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Negligible senescence in animals

negligible senescence ageless animals comparative gerontology rejuvenation regeneration developmental biology aging hormones immune

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#31 nowayout

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Posted 20 August 2015 - 01:50 PM

 

What is pretty clear however, is that despite the average maternal age of first birth being 26-29 for most modern countries, our children aren't starting off any older. Even a small accumulation of age from generation to generation (2%) would mean that we start off with a cellular age of 20 from ancestors 2000 years ago.

 

You are clearly correct.  To some extent this discussion brings one back to the basic question of what aging is.  It seems likely that concentrating excessively on understanding putative aging of the cell (germ or somatic) is the easier thing to do but may also set us up for failure.  It seems likely that much of what we think of as aging lies in accumlation of defects in the collective behavior of cells that individually may have nothing wrong with them, and also involves to a great extent accumulating defects in extracellular structures (e.g. matrices) that may house perfectly healthy cells.

 

By definition, germ cells cannot suffer from these kinds of aging. 


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#32 lucid

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Posted 20 August 2015 - 03:59 PM

 

 

What is pretty clear however, is that despite the average maternal age of first birth being 26-29 for most modern countries, our children aren't starting off any older. Even a small accumulation of age from generation to generation (2%) would mean that we start off with a cellular age of 20 from ancestors 2000 years ago.

 

You are clearly correct.  To some extent this discussion brings one back to the basic question of what aging is.  It seems likely that concentrating excessively on understanding putative aging of the cell (germ or somatic) is the easier thing to do but may also set us up for failure.  It seems likely that much of what we think of as aging lies in accumlation of defects in the collective behavior of cells that individually may have nothing wrong with them, and also involves to a great extent accumulating defects in extracellular structures (e.g. matrices) that may house perfectly healthy cells.

 

By definition, germ cells cannot suffer from these kinds of aging. 

 

Interestingly, trees suffer from aging at an organism level even though they are mostly immune to cellular aging. More interestingly they don't age at a tissue or microscopic level (i.e: extracellular structure) in the outer layer of the tree where the living tissue exists. Trees end up dying from structural decay as the inside of the tree ends up rotting out - the resulting structural failure often results in open wounds that become fatal - otherwise, the outer living cells and tissue are both biologically "young" only the macroscopic structure of the tree is old.



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#33 erzebet

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Posted 02 October 2015 - 07:19 PM

UPDATE: I finally completed the book and published it!

 

Aging is a puzzle to solve.
This process is traditionally studied in a couple of biological models like fruit flies, worms and mice. What all these species have in common is their fast aging. This is excellent for lab budgets. It is a great short-term strategy. Who has time to study species that live for decades?

But lifespan differences among species are magnitudes of order larger than any lifespan variation achieved in the lab. This is the reason for which I studied countless information resources in an attempt to gather highly specialized research into one easy-to-follow book. I wanted to see the forest among the trees. I wanted to expose the aging gap between species in an easy-to-follow and logical sequence. This book is my attempt at doing just that.

What are the mechanisms underlying the aging gap between species? I intentionally chose to write the answer to this question in plain English. Aging research is too important to hide it behind the closed doors of formal scientific jargon. This book could not have existed if green tea, libraries and the Internet were not invented. The amount of data I had to browse in order to keep the essential patterns is huge. Yet this book is not exhaustive. This is not a dry academic textbook. I tried to instill life in a topic that is hugely important for the extension of human lifespan. Only you can decide if I achieved this.

 

createspace-frontcover.jpg

 

You can find it here:

http://longevitylett...etween-species/


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#34 Never_Ending

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Posted 31 January 2016 - 01:53 AM

You are clearly correct.  To some extent this discussion brings one back to the basic question of what aging is.  It seems likely that concentrating excessively on understanding putative aging of the cell (germ or somatic) is the easier thing to do but may also set us up for failure.  It seems likely that much of what we think of as aging lies in accumlation of defects in the collective behavior of cells that individually may have nothing wrong with them, and also involves to a great extent accumulating defects in extracellular structures (e.g. matrices) that may house perfectly healthy cells.

 

 

By definition, germ cells cannot suffer from these kinds of aging. 

 

 

Brings up a good concept but there might be a couple issues with it. The concept you bring up more so applies to a system where the original blueprint is externally determined. Since cells operate within the body in a dynamic but strictly internally controlled manner by the underlying DNA etc this doesn't quite apply.(ie the guiding hand is located within the parts itself).  For a system such as the human body to function in a COLLECTIVELY DYSFUNCTIONAL state would require the individual parts to be somewhat awry.
 

However in an externally designed system you are right that collective dysfunction doesn't mean individual parts are defective.

 

Also small changes in the cell seemingly insignificant can have big effects when interacting collectively such as the ones we see in degenerative diseases as well as aging.

 

So although looking at certain cells is not the whole picture , its not comprehensive , but it's still valid.



#35 erzebet

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Posted 24 February 2016 - 05:23 AM

One thing I studied in depth while writing this book is the link between growth, telomerase and aging. And what I noticed is that expressing telomerase in adult somatic cells is related more to regeneration than to a lack of aging or senescence. But  I won't spoil your joy here when I wrote my conclusions in a logical format here:

http://longevitylett...rase-and-aging/


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#36 corb

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Posted 25 February 2016 - 02:10 AM

One thing I studied in depth while writing this book is the link between growth, telomerase and aging. And what I noticed is that expressing telomerase in adult somatic cells is related more to regeneration than to a lack of aging or senescence. But  I won't spoil your joy here when I wrote my conclusions in a logical format here:

http://longevitylett...rase-and-aging/

 

I recently posted in the telomerase forum about a paper I found, which agrees with that notion.

 

 

This point is reinforced in a separate, yet conceptually connected experiment. Analyses of cells immortalised by telomerase showed late (p50) passage cells to have aged, even without having been subjected to any known senescence inducers (Figure 3). These cells continue to proliferate in culture beyond passage 50 and do not exhibit any signs of senescence, demonstrating that the process of cellular ageing continues unabated in cells whose telomeres were maintained. This shows that removal of the inducers of senescence does not halt ageing, once again underlining the fact that cellular ageing is a process that is distinct from senescence.

 

 

Collectively, these two sets of observation make an effective case for the uncoupling of senescence from cellular ageing. This however, appears at first sight to be inconsistent with the fact that senescent cells contribute to the physical manifestation of organism ageing, as demonstrated elegantly by Baker et al., where removal of senescent cells slowed down ageing. In the light of our observations however, it is proposed that cellular senescence is a state that cells are forced into as a result of external pressures such as DNA damage, ectopic oncogene expression and exhaustive proliferation of cells to replenish those eliminated by external/environmental factors. These senescent cells, in sufficient numbers, will undoubtedly cause the deterioration of tissues, which is interpreted as organism ageing.

 

http://www.impactjou...83&path[]=21162


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#37 eighthman

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Posted 26 February 2016 - 02:09 AM

It seems that the definition of 'senescence' is critical (I hope I haven't missed any explicit discussion of that).  One meaning is just a stage in which growth and division stops. So, that could be like 18 -20 generally, right?  At that 'senescent' stage, you're still young...... so ageing must be the accumulation of damage and junk, not 'senescence'.  Unless your whole body is going to turn into cancer (cell division that doesn't stop), senescence is necessary......and are we making a mistake by associating senescence with being old when it really isn't?



#38 Never_Ending

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Posted 26 February 2016 - 02:29 PM

It seems that the definition of 'senescence' is critical (I hope I haven't missed any explicit discussion of that).  One meaning is just a stage in which growth and division stops. So, that could be like 18 -20 generally, right?  At that 'senescent' stage, you're still young...... so ageing must be the accumulation of damage and junk, not 'senescence'.  Unless your whole body is going to turn into cancer (cell division that doesn't stop), senescence is necessary......and are we making a mistake by associating senescence with being old when it really isn't?

 

When division or replacement of new cells is deteriorated or replaced by less efficient cells then that's basically senescence.... since body does damage on itself by normal functioning it then ages (when adaptation is not self-correcting for this issue)

 

A 20 year old is young AND aging..... (without intervention that's the case). Only when it gets bad enough it starts to show on the appearance.


Edited by Never_Ending, 26 February 2016 - 02:35 PM.


#39 eighthman

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Posted 26 February 2016 - 05:45 PM

Ah, but you see......there is a confusing 'mixing' of two definitions here:  one is just the cessation of growth and division ( typically in youth) and the other definition involves actual deterioration of those cells.  

 

Additionally, could it not be argued that worrying about "senescence" is the wrong approach anyway?  I would think the desired outcome would be apoptosis of degraded cells, then macrophages/Lymph system disposal, then stem cells create replacements WITHIN A CONTEXT of general cessation of division and growth, i.e. "senescence".  So, you begin with general cessation and work from there.

 

We need two treatments thereby to kill off the old crappy stuff and then stimulate new cells to take their place.



#40 xEva

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Posted 26 February 2016 - 07:38 PM

One thing I studied in depth while writing this book is the link between growth, telomerase and aging. And what I noticed is that expressing telomerase in adult somatic cells is related more to regeneration than to a lack of aging or senescence. But  I won't spoil your joy here when I wrote my conclusions in a logical format here:
http://longevitylett...rase-and-aging/


thanks erzebet! that's very interesting. May I ask, what's your native tongue?

I finished reading your page on telomeres and I do have a question re telomere attrition rates in various species -- do you happen to have these data?

Since Maria Blasco study of 2012 that showed that mice have 100 times faster telomere attrition rate than humans, I was wondering if a simple calculation that takes into the account the telomere length at birth and telomere attrition rate correlate with the lifespan of a species. The data missing is the telomere attrition rate for various species. Would you know where I could get it?

thanks :)

Edited by xEva, 26 February 2016 - 07:55 PM.


#41 niner

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Posted 27 February 2016 - 02:50 AM

Ah, but you see......there is a confusing 'mixing' of two definitions here:  one is just the cessation of growth and division ( typically in youth) and the other definition involves actual deterioration of those cells.  

 

Additionally, could it not be argued that worrying about "senescence" is the wrong approach anyway?  I would think the desired outcome would be apoptosis of degraded cells, then macrophages/Lymph system disposal, then stem cells create replacements WITHIN A CONTEXT of general cessation of division and growth, i.e. "senescence".  So, you begin with general cessation and work from there.

 

We need two treatments thereby to kill off the old crappy stuff and then stimulate new cells to take their place.

 

There's some confusion here.  When a child becomes an adult, they stop growing (i.e., development is complete) but cells continue to divide in order to replace cells that have died.  Cellular senescence is a specific state that a cell might attain as a result of the DNA damage response, having critically short telomeres, or various other events.  The senescent state is something of a "zombie" state for cells, in which they no longer divide, but they don't undergo apoptosis like a well-behaved cell would do.  The problem with having non-dividing zombie cells around is that they pump out various toxic molecules, causing problems for the surrounding tissue.  That's why we want to kill them.


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#42 eighthman

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Posted 27 February 2016 - 02:47 PM

"There's some confusion here".  I absolutely agree! The definitions lack precision.

 

https://www.google.c...ence definition

 

Cells simply stop growing and dividing.....as when 18 -20?  Or senescence is defined as the stage between maturity and death, as with a leaf (Merrill dictionary). Or senescence is commonly defined as simply old, the 'zombie state' you talk about.  I assume THAT state is what is commonly meant in aging research rather than a neutral cessation of growth when (still youthful) maturity is reached.

 

So, kill 'em with senolytics and replace 'em with stem cells..... or keep 'em clean with autophagy.  That seems to be the choice.



#43 niner

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Posted 27 February 2016 - 05:04 PM

If you want to understand this, you need to know some basic biology.  "Development" is the playing out of a biological program that begins with a fertilized egg and ends with an adult.  When development is over, cells continue to divide, die, and be replaced by more cells.  Reaching the end of the developmental program does NOT mean that cells stop dividing.

 

The kind of senescence we are talking about is cellular senescence.



#44 eighthman

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Posted 27 February 2016 - 05:24 PM

Uh, yeah, right..

 

From the link you cite: "As such, cellular senescence represents a change in "cell state" rather than a cell becoming "aged" as the name CONFUSINGLY suggests".

 

Exactly.



#45 erzebet

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Posted 28 February 2016 - 08:00 AM

 

One thing I studied in depth while writing this book is the link between growth, telomerase and aging. And what I noticed is that expressing telomerase in adult somatic cells is related more to regeneration than to a lack of aging or senescence. But  I won't spoil your joy here when I wrote my conclusions in a logical format here:
http://longevitylett...rase-and-aging/


thanks erzebet! that's very interesting. May I ask, what's your native tongue?

I finished reading your page on telomeres and I do have a question re telomere attrition rates in various species -- do you happen to have these data?

Since Maria Blasco study of 2012 that showed that mice have 100 times faster telomere attrition rate than humans, I was wondering if a simple calculation that takes into the account the telomere length at birth and telomere attrition rate correlate with the lifespan of a species. The data missing is the telomere attrition rate for various species. Would you know where I could get it?

thanks :)

 

 

Hi xEva,

 

My native tongue is Romanian. (Is the topic order strange or anything with my English?:) )

 

Coming back to the telomere attrition data question, the most extensive paper on comparative telomeres I found is this:

 

http://www.ncbi.nlm....les/PMC2928394/

 

if it is of any help. Please update us with your findings!

 

 



#46 nowayout

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Posted 08 March 2016 - 04:39 PM

 

You are clearly correct.  To some extent this discussion brings one back to the basic question of what aging is.  It seems likely that concentrating excessively on understanding putative aging of the cell (germ or somatic) is the easier thing to do but may also set us up for failure.  It seems likely that much of what we think of as aging lies in accumlation of defects in the collective behavior of cells that individually may have nothing wrong with them, and also involves to a great extent accumulating defects in extracellular structures (e.g. matrices) that may house perfectly healthy cells.

 

 

By definition, germ cells cannot suffer from these kinds of aging. 

 

 

Brings up a good concept but there might be a couple issues with it. The concept you bring up more so applies to a system where the original blueprint is externally determined. Since cells operate within the body in a dynamic but strictly internally controlled manner by the underlying DNA etc this doesn't quite apply.(ie the guiding hand is located within the parts itself).  For a system such as the human body to function in a COLLECTIVELY DYSFUNCTIONAL state would require the individual parts to be somewhat awry.

 

Yes, except that significant pieces of the body are not cells and are not renewed by cells, or cannot be perfectly repaired by even perfectly functioning cells, which can for the most part only act locally and don't have the global awareness that would be required to repair degeneration of macrostructures, e.g., the polymer matrices that shape our organs. An example is the vitreous humor (gel in the eye) which is produced once and for all in infancy and never replenished thereafter; even if all your cells in your adult body were in perfectly working condition, there is no way they can fix the age-related degeneration of the polymers that make up the vitreous humor.

 

Gross aging-related structural changes can be also seen on biopsy of other organs such as the vertebral discs, the skin, the blood vessel walls, the testes, and so on. At least some of these changes occur because of degeneration of long-lasting matrices that are not renewable even by well-functioning cells. Can we really expect even well-functioning cells acting locally to correctly repair large-scale defects in three-dimensional structures once the signals that shape these organs during development are not there any more? In all likelihood it will be easier to grow new organs than to replace the connective framework of an aged organ. 

 

For these reasons, I suspect that, in addition to cell-level pharmaceutical interventions, any successful anti-aging program will probably involve a lot more surgery than is generally talked about.

 



#47 erzebet

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Posted 11 March 2016 - 05:57 PM

The composition of cell membranes varies wildly among species and this may underlie their different metabolic rates and subsequent lifespans.
And depending on their environment, cells will actively modify their permeability by varying the type of fatty acids in their membranes.
Saturated and monounsaturated ones are largely resistant to peroxidation. Polyunsaturated ones - not so much.

 

http://longevitylett...-of-metabolism/


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#48 Never_Ending

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Posted 12 March 2016 - 01:47 AM

 

 

You are clearly correct.  To some extent this discussion brings one back to the basic question of what aging is.  It seems likely that concentrating excessively on understanding putative aging of the cell (germ or somatic) is the easier thing to do but may also set us up for failure.  It seems likely that much of what we think of as aging lies in accumlation of defects in the collective behavior of cells that individually may have nothing wrong with them, and also involves to a great extent accumulating defects in extracellular structures (e.g. matrices) that may house perfectly healthy cells.

 

 

By definition, germ cells cannot suffer from these kinds of aging. 

 

 

Brings up a good concept but there might be a couple issues with it. The concept you bring up more so applies to a system where the original blueprint is externally determined. Since cells operate within the body in a dynamic but strictly internally controlled manner by the underlying DNA etc this doesn't quite apply.(ie the guiding hand is located within the parts itself).  For a system such as the human body to function in a COLLECTIVELY DYSFUNCTIONAL state would require the individual parts to be somewhat awry.

 

Yes, except that significant pieces of the body are not cells and are not renewed by cells, or cannot be perfectly repaired by even perfectly functioning cells, which can for the most part only act locally and don't have the global awareness that would be required to repair degeneration of macrostructures, e.g., the polymer matrices that shape our organs. An example is the vitreous humor (gel in the eye) which is produced once and for all in infancy and never replenished thereafter; even if all your cells in your adult body were in perfectly working condition, there is no way they can fix the age-related degeneration of the polymers that make up the vitreous humor.

 

Gross aging-related structural changes can be also seen on biopsy of other organs such as the vertebral discs, the skin, the blood vessel walls, the testes, and so on. At least some of these changes occur because of degeneration of long-lasting matrices that are not renewable even by well-functioning cells. Can we really expect even well-functioning cells acting locally to correctly repair large-scale defects in three-dimensional structures once the signals that shape these organs during development are not there any more? In all likelihood it will be easier to grow new organs than to replace the connective framework of an aged organ. 

 

For these reasons, I suspect that, in addition to cell-level pharmaceutical interventions, any successful anti-aging program will probably involve a lot more surgery than is generally talked about.

 

 

Sure some structures like that exist like vitreous humor and certain joint cartilages etc... That is not some new set back people have known this for a long time. Also, what about non-cellular intravenous things such as compounds and nanobots....? Are those not possible according to you?(with up coming development)


Edited by Never_Ending, 12 March 2016 - 01:48 AM.


#49 niner

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Posted 12 March 2016 - 02:06 AM

 

Yes, except that significant pieces of the body are not cells and are not renewed by cells, or cannot be perfectly repaired by even perfectly functioning cells, which can for the most part only act locally and don't have the global awareness that would be required to repair degeneration of macrostructures, e.g., the polymer matrices that shape our organs. An example is the vitreous humor (gel in the eye) which is produced once and for all in infancy and never replenished thereafter; even if all your cells in your adult body were in perfectly working condition, there is no way they can fix the age-related degeneration of the polymers that make up the vitreous humor.

 

Gross aging-related structural changes can be also seen on biopsy of other organs such as the vertebral discs, the skin, the blood vessel walls, the testes, and so on. At least some of these changes occur because of degeneration of long-lasting matrices that are not renewable even by well-functioning cells. Can we really expect even well-functioning cells acting locally to correctly repair large-scale defects in three-dimensional structures once the signals that shape these organs during development are not there any more? In all likelihood it will be easier to grow new organs than to replace the connective framework of an aged organ. 

 

For these reasons, I suspect that, in addition to cell-level pharmaceutical interventions, any successful anti-aging program will probably involve a lot more surgery than is generally talked about.

 

Sure some structures like that exist like vitreous humor and certain joint cartilages etc... That is not some new set back people have known this for a long time. Also, what about non-cellular intravenous things such as compounds and nanobots....? Are those not possible according to you?(with up coming development)

 

It's more than just "some structures"-- The extracellular matrix (ECM) is about a third of the body's dry mass.  It might be a challenge to deliver useful therapeutics to the ECM, although at some point I think we will probably be able to do it, at least to some extent.  I don't hold out much hope for "nanobots".  I expect that eventual therapies will be macromolecular.


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#50 erzebet

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Posted 13 March 2016 - 01:31 PM

The extracellular matrix is key in delivering therapies to combat aging. Cells are able to migrate and proliferate thanks to the growth signals sent by the extracellular matrix. When the former becomes full of cross-linked proteins and rigidity sets in, stem cells are unable to act even if viable. Fibrosis is incomplete regeneration and solving it is half the problem in solving aging. Wound healing is complete in fetuses (meaning no scars and the new tissue is as good as the former injured one) and incomplete in adults (the collagen in scars means that the new tissue will never be the same, hence the minute fibroses in vessels, in the heart, in the skin becoming drier and wrinkled and so on).



#51 nowayout

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Posted 14 March 2016 - 05:52 PM

 

 

Yes, except that significant pieces of the body are not cells and are not renewed by cells, or cannot be perfectly repaired by even perfectly functioning cells, which can for the most part only act locally and don't have the global awareness that would be required to repair degeneration of macrostructures, e.g., the polymer matrices that shape our organs. An example is the vitreous humor (gel in the eye) which is produced once and for all in infancy and never replenished thereafter; even if all your cells in your adult body were in perfectly working condition, there is no way they can fix the age-related degeneration of the polymers that make up the vitreous humor.

 

Gross aging-related structural changes can be also seen on biopsy of other organs such as the vertebral discs, the skin, the blood vessel walls, the testes, and so on. At least some of these changes occur because of degeneration of long-lasting matrices that are not renewable even by well-functioning cells. Can we really expect even well-functioning cells acting locally to correctly repair large-scale defects in three-dimensional structures once the signals that shape these organs during development are not there any more? In all likelihood it will be easier to grow new organs than to replace the connective framework of an aged organ. 

 

For these reasons, I suspect that, in addition to cell-level pharmaceutical interventions, any successful anti-aging program will probably involve a lot more surgery than is generally talked about.

 

Sure some structures like that exist like vitreous humor and certain joint cartilages etc... That is not some new set back people have known this for a long time. Also, what about non-cellular intravenous things such as compounds and nanobots....? Are those not possible according to you?(with up coming development)

 

It's more than just "some structures"-- The extracellular matrix (ECM) is about a third of the body's dry mass.  It might be a challenge to deliver useful therapeutics to the ECM, although at some point I think we will probably be able to do it, at least to some extent.  I don't hold out much hope for "nanobots".  I expect that eventual therapies will be macromolecular.

 

 

 

The extracellular matrix is key in delivering therapies to combat aging. Cells are able to migrate and proliferate thanks to the growth signals sent by the extracellular matrix. When the former becomes full of cross-linked proteins and rigidity sets in, stem cells are unable to act even if viable. Fibrosis is incomplete regeneration and solving it is half the problem in solving aging. Wound healing is complete in fetuses (meaning no scars and the new tissue is as good as the former injured one) and incomplete in adults (the collagen in scars means that the new tissue will never be the same, hence the minute fibroses in vessels, in the heart, in the skin becoming drier and wrinkled and so on).

 

Are there any road maps, even in principle, for approaching renewal or replacement of the extracellular matrix? I suppose some work being done in artificial organs for transplant is relevant (I mean the work involving washing out cells from a donor organ leaving the matrix and then repopulating with the recipient's own stem cells; also the research on 3-D printing of matrices.)

 

These would involve surgery, which is feasible for individual organs, but not for, say, the entire vascular system, skin, fat tissue, etc. Is there anything on the horizon on in-place replacement or regeneration of extracellular matrices? Right now this seems so remote as to not even be on the radar, but I'd be happy to be told I'm wrong. 


Edited by nowayout, 14 March 2016 - 05:58 PM.


#52 alc

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Posted 15 March 2016 - 02:11 AM

The extracellular matrix is key in delivering therapies to combat aging ...

 

You might be familiar with Histogen's work on this ECM. If not here is the link:

 

"Multipotent Cell-Secreted Extracellular Matrix Supports Cartilage Formation"

 

http://www.histogen....s_events.htm#52

 

they do interesting work.

(from the article above

"Histogen has previously shown that hypoxia-induced multipotent cells produce soluble and insoluble materials that contain components associated with stem cell niches in the body and with scarless healing. These proteins include a variety of laminins, osteonectin, decorin, hyaluronic acid, collagen type IV, SPARC, CXCL12, NID1, NID2, NOTCH2, tenascin, thrombospondin, fibronectin, versican, and fibrillin-2. In vitro studies further demonstrated that the CCM and ECM promote the adhesion, proliferation and migration of bone marrow-derived human mesenchymal stem cells (MSCs)."

)

 

This might  be helpful on your research.

 

btw:  Bucurestiul are zone foarte frumoase (dar si unele nu prea intretinute ... ) Dar cel mai mult imi plac constructiile din perioada interbelica. Mut noroc cu studiile in gero + reverse aging. Am sa-ti cumpar/citesc cartea in viitor.


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#53 erzebet

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Posted 15 March 2016 - 05:35 AM

alc, thank you for the research link and for your words in Romanian :)



#54 alc

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Posted 16 March 2016 - 10:06 PM

@ erzebet - thanks, I sent you a PM.



#55 Never_Ending

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Posted 17 March 2016 - 06:52 PM

 

Are there any road maps, even in principle, for approaching renewal or replacement of the extracellular matrix? I suppose some work being done in artificial organs for transplant is relevant (I mean the work involving washing out cells from a donor organ leaving the matrix and then repopulating with the recipient's own stem cells; also the research on 3-D printing of matrices.)
 

 

These would involve surgery, which is feasible for individual organs, but not for, say, the entire vascular system, skin, fat tissue, etc. Is there anything on the horizon on in-place replacement or regeneration of extracellular matrices? Right now this seems so remote as to not even be on the radar, but I'd be happy to be told I'm wrong

 

 

You're wrong, just joking :)  But to be serious I think that the answer is that they're working on it. In theory it seems they can find composition differences among the different structures and find compounds that would seek out the similar composition and work by injection to target and reinforce these areas of the matrix. I would doubt that it has to be surgery related because surgery tends to be crude compared to  injections and the whole idea is to rebuild someone evenly not  stick in parts and pieces.

edit- but maybe parts and pieces are the early steps
 


Edited by Never_Ending, 17 March 2016 - 06:54 PM.


#56 erzebet

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Posted 23 March 2016 - 03:26 PM

And speaking of aging and the extracellular matrix, I wrote another blog post on the regeneration gap between the young and the old and the two cell types responsible for it: the fibroblast and the platelet.

 

 

http://longevitylett...onsible-for-it/


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#57 Logjam

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Posted 22 April 2016 - 04:36 PM

Why surgery?  There are interesting datapoints on p21 that speak to much less invasive therapies.  For example, mice that don't express p21 will regrow limbs.  Transiently suppress p21 and you might get better healing.  The program is still there.  It's just been switched off by things like p15, p16, and p21 that regulate the cell cycle.

 

http://www.pnas.org/...3/5845.abstract

 

It's a series of evolved mechanisms and backup plans to stop uncontrolled growth in a complex organism with lots of feedback loops that might cause said growth by sending errant instructions.

 

For example, you could say it would be nice if we could regrow certain endocrine-related cells, but a feedback loop and lack of regulation of growth causes acromegaly.

 

The body wants to stop that.  When it fails, the results can be dire.  We're big warm blooded animals with quick metabolisms (esp. in the brain) and lots of complexity.  We probably need these 'checkpoints.'  Maybe lobsters don't?

 

 

 

You are clearly correct.  To some extent this discussion brings one back to the basic question of what aging is.  It seems likely that concentrating excessively on understanding putative aging of the cell (germ or somatic) is the easier thing to do but may also set us up for failure.  It seems likely that much of what we think of as aging lies in accumlation of defects in the collective behavior of cells that individually may have nothing wrong with them, and also involves to a great extent accumulating defects in extracellular structures (e.g. matrices) that may house perfectly healthy cells.

 

 

By definition, germ cells cannot suffer from these kinds of aging. 

 

 

Brings up a good concept but there might be a couple issues with it. The concept you bring up more so applies to a system where the original blueprint is externally determined. Since cells operate within the body in a dynamic but strictly internally controlled manner by the underlying DNA etc this doesn't quite apply.(ie the guiding hand is located within the parts itself).  For a system such as the human body to function in a COLLECTIVELY DYSFUNCTIONAL state would require the individual parts to be somewhat awry.

 

Yes, except that significant pieces of the body are not cells and are not renewed by cells, or cannot be perfectly repaired by even perfectly functioning cells, which can for the most part only act locally and don't have the global awareness that would be required to repair degeneration of macrostructures, e.g., the polymer matrices that shape our organs. An example is the vitreous humor (gel in the eye) which is produced once and for all in infancy and never replenished thereafter; even if all your cells in your adult body were in perfectly working condition, there is no way they can fix the age-related degeneration of the polymers that make up the vitreous humor.

 

Gross aging-related structural changes can be also seen on biopsy of other organs such as the vertebral discs, the skin, the blood vessel walls, the testes, and so on. At least some of these changes occur because of degeneration of long-lasting matrices that are not renewable even by well-functioning cells. Can we really expect even well-functioning cells acting locally to correctly repair large-scale defects in three-dimensional structures once the signals that shape these organs during development are not there any more? In all likelihood it will be easier to grow new organs than to replace the connective framework of an aged organ. 

 

For these reasons, I suspect that, in addition to cell-level pharmaceutical interventions, any successful anti-aging program will probably involve a lot more surgery than is generally talked about.

 

 


Edited by Logjam, 22 April 2016 - 05:00 PM.

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#58 Logjam

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Posted 22 April 2016 - 04:48 PM

Somewhat interestingly, p21 is also a checkpoint on the way to acromegaly:

http://www.pnas.org/.../17498.full.pdf

 

So you might regrow a limb, but if you do that for too long, you could end up with an adenoma, a really malicious "benign" tumor that will cause massive dysregulation and feedback loops you can't stop.  In terms of cost-benefit, that seems like a good deal.  Acromegaly sucks, so it's a priority to stop it.  That could relate to why true malignancies of the pituitary are rare.

 

High pituitary p21 levels appear to promote senescence and restrain pituitary tumor growth and may underlie the failure of invariably benign pituitary tumors to progress to true malignancy.

 

Telomeres are probably the last "hack" checkpoint on cell recursion, but there's a bunch of stuff from various other systems that says replicate or don't replicate.  And cells express tumor suppressors like the family of pXX's to decide if they will respond.

 

Regulating pXX's to get better growth is a potential vector for anti-aging, and we may be surprised by what programs we can turn on with small molecules.


Edited by Logjam, 22 April 2016 - 05:10 PM.


#59 erzebet

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Posted 29 April 2016 - 02:20 PM

Your mention of p21 here is interesting, however I checked the paper you provided thinking I'll stumble upon appendage regeneration (like limb regeneration) in that strain of mice, but they regenerate their ear lobe closure only.

 

Any woman who hasn't been wearing ear rings for a long time knows that the ear lobe hole closes after a couple of years.

 

 

Why surgery?  There are interesting datapoints on p21 that speak to much less invasive therapies.  For example, mice that don't express p21 will regrow limbs.  Transiently suppress p21 and you might get better healing.  The program is still there.  It's just been switched off by things like p15, p16, and p21 that regulate the cell cycle.

 

http://www.pnas.org/...3/5845.abstract

 

It's a series of evolved mechanisms and backup plans to stop uncontrolled growth in a complex organism with lots of feedback loops that might cause said growth by sending errant instructions.

 

For example, you could say it would be nice if we could regrow certain endocrine-related cells, but a feedback loop and lack of regulation of growth causes acromegaly.

 

The body wants to stop that.  When it fails, the results can be dire.  We're big warm blooded animals with quick metabolisms (esp. in the brain) and lots of complexity.  We probably need these 'checkpoints.'  Maybe lobsters don't?

 

 

 

You are clearly correct.  To some extent this discussion brings one back to the basic question of what aging is.  It seems likely that concentrating excessively on understanding putative aging of the cell (germ or somatic) is the easier thing to do but may also set us up for failure.  It seems likely that much of what we think of as aging lies in accumlation of defects in the collective behavior of cells that individually may have nothing wrong with them, and also involves to a great extent accumulating defects in extracellular structures (e.g. matrices) that may house perfectly healthy cells.

 

 

By definition, germ cells cannot suffer from these kinds of aging. 

 

 

Brings up a good concept but there might be a couple issues with it. The concept you bring up more so applies to a system where the original blueprint is externally determined. Since cells operate within the body in a dynamic but strictly internally controlled manner by the underlying DNA etc this doesn't quite apply.(ie the guiding hand is located within the parts itself).  For a system such as the human body to function in a COLLECTIVELY DYSFUNCTIONAL state would require the individual parts to be somewhat awry.

 

Yes, except that significant pieces of the body are not cells and are not renewed by cells, or cannot be perfectly repaired by even perfectly functioning cells, which can for the most part only act locally and don't have the global awareness that would be required to repair degeneration of macrostructures, e.g., the polymer matrices that shape our organs. An example is the vitreous humor (gel in the eye) which is produced once and for all in infancy and never replenished thereafter; even if all your cells in your adult body were in perfectly working condition, there is no way they can fix the age-related degeneration of the polymers that make up the vitreous humor.

 

Gross aging-related structural changes can be also seen on biopsy of other organs such as the vertebral discs, the skin, the blood vessel walls, the testes, and so on. At least some of these changes occur because of degeneration of long-lasting matrices that are not renewable even by well-functioning cells. Can we really expect even well-functioning cells acting locally to correctly repair large-scale defects in three-dimensional structures once the signals that shape these organs during development are not there any more? In all likelihood it will be easier to grow new organs than to replace the connective framework of an aged organ. 

 

For these reasons, I suspect that, in addition to cell-level pharmaceutical interventions, any successful anti-aging program will probably involve a lot more surgery than is generally talked about.

 

 

 


Regeneration is growth plus differentiation plus restoring polarity in the organism. What primitive animals do better than us is restoring polarity even when the body has been separated in its constituent cells. And what complex animals do better is differentiation, especially when young and healthy.

 

http://longevitylett...imals-and-back/

 

Regeneration-simple-vs-complex.jpg

 



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#60 Logjam

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Posted 29 April 2016 - 03:35 PM

I believe they used that as a benchmark to keep the study short RE: "Using the ear hole closure phenotype, a genetically mapped and reliable quantitative indicator of regeneration in the MRL mouse."  The data are there in other studies that knocking down p21 has the effect:

 

The MRL mouse and its close relatives (“healer” strains) have unique healing and regenerative capabilities, including the complete closure and tissue regeneration of through-and-through ear hole puncture wounds with the formation of a circular blastema (3), the regrowth of articular cartilage (4), and the partial regeneration of amputated digits (56).

 

 The functional role of p21 has been demonstrated in a p21 knockout mouse, which displays the same range of cellular effects as seen in the MRL mouse and reproduces appendage regeneration in vivo.

 

Maybe I should have cited those other references instead.  What's clear to me is that knocking down tumor suppressors transiently can cause regrowth and healing in some cases (at least in mice).  We should look for things to do that.  It's worth testing in humans eventually.  Doing it for more time than necessary or more time than evolution has decided the window should be will probably cause cancer or increase the odds at least, but if it stimulates brain cells or nerve cells or beta cells, it might be worth it. 


Edited by Logjam, 29 April 2016 - 04:09 PM.

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Also tagged with one or more of these keywords: negligible senescence, ageless animals, comparative gerontology, rejuvenation, regeneration, developmental biology, aging, hormones, immune

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