Science of Ageing

Discussions on topics related to biochemistry and molecular biology, functional genomics, etc.

Science of Ageing

Postby BioWizard on May 30th, 2009, 12:25 am 

Very often, I hear people talk about ageing in terms of entropic decay, as if ageing of a multicellular organism is nothing more than wear and tear, a machine getting rusty over time until it breaks down. Well, it's not. Ageing is an active cellular program, much like differentiation and apoptosis. Cells age after they differentiate and turn senescent. Germ cells don't age, and because they maintain genetic continuity over generations, ageing would defeat the purpose and thus did not evolve to occur in those cells. Other cells that evade the ageing program are cancer cells (which highlights an important role for cellular ageing in multicellular organisms - tumor control).

So many misconceptions surround this subject, a lot of which are viciously capitalized on my the cosmetic and food industry. Antioxidants and reactive oxygen species. Oxidative damage, symptom or cause? How do telomeres factor into all of this?

A lot of questions with no single reliable source of conclusive answers. Because of that, I've decided to start this thread, in which I wish to explore the most recent scientific findings on the subject and tease out information from misinformation, fact from media/industry myth. Everyone is welcome to contribute provided only credible sources are used (only papers from peer reviewed journals). Questions are welcome along the way, but please try not to derail the thread with too many questions. If you would like to discuss any particular point with any details, please start a separate thread for it.
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Re: Science of Ageing

Postby Paralith on May 30th, 2009, 1:29 am 

One of my professors is developing a life history based theory of aging, which unfortunately is as yet unpublished, so I can't point you towards any supporting information at this point. I won't go into it in detail myself, but part of his theory involves an increasing cost to maintenance and repair of somatic structures as the life course goes on - over time the body experiences various insults from disease, injury, stress, and the build up of metabolic wastes, and the cost of maintaining a well-functioning body in the face of these insults increases over time. At least, that's how I understand it, and I could be understanding it wrong. So Bio, are you basically saying that this isn't true? I have to say that seems kind of counter-intuitive to me. We see every day humans experiencing increasing decrepitude as they age, even long before they enter stages we would call old or elderly. Children and teenagers seem to bounce back from injury much more easily than thirty and fourty year olds. You're saying this is all specifically programmed, and not (at least partially) the result of wear and tear on the body?
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Re: Science of Ageing

Postby BioWizard on May 30th, 2009, 7:39 am 

Paralith wrote:but part of his theory involves an increasing cost to maintenance and repair of somatic structures as the life course goes on - over time the body experiences various insults from disease, injury, stress, and the build up of metabolic wastes, and the cost of maintaining a well-functioning body in the face of these insults increases over time. At least, that's how I understand it, and I could be understanding it wrong. So Bio, are you basically saying that this isn't true?


I'm saying it might be missing the point, and that ageing is a lot more than entropic decay and simple wear and tear. When you're young, your injuries get repaired faster, and then slower and slower as you grow older, until they stop and rapid breakdown kicks in. In cells, decay is always taking place. Proteins are being unfolded and degraded, DNA and RNA are being oxidized and turned over, and so on. Everything is constantly decaying and turned over, starting from when you are a single cell. However, the difference between cells in a young organism and cells in an old organism is that in the latter, the production of new cellular components to replace the damaged ones slows down, and the rate of elimination of damaged components slows down too, leading to accumulation of oxidized and damaged molecules - aka cellular ageing. On the level of tissue, decay and turn over is also no stranger. When you are young, your cells decay and die, probably at even a higher rate than when you are old. However, the supply of cells simply gets replenished faster, and the tissue remains healthy (assuming no disease factors). As one ages, the rate of producing new cells seems to slow down, and since the new cells produced are also tired ones, with accumulated damage (from the previously mentioned phenomenon of cellular ageing), the tissue gets less and less healthy over time. Which is probably why organs with lowest rates of cellular turnover are the most suscupetible to tissue/organ ageing when cellular ageing programs kick in.

As for cost/maintenance issues, I think that is more related to the evolutionary processes that shape the ageing phenomenon (clearly not all organisms age the same, and some don't at all), and I would like to explore that too later, but probably in a separate thread in Biology. Here, I want to focus on the mechanisms and biochemical triggers of the ageing process (program?).

Paralith wrote:I have to say that seems kind of counter-intuitive to me. We see every day humans experiencing increasing decrepitude as they age, even long before they enter stages we would call old or elderly. Children and teenagers seem to bounce back from injury much more easily than thirty and fourty year olds. You're saying this is all specifically programmed, and not (at least partially) the result of wear and tear on the body?


Wear and tear and entropic decay are not the cause of ageing, rather they're a property of ageing, a mediator. But entropic decay is a property of the universe and everything in it. Clearly, however, not everything decays all the time, and you can go in the opposite direction if you provide sufficient enthalpy to counteract the effect of entropy. So it's not like entropy kicks in at increasing amounts as one ages, it's always there. Everything decays unless you put in energy to replenish and repair. What does change as you age however is the rate at which new components are made and damaged components are removed, and we know that rates of cellular events depend on the activity of the enzymes catalyzing them. This can be affected by the rates of expression of the genes coding them, the structure of the substrates, and the rate of degradation of the enzymes, amongst other things, all events that are known to be controllable by cellular programs. If it were simply passive entropic decay, all cell types would age the same way and at the same rate, but they don't. Thus, equating entropic decay with ageing is equating a phenomenon with one of its symptoms, and possibly overlooking the real triggers and mechanisms. These are some of the ideas and controversies I would like to explore by checking them against the scientific literature.
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Re: Science of Ageing

Postby ronjanec on May 30th, 2009, 8:44 am 

I was wrong when I made the blanket statement that "a person basically ages because of the cumlative effects of internal and external wear and tear on the body", and I now understand that there are other factors involved in this. I still believe wear and tear over time has something to do with this, but it is not the only reason a person or thing ages like I implied in my previous post. I will of course adjust my comments on this in the future.
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Re: Science of Ageing

Postby Paralith on May 30th, 2009, 11:39 am 

BioWizard wrote:If it were simply passive entropic decay, all cell types would age the same way and at the same rate, but they don't. Thus, equating entropic decay with ageing is equating a phenomenon with one of its symptoms, and possibly overlooking the real triggers and mechanisms.


Thank you Bio, your post cleared that up perfectly, and I especially like the section I quoted above. Perhaps when the subject of aging comes up in Bio I'll try to summarize my professor's ideas on the evolution of aging.
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Re: Science of Ageing

Postby BioWizard on May 30th, 2009, 1:28 pm 

Paralith wrote:Thank you Bio, your post cleared that up perfectly, and I especially like the section I quoted above. Perhaps when the subject of aging comes up in Bio I'll try to summarize my professor's ideas on the evolution of aging.


Excellent. Next, I would like to start with the involvement of telomeres with cellular ageing an senescence. If you biologists have any interesting papers with comparative studies, go ahead and link them. Otherwise I will start digging into pubmed after I'm done harvesting my cultures.
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Re: Science of Ageing

Postby psionic11 on May 30th, 2009, 7:19 pm 

Some questions, if I may. Scarring and ageing.

1) As I understand it, telomeres "degrade" over time, so that over an organism's lifetime, global changes take place which we see as an aging organism and aging tissues. This is in addition to effects from metabolism. Correct so far?

2) Many environmental factors -- overexposure to sunlight, hazardous chemicals, loss of mass, nutritional deficiencies -- interfere with the normal healing process, leaving scars or missing parts on the organism. At the heart of the scar is damaged or missing DNA, which is why the regeneration process doesn't result in complete regeneration. Correct?

So, besides normal wear and tear at the cellular, resulting in a cumulative inability to correctly render complete regeneration at the macroscopic level, there are the telomeres and other drastic events which contribute to or hasten the ageing process. Also correct?

Basically, in theory, inorder to completely counteract or stave off ageing and scarring effects, the complete DNA info needs to be there. Ageing could be reversed if compelte DNA info could be resuscitated locally, say by reverting sample tissue in the area to be regenerated back to a pluripotent state, correct?

Geez, hope I didn't make too many errors here.
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Re: Science of Ageing

Postby BioWizard on May 30th, 2009, 8:27 pm 

psionic11 wrote:Some questions, if I may. Scarring and ageing.

1) As I understand it, telomeres "degrade" over time, so that over an organism's lifetime, global changes take place which we see as an aging organism and aging tissues. This is in addition to effects from metabolism. Correct so far?

2) Many environmental factors -- overexposure to sunlight, hazardous chemicals, loss of mass, nutritional deficiencies -- interfere with the normal healing process, leaving scars or missing parts on the organism. At the heart of the scar is damaged or missing DNA, which is why the regeneration process doesn't result in complete regeneration. Correct?

So, besides normal wear and tear at the cellular, resulting in a cumulative inability to correctly render complete regeneration at the macroscopic level, there are the telomeres and other drastic events which contribute to or hasten the ageing process. Also correct?

Basically, in theory, inorder to completely counteract or stave off ageing and scarring effects, the complete DNA info needs to be there. Ageing could be reversed if compelte DNA info could be resuscitated locally, say by reverting sample tissue in the area to be regenerated back to a pluripotent state, correct?

Geez, hope I didn't make too many errors here.


All very good questions. I will address the part about telomeres in my next post (after I look up some recent reviews to make sure my information is up to date), and leave the second part for when I discuss oxidative stress. But for now, my drinking buddies await!

If anyone is already up to date (as in last month, not last decade) on the field, feel free to fill us in.
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Re: Science of Ageing

Postby Paris on May 31st, 2009, 9:44 am 

BioWizard wrote:As for cost/maintenance issues, I think that is more related to the evolutionary processes that shape the ageing phenomenon (clearly not all organisms age the same, and some don't at all),…


I agree, BioWizard. Unicellular organisms seemingly never die due to age. And there is at least one multi-cellular organism that never dies: Turritopsis nutricula.

Unlike other hydrozoan species, it reverts to the polyp stage after becoming sexually mature. Theoretically, this cycle can repeat endlessly, rendering it biologically immortal.

It is thought to achieve this feat through the cell development process of transdifferentiation, in which cells transform from one type to another.

Usually, the switching of cell specialization is seen only when parts of an organ regenerate. However, in the Turritopsis this change of cell roles happens in their entire body during their life cycle (Reversing the Life Cycle: Medusae Transforming into Polyps and Cell Transdifferentiation in Turritopsis nutricula (Cnidaria, Hydrozoa) [The Biological Bulletin, Vol 190, Issue 3 302-312]).

There is also a study on another hydrozoan, Laodicea undulate, which is also capable of ontogenic reversal on favourable environmental conditions but unlike Turritopsis, it eventually ages and dies (Evidence of reverse development in Leptomedusae (Cnidaria, Hydrozoa): the case of Laodicea undulate [Marine Biology, Volume 149, Number 2 / May, 2006] ).
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Re: Science of Ageing

Postby BioWizard on May 31st, 2009, 5:50 pm 

So let's proceed with this thing. But before we start discussing telomeres and oxidative stress, I want to clarify a few things.

We always hear about ageing as oxidative damage to molecules, accumulation of toxins in cells, genomic instability, telomere shotening, tissue degeneration, and so on. So which of these processes is the cause of ageing?

Molecular ageing, which represents the alterations that affect the chemistry and/or structure of biomolecules and interfere with their normal functions. These include oxidative damage to DNA, misfolding and modification of proteins, attrition of chromosomes, and so on. Naturally, these processes occur in all cells regardless of age. However, the cells are equipped with specialized machineries that break down these old and tired molecules, after which they would be replaced by newly synthesized ones. As long as the rate of synthesis and degradation are balanced, the effects of molecular ageing are completely reversible.

Cellular Ageing, which is a direct consequence of molecular ageing AFTER the senescence program is deployed within a cell. When as stem cells differentiate, they become specialized somatic cells. As the differentiation program occurs, telomerase activity goes away, causing the telomere ends of chromosomes to shorten. This acts as a signal for the cell to stop dividing when the telomeres reach a certain thershold. When this happens, the cell is said to have become senescent, and it no longer divides, and diverts its energy to perform whatever specialized function it acquired through the differentiation process (neuron, hepatic cell, etc). As time goes by, molecular ageing takes place, and the cell deals with it by breaking down and recycling damaged molecules. If, however, the cell for whatever reason accumulated more damage than it's ability to fix, self destructive pathways become activated. When a cell senses that it is damaged beyond repair, certain pathways are upregulated in response to this, and they induce cell death (apoptosis). The dead cell is then removed by macrophages or simply absorbed by nearby cells, which break down its components and use them as building blocks. This insures that cells that have accumulated enough damage to compromise their function are removed. More importantly, it makes sure that cells which have acquired too much genomic instability (to cause them to divide uncontrollably, escape the ageing program, and so become pro-cancerous) end up self destructing instead of forming cancers and killing the organism. Now, apart from all of this, not all cells within the body age and die at the same rate. Endothelial cells turn over at a very fast rate. Muscle cells turn over at a slightly slower rate. Neurons are known to last much longer. Thus, the correlation between molecular damage and a cell's lifespan is a loose one, except in extreme cases where the damage is so severe that it kills the cell.

Now why would somatic cells in an organism want to stop dividing at some point? A simple answer can be: structure. It would be very difficult to develop a biological structure if the rate of growth of its component cells was not controlled. If cellular turnover was not tightly controlled in multicellular organisms, development would not be possible. It is also speculated that by allowing somatic cells to divide a limited number of times, you minimize the chance of them acquiring too much mutations from replication errors, and thus becoming dysfunctional or turning pro-cancerous.

Tissue ageing, which is a direct consequence of cellular ageing. When cells within a tissue senesce, age, and die, the tissue loses functional units. However, in young individuals, these cells are constantly being replaced by fresh new ones, and the tissue is not only maintained, but also growth is achieved. At a certain age, the rates are balanced so that function is maintained without growth. As more time goes by, the rate of replenishment slows down, and the tissue is left with an increasing proportion of tired cells, leading to functional degeneration. These rates are probably controlled by variations in hormonal levels that occur as the individual ages. It is evident from the fact that lifespan variation between unrelated species is much larger than life span variation within a given specie that these processes are also genetically controlled. So, under normal conditions, a mouse is expected to live around the average lifespan of a mouse, while a chimp is expected to live the average lifespan of a chimp. Thus, again, ageing appears to be an active genetic program rather than a passive decay of biological components.
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Re: Science of Ageing

Postby BioWizard on May 31st, 2009, 6:45 pm 

Here is a relatively recent paper that was published in cell end of last year.

Telomerase reverse transcriptase delays aging in cancer-resistant mice.Tomás-Loba A, Flores I, Fernández-Marcos PJ, Cayuela ML, Maraver A, Tejera A, Borrás C, Matheu A, Klatt P, Flores JM, Viña J, Serrano M, Blasco MA.
Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre CNIO, Madrid, Spain.

Telomerase confers limitless proliferative potential to most human cells through its ability to elongate telomeres, the natural ends of chromosomes, which otherwise would undergo progressive attrition and eventually compromise cell viability. However, the role of telomerase in organismal aging has remained unaddressed, in part because of the cancer-promoting activity of telomerase. To circumvent this problem, we have constitutively expressed telomerase reverse transcriptase (TERT), one of the components of telomerase, in mice engineered to be cancer resistant by means of enhanced expression of the tumor suppressors p53, p16, and p19ARF. In this context, TERT overexpression improves the fitness of epithelial barriers, particularly the skin and the intestine, and produces a systemic delay in aging accompanied by extension of the median life span. These results demonstrate that constitutive expression of Tert provides antiaging activity in the context of a mammalian organism.


Several important things are elucidated by this study. First, it supports the view that limiting somatic cell divisions by telomere attrition decreases cancer risk. Second, it demonstrates that telomerase can be activated in somatic cells without detrimental effects PROVIDED the tumor suppressor pathways are also upregulated. So for their model, they crossed transgenic mice overexpressing telomerase in somatic tissue with mice that overexpress p53, p16, and p19ARF. This protected the mice from increased tumor incidence while allowing them to enjoy significantly increased health benefits and delaying of degenerative ageing processes. This is probably more due to decreasing of tissue ageing than cellular ageing (since cells are dispensible as long as the tissue is forming new ones). The reason the tissue was having a healthy supply of new cells for a longer time probably has to do with delayed cellular ageing in progenitor and stem cells. The authors say that the expression of telomerase also had proliferative effects on stem cells.

So what do we learn from this? Increased telomerase activity promotes proliferation of stem cells and delays their ageing/death, resulting in delayed tissue ageing (because tissue enjoys a supply of "young" cells for a longer period of time). This comes at a high cost of increasing cancer risk in somatic cells (which is probably severe enough to offset any beneficial effects). Overexpressing tumor suppressor genes however offsets this risk, showing that in principle, evolution can significantly extend the lifespan of an organism by a handful of tweaks. This I think is a very important point, as it once again highlights the genetic control of the ageing process. Lifespan appears to be an evolutionarily tweaked value, which I probably depends on many factors including population size, reproductive cycle, and other characteristics affecting the evolution of a specie.
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Re: Science of Ageing

Postby psionic11 on June 1st, 2009, 11:03 am 

Very interesting experiments. I suppose a good deal of this kind knowledge can be found in cloning experiments worldwide.

Hopefully still on topic, but let's suppose a specific combination of telomerase + tumor inhibitors is found which consistently results in a steady stream of "young" growing cells to supply the tissues.

Would this tonic be global in effect? A single oral source triggering uniform, global cellular re-growth in all the major cell types that normally experience growth spurts in young and developing animals? Or do different cell types/tissue groups have different programs regarding rates of regeneration and maintenance? Would, say, the kidneys and nerves/brain be left out?

Next, isn't there more than just cell replication to factor in? An organism's systems function on several levels, with other seemingly removed systems influencing local behaviors and responses, right? Similar to how we don't look at epinephrine/adrenalin as some isolated chemical that happens to make heart cells beat faster, but instead see it as a hormone involved in many diverse functional areas, resulting in a holistic "fight or flight" response, surely there must then be some particular interdependencies at the cellular and tissue levels that regulate regeneration rates, and in some cases, whether or not particular bits of the tissue get regenerated at all. Tissues have not only a particular function expressed in a normal resting state adult individual, but also histories (developmental stages and prolonged environmental reactions, like liver cells in a lifetime alcoholic).

In short, while no doubt useful finding a tonic that promotes a greater rate of new cell growth (hence lessened tissue attrition) via elongation of telomeres without the cancerous side-effects, there must be some other systemic factors that would hinder a global recuperation, yes? The experiment above mentions the targetted rejuvenation or maintenance of epithelial tissues, which any pharmaceutical would pounce upon (younger skin in a bottle), but what about glands and hormones, joints and nerves, extra molars and menopause, scarring and wrinkles, melatonin and testosterone, vision and hearing, muscle strength and overall energy level, mental acuity and immune response?

Such a tonic would have different results when administered to an octogenarian, to a post-menopause or a pre-menopause woman, to a juvenile, to a pre-25 male, to a healthy 33 year old versus a sickly 33 year old, right?

Do we merely tell a telomere how to stay long?
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Re: Science of Ageing

Postby BioWizard on June 1st, 2009, 2:40 pm 

psionic11 wrote:Very interesting experiments. I suppose a good deal of this kind knowledge can be found in cloning experiments worldwide.

Hopefully still on topic, but let's suppose a specific combination of telomerase + tumor inhibitors is found which consistently results in a steady stream of "young" growing cells to supply the tissues.

Would this tonic be global in effect? A single oral source triggering uniform, global cellular re-growth in all the major cell types that normally experience growth spurts in young and developing animals? Or do different cell types/tissue groups have different programs regarding rates of regeneration and maintenance? Would, say, the kidneys and nerves/brain be left out?


Very good question. According to the paper, most pronounced effects were seen in epithelial tissue and gastrointestinal tract, which have very high cellular turn over rate. However, they reported increased fittness in tissues that do not even express the telomerase, such as brain and muscle, which further suggests that the overall effect was due to increased lifespan and proliferative power of stem cells rather than the somatic cells themselves.

psionic11 wrote:Next, isn't there more than just cell replication to factor in? An organism's systems function on several levels, with other seemingly removed systems influencing local behaviors and responses, right? Similar to how we don't look at epinephrine/adrenalin as some isolated chemical that happens to make heart cells beat faster, but instead see it as a hormone involved in many diverse functional areas, resulting in a holistic "fight or flight" response, surely there must then be some particular interdependencies at the cellular and tissue levels that regulate regeneration rates, and in some cases, whether or not particular bits of the tissue get regenerated at all. Tissues have not only a particular function expressed in a normal resting state adult individual, but also histories (developmental stages and prolonged environmental reactions, like liver cells in a lifetime alcoholic).


Sure, but if you can replace old and tired cells with a constant supply of new fresh ones, then your problems reduce to recovering from injury and coping with environmental stresses.

In short, while no doubt useful finding a tonic that promotes a greater rate of new cell growth (hence lessened tissue attrition) via elongation of telomeres without the cancerous side-effects, there must be some other systemic factors that would hinder a global recuperation, yes? The experiment above mentions the targetted rejuvenation or maintenance of epithelial tissues, which any pharmaceutical would pounce upon (younger skin in a bottle), but what about glands and hormones, joints and nerves, extra molars and menopause, scarring and wrinkles, melatonin and testosterone, vision and hearing, muscle strength and overall energy level, mental acuity and immune response?


Indeed. But that's somewhat stating the obvious. Like I said, there's three levels of processes that lead to ageing, and cell lifespan is but one of them. No tonic will do you good if say a predator rips you in half.

psionic11 wrote:Such a tonic would have different results when administered to an octogenarian, to a post-menopause or a pre-menopause woman, to a juvenile, to a pre-25 male, to a healthy 33 year old versus a sickly 33 year old, right?


I honestly don't have enough data to be able to answer that question, so I rather not speculate.

psionic11 wrote:Do we merely tell a telomere how to stay long?


I will say more telomeres in coming posts, but I'll quickly add that telomere length is not strictly correlated with cell ageing and the lengths and thresholds depend on cell types and vary across organisms in a nonlinear fashion. So the question warrants more than a simplistic answer. More to come later.
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Re: Science of Ageing

Postby pegasus on June 9th, 2009, 10:40 am 

The following review may be helpful in understanding the basic framework from the science of ageing:

http://www.landesbioscience.com/journals/cc/article/BlagosklonnyCC7-21.pdf
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Re: Science of Ageing

Postby BioWizard on June 9th, 2009, 10:44 am 

Now that we've outlined the three levels of ageing, let's explore further the involvement of telomerese in what I'm calling the ageing program (as opposed to mere entropic decay).

Do stem cells in adults have telomerase activity? Yes they do, and this activity gets quenched as soon as these cells begin on the differentiation route towards becoming somatic cells.

Differentiation rather than aging of muscle stem cells abolishes their telomerase activity.O'Connor MS, Carlson ME, Conboy IM.
Dept. of Bioengineering, University of California, Berkeley, CA 94720.

A general feature of stem cells is the ability to routinely proliferate to build, maintain, and repair organ systems. Accordingly, embryonic and germline, as well as some adult stem cells, produce the telomerase enzyme at various levels of expression. Our results show that, while muscle is a largely postmitotic tissue, the muscle stem cells (satellite cells) that maintain this biological system throughout adult life do indeed display robust telomerase activity. Conversely, primary myoblasts (the immediate progeny of satellite cells) quickly and dramatically downregulate telomerase activity. This work thus suggests that satellite cells, and early transient myoblasts, may be more promising therapeutic candidates for regenerative medicine than traditionally utilized myoblast cultures. Muscle atrophy accompanies human aging, and satellite cells endogenous to aged muscle can be triggered to regenerate old tissue by exogenous molecular cues. Therefore, we also examined whether these aged muscle stem cells would produce tissue that is "young" with respect to telomere maintenance. Interestingly, this work shows that the telomerase activity in muscle stem cells is largely retained into old age wintin inbred "long" telomere mice and in wild-derived short telomere mouse strains, and that age-specific telomere shortening is undetectable in the old differentiated muscle fibers of either strain. Summarily, this work establishes that young and old muscle stem cells, but not necessarily their progeny, myoblasts, are likely to produce tissue with normal telomere maintenance when used in molecular and regenerative medicine approaches for tissue repair. (c) 2009 American Institute of Chemical Engineers Biotechnol. Prog., 2009.


So the old view that telomere attrition is merely due to divisions is not exactly accurare. Cells can divide all they want without losing telomere length. It is the specific interplay between the differentiation PROGRAM and the cell's "stemness" that determines telomere length.

It would appear as if the telomere shortening is a process that was actually evolved specifically to "count" cell divisions, so that a tissue can control the number of divisions a differentiating cell can undergo. As I mentioned earlier, this is important for "structure", and it also seems to play a role in keeping cancer in check.

And yet, it's not that simple either. Consider the following study:

Telomeres shorten while Tert expression increases during ageing of the short-lived fish Nothobranchius furzeri.Hartmann N, Reichwald K, Lechel A, Graf M, Kirschner J, Dorn A, Terzibasi E, Wellner J, Platzer M, Rudolph KL, Cellerino A, Englert C.
Leibniz Institute for Age Research - Fritz Lipmann Institute, Beutenbergstrasse 11, 07745 Jena, Germany. hartmann@fli-leibniz.de

Age research in vertebrates is often limited by the longevity of available models. The teleost fish Nothobranchius furzeri has an exceptionally short lifespan with 3.5 months for the laboratory strain GRZ and about 6 months for the wild-derived strain MZM-0403. Here we have investigated telomere length in muscle and skin tissue of young and old fish of both strains using different methods. We found age-dependent telomere shortening in the MZM-0403 strain with the longer lifespan, whereas the short-lived GRZ strain showed no significant telomere shortening with advanced age. Sequencing of the two main telomerase genes Tert and Terc revealed that both genes are highly conserved between the N. furzeri strains while there is little conservation to other fish species and humans. Both genes are ubiquitously expressed in N. furzeri and expression levels of Tert and Terc correlate with telomerase activity in a tissue-specific manner. Unexpectedly, the expression level of Tert is increased in aged muscle and skin tissue of MZM-0403 suggesting that telomeres shorten upon ageing despite increased Tert expression and hence high telomerase activity. We further conclude that the extremely short lifespan of the GRZ strain is not caused by diminished telomerase activity or accelerated telomere shortening.


This study shows that regulating telomerase activity is not the only mechanism by which telomere length can be modified. Also, it shows that telomere length need not shorten organism-wide for it to age. The short-lived fish was still ageing in a manner that is not associated with global telomere shortening (even though the telomeres were still shortening during differentiation).

Another point here is that there is no absolute correlation between telomere length and ageing. For example, mice have telomeres that are a couple hundred times longer than those of humans. And yet, humans age much slower with a much longer lifespan.

The evolution of aging phenotypes in snakes: a review and synthesis with new data.Bronikowski AM.
Ecology, Evolution and Organismal Biology, Iowa State University, 253 Bessey Hall, Ames, IA, 50011, USA, abroniko@iastate.edu.

Reptiles are underutilized vertebrate models in the study of the evolution and persistence of senescence. Their unique physiology, indeterminate growth, and increasing fecundity across the adult female lifespan motivate the study of how physiology at the mechanistic level, life history at the organismal level, and natural selection at the evolutionary timescale define lifespan in this diverse taxonomic group. Reviewed here are, first, comparative results of cellular metabolic studies conducted across a range of colubrid snake species with variable lifespan. New results on the efficiency of DNA repair in these species are synthesized with the cellular studies. Second, detailed studies of the ecology, life history, and cellular physiology are reviewed for one colubrid species with either short or long lifespan (Thamnophis elegans). New results on the rate of telomere shortening with age in this species are synthesized with previous research. The comparative and intraspecific studies both yield results that species with longer lifespans have underlying cellular physiologies support the free-radical/repair mechanistic hypothesis for aging. As well, both underscore the importance of mortality environment for the evolution of aging rate.


Even though I don't want to go into discussing the evolution of ageing in this thread, I thought this comparative study highlights how the oxidative damage and other cell ageing processes seem to be more mediators of ageing rather than causes. This is evident in the fact that different species utilize them differently to control their lifespans and mortality rates.

Association Between Telomere Length, Specific Causes of Death, and Years of Healthy Life in Health, Aging, and Body Composition, a Population-Based Cohort Study.Njajou OT, Hsueh WC, Blackburn EH, Newman AB, Wu SH, Li R, Simonsick EM, Harris TM, Cummings SR, Cawthon RM; for the Health ABC study.
Departments of Medicine and Institute for Human Genetics, 513 Parnassus Street, HSE 672, University of California, San Francisco, San Francisco, CA 94143-0794. wen-chi.hsueh@ucsf.edu.

Although telomere length (TL) is known to play a critical role in cellular senescence, the relationship of TL to aging and longevity in humans is not well understood. In a large biracial population-based cohort, we tested the hypotheses that elderly persons with shorter TL in peripheral white blood cells have poorer survival, shorter life span, and fewer years of healthy life (YHL). Associations were evaluated using Cox proportional hazard models and linear regression analyses where appropriate. TL (in kilo base pairs) was not associated with overall survival (hazard ratio 1.0; 95% confidence interval 0.9-1.1) or death from any specific underlying cause including infectious diseases, cancer, or cardiac and cerebrovascular diseases. TL, however, was positively associated with more YHL (beta = 0.08 +/- 0.04, p = .03). Findings suggest that TL may not be a strong biomarker of survival in older individuals, but it may be an informative biomarker of healthy aging.
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Re: Science of Ageing

Postby BioWizard on June 9th, 2009, 10:48 am 

pegasus wrote:The following review may be helpful in understanding the basic framework from the science of ageing:

http://www.landesbioscience.com/journals/cc/article/BlagosklonnyCC7-21.pdf


TOR is definitely an interesting place to start investigating the signalling pathways responsible for the ageing program. I will read the review and comment on it. Thanks!
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Re: Science of Ageing

Postby psionic11 on June 10th, 2009, 11:09 pm 

I'm reading the pdf to get more of a grip on the current theories regarding the science of aging.

Still, would be very helpful if I could get a quick synopsis of what ToR is. Target of rapamycin, or in mammals, mToR, but even Wiki doesn't shed light on what this is. Some sort of metabolic pathway? I get the gist of the pdf so far, but feel I need a eureka moment to fill in the blank spots of what the article seems to take for granted. Thanks.
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Re: Science of Ageing

Postby MrMistery on June 12th, 2009, 10:11 am 

TOR is a protein kinase. The pathway it functions in is, to put it simply, the pathway that senses external signals (nutrient levels and, in higher organisms, some hormone levels) and tells a cell how big to grow.

And that PDF quite probably has the funniest writing style i've ever seen in a peer-reviewed paper.
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Re: Science of Ageing

Postby psionic11 on June 12th, 2009, 2:14 pm 

Aha, thanks for that, it helps a lot. TOR basically a sensor and growth regulator of sorts.

And good to know about that paper's style. I'm halfway done, and don't have much exposure to these sorts of writings. Over 50 references, and seemingly just one of many papers the author may have written. That's a lot of documentation, which I suppose is warranted or demanded by the scientific community. And yes, some of his statements and analogies seem quite controversial and conversational.

It is enlightening, and fundamentally changing, to discover that antioxidants are not all they seem hyped to be. But surely aging is a programmed organismal process, despite the author denying it is....?
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Re: Science of Ageing

Postby MrMistery on June 12th, 2009, 3:08 pm 

why must it be?
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Re: Science of Ageing

Postby psionic11 on June 12th, 2009, 4:48 pm 

To imply that aging has no programming or process in place would mean that aging would happen spontaneously. Given that any given species has an average or mean lifetime, has certain other programs dependent on aging (metamorphosis, puberty, menopause, death after mating, etc), there must be certain mechanisms in place that produce predictable outcomes.

Otherwise we would witness very greatly varying lifetimes, both within species and among species, where senescence would've been a product of relative randomness, correct?
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Re: Science of Ageing

Postby MrMistery on June 12th, 2009, 5:38 pm 

not necessarily. there is indeed a very well defined mechanism of aging, but that doesn't mean that there is a mechanism dedicated to aging. for example, what that author is postulating is that aging is simply a result of TOR kinase function.
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Re: Science of Ageing

Postby BioWizard on June 12th, 2009, 7:14 pm 

Actually what psionic said makes sense and agrees with the rest of the data presented in this thread. The review cited by pegasus (which I haven't yet read) is just one person's speculation and doesn't have the final word on anything presented here.
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Re: Science of Ageing

Postby MrMistery on June 12th, 2009, 8:59 pm 

honestly, I haven't read all the data presented here. And I wasn't saying he is wrong, what I am saying is that if aging is indeed the result of some regulatory circuits gone haywire, then it makes sense that different organisms age at different rates since those would be different. This does not automatically mean (although it may be exactly what happens) that aging is done "on purpose", so to speak.
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Re: Science of Ageing

Postby BioWizard on June 13th, 2009, 7:03 am 

MrMistery wrote:honestly, I haven't read all the data presented here. And I wasn't saying he is wrong, what I am saying is that if aging is indeed the result of some regulatory circuits gone haywire, then it makes sense that different organisms age at different rates since those would be different. This does not automatically mean (although it may be exactly what happens) that aging is done "on purpose", so to speak.


"Circuits gone haywire" is more descriptive of events like cancer, which not all cells commit to and occurs under specific conditions, producing cells that can escape cell cycle control in any of a large number of ways (random failure). Ageing on the other hand seems to be more of a cellular program which all cells do indeed undergo - accompanied with well defined morphological and biochemical changes that depend on cell type. It appears to be a well controlled program that controls both the lifespan of somatic cells as well as the organism they compose. You should read the first posts so that I don't have to sound redundant.
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Re: Science of Ageing

Postby lucaspa on June 13th, 2009, 3:54 pm 

pegasus wrote:The following review may be helpful in understanding the basic framework from the science of ageing:

http://www.landesbioscience.com/journals/cc/article/BlagosklonnyCC7-21.pdf


With respect, this is an advertisement by the author -- Blagosklonny -- for the author! If you look in the reference list, the papers linking TOR to aging have Blagoskonny as the author! So this isn't a balanced look at the "science of ageing", but rather a very biased appeal by Blagosklonny for his particular theory.

Now, this is fairly common in science. You do a few peer-reviewed papers and think you have a more widespread story/theory. Then you write a review paper laying out your new story (theory) and arguing for it and against the rival theories. However, the danger is for a layman to take this type of thing as an objective, even-handed, critical review of an area of science.
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Re: Science of Ageing

Postby lucaspa on June 13th, 2009, 4:06 pm 

psionic11 wrote: But surely aging is a programmed organismal process, despite the author denying it is....?


Why would you think so? Why would natural selection select for aging? What selective advantage would result to the individual that aged? What we know as aging is a decrease in functionality and thus a more limited ability to compete for scarce resources.

While I disagree with much of what Blagovsklonny writes, I do agree that he as a good point that aging would be either a developmental program essential to get the individual to reproduction but then be disadvantageous after reproduction has occurred or an insult that accumulates over time. As you can see, I think the ROS theory also fits with evolution: there is a repair mechanism but natural selection has only made it good enough to get the organism past the age of reproduction, and then as the oxidative damage accumulates, finally hits dangerous levels.
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Re: Science of Ageing

Postby MrMistery on June 13th, 2009, 4:20 pm 

I think the author makes it pretty clear in that paper that his model is not the only one, or even the most widely accepted one. And there is nothing wrong with proposing new models if your model can explain some of the data.
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Re: Science of Ageing

Postby BioWizard on June 13th, 2009, 4:41 pm 

I would appreciate it if we can keep the topic focused on the OP and not get it completely side tracked (without me having to perform surgery on it).

1- The review posted by pegasus is just an addition to the pot. Perhaps it's interesting, perhaps it's not. Either way, it neither sums up the subject of this thread nor does it serve as a conclusion. It's just one of many papers that were, or are to be, posted.

2- The evolution of ageing is a separate topic, as I said earlier, which should be discussed in the biology forum. Ageing is certainly subject to evolution, and its benefits include, though may not be limited to, increasing genetic diversity without exhausting resources. That is, allowing a population to constantly produce new genetic variants (via reproduction) without it growing indefinitely (old individuals age and die), and thus without starving the population by consuming all resources. If you don't believe that survival to reproductive age is the gold standard to evolution and that the "goal" is to "perfect" design, that's another issue. As a matter of fact, the very observation that organisms age and that ageing did evolve as a feature of most (but not all) multicellular organisms is by itself proof that survival to reproductive age, rather than indefinite and unhampered survival, is the gold standard of evolution. Tinkering with just a handful of genes can drastically alter the ageing patterns and overall lifespan of an organism (I will provide references). Here, however, I am examining the biochemical and cytological aspects of ageing, the evolution of which notwithstanding.

So... enough digression about the review and the evolution of ageing. Let's continue to focus on the signalling pathways and the cellular triggers and mechanistics of the ageing program. If you're still asking "why do you think there's a program?", then maybe you need to read the posts from the top.
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Re: Science of Ageing

Postby lucaspa on June 15th, 2009, 7:25 am 

MrMistery wrote:I think the author makes it pretty clear in that paper that his model is not the only one, or even the most widely accepted one. And there is nothing wrong with proposing new models if your model can explain some of the data.


What the author does is contrast his theory to the ROS theory. In the process, he is universally critical of the ROS theory. As I said, this is a fairly common review type article within science. I've written one similar myself. What I objected to was using the article as an even-handed, objective summary of the state of aging research. It's not. It's biased toward Blagovsklonny's theory and you need to read it in that light.

There are some errors in the review. For instance, on page 5 he states that osteoporosis is due to increased activity of osteoclasts and cites one reference. He ignores the rest of the literature which definitively shows that osteoclastic activity is normal. Instead, osteoporosis results from a lag in bone formation so that the new bone does not replace the old. But that view of osteoporosis does not support Blagovsklonny's TOR theory. However, unless one were familiar with the bone biology literature (which I am), you wouldn't catch the error. It makes me wonder how many other errors like that are in the paper.
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