the world 150,000 people die; two-thirds from age-related diseases like cancer and heart disease. Many of these conditions lead to lengthy hospital stays and costly medical treatments. An aging world population is driving some countries to fund biological research aimed at preventing the development of life-shortening diseases. Recently, scientists have discovered that removing old, harmful cells delays the onset of age-related conditions in laboratory animals. The latest developments in aging research and what they could mean for human health.

Guests

David Walker assistant professor of integrative biology and physiology at UCLA
Jan van Deursen professor, biochemistry/molecular biology, The Mayo Clinic
Felipe Sierra director, division of aging biology, National Institute on Aging at NIH

#77 PWAIN

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Posted 28 November 2011 - 05:17 AM

There must be a way to create a vaccine that teaches the immune system to target these cells and eliminate them. With the vaccine research going on with cancers, I think we may start to see some results in the next few years.

#78 niner

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Posted 29 November 2011 - 03:47 AM

There must be a way to create a vaccine that teaches the immune system to target these cells and eliminate them. With the vaccine research going on with cancers, I think we may start to see some results in the next few years.


A senescent cell, by its very nature, is biochemically different than a younger cell. In order to be recognized by the immune system, that difference needs to be expressed on the surface of the cell, which may or may not be the case. If it's not, we could still attack the senescent cells internally, using a small molecule that preferentially kills them. From the sound of it, anything that could preferentially kill them would do, even if it killed some healthy cells in the process, since there's a fairly large excess of healthy cells, and even moderate reductions in senescent cells would be helpful.

Because it's pretty easy to create senescent cells, it should be pretty easy to set up an assay to look at lots of different chemicals in order to find something that would preferentially target the senescent cells. I've heard that there are already people looking at this. It would be really cool if someone did this with all the compounds on the GRAS list, so we could take them without worrying about endless trials and FDA approval. However, there wouldn't be much profit in that, so it probably won't happen. Maybe there's a role for some underground biohacking here...
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#79 AgeVivo

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Posted 03 December 2011 - 02:54 PM

Would be nice if Longecity could fund research targetting senescent cells, in order then to develop a vaccine for example

Perhaps a fundraiser could be opened not for one specific theme, but for a list of such specific ideas that we would like to see going on with high visibility.

#80 maxwatt

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Posted 03 December 2011 - 04:35 PM

You would need to find a marker unique to senescent cells for such a vaccine to target. That's the hard part.

#81 AgeVivo

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Posted 03 December 2011 - 08:53 PM

Finding smthg that preferentially targets scenescent cells may or may not be so hard. Niner proposes a potential approach, that I imagine could be financied by LongeCity:

A senescent cell, by its very nature, is biochemically different than a younger cell. In order to be recognized by the immune system, that difference needs to be expressed on the surface of the cell, which may or may not be the case. If it's not, we could still attack the senescent cells internally, using a small molecule that preferentially kills them. From the sound of it, anything that could preferentially kill them would do, even if it killed some healthy cells in the process, since there's a fairly large excess of healthy cells, and even moderate reductions in senescent cells would be helpful.

Because it's pretty easy to create senescent cells, it should be pretty easy to set up an assay to look at lots of different chemicals in order to find something that would preferentially target the senescent cells. I've heard that there are already people looking at this. It would be really cool if someone did this with all the compounds on the GRAS list, so we could take them without worrying about endless trials and FDA approval. However, there wouldn't be much profit in that, so it probably won't happen. Maybe there's a role for some underground biohacking here...

Niner, how complex do you think this could be 1) at home (...) 2) in a pure cell lab 3) in a rodent+cell lab? How much timeand moneu could it take?

#82 revenant

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Posted 03 December 2011 - 11:58 PM

I wonder if cell surface bound IL-1α could be a target? Perhaps a non-neutralizing IL-1α antibody could be used to tag senescent cells for elimination. Possibly even develop an antibody that "defangs" senescent cells by interupting the cytokine signaling.
http://freepdfhostin.../d77cd2cd37.pdf
http://jcb.rupress.o...47.figures-only

Edited by revenant, 04 December 2011 - 12:53 AM.


#83 niner

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Posted 04 December 2011 - 04:58 AM

Finding smthg that preferentially targets scenescent cells may or may not be so hard. Niner proposes a potential approach, that I imagine could be financied by LongeCity:

A senescent cell, by its very nature, is biochemically different than a younger cell. In order to be recognized by the immune system, that difference needs to be expressed on the surface of the cell, which may or may not be the case. If it's not, we could still attack the senescent cells internally, using a small molecule that preferentially kills them. From the sound of it, anything that could preferentially kill them would do, even if it killed some healthy cells in the process, since there's a fairly large excess of healthy cells, and even moderate reductions in senescent cells would be helpful.

Because it's pretty easy to create senescent cells, it should be pretty easy to set up an assay to look at lots of different chemicals in order to find something that would preferentially target the senescent cells. I've heard that there are already people looking at this. It would be really cool if someone did this with all the compounds on the GRAS list, so we could take them without worrying about endless trials and FDA approval. However, there wouldn't be much profit in that, so it probably won't happen. Maybe there's a role for some underground biohacking here...

Niner, how complex do you think this could be 1) at home (...) 2) in a pure cell lab 3) in a rodent+cell lab? How much timeand moneu could it take?


I see it as a problem with three parts. The first part would be getting a "representative" human cell line cultured in two populations: One that was senescent and the other that was mitotically competent. The second part would be developing an assay. This would involve treating both types of cells with a compound at some concentration, and having an easy way to detect some form of lethality. It might be looking for a marker of apoptosis, or it might be an optical method, essentially looking at cells under a microscope. The best thing would be something that was fast and could be automated in a 96 well plate or similar. The third part of the problem would be obtaining the GRAS compounds. Ideally, we'd find someone who already has them in solution, put up on plates, and ready to be loaded onto the screening robot. The worst case scenario would involve purchasing small quantities of a lot (~4000?) of compounds, putting them up in an appropriate solvent like DMSO, and preparing them for screening.

I think part 1 is relatively easy, if you are familiar with cell culture. I might be imagining that, since I'm not a cell biologist. The assay development is kind of a question mark. Maybe easy, maybe hard. (Maybe real hard...) You'd need to know your way around the lab. The last part, obtaining the compounds and setting them up for screening is the real killer. Unless you already had the compounds, it would be very expensive to do them all. It would probably be a couple hundred thousand dollars and months of lab time. It might be reasonable to look at a few hundred though, and choosing them intelligently might be almost as good as blindly screening a lot of them.

Since the idea behind the GRAS compounds is that they are already considered safe for human consumption, it would make sense to test them at a concentration that could be achieved in the body, rather than an artificially high concentration. If you were looking for leads at a pharmaceutical company, you might use a fairly high concentration in order to see if you have any activity, then synthesize analogs to attempt to improve activity.

Probably the best way to go about this would be to find people who already have the expertise and tools, and get them to collaborate. There are probably a lot of academic and industrial labs that could do part 1, a few academic and more industrial labs that could do part 2, and a few industrial labs that would have the GRAS compounds ready to go.

There are contract research labs in various countries that would do at least some if not all phases of this. I don't know what they would charge, but my guess would be "a lot", at least by our standards. It would be less if you already had the assay developed and working reliably. It might be possible to tempt some organization like Isagenix to part with compound samples if they are then allowed to market the results. If you don't expect to make any money with it, it gives you a leg up in terms of bargaining with people who do want the money.

#84 DeadMeat

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Posted 04 December 2011 - 03:51 PM

Kevin Perrott is working on this for SENS.
http://www.sens.org/...ng-sasp-at-buck

Senescence is a genetic program which normal dividing cells invoke in order to prevent excessive cellular growth. This is initially a protective mechanism, preventing cells undergoing stresses such as DNA damage from becoming cancerous, and keeping the wound-healing response from overstepping its bounds and generating an overgrowth of fibrous connective tissue. Senescence stops such cells from dividing; the problem is that some senescent cells persist long after their usefulness has expired, ignoring signals for programmed cell death (apoptosis) while growing larger and, often, secreting various inflammatory molecules that disrupt the environment in which neighboring cells have to function. These inflammatory molecules can have many effects, from the induction of an immune response to the degradation of the extracellular environment and alteration of the behavior of neighboring cells. Targeting senescent cells both for elimination and for the modulation of their secretions is the focus of a major extramural project of SENS Foundation.

This project is being performed by doctoral candidate Kevin Perrott in Dr. Judith Campisi's laboratory at the Buck Institute for Research on Aging. Dr. Campisi is a noted pioneer in the field of senescence, having been the first to develop an assay able to identify senescent cells. Subsequently it was her lab which discovered their pro-inflammatory secretions, called the "Senescence Associated Secretory Phenotype", or SASP. In the course of his thesis work in Dr. Campisi's lab, Perrott is using high-throughput screening methods to identify and characterize novel substances able to either induce senescent cells to commit suicide, or to alter the SASP, mitigating its deleterious impact by lowering the secretion of IL-6 and other pro-inflammatory markers.

The Prestwick Library was the first source of compounds which were screened. Its more than 1400 compounds were applied to irradiated cells and their non-irradiated controls, and the cells' viability and secretion of IL-6 were examined. So far, no candidates have emerged which selectively kill senescent cells, but there have been a handful that are able to reduce the pro-inflammatory nature of the SASP. These compounds are being followed up on to determine their mechanisms of action and ultimately their effects in mouse models. Other much larger libraries of compounds are now being pursued with an eye to the genetic elements underlying their effects on the SASP, and a focus on those with the greatest potential therapeutic effects.


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#85 Mind

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Posted 04 December 2011 - 04:38 PM

Thanks for the update Deadmeat. Good to know this is getting some traction.

Also, just a little story about how current government agencies and their enormous budgets are not being leveraged toward research with a big pay-off (like this senescent cell research). It is up to us to move this stuff forward. Bureaucrats only have enough foresight to protect their bureaucracy.

#86 mpe

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Posted 05 December 2011 - 01:49 AM

Just a thought.
The immune system naturally removes senescent cells from our bodies.
With aging the immune system slows down, its composition changes or otherwise becomes less efficient.
The number of senescent cells gradually increase over time.

Perhaps a lab could expose senescent cells to different types of immune cells to see which if any attack the senescent cells.
Having found that cell type, expand its population or concentrate one from a youthfull source.
Transfuse those cells on masse into an old non genetically modified test animal and see if it results in the significant clearance of senescent cells.

This way you dont have to identify senescent cells, antibodies, small molecules etc, the immune system does it for you.
All of this presupposes that the immune system infact clears senescent cells.
After all it worked for Cui with cancer.
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#87 okok

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Posted 05 December 2011 - 01:48 PM

A quick search for monoclonal antibodies and senescent cells brought up a 1990 study:<br><br>
' class='bbc_url' title='External link' rel='nofollow external'>http://www.ncbi.nlm.nih.gov/pubmed/1689321']J Cell Physiol. 1990 Feb;142(2):425-33. <br>Novel monoclonal antibodies identify antigenic determinants unique to cellular senescence.<br>Porter MB, Pereira-Smith OM, Smith JR. <br>Roy M. and Phyllis Gough Huffington <br>Center on Aging, Baylor College of Medicine, Houston, Texas 77030. <br><br>Abstract<br>Normal human diploid fibroblasts exhibit a limited lifespan in vitro and are used as a model to study in vivo aging. Monoclonal antibodies were generated against partially purified surface membranes from human diploid fibroblasts at the end of their lifespan (senescent). Three hybridomas were isolated that secreted antibodies reacting to cellular determinants expressed specifically on senescent human fibroblasts of different origin, including neonatal foreskin, embryonic lung, and adult skin punch biopsy, but not expressed on matched young cells. The antibodies did not bind to immortal human cells and normal young cells made reversibly nondividing, indicating the antigens are not expressed in cells that are not senescent. The antibodies identified senescent cells in a mixed cell population and expression of the senescent cell antigens correlated strongly with the cells inability to synthesize DNA at the onset of senescence. The antigens appeared to be cell surface or extracellular matrix associated, and the epitopes were destroyed by mild trypsin treatment. Western analysis indicated all three antibodies reacted with fibronectin. Though the antigenic determinants on the fibronectin molecule were not accessible in the intact young cell, the epitopes were present in fibronectin extracted from both senescent and young cells, as well as purified human plasma fibronectin. These antibodies and the senescent specific expression of the antigens provide powerful tools to investigate the mechanisms leading to in vitro senescence. This may enable us to investigate directly the relationship between cellular aging and aging of the individual.

→ source (external link)

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#88 hav

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Posted 05 December 2011 - 06:51 PM

Interesting stuff. Dug into it a bit and I think this is the free full-text report of the Mayo Clinic study:

http://www.scribd.co...-Disorders-2011

And this blog I found nicely sums up the special breeding reported above by Niner that was used in the Mayo Clinic study:

http://www.markpine.us/?tag=ap20187

I found this quote from the blog especially interesting:

On average, the mice that received AP20187 did not live longer as a result of the treatment. According to the article in the NYT, the lead scientist, Jan M. van Duersen, attributed the absence of an effect on longevity to the use of the rapidly aging progeroid mice that die of heart disease. In the report in Nature, the scientists noted that the heart is one of the tissues in the animals’ bodies that does not express the Ink4a gene and is thus not amenable to the anti-ageing effects of AP20187 treatment.


... sounds like you shouldn't stop taking resveratrol for this stuff.

Also found a few related studies listed on PubMed using the "death switch" key phrase. Looks like the drug is being investigated as a cancer treatment.

Howard

Edited by hav, 05 December 2011 - 06:59 PM.


#89 steampoweredgod

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Posted 19 December 2011 - 02:00 AM

The accumulation of non-replicative, non-functional, senescent T cells with age is avoided in calorically restricted mice by an enhancement of T cell apoptosis-link


Calorie Restriction appears to increase apoptosis of senescent cells in the immune system, might it do similar elsewhere?

A recent discovery that rapamycin suppresses a pro-senescent phenotype in progeric cells not only suggests a non-toxic therapy for progeria but also implies its similarity with normal aging. For one, rapamycin is also known to suppress aging of regular human cells. Here I discuss four potential scenarios, comparing progeria with both normal and accelerated aging. This reveals further indications of rapamycin both for accelerated aging in obese and for progeria.-link

In human and rodent cell lines, rapamycin (an inhibitor of mTOR) dramatically decelerated loss of proliferative potential caused by ectopic p21, p16 and sodium butyrate-induced p21. Thus, when the cell cycle was arrested by these factors in the presence of rapamycin, cells retained the capacity to resume proliferation, once p21, p16 or sodium butyrate were removed. While rapamycin prevented the permanent loss of proliferative potential in arrested cells, it did not force the arrested cells into proliferation. During cell cycle arrest, rapamycin transformed the irreversible arrest into a reversible condition. Our data demonstrate that senescence can be pharmacologically suppressed.-link

I put emphasis on the preservation of PP[proliferative potential] by rapamycin (rather than, for example, on the suppression of the hyper-secretory phenotype, which rapamycin also inhibits), simply because PP is viewed as a definitive marker of senescence. Therefore, rapamycin is a gerosuppressant by the current definition of cellular senescence [64]. However, it is suppression of other markers of senescent phenotype such as hyper-secretion and other hyper-functions that are most clinically relevant.

By simultaneously suppressing the senescent phenotype and causing arrest, rapamycin can be viewed as an ultimate tumor-suppressant. In fact, the hyper-secretory, pro-inflammatory, pro-angiogenic phenotype are markers of both senescence and cancer. I suggest that the cancer-preventive effect of rapamycin [65] is not because (or not only because) of cell cycle arrest but because of suppression of the senescent phenotype, especially in normal cells.-link

Here we demonstrate that p53-induced quiescence actually results from suppression of senescence by p53. In previous studies, suppression of senescence by p53 was masked by p53-induced cell cycle arrest. Here, we separated these two activities by inducing senescence through overexpression of p21 and then testing the effect of p53 on senescence. We found that in p21-arrested cells, p53 converted senescence into quiescence. Suppression of senescence by p53 required its transactivation function. Like rapamycin, which is known to suppress senescence, p53 inhibited the mTOR pathway. We suggest that, while inducing cell cycle arrest, p53 may simultaneously suppress the senescence program, thus causing quiescence and that suppression of senescence and induction of cell cycle arrest are distinct functions of p53. Thus, in spite of its ability to induce cell cycle arrest, p53 can act as a suppressor of cellular senescence....
First, it is known that p53 inhibits the mTOR (mammalian target of rapamycin) pathway (8–12). Second, it is known that inhibition of mTOR by rapamycin converts senescence into quiescence (13–15). In turn, this predicts that p53, like rapamycin, may suppress senescence. Here we confirmed this prediction.-link


Inhibiting mtor appears to result in reduced probability of a cell becoming senescent, and in those cells that do become senescent inhibiting their senescent phenotype.

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#90 bdelfin

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Posted 25 December 2011 - 09:12 AM

I'm a little confused. On the one hand, we have the experiment where boosting telomerase, P53, and P16 resulted in longer-lived, healthier, nearly cancer-free mice. But according to this new study on human mesenchymal stem cells:

http://www.ncbi.nlm....pubmed/22038097

"Conversely, overexpression of SIRT1 delays senescence in B-MSCs that have undergone prolonged in vitro culturing and the cells do not lose adipogenic and osteogenic potential. In addition, we found that the delayed accumulation of the protein p16 is involved in the effect of SIRT1."

So on balance, does activating P16 help or hurt for lifespan if you don't count cancer? Because I'm starting to wonder if saikosaponin A has a place in my regimen. Does promoting P16 cause me to lose stem cells more quickly? I take a number of supplements that already trigger apoptosis in cancer cells or have other anti-cancer effects. Given that, am I better off simply removing any additional P16 stimulation? I'm already 39, so my expression of P16 is already on the rise...





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