89 replies to this topic

[HighDesertWizard]

 

 

I find it useful to reference studies whenever possible... And to talk about Telomerase and Cancer without reference to NF-kB is a useless discussion...

 

Telomerase directly regulates NF-B-dependent transcription

 

Although elongation of telomeres is thought to be the prime function of reactivated telomerase in cancers, this activity alone does not account for all of the properties that telomerase reactivation attributes to human cancer cells. Here, we uncover a link between telomerase and NF-κB, a master regulator of inflammation. We observe that while blocking NF-κB signalling can inhibit effects of telomerase overexpression on processes relevant to transformation, increasing NF-κB activity can functionally substitute for reduced telomerase activity. Telomerase directly regulates NF-κB-dependent gene expression by binding to the NF-κB p65 subunit and recruitment to a subset of NF-κB promoters such as those of IL-6 and TNF-α, cytokines that are critical for inflammation and cancer progression. As NF-κB can transcriptionally upregulate telomerase levels, our findings suggest that a feed-forward regulation between them could be the key mechanistic basis for the coexistence of chronic inflammation and sustained telomerase activity in human cancers.

 

 

Do you think it's possible that since NF-kB is proinflamatory that telomerase is upregulated as a homeostatic mechanism to ensure that the organism does not loose too much in terms of lifespan as well as healthspan?   Anyhow very interesting and productive to bring that up, there is probably even more that we've yet to discover.

 

I've spent some time logging evidence about the biologically intimate relationship between NF-kB and Telomerase here. I believe NF-kB and Telomerase are key intracellular, organism mechanism elements that shape aging and rejuvenation. They aren't the only important elements. I am a Telomerase Expression Enthusiast--i.e., in the Bill Andrews camp and not the Aubrey de Grey camp--but, unlike Andrews, I don't think Telomerase Expression is the key intracellular driver.

 

I believe NF-kB Cytokine Transcription, especially in splenic macrophages, is the key intracellular driver of aging. I have been and I will be providing evidence for this opinion here. To falsify this opinion, there's already a lot of evidence that would have to be overturned. I don't think it can or will be overturned.

 

At the end of the day, isn't that what our spending time here is all about? To find key evidence driving survival probabilities that cannot be falsified?

 

My point in making the two posts I made above was this...

• The last 2-3 years of research highlights that, the continuous loop of Telomerase expression in Tumor cells profoundly implicates NF-kB expression. For gosh sakes, we now have 2 studies with graphic figure depictions (shown above) of NF-kB appearing in that loop.
   
• To have a discussion, then, about Telomerase and Cancer without mentioning NF-kB is a little silly.

[Antonio2014]

 

You dismissed the article only by who is his author, not even reading it, nor discussing any of its points. In the article, your de Pinho's article and others are discussed and put in context. It demonstrates that the rejuvenation claims of de Pinho and Blasco are unfounded. And if you had read it, you would know that the author is Michael Rae, not Aubrey de Grey.

 

That's not what my point was,  regardless of the author SENS is against telomerase lengthening and that has been Aubrey De Grey's view it and effects which articles they choose to feature.  I never said that your article is disregarded I simply said I would have to quote a source with an orientation of pro telomerase (which their are many) for it to be an even field. I was merely noting this.

 

You are again doing an ad hominem here, still refusing to comment on the contents of the article. I put in bold the ad hominem part, where you implicitly claim that his judgement is biased because he doesn't think telomerase therapy rejuvenates. Also, the part I underlined is plainly wrong and unpolite, since the articles he featured are articles that claim rejuvenation effects of telomerase (among them, the one that you linked).

[Rocket]

 

If it was merely a race for survival by all means the pressure would be massive for an organism to leave telomerase active in all areas once such a valuable pathway is present.

 

Nope. Telomerase is inactive in most human cells for good reasons: to prevent cancer. Hydras don't inactivate it because basically all their cells are stem cells. If you cut a hydra into pieces, each piece grows to form a full hydra. With our big number of cells and long lifespan, having all our cells being stem cells would kill us by cancer too soon.
 

 

 

Telomerase does not cause cancer.  If that were the reason, if it were so simple, then an organism that is growing and continually adding more and more cells to it's body day after day, and year after year, would be doomed to never reach adulthood.  But this isn't the case, is it? Trillions of cells added from the day the egg was fertilized and caner is almost unheard of.  Trillions of chances for just one cell to go bad and cause cancer and kill the organism, and it's almost unheard of.

 

The older the organism becomes, with ever shortening telomeres, and ever declining hormones, and an ever declining immune system.... those organisms have the highest probability of cancer.

 

I am reminded of the research published last year from Stanford in which telomerase was activated in  old skin cells and the cells grew without abandon just as if they were young cells.  Guess what? No cancer.

 

I suppose all the epithalon users and TA65 customers are dooming themselves to cancer.  And what about Liz Parrish? Doomed as well. 

 

And then there is TSA, which not only extends telomeres, activates GDF11, but has anti-cancer benefits in breast cancer. Hmm, longer telomeres and anti-cancer at the same time? 

 

 

 

Edited by Rocket, 18 January 2016 - 09:32 PM.

[Never_Ending]

 

 

You dismissed the article only by who is his author, not even reading it, nor discussing any of its points. In the article, your de Pinho's article and others are discussed and put in context. It demonstrates that the rejuvenation claims of de Pinho and Blasco are unfounded. And if you had read it, you would know that the author is Michael Rae, not Aubrey de Grey.

 

That's not what my point was,  regardless of the author SENS is against telomerase lengthening and that has been Aubrey De Grey's view it and effects which articles they choose to feature.  I never said that your article is disregarded I simply said I would have to quote a source with an orientation of pro telomerase (which their are many) for it to be an even field. I was merely noting this.

 

You are again doing an ad hominem here, still refusing to comment on the contents of the article. I put in bold the ad hominem part, where you implicitly claim that his judgement is biased because he doesn't think telomerase therapy rejuvenates. Also, the part I underlined is plainly wrong and unpolite, since the articles he featured are articles that claim rejuvenation effects of telomerase (among them, the one that you linked).

 

 

No I disagree , It was my impression of his view from one of his interviews and that barely qualifies as ad hominem it's almost as if that term is forced onto what I was noting. Also the underlined part is not impolite because it's reasonable to say anyone with a certain viewpoint will unconsiously be more likely to choose articles in line with their view to feature on their website. If you want to continue with this we can because I won't follow suit with being accused of things like that  just because you don't like the way I wrote certain sentences.

 

Especially since SENS is one of my favorite sites as well... I was only disagreeing with just one of their topics.
 

Edited by Never_Ending, 18 January 2016 - 10:09 PM.

[Never_Ending]

 

 

I've spent some time logging evidence about the biologically intimate relationship between NF-kB and Telomerase here. I believe NF-kB and Telomerase are key intracellular, organism mechanism elements that shape aging and rejuvenation. They aren't the only important elements. I am a Telomerase Expression Enthusiast--i.e., in the Bill Andrews camp and not the Aubrey de Grey camp--but, unlike Andrews, I don't think Telomerase Expression is the key intracellular driver.

 

I believe NF-kB Cytokine Transcription, especially in splenic macrophages, is the key intracellular driver of aging. I have been and I will be providing evidence for this opinion here. To falsify this opinion, there's already a lot of evidence that would have to be overturned. I don't think it can or will be overturned.

 

At the end of the day, isn't that what our spending time here is all about? To find key evidence driving survival probabilities that cannot be falsified?

 

My point in making the two posts I made above was this...

• The last 2-3 years of research highlights that, the continuous loop of Telomerase expression in Tumor cells profoundly implicates NF-kB expression. For gosh sakes, we now have 2 studies with graphic figure depictions (shown above) of NF-kB appearing in that loop.
   
• To have a discussion, then, about Telomerase and Cancer without mentioning NF-kB is a little silly.

 

 

Ok I also believe that NF-kB has a role in it and silent inflammation in general , however would your view be that inflammation is the only driver of aging? because we know that telomeres being shorter than a certain amount affects replication on it's own. Let me know if I misunderstood thanks

[niner]

My point in making the two posts I made above was this...

• The last 2-3 years of research highlights that, the continuous loop of Telomerase expression in Tumor cells profoundly implicates NF-kB expression. For gosh sakes, we now have 2 studies with graphic figure depictions (shown above) of NF-kB appearing in that loop.
   
• To have a discussion, then, about Telomerase and Cancer without mentioning NF-kB is a little silly.

 

Could you help me understand the significance of NF-kB in the context of this thread?  In the review of Non-Canonical Functions of Telomerase, they said:
 

This feed-forward signaling loop that is proposed to exist between TERT and NF-kB signaling as well as TERT and Wnt/b-catenin signaling in cancers is a likely mechanism for the concomitant activation of NF-kB- and Wnt/b-catenin–dependent transcription following TERT overexpression, thereby driving the prolonged expression of target genes critical for the maintenance of tumor survival and proliferation (Fig. 1).

This suggests that Blasco's AAV-mTERT mice should have gotten cancer, but it doesn't sound like they did, particularly much.  What's the connection?

[niner]

 

 

If it was merely a race for survival by all means the pressure would be massive for an organism to leave telomerase active in all areas once such a valuable pathway is present.

 

Nope. Telomerase is inactive in most human cells for good reasons: to prevent cancer. Hydras don't inactivate it because basically all their cells are stem cells. If you cut a hydra into pieces, each piece grows to form a full hydra. With our big number of cells and long lifespan, having all our cells being stem cells would kill us by cancer too soon.

 

Telomerase does not cause cancer.  If that were the reason, if it were so simple, then an organism that is growing and continually adding more and more cells to it's body day after day, and year after year, would be doomed to never reach adulthood.  But this isn't the case, is it? Trillions of cells added from the day the egg was fertilized and caner is almost unheard of.  Trillions of chances for just one cell to go bad and cause cancer and kill the organism, and it's almost unheard of.

 

Rocket, I don't think that Antonio is saying telomerase causes cancer.  He's referring to the role of telomeres as a mechanism for preventing cells from dividing endlessly-- i.e., preventing cancer.  Telomerase that is active in all somatic cells would subvert this important role of telomeres.  If we can turn on telomerase in those cells where it is needed, have it lengthen the short telomeres, then be repressed again, that would seem to be the best of both worlds.

[Santi]

I thought that this argument about if we should increase or decrease telomerase to extend lifespan has already been settled. There are humans with gene variations in hTERT and hTERC which cause them to have increased telomerase and then there are other humans with greatly decreased or no telomerase.

They found humans with hyperactive telomerase when looking at genetic reasons why centenarians live longer than normal people. They found humans with dysfunctional or no telomerase when examining why some people have certain disease states such as bone marrow failure.


Genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians

https://www.ncbi.nlm...les/PMC2868292/


Human diseases of telomerase dysfunction: insights into tissue aging

http://www.ncbi.nlm....les/PMC2190725/

[niner]

Telomerase dysfunction leading to disease doesn't surprise me, given its multiple functions, but then there's this:
 

Am J Physiol Regul Integr Comp Physiol. 2007 Dec;293(6):R2210-7. Epub 2007 Sep 26.
Leukocytes of exceptionally old persons display ultra-short telomeres.
Kimura M, Barbieri M, Gardner JP, Skurnick J, Cao X, van Riel N, Rizzo MR, Paoliso G, Aviv A.

With a view to understanding the association between leukocyte telomere length and the human lifespan, we performed genome-wide telomere length analyses by the terminal restriction fragment length (TRFL) and single molecule telomere length analysis (STELA) of the X and Y chromosomes in leukocytes of exceptionally old (aged 90-104 yr) and younger (aged 23-74 yr) individuals. We found that the mean TRFL of 82 exceptionally old individuals was within a range projected by age-dependent TRFL attrition of 99 younger individuals. However, compared with the younger individuals, exceptionally old persons exhibited peaking of the TRFL distribution with overrepresentation of ultra-short telomeres. These findings were confirmed by the STELA. Women had longer mean TRFL than men (6.10 vs. 5.86 kb), and exceptionally old women exhibited fewer ultra-short telomeres than exceptionally old men. Our results have implications for gerontological studies of the limitation of lifespan in humans.

PMID: 17898116 Free full text

and this:
 

EBioMedicine. 2015 Jul 29;2(10):1549-58. doi: 10.1016/j.ebiom.2015.07.029. eCollection 2015.
Inflammation, But Not Telomere Length, Predicts Successful Ageing at Extreme Old Age: A Longitudinal Study of Semi-supercentenarians.
Arai Y, Martin-Ruiz CM, Takayama M, Abe Y1, Takebayashi T, Koyasu S, Suematsu M, Hirose N, von Zglinicki T.

To determine the most important drivers of successful ageing at extreme old age, we combined community-based prospective cohorts: Tokyo Oldest Old Survey on Total Health (TOOTH), Tokyo Centenarians Study (TCS) and Japanese Semi-Supercentenarians Study (JSS) comprising 1554 individuals including 684 centenarians and (semi-)supercentenarians, 167 pairs of centenarian offspring and spouses, and 536 community-living very old (85 to 99 years). We combined z scores from multiple biomarkers to describe haematopoiesis, inflammation, lipid and glucose metabolism, liver function, renal function, and cellular senescence domains. In Cox proportional hazard models, inflammation predicted all-cause mortality with hazard ratios (95% CI) 1.89 (1.21 to 2.95) and 1.36 (1.05 to 1.78) in the very old and (semi-)supercentenarians, respectively. In linear forward stepwise models, inflammation predicted capability (10.8% variance explained) and cognition (8(.)6% variance explained) in (semi-)supercentenarians better than chronologic age or gender. The inflammation score was also lower in centenarian offspring compared to age-matched controls with Δ (95% CI) = - 0.795 (- 1.436 to - 0.154). Centenarians and their offspring were able to maintain long telomeres, but telomere length was not a predictor of successful ageing in centenarians and semi-supercentenarians. We conclude that inflammation is an important malleable driver of ageing up to extreme old age in humans.

PMID: 26629551 PMCID: PMC4634197 Free PMC Article

 

 

 

It still seems a bit ambiguous.  I think telomeres are important, but I just don't think we have the whole story yet.

[Antonio2014]

Telomerase does not cause cancer.  If that were the reason, if it were so simple, then an organism that is growing and continually adding more and more cells to it's body day after day, and year after year, would be doomed to never reach adulthood.  But this isn't the case, is it? Trillions of cells added from the day the egg was fertilized and caner is almost unheard of.  Trillions of chances for just one cell to go bad and cause cancer and kill the organism, and it's almost unheard of.

 

I never said it was THE reason. I only said that an always on telomerase (or ALT) on every cell of something so big an so long-lived as a human body will greatly increase its cancer rate. Of course, I'm not saying that it will increase mutation rate or whatever, only that it removes one step in the path to cancer for every single cell in your body. As I said, cancerous cells absolutly need to switch on telomerase (or ALT).

 

I am reminded of the research published last year from Stanford in which telomerase was activated in  old skin cells and the cells grew without abandon just as if they were young cells.  Guess what? No cancer.

 

Link?

 

 

I suppose all the epithalon users

 

I didn't know about epithalon and can't find any information apart from that of epithalon sellers. It even doesn't appear on Wikipedia. Do you have any paper?

 

 

and TA65 customers

 

The same for this.

 

 

And what about Liz Parrish? Doomed as well. 

 

Well, you surely don't have any data to prove that Liz Parrish is safe, don't you? Her experiment has barely started. Mentioning this proves absolutly nothing.

 

 

And then there is TSA, which not only extends telomeres, activates GDF11, but has anti-cancer benefits in breast cancer. Hmm, longer telomeres and anti-cancer at the same time?

 

Link.

Edited by Antonio2014, 19 January 2016 - 09:56 AM.

[Antonio2014]

Also the underlined part is not impolite because it's reasonable to say anyone with a certain viewpoint will unconsiously be more likely to choose articles in line with their view to feature on their website.

 

Again, he choosed articles CLAIMING THAT TELOMERASE REJUVENATES. Heck, he was discussing just those articles, explaining them and demonstrating why their claims are unfounded. Dismissing his discussion because you think he is biased since he is proSENS is what ad hominem is.

 

An ad hominem (Latin for "to the man" or "to the person"^[1]), short for argumentum ad hominem, is an attack on an argument made by attacking the character, motive, or other attribute of the person making the argument, rather than attacking the argument directly.

 

https://en.wikipedia...wiki/Ad_hominem

[Antonio2014]

Genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians

https://www.ncbi.nlm...les/PMC2868292/

 

It shows correlation, doesn't prove causation. Telomere lenght in leukocytes is highly variable and depends on several things, like rate of renewal of leukocytes, efficiency of stem cells in bone marrow, etc. Short telomeres seem more as a consequence of aging than a cause of aging. That is, if you live longer, you will probably have healthier stem cells, a stronger immune system, etc., and they will thus produce longer telomeres (in average).

 

Here is an open-access review paper: https://www.fightagi...e-of-damage.php

Edited by Antonio2014, 19 January 2016 - 09:51 AM.

[Santi]

To add to the discussion since this thread is about the convergence of two theories of aging, the current thought from the programmed aging group is that the aging program/clock is an epigenetic program in the epigenome. They seemed to have moved past telomere length as the aging clock as was argued by some people in the 90s-00s.

The following paper I think does a decent job discussing epigenetics in aging and touches on how epigenetic changes are both responsive to and effectors of the aging process. If this is the case it would show a merging of the two theories, of the programmed aging group's epigenetic program causing aging but also responding to natural forms of aging damage focused on by the wear and tear group. I am interested to hear the groups thoughts on this.


Ref:
Aging, Rejuvenation, and Epigenetic Reprogramming: Resetting the Aging Clock

http://www.sciencedi...092867412000049


Select quotes:
"The observations that the aging clock can be halted in the C. elegans dauer state, reset at fertilization, and potentially rewound by the environmental influences described above suggest strongly that the manifestations, and possibly the causes, of aging may be largely epigenetic. The hypothesis is further supported by the recent finding of transgenerational epigenetic inheritance of extended life span in C. elegans (Greer et al., 2011).

Beyond the genome and the epigenome, cellular aging is characterized by the accumulation of damaged macromolecules, including proteins and lipids, and highly stable aggregates of those molecules (Campisi and Vijg, 2009). These, too, are manifestations of aging that are also potentially “reversible,” either by dilution in dividing cells or by disaggregation and degradation followed by replacement with new undamaged macromolecules. Only mutated and deleted DNA sequences, for which no template, code, or cellular machinery exists to guide their correction, are inaccessible to the rejuvenation process. The notion that aging is at least in part, if not largely, a manifestation of epigenetic changes, including those that may be secondary to genomic mutations, offers a theoretical construct for understanding the mechanisms of rejuvenation. If so, it should be possible to characterize “young” and “old” cells by specific transcriptional and epigenetic profiles and states."

"Clearly, epigenetic changes are both responsive to and effectors of the aging process. With DNA damage and environmental stresses like inflammation leading to changes in chromatin, the epigenome clearly adapts to age-related changes in the genome and the local milieu. Perhaps the epigenome is a general sensor of cellular dysfunction, sensing metabolic and proteomic changes that accompany aging as well. However, the epigenome is also an effector of the aging process, enforcing different patterns of gene expression in old cells and young cells and, in many cases, resulting in cellular phenotypes associated with aging such as senescence and metaplasia."

[Never_Ending]

To add to the discussion since this thread is about the convergence of two theories of aging, the current thought from the programmed aging group is that the aging program/clock is an epigenetic program in the epigenome. They seemed to have moved past telomere length as the aging clock as was argued by some people in the 90s-00s.

The following paper I think does a decent job discussing epigenetics in aging and touches on how epigenetic changes are both responsive to and effectors of the aging process. If this is the case it would show a merging of the two theories, of the programmed aging group's epigenetic program causing aging but also responding to natural forms of aging damage focused on by the wear and tear group. I am interested to hear the groups thoughts on this.


Ref:
Aging, Rejuvenation, and Epigenetic Reprogramming: Resetting the Aging Clock

http://www.sciencedi...092867412000049


Select quotes:
"The observations that the aging clock can be halted in the C. elegans dauer state, reset at fertilization, and potentially rewound by the environmental influences described above suggest strongly that the manifestations, and possibly the causes, of aging may be largely epigenetic. The hypothesis is further supported by the recent finding of transgenerational epigenetic inheritance of extended life span in C. elegans (Greer et al., 2011).

Beyond the genome and the epigenome, cellular aging is characterized by the accumulation of damaged macromolecules, including proteins and lipids, and highly stable aggregates of those molecules (Campisi and Vijg, 2009). These, too, are manifestations of aging that are also potentially “reversible,” either by dilution in dividing cells or by disaggregation and degradation followed by replacement with new undamaged macromolecules. Only mutated and deleted DNA sequences, for which no template, code, or cellular machinery exists to guide their correction, are inaccessible to the rejuvenation process. The notion that aging is at least in part, if not largely, a manifestation of epigenetic changes, including those that may be secondary to genomic mutations, offers a theoretical construct for understanding the mechanisms of rejuvenation. If so, it should be possible to characterize “young” and “old” cells by specific transcriptional and epigenetic profiles and states."

"Clearly, epigenetic changes are both responsive to and effectors of the aging process. With DNA damage and environmental stresses like inflammation leading to changes in chromatin, the epigenome clearly adapts to age-related changes in the genome and the local milieu. Perhaps the epigenome is a general sensor of cellular dysfunction, sensing metabolic and proteomic changes that accompany aging as well. However, the epigenome is also an effector of the aging process, enforcing different patterns of gene expression in old cells and young cells and, in many cases, resulting in cellular phenotypes associated with aging such as senescence and metaplasia."

 

Interesting concept,  I think there is potential for this epigentic theory and is likely a factor. However since epigenetic changes are heavily environmental it would seem there would be more variance to the aging patterns with some people perhaps breaking through to much longer lifespans like 150 etc if the driver was epigenetic at its core.  However if it was wear and tear related at it's core with epigenetics playing into the cascade of events that would seem more likely. I think that to move past telomere length as a clock would require a specific fault in the telomere theory or else it seems quite feasible as the way the Hayflick limit works.(the validity shouldn't be judged based on how fresh the trend is)

[niner]

 

We have seen from Maria Blasco's lab that expressing extra telomerase in mice is good for a 13% increase in lifespan when started in old age, and 24% when started at one year.

 

No, that is unproven. Read the link I posted above.

 

In the link you posted, Michael has some quibbles, but they aren't enough to dismiss Blasco's work.  There are a handful of mouse husbandry wizards who can create such a stress-free mouse habitat that their mice live longer than everyone else's mice.  Michael argues that Blasco's control mice didn't live as long as the wizard's mice, so the increase in median lifespan isn't really meaningful.  I don't buy that argument.  As mice age, they become more susceptible to stress.  The whole point of having a control group is to have equal stress levels.  These mice might have been more stressed than the wizard's mice, but the mTERT-transduced mice lived longer, period.  He argued that the study wasn't adequately powered to determine max LS.  OK, fine.  I'm talking about median LS, and I suspect the study was adequately powered for that.  Another argument was that there could have been some crypto-CR in the treatment mice that happened in an interval when they weren't checking for it.  When they did check for it, it wasn't happening.  That is just grasping at straws.   He mentioned the numerous biomarkers that improved in the treatment group, so there's more to the story than just lifespan.  I'm afraid that if we start using words like "known" or "proven", we'll just get into an epistemological quagmire.  I think we have some pretty good evidence that extra telomerase does good things for mice.  Whether or not it's good for humans remains to be seen.

[niner]

 I think that to move past telomere length as a clock would require a specific fault in the telomere theory or else it seems quite feasible as the way the Hayflick limit works.

 

It's clear that the Hayflick limit is a consequence of telomere shortening, but what isn't clear (and I'm not sure you are saying this) is the effect on human lifespan.  The Hayflick limit applies primarily to cells in culture.  Most human somatic cells in vivo don't divide enough times to trigger the limit.

[Antonio2014]

To add to the discussion since this thread is about the convergence of two theories of aging, the current thought from the programmed aging group is that the aging program/clock is an epigenetic program in the epigenome. They seemed to have moved past telomere length as the aging clock as was argued by some people in the 90s-00s.

The following paper I think does a decent job discussing epigenetics in aging and touches on how epigenetic changes are both responsive to and effectors of the aging process. If this is the case it would show a merging of the two theories, of the programmed aging group's epigenetic program causing aging but also responding to natural forms of aging damage focused on by the wear and tear group. I am interested to hear the groups thoughts on this.


Ref:
Aging, Rejuvenation, and Epigenetic Reprogramming: Resetting the Aging Clock

http://www.sciencedi...092867412000049

 

Thanks for the useful link. Indeed, SRF is funding research to clarify this: http://www.sens.org/...gle-aging-cells
 

Edited by Antonio2014, 20 January 2016 - 08:52 AM.

[Antonio2014]

In the link you posted, Michael has some quibbles, but they aren't enough to dismiss Blasco's work.  There are a handful of mouse husbandry wizards who can create such a stress-free mouse habitat that their mice live longer than everyone else's mice.  Michael argues that Blasco's control mice didn't live as long as the wizard's mice, so the increase in median lifespan isn't really meaningful.

 

I think you are missinterpreting what Rae says. I will quote it:

 

the reported survival data -- even for treated animals -- were, once again, well within the range typical for well-husbanded, untreated control mice reported in other studies.

 

It doesn't seem that he is talking about husbandry efficiency that only a few researchers can attain.

 

He argued that the study wasn't adequately powered to determine max LS.  OK, fine.  I'm talking about median LS, and I suspect the study was adequately powered for that.

 

Ok, you are not interested in the maximal lifespan of mice, only in the median lifespan. But, for this treatment to be useful in humans, it's maximal lifespan what is important, since our median lifespan is already near our maximal lifespan, thanks to our success in preventing non age-related causes of death.

 

Another argument was that there could have been some crypto-CR in the treatment mice that happened in an interval when they weren't checking for it.  When they did check for it, it wasn't happening.  That is just grasping at straws.   He mentioned the numerous biomarkers that improved in the treatment group, so there's more to the story than just lifespan.  I'm afraid that if we start using words like "known" or "proven", we'll just get into an epistemological quagmire.

 

It's not grasping at straws at all. CR control was really poor, and more so for mice, who are much more affected by it than humans:

 

Additionally, there was relatively little effort invested in ruling out a possible effect of Calorie restriction (CR) in this study. [...] The authors of the current study did report that they "did not find significant differences in body fat content or in body weight of the different mouse cohorts,"(9) but this was apparently based on a single measurement of these parameters before and sometime after treatment. Such measurements are far from sufficient to rule out CR in murine lifespan study. As exhaustively documented in a widely-overlooked review of the history of such studies by the highly experienced and painstaking Dr. Stephen Spindler, seemingly minor and temporary changes in energy intake can exert significant effects on health and longevity outcomes. We highlighted this invaluable paper in a previous post because demonstrates how critical it is to the design of robust murine lifespan studies to incorporate robust and regular measures of food intake. The lack of such measures leaves the proper interpretation of nearly all reports of decelerated degenerative aging and expansion of the bounds of the lifespan in doubt -- including this one.

 

As for biomarkers, CR improves many biomarkers in humans, but doesn't seem to have much effect on our lifespan.

 

I think we have some pretty good evidence that extra telomerase does good things for mice.  Whether or not it's good for humans remains to be seen.

 

I think the other posters were arguing about telomerase effects on humans, using mice only as a means to prove its effects on humans.

Edited by Antonio2014, 20 January 2016 - 09:28 AM.

[Santi]

 

 

Interesting concept,  I think there is potential for this epigentic theory and is likely a factor. However since epigenetic changes are heavily environmental it would seem there would be more variance to the aging patterns with some people perhaps breaking through to much longer lifespans like 150 etc if the driver was epigenetic at its core.  However if it was wear and tear related at it's core with epigenetics playing into the cascade of events that would seem more likely.

 

 

There is not much variation in the epigenetic clock. 

"The epigenetic clock leads to a chronological age prediction that has a Pearson correlation coefficient of r=0.96 with chronological age. Thus the age correlation is close to its maximum possible correlation value of 1. Other biological clocks are based on a) telomere length, b) p16INK4a expression levels (also known as INK4a/ARF locus),^[18]and c) microsatellite mutations. The correlation between chronological age and telomere length is r=−0.51 in women and r=−0.55 in men."

 

The pre-eminent example for an epigenetic clock is Horvath's clock, which is based on 353 epigenetic markers on the human genome. 

 

"The 353 markers measure DNA methylation of CpG dinucleotides. Estimated age ("predicted age" in mathematical usage), also referred to as DNA methylation age, has the following properties: first, it is close to zero for embryonic and induced pluripotent stem cells; second, it correlates with cell passage number; third, it gives rise to a highly heritable measure of age acceleration; and, fourth, it is applicable to chimpanzee tissues (which are used as human analogs for biological testing purposes). Organismal growth (and concomitant cell division) leads to a high ticking rate of the epigenetic clock that slows down to a constant ticking rate (linear dependence) after adulthood (age 20). The fact that DNA methylation age of blood predicts all-cause mortality in later life even after adjusting for known risk factors suggests that it relates to a process that causes aging. Similarly, markers of physical and mental fitness are associated with the epigenetic clock (lower abilities associated with age acceleration).

Salient features of Horvath's epigenetic clock include its high accuracy and its applicability to a broad spectrum of tissues and cell types. Since it allows one to contrast the ages of different tissues from the same subject, it can be used to identify tissues that show evidence of accelerated age due to disease."

 

 

 I think that to move past telomere length as a clock would require a specific fault in the telomere theory or else it seems quite feasible as the way the Hayflick limit works.(the validity shouldn't be judged based on how fresh the trend is)

Telomere length is definitely some sort of clock as eventually cells which divide reach the Hayflick limit if their telomere length is not extended. However looking at the evidence I think most people can agree that teomere length is not the main diver of aging. However the epigenetic clock is very highly correlated with mortality risk, even higher than age. Also my understanding is that cells taken from older individuals and have their epigenetic "program" reset become like young cells again. I have to look for sources to verify that this is the case in all types of cells. I know in neurons it was said that when their epigenetic program is reset they were "indistinguishable between young and old derived samples."  

[niner]

 

In the link you posted, Michael has some quibbles, but they aren't enough to dismiss Blasco's work.  There are a handful of mouse husbandry wizards who can create such a stress-free mouse habitat that their mice live longer than everyone else's mice.  Michael argues that Blasco's control mice didn't live as long as the wizard's mice, so the increase in median lifespan isn't really meaningful.

 
I think you are missinterpreting what Rae says. I will quote it:
 

the reported survival data -- even for treated animals -- were, once again, well within the range typical for well-husbanded, untreated control mice reported in other studies.

 
It doesn't seem that he is talking about husbandry efficiency that only a few researchers can attain.

"other studies" means two or more reported experiments, so it's not obvious that lots of people can get the lifespans that a guy like Spindler gets.  The fact remains that given the conditions that the Blasco mice lived under, the treatment group lived longer than the control group. I find it hard to dismiss that out of hand, although of course we'd like to see replication.
 

 

He argued that the study wasn't adequately powered to determine max LS.  OK, fine.  I'm talking about median LS, and I suspect the study was adequately powered for that.

 
Ok, you are not interested in the maximal lifespan of mice, only in the median lifespan. But, for this treatment to be useful in humans, it's maximal lifespan what is important, since our median lifespan is already near our maximal lifespan, thanks to our success in preventing non age-related causes of death.

Are you saying that curve-squaring doesn't matter? Our median LS is pretty far from 123 years, although you might be speaking of a top decile LS as the maximum.  Most of us die not terribly far from the median, so adding a significant number of years to most people's life is better than adding the same amount of years to only the longest-lived among us.
 

As for biomarkers, CR improves many biomarkers in humans, but doesn't seem to have much effect on our lifespan.
 

I think we have some pretty good evidence that extra telomerase does good things for mice.  Whether or not it's good for humans remains to be seen.

 
I think the other posters were arguing about telomerase effects on humans, using mice only as a means to prove its effects on humans.

I'm not sure we have the data to say what CR will do to human lifespan, but I doubt it's going to be enough to be worth the cost. If anyone thinks they can prove the effect of anything on humans using the mouse result, they are mistaken.

[Antonio2014]

"other studies" means two or more reported experiments, so it's not obvious that lots of people can get the lifespans that a guy like Spindler gets.

 

Huh? "Other studies" means "other studies", doesn't mean "other few studies", no matter how you torture the language.

 

 

Are you saying that curve-squaring doesn't matter? Our median LS is pretty far from 123 years, although you might be speaking of a top decile LS as the maximum.  Most of us die not terribly far from the median, so adding a significant number of years to most people's life is better than adding the same amount of years to only the longest-lived among us.

 

See the deaths by age for women in Spain in 2012:

 

 

(Data from http://www.mortality.org )

 

There is not much to be gained by increasing the mean lifespan and not the maximal lifespan. Mortality is already quite compressed against the wall of the maximal lifespan of the population, around 110 years.

 

I'm not sure we have the data to say what CR will do to human lifespan, but I doubt it's going to be enough to be worth the cost. If anyone thinks they can prove the effect of anything on humans using the mouse result, they are mistaken.

 

If CR were as impressive in humans as in mice (30-40 % lifespan increase) we would already knew centuries ago. Also, the two large scale experiments with monkeys didn't have impressive results either. Nevertheless, CR does improve many biomarkers in humans. That's why I'm not much impressed by Blasco's and de Pinho's biomarkers. That's my point.

Edited by Antonio2014, 21 January 2016 - 08:22 AM.

[Never_Ending]

Regarding CR and humans,  no they haven't definitively proved it, no they haven't done much studies on it. There's a lot of variance between individuals and relative to other species for lab study humans have a much longer lifespan so that makes studies hard to do.

 

However, we already know that larger complex organisms pretty much build off of the genetic and biological foundation of more primitive organisms. Biology is very "conservative" in that sense.  CR has been shown in species IE nematodes to mice and an array of other species.  So people want to say there can be NO speculation regarding what effect it would have on humans? Ok shouldn't be too hard to abide by that technicality as no one remarked it being proven in the first place....  

 

But .....before making remarks about how unlikely it will have an effect in humans,  one shouldn't forget to abide by that same technicality. 

[niner]

 

"other studies" means two or more reported experiments, so it's not obvious that lots of people can get the lifespans that a guy like Spindler gets.

 
Huh? "Other studies" means "other studies", doesn't mean "other few studies", no matter how you torture the language.

"Other studies" is plural. Any number greater than one is enough to meet this description. That's the definition of a plural; it has nothing to do with "torturing the language".  "Other studies" tells us NOTHING about the number, other than that it is greater than one. You can no more say it's "a lot" than I can say it's "a few".
 

 

Are you saying that curve-squaring doesn't matter? Our median LS is pretty far from 123 years, although you might be speaking of a top decile LS as the maximum.  Most of us die not terribly far from the median, so adding a significant number of years to most people's life is better than adding the same amount of years to only the longest-lived among us.

 
See the deaths by age for women in Spain in 2012:
 

 
(Data from http://www.mortality.org )
 
There is not much to be gained by increasing the mean lifespan and not the maximal lifespan. Mortality is already quite compressed against the wall of the maximal lifespan of the population, around 110 years.

That graph proves my point. The entire area under the curve represents people who could have lived longer, in most cases a lot longer, if the mortality curve were squared out to 110. That's a lot of person-years of life that you'd be giving up by dismissing a curve-squaring intervention. I'm not trying to argue that curve-squaring should be prioritized wildly higher than shifting the max, I'm just saying that it doesn't make sense to ignore curve-squaring if we can do it.
 

[Rocket]

Regarding CR and humans, no they haven't definitively proved it, no they haven't done much studies on it. There's a lot of variance between individuals and relative to other species for lab study humans have a much longer lifespan so that makes studies hard to do.

However, we already know that larger complex organisms pretty much build off of the genetic and biological foundation of more primitive organisms. Biology is very "conservative" in that sense. CR has been shown in species IE nematodes to mice and an array of other species. So people want to say there can be NO speculation regarding what effect it would have on humans? Ok shouldn't be too hard to abide by that technicality as no one remarked it being proven in the first place....

But .....before making remarks about how unlikely it will have an effect in humans, one shouldn't forget to abide by that same technicality.

Unfortunately, throughout the millenia, there are no historically long lived humans, supercentenarians, as a result of living on reduced calories. Surely by now, if CR led to 150yo humans, it would have been discovered!

CR seems good in humans for lipids and blood pressure and biomarkers of good health, little more. Its also good for making people physically weak and unnaturally skinny. It does not slow the aging process. It may even may make things like sarcopenia worse!

Edited by Rocket, 22 January 2016 - 02:19 AM.

[niner]

CR seems good in humans for lipids and blood pressure and biomarkers of good health, little more. Its also good for making people physically weak and unnaturally skinny. It does not slow the aging process. It may even may make things like sarcopenia worse!

 

I can't argue with any of this, except the part about slowing the aging process.  It does slow the aging process, through improved autophagy, mtor signalling, and probably other things.

[Antonio2014]

However, we already know that larger complex organisms pretty much build off of the genetic and biological foundation of more primitive organisms. Biology is very "conservative" in that sense.  CR has been shown in species IE nematodes to mice and an array of other species.  So people want to say there can be NO speculation regarding what effect it would have on humans? Ok shouldn't be too hard to abide by that technicality as no one remarked it being proven in the first place....  

 

But .....before making remarks about how unlikely it will have an effect in humans,  one shouldn't forget to abide by that same technicality. 

 

You should follow your own advice. There are huge amounts of experimental data that show that CR life extension and regular, non-CR lifespan are inversely related. For C. elegans, you can easily obtain around 700% life extension by CR, for fruit flies it's more like 200-300%, and for mice only 30-40% increase. For monkeys, the two long-term experiments done barely show any increase. http://www.sens.org/...en-and-mimetics
 

[Antonio2014]

 

 

"other studies" means two or more reported experiments, so it's not obvious that lots of people can get the lifespans that a guy like Spindler gets.

 
Huh? "Other studies" means "other studies", doesn't mean "other few studies", no matter how you torture the language.

"Other studies" is plural. Any number greater than one is enough to meet this description. That's the definition of a plural; it has nothing to do with "torturing the language".  "Other studies" tells us NOTHING about the number, other than that it is greater than one. You can no more say it's "a lot" than I can say it's "a few".
 

 

Are you saying that curve-squaring doesn't matter? Our median LS is pretty far from 123 years, although you might be speaking of a top decile LS as the maximum.  Most of us die not terribly far from the median, so adding a significant number of years to most people's life is better than adding the same amount of years to only the longest-lived among us.

 
See the deaths by age for women in Spain in 2012:
 

 
(Data from http://www.mortality.org )
 
There is not much to be gained by increasing the mean lifespan and not the maximal lifespan. Mortality is already quite compressed against the wall of the maximal lifespan of the population, around 110 years.

That graph proves my point. The entire area under the curve represents people who could have lived longer, in most cases a lot longer, if the mortality curve were squared out to 110. That's a lot of person-years of life that you'd be giving up by dismissing a curve-squaring intervention. I'm not trying to argue that curve-squaring should be prioritized wildly higher than shifting the max, I'm just saying that it doesn't make sense to ignore curve-squaring if we can do it.
 

 

I will not waste my time replying to these pointless arguments.
 

[Rocket]

 

CR seems good in humans for lipids and blood pressure and biomarkers of good health, little more. Its also good for making people physically weak and unnaturally skinny. It does not slow the aging process. It may even may make things like sarcopenia worse!

 

I can't argue with any of this, except the part about slowing the aging process.  It does slow the aging process, through improved autophagy, mtor signalling, and probably other things.

 

 

I forgot about mtor and autophagy, primarily because in large mamals, CR seems do very little (visually) towards slowing aging the process.  If you look at pics of CR practitioners they all look their age, grey haired, wrinkled, and so pencil thin skinny it's a wonder they go outside on a cold windy day.  They are all going to die at an appropriate age for their birth year.  Hence, I say that CR does not slow the aging process.  If CR truly slowed aging, I would expect a 70yo CR person to look like a healthy 55yo with similar energy and vitality, but that's not what you find. What do you find is a 70yo CR follower looking like a 70yo person, only skinnier and maybe with better lipids and BP.

 

I guess I would chalk up autophagy and mtor to just more biomarkers of healthy, and not towards slowing the aging process. 

 

The only group of people that I know of that truly defy the aging process both visually and physically are the serious body builders.  Muscle mass and strength and body composition go a long, long way towards mitigating the aging process.

Edited by Rocket, 22 January 2016 - 02:54 PM.

[Never_Ending]

 

However, we already know that larger complex organisms pretty much build off of the genetic and biological foundation of more primitive organisms. Biology is very "conservative" in that sense.  CR has been shown in species IE nematodes to mice and an array of other species.  So people want to say there can be NO speculation regarding what effect it would have on humans? Ok shouldn't be too hard to abide by that technicality as no one remarked it being proven in the first place....  

 

But .....before making remarks about how unlikely it will have an effect in humans,  one shouldn't forget to abide by that same technicality. 

 

You should follow your own advice. There are huge amounts of experimental data that show that CR life extension and regular, non-CR lifespan are inversely related. For C. elegans, you can easily obtain around 700% life extension by CR, for fruit flies it's more like 200-300%, and for mice only 30-40% increase. For monkeys, the two long-term experiments done barely show any increase. http://www.sens.org/...en-and-mimetics
 

 

 

Wait so you basically are agreeing with me?   The whole point of my post was to highlight the potential for CR while drawing upon common criticisms. What do you mean by follow my own advice??? Please clarify

[Never_Ending]

Unfortunately, throughout the millenia, there are no historically long lived humans, supercentenarians, as a result of living on reduced calories. Surely by now, if CR led to 150yo humans, it would have been discovered!

CR seems good in humans for lipids and blood pressure and biomarkers of good health, little more. Its also good for making people physically weak and unnaturally skinny. It does not slow the aging process. It may even may make things like sarcopenia worse!

 

 

It's not that simple.   CR in the past is related to malnutrition and lack of food those conditions are bordering on a harsh conditions scenario and although that might fall under CR by caloric intake may perhaps die early do to malnutrition and just overall lack of healthcare.

 

Purposeful CR (without going into overdrive like making someone too skinny or weak), could have benefits and I didn't say they would be as profound as in mice either.

 

Without going into strawman arguments like  saying someone doing it to the extreme or some one practicing CR while doing other unhealthy habits. (as for lipids etc and many separate effects well , everything works through some mechanism doesn't it? Thats like saying it's not the radiation that's bad it's the DNA damage, oh no it's not the DNA damage it's the expression of the DNA damage...that kind of reductionistic approach can be used on anything)

 

Rebuttals that fall into those categories are off-centered

So far CR still seems like it likely will have many benefits when practiced in a reasonable manner

Edited by Never_Ending, 22 January 2016 - 03:55 PM.