129 replies to this topic

[Logan]

I'd question whether activating tumor suppressor genes is really a good idea. They suppress tumors by triggering the apoptotic cascade. If you can selectively trigger apoptosis in senescent cells, that's great, but I don't think we have any compounds that do this as of yet. You wouldn't want to kill off healthy cells in an attempt to upregulate p16 expression.

Furthermore, activating tumor suppressors can dampen the replicative ability of cells, and you don't want to do this to immune cells which undergo clonal expansion. You may essentially prevent your immune system from adequately responding to pathogens.

Wasn't part of the major discovery in this study that we CAN, at least in mice, destroy senescent cells without destroying healthy one??? For some reason I understood, at least from how the article explained it, that activating expression of gene P16 did kill off senescent cells, without compromising healthy cells. If I'm misunderstanding things, or seeing them too simply, please help me out here

[Anthony_Loera]

Activating P16 wouldn't do anything for you; it might even be bad. What you have to do is figure out a way to kill the cells that are expressing P16INK4a.

Activating P16 to Kill Senescent Cells Expressing P16, doesn't sound right.

I would have to ask folks to consider Curcumin to possibly limit scenescent cells, while more is done to find out how to kill the scenescent cells off:

http://www.ncbi.nlm....pubmed/21253949

http://www.sciencedi...531556508000041

http://www.cjim.cn/c....asp?bsid=56157


Cheers
A

Edited by Anthony_Loera, 04 November 2011 - 05:10 PM.

[saxiephon]

How about low dose lenalidomide (1-3 mg every 5 days)?

Scientists at the University of California San Francisco and the National Institute on Aging have successfully reversed age-related deterioration in immune cell function using lenalidomide.

http://www.lef.org/m...an-Cells_01.htm

[Mind]

Please look through the "recent topics" before posting a new breaking news story. I have already merged this thread 5 times. Even I miss something once in a while and make a redundant post. Just take a look, for a second, before posting. Part of running an efficient and productive forum is keeping things tidy. If we are all commenting in the same thread about the same topic, we can come to conclusions faster and not have any important thoughts get lost in duplicate, triplicate, quadruplicate, etc, threads.

I love the focus on turning this research into therapy! Keep it up.

[Elus]

Wasn't part of the major discovery in this study that we CAN, at least in mice, destroy senescent cells without destroying healthy one??? For some reason I understood, at least from how the article explained it, that activating expression of gene P16 did kill off senescent cells, without compromising healthy cells. If I'm misunderstanding things, or seeing them too simply, please help me out here

The made a genetically engineered mouse. When they gave this mouse a drug, the artificial gene in the mouse responded to the drug and started getting rid of senescent cells. Here's the relevant part of the abstract:

"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."

We humans do not have this gene implanted in our cells. Therefore, we would not respond to the drug they used in their paper. You'd need to basically put this gene into the egg or sperm and then fertilize; this would produce an adult human with the correct gene to respond to such a treatment. You could also use gene therapy, but that's still being worked on.

Edited by Elus, 04 November 2011 - 09:35 PM.

[Logan]

Wasn't part of the major discovery in this study that we CAN, at least in mice, destroy senescent cells without destroying healthy one??? For some reason I understood, at least from how the article explained it, that activating expression of gene P16 did kill off senescent cells, without compromising healthy cells. If I'm misunderstanding things, or seeing them too simply, please help me out here

The made a genetically engineered mouse. When they gave this mouse a drug, the artificial gene in the mouse responded to the drug and started getting rid of senescent cells. Here's the relevant part of the abstract:

"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."

We humans do not have this gene implanted in our cells. Therefore, we would not respond to the drug they used in their paper. You'd need to basically put this gene into the egg or sperm and then fertilize; this would produce an adult human with the correct gene to respond to such a treatment. You could also use gene therapy, but that's still being worked on.

O.k. that makes perfect sense, thanks man.

[Logan]

But wait, what are they going to do when they try a similar experiment on healthy/normal mice? Any ideas?

[corb]

We humans do not have this gene implanted in our cells

Wrong. Most of us have it. It's a tumor inhibitor senescent cells start to express when they reach their hayflick limit.

http://en.wikipedia....wiki/P16_(gene)

The mice were genetically engineered to age faster, with an over expressed p16 gene. p16 slows down cell replication - when cells slows down so does tissue regeneration and tissues AGE .

First they deactivated the gene and the mice started aging normally. Then they did one better - they removed all the cells that expressed p16 and the mice became healthier.

Next time read the article and not just the abstract.

[Elus]

We humans do not have this gene implanted in our cells

Wrong. Most of us have it. It's a tumor inhibitor senescent cells start to express when they reach their hayflick limit.

http://en.wikipedia....wiki/P16_(gene)

The mice were genetically engineered to age faster, with an over expressed p16 gene. p16 slows down cell replication - when cells slows down so does tissue regeneration and tissues AGE .

First they deactivated the gene and the mice started aging normally. Then they did one better - they removed all the cells that expressed p16 and the mice became healthier.

Next time read the article and not just the abstract.

I believe you've misread my post, Corb. INK-ATTAC transgene was inserted into mice and caused removal of senescent cells upon induction with a drug. Humans cells do not contain the INK-ATTAC transgene, and will therefore not respond to drugs which activate INK-ATTAC.

If you believe I am incorrectly assessing the function of INK-ATTAC, please let me know. As far as I'm concerned, INK-ATTAC is crucial to the removal of senescent cells and we humans do not have INK-ATTAC.

Edited by Elus, 07 November 2011 - 09:52 AM.

[Logan]

But wait, what are they going to do when they try a similar experiment on healthy/normal mice? Any ideas?

Btw, they did say they were going to perform similar experiments on healthy/normal mice(maybe that are naturally aged?) to see if they get similar results. I'm only bringing this up because it was mentioned that the drug used would only work on the mice that were genetically enginered, which made sense. It simply sounded like they were going to do a similar test again on mice that were not genetically enginered. Are they going to use the same drug?? Anyone have any idea what else they might do, what other approach they might use, if using this drug would be pointless?

I going to guess that they are planning on using the same treatment hoping to get similar results.

[Inkstersco]

Another part of the SENS program appears to be taking shape. A long. Way to go though

The research at Mayo is not a part of the SENS program as such. It is actually an independent initiative, but you're right -- it does serve to demonstrate, up to a point, the safety and efficacy of the ApoptoSENS approach.

We've acknowledged the crucial importance of the study at SENS.Org here.

-Iain Inkster (SENS Foundation)

[ViolettVol]

Here's a stupid question, but I'm trying to bring all this to what can be done now - is cleansing our body of toxins in any way similar to that drug cleansing those senescent cells? Does it help get rid of senescent cells? Can we do anything supplement-wise NOW?

[Elus]

Another part of the SENS program appears to be taking shape. A long. Way to go though

The research at Mayo is not a part of the SENS program as such. It is actually an independent initiative, but you're right -- it does serve to demonstrate, up to a point, the safety and efficacy of the ApoptoSENS approach.

We've acknowledged the crucial importance of the study at SENS.Org here.

-Iain Inkster (SENS Foundation)

Hi Mr. Inkster,

Do you have any thoughts as to what might happen if senescent cells are removed from normal mice? Do mice live long enough to experience senescence?

Also, how do you think the approach used in this new paper could be applied to humans (eventually?), if at all.

Thanks,
Elus

Edited by Elus, 07 November 2011 - 02:43 PM.

[maxwatt]

i believe their approach with normally aging mice, will be to insert the INK-ATTAC marker into the P16 gene of normally aging mice; the marker enables the drug they use to selectively kill P16 expressing cells. This will show whether the approach works in a genetically normal line of mice. Or at least genetically normal until the 16 gene was modified with a marker. This is not going to be as simple as putting some substance into a capsule. While some things such as curcumin or resveratrol stimulate apoptosis of some cells, e.g. those with defective mitochondria. But they appear not to selectively target P16 over-expressing cells.

[Krell]

I wonder if this is related to the rejuvenation that is seen in old mice when their circulatory system is connected to a young mouse?

http://www.eurekaler...mc-ss082911.php

Perhaps you can get similar rejuvenation effects either by removing the senescent cells or by removing/diluting some chemicals in the blood given off by the senescent cells?

[ViolettVol]

I wonder if this is related to the rejuvenation that is seen in old mice when their circulatory system is connected to a young mouse?

http://www.eurekaler...mc-ss082911.php

Perhaps you can get similar rejuvenation effects either by removing the senescent cells or by removing/diluting some chemicals in the blood given off by the senescent cells?

I'm really no scientist so my questions sound stupid and I know it, but is there any way we can use what this research has shown to somehow start acting on our bodies now - like take an analogy and do something? Somehow encourage the body to get rid of senescent cells with supps? Does this research inform us in any way for example which of the debated supps are better?

[niner]

I'm really no scientist so my questions sound stupid and I know it, but is there any way we can use what this research has shown to somehow start acting on our bodies now - like take an analogy and do something? Somehow encourage the body to get rid of senescent cells with supps? Does this research inform us in any way for example which of the debated supps are better?

Not a stupid question at all, Violett. I'm at a loss for a solid answer, though. One thing that comes to mind is hormesis, where you subject an organism to a stress and it responds in a way that makes it stronger. Exercise is probably the classic example. Would it be possible to stress senescent cells enough to make them commit apoptotic suicide, without doing more harm to the remaining cells? Maybe. We could expose ourselves to a "just right" dose of ionizing radiation.... but the consequences of getting the dose wrong are pretty severe, so I'm not recommending that. The ideal thing would be something like a monoclonal antibody that recognizes something unique to the surface of the senescent cell, binds to it, and delivers an attached lethal payload. This approach has been played with for years as an anti-cancer therapy. First we'd have to find something that's novel on the surface of a senescent cell. Could we find a simple chemical agent that was lethal to senescent cells, but not to healthy cells? That would be the bomb. I could imagine a high throughput screening approach to look for such a thing, or at least medium throughput.

I can't think of anything off the shelf that we could take today, though. For the time being, the best thing would probably be to get all the micronutrients you need, get the right macronutrients (i.e. eat a good diet), exercise, and stay healthy. That will at least give you the best chance of not creating very many senescent cells between now and the time that we have a good way to get rid of them.

If anyone can think of ways to get rid of senescent cells, let us know.

[Mind]

If anyone can think of ways to get rid of senescent cells, let us know.

I imagine SENS has a good knowledge base built up on senescent cells and their removal. If not, perhaps it is a good small project for our science initiative. Maybe we could provide some money for an undergrad to do a literature review on this topic, keeping in mind this recent research. Maybe we could fund someone in the SENS academic initiative. We could build up the knowledge base, maybe create a small detailed wiki specifically on senescent cells and their removal. Just a thought.

[corb]

Does this research inform us in any way for example which of the debated supps are better?

I'm going to give you the short but definitive answer - I don't think most people would willingly take such a "supplement" (chemotherapy - yeah the thing they use on cancer patients), considering how it's going to be toxic and would be more harmful than helpful in the long run. Cancer wouldn't be as lethal as it is right now if we had an effective way to target cells.

Gene therapy is the only way this can be done somewhat safely. Lymphocytes could be modified to attack senescent cells, or we could coax our own bodies to create modified lymphocytes with an immunization shot.

[VidX]

Haven't red yet, but V.Gulliano doesn't seem to be too excited about this. His review/analysis: http://www.anti-agin...g-contribution/

Edited by VidX, 09 November 2011 - 03:26 AM.

[corb]

Haven't red yet, but V.Gulliano doesn't seem to be too excited about this. His review/analysis: http://www.anti-agin...g-contribution/

I read it and he sounds, well for a lack of a better word - butthurt. Not saying I disagree with most of his observations, on the contrary, but half of the "article" is a rant - "we knew", "we suspected", "we wrote it on a sticky note" - he obviously forgot theories and observations have to be proven before they become a fact.

He is particularly right about one thing though, it's too early to blow this out of proportion, let's wait for a research with untampered mice.

[Anthony_Loera]

If anyone can think of ways to get rid of senescent cells, let us know.

I imagine SENS has a good knowledge base built up on senescent cells and their removal. If not, perhaps it is a good small project for our science initiative. Maybe we could provide some money for an undergrad to do a literature review on this topic, keeping in mind this recent research. Maybe we could fund someone in the SENS academic initiative. We could build up the knowledge base, maybe create a small detailed wiki specifically on senescent cells and their removal. Just a thought.

Mind, I think this would be great.

I am willing to put up $1000 of my personal funds if this becomes a project here at Longecity for an undergrad to do a literature review, and share it with all of us.

A

Edited by Anthony_Loera, 09 November 2011 - 09:35 PM.

[Mind]

I could probably kick in $100 or so, but I want to save some for our possible cryonics research as well.

Thanks so much for the offer Anthony!

I'll put this idea in the "idea section" and see if we can flesh it out. I don't want this thread to drift too off topic, since it has some good momentum right now.

[niner]

Haven't red yet, but V.Gulliano doesn't seem to be too excited about this. His review/analysis: http://www.anti-agin...g-contribution/

I read it and he sounds, well for a lack of a better word - butthurt. Not saying I disagree with most of his observations, on the contrary, but half of the "article" is a rant - "we knew", "we suspected", "we wrote it on a sticky note" - he obviously forgot theories and observations have to be proven before they become a fact.

He is particularly right about one thing though, it's too early to blow this out of proportion, let's wait for a research with untampered mice.

Did we read the same article? Where was all that stuff? Rant? From Vince?

[xEva]

I would bet my hard-earned $ that dry fasting clears senescent cells.

[revenant]

<sub>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</sub>

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.

Edited by revenant, 10 November 2011 - 03:40 AM.

[Elus]

Michael Rae does a review of the article here: http://sens.org/node/2449

[mpe]

Let's say you could kill off senesent cells either by the immune system or chemo. Wouldn't such a large number of dying or dead cells cause significant problems for the elderly by itself ? After all you don't want a successful treatment and dead patient.

[corb]

Let's say you could kill off senesent cells either by the immune system or chemo. Wouldn't such a large number of dying or dead cells cause significant problems for the elderly by itself ? After all you don't want a successful treatment and dead patient.

Shouldn't be a problem if they are removed gradually and efficiently so that the apoptosis doesn't spread to healthy cells - senescent cells cannot reproduce and work sub-efficiently so their loss shouldn't impair the functioning of the organs and tissues, but if they are removed fast in certain connective tissues it could cause a problem.

I would bet my hard-earned $ that dry fasting clears senescent cells.

Fasting doesn't cure arthritis and rheumatism. You just lost your hard earned $.

[revenant]

Let's say you could kill off senesent cells either by the immune system or chemo. Wouldn't such a large number of dying or dead cells cause significant problems for the elderly by itself ? After all you don't want a successful treatment and dead patient.

Even in the very old, senescent cells comprise a low ratio to viable cells. It doesn't take many senescent cells to wreak havoc. If all the senescent cells in your body died off at once, I don't think you would even notice it..until you started feeling better.