LONGECITY

http://www.grg.org/r...yflickChapt.htm

People here may not agree with Hayflicks opinions about life extension but is this a good article to use when reading about aging?

How would you respond to his arguments about the possibilities of life extension?

Anybody who've discovered this thread?

...the approximate 25-year increase in life expectancy that occurred in the United States from [1900 - 2000] will be impossible to achieve in the 21st Century, if ever.

His confidence that something can't be accomplished overreaches as he can't predict what the future of advancing technology holds and when new approaches to tackling complexity of aging might emerge.

It's understandable how one can become pessimistic when he/she spends an entire career studying a phenomenon but no clear answers present themselves as to how changes can be implemented. This is why it's always a good idea to pass the torch to the next generation of researchers / dreamers who tend to be more optimistic, even if more naive. They can pour over the prior generation's research and build new tools to solve the problems that seemed intractable using new technologies, datapoints and techniques.

The only known way that the aging process can be circumvented in inanimate objects is by the replacement of old parts with new. Although parts replacement is possible in organisms including humans, the only certainty is that replacing old organs with young organs increases life expectancy. This result is no different from the many other medical, hygienic, and safety procedures that have been implemented to avoid or postpone death. None treat the fundamental process of aging.

I tend to agree that damage control isn't a sufficient strategy. We can reap significant returns from simply replacing broken parts and repairing damaged endpoints but it's only a stopgap solution that buys us time. Even finding molecular targets that upregulate damage repair mechanisms or slow the deleterious changes and activating those for the sake of prevention will only work for so long. Ultimately we must replace the functional components themselves with more robust synthetic versions as the current versions are far too unreliable and expensive to maintain for those that want to live well beyond what evolution provides us.

LH's discovery of cell division limits looks more and more ordinary when you read some of the inane stuff that he writes like:

"Aging is not a programmed process governed directly or entirely by genes. It is mostly those who work with invertebrates who have interpreted their findings to involve genes in the aging process. They have failed to appreciate that the genes that they have identified are involved in longevity determination and not in aging."

Conboy et al and their work on heterochronic parabiosis (in mammals) have pretty much blown that one out of the water.

LH's discovery of cell division limits looks more and more ordinary when you read some of the inane stuff that he writes like:

"Aging is not a programmed process governed directly or entirely by genes. It is mostly those who work with invertebrates who have interpreted their findings to involve genes in the aging process. They have failed to appreciate that the genes that they have identified are involved in longevity determination and not in aging."

Conboy et al and their work on heterochronic parabiosis (in mammals) have pretty much blown that one out of the water.

But aging isn't caused by "death genes" in humans? It is not evolutionary intent but evolutionary neglect........

Hayflick seems very pessimistic about human aging. Why? Doesn't he believe he may have a fighting chance at living very long or even a small chance at immortality if he champions our cause?

One may understand why Hayflick is like he is having worked about aging his whole life without finding any solution to it.

You would probably need to read the entire article to confirm but from the title, apparently he changed his mind recently...

LH 2007: Biological Aging Is No Longer an Unsolved Problem

Could anyone access that article? Apparently he continues working although he's 80 years old although being against the idea of life extension. a little double-natured........

80 years old huh, he sure tries to live long, but he may just be against the idea of immortality and thinks that's not scientifically feasible, but of course every sane person wants to live as long as he/she could including hayflick

if Hayflick has no religion or any fairy-tale backup to ease his mind ( I doubt he believes in god or heaven), as he approaches the very end of his life, he must rethink his views. anyone who does not want to die would likely change mind on things

maybe we've got ourselves a deathbed convert
Edited by HYP86, 01 July 2008 - 02:20 AM.

LH's discovery of cell division limits looks more and more ordinary when you read some of the inane stuff that he writes like:

"Aging is not a programmed process governed directly or entirely by genes. It is mostly those who work with invertebrates who have interpreted their findings to involve genes in the aging process. They have failed to appreciate that the genes that they have identified are involved in longevity determination and not in aging."

Conboy et al and their work on heterochronic parabiosis (in mammals) have pretty much blown that one out of the water.

But aging isn't caused by "death genes" in humans? It is not evolutionary intent but evolutionary neglect........

Evolutionary neglect should see a stochastic disruption of physiological processes. Evolutionary intent, on the other hand, would proceed along a well defined trajectory (development and aging).

There are many death genes in humans and all life forms. The most obvious ones are those that cause apoptosis. A process that occurs with great frequency during development.

Apoptosis is a finely orchestrated event, i.e, it is programmed to respond according to a specific range of stimuli. Consider the phenomenon first described by the author of the paper being discussed (the Hayflick limit). With each cell division there is the ticking of a molecular clock. When the clock reaches a certain time, apoptosis is triggered. It is not hard to see the evolutionary intent on a single cell level. But what about an entire organism?

Aging, is also finely orchestrated. It is brought about by a systematic dampening down of stem niches that result in a reduction of regenerative potential permitting metabolic byproduct accumulation to reach toxic concentrations which eventually overwhelm tissues and organs. Conboy et al have shown that this dampening down effect is reversible. This would not be possible unless the dampening process was controlled - there are specific steps that stem cell niches follow as part of their aging subroutine.

LH's discovery of cell division limits looks more and more ordinary when you read some of the inane stuff that he writes like:

"Aging is not a programmed process governed directly or entirely by genes. It is mostly those who work with invertebrates who have interpreted their findings to involve genes in the aging process. They have failed to appreciate that the genes that they have identified are involved in longevity determination and not in aging."

Conboy et al and their work on heterochronic parabiosis (in mammals) have pretty much blown that one out of the water.

But aging isn't caused by "death genes" in humans? It is not evolutionary intent but evolutionary neglect........

Evolutionary neglect should see a stochastic disruption of physiological processes. Evolutionary intent, on the other hand, would proceed along a well defined trajectory (development and aging).

There are many death genes in humans and all life forms. The most obvious ones are those that cause apoptosis. A process that occurs with great frequency during development.

Apoptosis is a finely orchestrated event, i.e, it is programmed to respond according to a specific range of stimuli. Consider the phenomenon first described by the author of the paper being discussed (the Hayflick limit). With each cell division there is the ticking of a molecular clock. When the clock reaches a certain time, apoptosis is triggered. It is not hard to see the evolutionary intent on a single cell level. But what about an entire organism?

Aging, is also finely orchestrated. It is brought about by a systematic dampening down of stem niches that result in a reduction of regenerative potential permitting metabolic byproduct accumulation to reach toxic concentrations which eventually overwhelm tissues and organs. Conboy et al have shown that this dampening down effect is reversible. This would not be possible unless the dampening process was controlled - there are specific steps that stem cell niches follow as part of their aging subroutine.

Is aging orchestrated and "controlled" or is it rather the result of an arms race going on between competing regulatory mechanisms that are seeking their own optimal gene expression patterns within various organ systems? In this scenario, when one of the regulatory networks loses so does the organism as gene expression swings too far in one direction and homeostatic balance is lost thus leading to the symptoms, including loss in regenerative potential, you describe.

LH's discovery of cell division limits looks more and more ordinary when you read some of the inane stuff that he writes like:

"Aging is not a programmed process governed directly or entirely by genes. It is mostly those who work with invertebrates who have interpreted their findings to involve genes in the aging process. They have failed to appreciate that the genes that they have identified are involved in longevity determination and not in aging."

Conboy et al and their work on heterochronic parabiosis (in mammals) have pretty much blown that one out of the water.

But aging isn't caused by "death genes" in humans? It is not evolutionary intent but evolutionary neglect........

Evolutionary neglect should see a stochastic disruption of physiological processes. Evolutionary intent, on the other hand, would proceed along a well defined trajectory (development and aging).

There are many death genes in humans and all life forms. The most obvious ones are those that cause apoptosis. A process that occurs with great frequency during development.

Apoptosis is a finely orchestrated event, i.e, it is programmed to respond according to a specific range of stimuli. Consider the phenomenon first described by the author of the paper being discussed (the Hayflick limit). With each cell division there is the ticking of a molecular clock. When the clock reaches a certain time, apoptosis is triggered. It is not hard to see the evolutionary intent on a single cell level. But what about an entire organism?

Aging, is also finely orchestrated. It is brought about by a systematic dampening down of stem niches that result in a reduction of regenerative potential permitting metabolic byproduct accumulation to reach toxic concentrations which eventually overwhelm tissues and organs. Conboy et al have shown that this dampening down effect is reversible. This would not be possible unless the dampening process was controlled - there are specific steps that stem cell niches follow as part of their aging subroutine.

I've not heard about this

Any other studies than Conboy backing this up?

I've not heard about this

http://www.scienceda...80615142255.htm

Any other studies than Conboy backing this up?

Backing what up? mygene's assertion that there is a controlled aging subroutine is speculation on his part. The Conboy research shows that gene expression levels can be adjusted such that HSCs effectiveness can be improved by tinkering with particular pathways. It says nothing about an aging program that is being followed. There are several recent papers that demonstrate that stem cells show signs of aging and loss in fidelity. There is much more to aging than declining stem cell activity though.

Here's a pretty good read about stem cell aging...

I've not heard about this

Any other studies than Conboy backing this up?

Sure, with aging we get enhanced adipogenesis and decreased osteoblastogenesis. That is stem cells from the same pool increasingly favor turning into fat rather than bone (Justensen). With aging the lymphoid and myeloid potential of hematopoietic stem cells is reduced (see Linton and also Kim). Essentially, the microenvironment causes stem cells to follow a defined aging phenotype which is characterized initially by a skewing towards altered differentiation potential and ends with senescence and apoptosis. This is not particularly new. What Conboy did was to take these observations a step further and ask the question: can we reverse the aging phenotype in a predictable fashion by altering the microenvironment? And the answer is yes. She first demonstrated this by connecting the circulatory systems of an old and young mouse, a study which was also published in Nature in 2005. More recently she manipulated TGFb and Smad expression directly.

Does this support the notion that aging is programmed? If a program is a defined set of instructions that are implicitly followed and we can demonstrate that a cell will follow such an instruction set every time then the answer is yes.

mygene's assertion that there is a controlled aging subroutine is speculation on his part.

It is the conclusion implied by the authors of the Nature paper.

The Conboy research shows that gene expression levels can be adjusted such that HSCs effectiveness can be improved by tinkering with particular pathways.

HSCs = hematopoietic stem cells - these reside in bone marrow. Conboy looked at satellite cells which is a muscle stem cell. Her work is associated with these types of cells. By effectiveness you are meaning she reversed their aging phenotype.

It says nothing about an aging program that is being followed.

Is a program a sequence of instructions?

There are several recent papers that demonstrate that stem cells show signs of aging and loss in fidelity.

What Conboy did was reverse this.

There is much more to aging than declining stem cell activity though.

No doubt. However, it is difficult to conceive of many pathologies that would manifest in a sufficiently youthful cellular environment, i.e. an environment where stem cells did not exhibit aging.

By your criteria, every molecular change in an organism is programmed aging as they are all effectively just precursors to the ultimate changes that have deleterious changes.

Programmed aging implies an intent to bring about an aging phenotype which is characterized as a lower chance of an organisms survival.

This particular gene expression change could have easily been for other functional goals, e.g. to suppress oncogenes or proto-oncogenes rather than to guide the organism towards one with a lower chance of survival in a stepwise fashion.

By your criteria, every molecular change in an organism is programmed aging as they are all effectively just precursors to the ultimate changes that have deleterious changes.

Firstly, separate the term program from aging. It's important to appreciate that many of these aging processes, just like developmental ones, appear to follow a program. By program I mean changes that can be mapped as a distinct pattern able to be manipulated or reversed (subject to technical capacity and detailed knowledge of that pattern).

Programmed aging implies an intent to bring about an aging phenotype which is characterized as a lower chance of an organisms survival.

If something appears to follow a program then from an evolutionary consideration it follows that such a program confers a selective advantage. If you read Dawkins' Selfish Gene it may spare you the hypothesizing. He explains it pretty well. Single sentence summary: fitness of the gene pool has a higher priority than the fitness of the organism.

This particular gene expression change could have easily been for other functional goals, e.g. to suppress oncogenes or proto-oncogenes rather than to guide the organism towards one with a lower chance of survival in a stepwise fashion.

If so, there would be evidence of satellite cell transformation (tumorigenesis), which was not the case. Also helpful to consider was that satellite cells in young models were directed to an aging phenotype by a single growth factor and when this factor is inhibited in old cells it rejuvenates repair function.

By your criteria, every molecular change in an organism is programmed aging as they are all effectively just precursors to the ultimate changes that have deleterious changes.

Firstly, separate the term program from aging. It's important to appreciate that many of these aging processes, just like developmental ones, appear to follow a program. By program I mean changes that can be mapped as a distinct pattern able to be manipulated or reversed (subject to technical capacity and detailed knowledge of that pattern).

Programmed aging implies an intent to bring about an aging phenotype which is characterized as a lower chance of an organisms survival.

If something appears to follow a program then from an evolutionary consideration it follows that such a program confers a selective advantage. If you read Dawkins' Selfish Gene it may spare you the hypothesizing. He explains it pretty well. Single sentence summary: fitness of the gene pool has a higher priority than the fitness of the organism.

This particular gene expression change could have easily been for other functional goals, e.g. to suppress oncogenes or proto-oncogenes rather than to guide the organism towards one with a lower chance of survival in a stepwise fashion.

If so, there would be evidence of satellite cell transformation (tumorigenesis), which was not the case. Also helpful to consider was that satellite cells in young models were directed to an aging phenotype by a single growth factor and when this factor is inhibited in old cells it rejuvenates repair function.

So you meana ging is a natural developing process just like puberty?

So you mean aging is a natural developing process just like puberty?

Yes, it appears to follow a distinct pattern characterized by increased inhibition in adult stem cell regenerative function. When those stem cells are taken out of the 'aging' microenvironment their regenerative function returns to youthful levels. Just like with telomeric attrition in telomerase-negative cells it is suggested there is also a sensitivity to aging associated increased levels of systemic and localized TGF-beta in the stem cell microenvironment. Stem cells respond to increased levels of TGF-beta by shutting down.

There is a hypothesis stating that increased inhibition is necessary to reduce the risk of cancer because some older stem cells grow unstable with time. But young stem cells can also become tumorigenic when cultured in an inappropriate environment (i.e. embryonic stem cells). In any case, if a stem cell does not make a sufficient investment in genomic maintenance and metabolic byproduct clearance, its checkpoints will direct it to enter senescence and apoptosis.

From an evolutionary perspective it is energetically favorable to gradually shut down the regenerative capacity in an organism rather than sustain high levels of molecular activity to maintain stability. After all, once the genes have been passed along and recombined there is no pressing need to keep the organism alive for much longer.

From an evolutionary perspective it is energetically favorable to gradually shut down the regenerative capacity in an organism rather than sustain high levels of molecular activity to maintain stability.

What is the selective pressure that would cause evolution to invest any opportunity cost in gradually killing an organism rather than simply introducing a organism-wide kill-switch that fires based on some biological clock? ... Or better yet, why wouldn't it just nature do its work through thermodynamics? It's terribly good at reducing just about any system down into its component parts.

After all, once the genes have been passed along and recombined there is no pressing need to keep the organism alive for much longer.

This supports the argument that evolution doesn't care about aged organisms. E.g. Strength of selection declines with age (Medwar, 1946). Outside of introducing Lamarckism into the picture, how would post-reproductive lifespans be guided by evolution? This would imply that some environmental signals driven by population, resource availability or the smell of old persons would somehow alter the genetic programming of younger organisms still in their reproductive years.

A quick pubmed search shows that the the TGF-beta family of proteins has numerous functions across many cell types. Its regulation with age could be for many other reasons. For example, these stem cells may react to increasing TGF-beta as a natural swtiching signal by existing cells indicating that it has enough cells to peform the desired function. No more muscle cells thank you, we have enough to do the job. TGF-beta levels may be inadvertently increasing with age in this niche simply because the aged cells regulatory mechanisms are breaking down due to a loss in reliability and evolution didn't invest in mechanisms to sustain TGF-beta levels more optimally due to its loss of visibility into this phenomenon.
Edited by maestro949, 07 July 2008 - 01:40 AM.