• Log in with Facebook Log in with Twitter Log In with Google      Sign In    
  • Create Account
  LongeCity
              Advocacy & Research for Unlimited Lifespans

Photo
* * * * * 2 votes

Epigenetic clock and telomeres

horvath clock epigenetic clock telomeres

  • Please log in to reply
38 replies to this topic
⌛⇒ new years donation: support LE labs

#31 HighDesertWizard

  • Guest
  • 812 posts
  • 773
  • Location:Bend, Oregon, USA

Posted 20 May 2018 - 06:27 PM

It's a mistake to take one study especially seriously without trying to determine The Fit of its Findings with the Findings of other studies, especially if they appear to contradict each other.
 
I'm not clear about The Fit of the Horvath findings discussed above to the general findings of 1) Epel/Blackburn in numerous studies over a decade and 2) the combined findings in Belmonte's 2016 In Vivo Reprogramming study and in Blasco's In Vivo Reprogramming study published a few months.
 
As I understand it, the entirety of the Epel/Blackburn body of studies shows that a younger age is associated with greater Telomerase Expression and longer Telomere Length.
 
 
 

"We have found that when you induce cell dedifferentiation in an adult organism, the telomeres become longer, which is consistent with cellular rejuvenation", explains María A. Blasco, head of the CNIO Telomeres and Telomerase Group and leader of this research. This lengthening of the telomeres is an unequivocal sign of cell rejuvenation, which has been quantified for the first time here in a living organism.

Blasco and her colleagues have worked with the so-called "reprogrammable mice" -created by Manuel Serrano, also a CNIO researcher, whose group is also involved in this project. Broadly speaking, the cells of these transgenic animals carry the four Yamanaka factors (OSKM) whose expression is turned on when an antibiotic is administered....

 

What am I missing here? How do these study findings Fit with each other?

 


Edited by HighDesertWizard, 20 May 2018 - 06:29 PM.

  • like x 1

#32 QuestforLife

  • Member
  • 817 posts
  • 399
  • Location:UK

Posted 21 May 2018 - 12:41 PM

I agree HighDesertWizard that the Horvath Clock and various telomere study findings do not seem to fit well. I've made some suggestions for why this might be up thread, but the truth is no one has yet resolved this with actual data.

 

One thing to bear in mind, Horvath has recently published a newer methylation clock PhenoAge, which is designed to fit with mortality rather than chronological age (most of the epigenetic markers are at different sites), and this clock correlates weakly (but in the right direction) with leukocyte telomere length (which itself only has a tenuous connection to body-wide aging, due to the very rapid turnover of immune cells in the blood).

 

www.biorxiv.org/content/early/2018/03/05/276162

 

So we may find that it is confounding factors that are confusing greater chronological age with longer telomeres (in leukocytes). Time will tell.

 


  • like x 1

#33 HighDesertWizard

  • Guest
  • 812 posts
  • 773
  • Location:Bend, Oregon, USA

Posted 22 May 2018 - 05:44 AM

QuestforLife... I very much appreciate your reply...

 

I agree HighDesertWizard that the Horvath Clock and various telomere study findings do not seem to fit well. I've made some suggestions for why this might be up thread, but the truth is no one has yet resolved this with actual data.

 

The Epel / Blackburn study teams must have a dozen studies under their belts showing an inverse correlation between telomere length and aging. And Blasco's work does the same. How many apparently contrasting studies like this one by Horvath are there?
 

When will our objective as a Movement become more focused on ensuring that our beliefs and practices include All the Evidence that exists and not just the newest, new shiny study object to appear?
 

 

One thing to bear in mind, Horvath has recently published a newer methylation clock PhenoAge, which is designed to fit with mortality rather than chronological age (most of the epigenetic markers are at different sites), and this clock correlates weakly (but in the right direction) with leukocyte telomere length (which itself only has a tenuous connection to body-wide aging, due to the very rapid turnover of immune cells in the blood).
 
www.biorxiv.org/content/early/2018/03/05/276162

 
Yes. This is great. As our lifespans increase, we'll want to know how much time we have left. Knowing how old we are by some old measure won't be of much use. I was a little early here, but I did note the change in the measurement object. Someday, hopefully, we will need some algorithms to calculate average projected lifespan remaining...

 

 

 
So we may find that it is confounding factors that are confusing greater chronological age with longer telomeres (in leukocytes). Time will tell.

 

Two interesting phrases... We "may find confounding variables" and "Time will tell"?

 

I'm curious... How exactly will time tell? I can think of a few different things you might mean... Of course, I have an opinion too...

 

1... Thomas Kuhn pointed out, in his now classic book, The Structure of Scientific Revolutions, that older thought leaders had to retire or die off before new paradigms that better fit the most recent evidence could emerge and establish knowledge advance. So... perhaps, you were politely suggesting we needed our current batch of Thought Leaders to depart the scene before we can make progress... And that will take time....

 

Or perhaps you were suggesting we need 2) a lot more scientific study data to make major advances or 3) more time to process and integrate the knowledge that already exists but isn't clearly placed on our puzzle table?

 

---------------

 

I wonder... Despite our Movement's Thought Leaders not discussing it...

 

Suppose there existed an enormous body of evidence for an independent variable related to both Telomere Length and Epigenetic Methylation showing profound Survival Probability Benefit or the opposite, depending on how it got expressed or not... Might that be an important confounding variable we should take a look at? Even in this forum thread?

 

Put more strongly... Suppose this independent variable had also been shown in at least a few studies to be Causally Related to both Telomerase Expression and unhealthy Methylation outcomes...

 

And suppose this independent variable was in plain sight, itself, the subject of hundreds of studies by hundreds of scientists over decades...

 

And suppose this independent variable had been shown, not only to be related to the Telomerase/Telomere Length nexus of issues and Epigenetic Methylation, but also to almost all the other independent variables associated with aging that are often discussed, here, at Longecity... In short, not only would this variable be a Confounding Variable in the discussion of Telomerase/Telomeres/Methylation, it would also be a confounding variable for most/all the other variables associated with aging...

 

And suppose... Evolution had established a specific and complex Mechanism within us to specifically target that independent variable in a way shown in studies to increase average lifespan if we triggered in just the right way at just the right intervals...

 

<Sigh> Wouldn't it be great if we had that problem?

 

:)


Edited by HighDesertWizard, 22 May 2018 - 06:11 AM.


sponsored ad

  • Advert

#34 HighDesertWizard

  • Guest
  • 812 posts
  • 773
  • Location:Bend, Oregon, USA

Posted 22 May 2018 - 07:12 AM

About that independent variable... Hot off the press...

https://warwick.ac.u...r_bodies_fight/

 
Hotter bodies fight infections and tumours better – researchers show how
  • Higher body temperatures speed our bodies' responses to infections, wounds and tumours - researchers at the Universities of Warwick and Manchester prove
  • Slight rise in temperature and inflammation – such as a fever - speeds up cellular ‘clock’ in which proteins switch genes on and off to respond to infection
  • New understanding could lead to more effective and fast-working drugs which target a key inflammation protein found to be critical for the temperature response
  • Interdisciplinary team of Warwick mathematicians and Manchester biologists used modelling and lab experiments to jointly make discovery

 

"The researchers have demonstrated that small rises in temperature (such as during a fever) speed up the speed of a cellular ‘clock’ that controls the response to infections – and this new understanding could lead to more effective and fast-working drugs which target a key protein involved in this process.

 

"Biologists found that inflammatory signals activate ‘Nuclear Factor kappa B’ (NF-κB) proteins to start a ‘clock’ ticking, in which NF-κB proteins move backwards and forwards into and out of the cell nucleus, where they switch genes on and off.

 

"This allows cells to respond to a tumour, wound or infection. When NF-κB is uncontrolled, it is associated with inflammatory diseases, such as Crohn’s disease, psoriasis and rheumatoid arthritis.

 

"At a body temperature of 34 degrees, the NF-κB clock slows down. At higher temperatures than the normal 37 degree body temperature (such as in fever, 40 degrees), the NF-κB clock speeds up."

 

=============================

 

Frankly, I have only just recently become aware that NF-kB could Translocate Out of the Nucleus after having Translocated Into It... There are several studies now with pics of this...

 

Notice that, in the pic below, RelA is shown often... RelA is the gene for the NF-kB p65 subunit... And p65 plays a role in both Telomerase Expression and in Epigenetic Methylation... I'm just getting into those details and not sure what study is best to link to... But you can see for yourself this is true with these search phrases, "p65 telomerase", "p65 epigenetic methylation".

 

xEva... I've had similar questions to the ones you asked above... Note there may be answers to your questions implicit in these studies... Apparently, NF-kB can translocate in and out of the nucleus without cell division and can trigger Telomerase and Methylation each time that it does... That's my take on the meaning of this... Frankly, I've been thinking for several months now that this was the fact that would account for rapid increases and decreases in Telomere Length and accelerated Epigenetic change... For me, this Warwick study is confirmation that I've been thinking about this in the right way...

 

What else to keep your eye on? Some important background from some posts I made in 2015 here... Note... The linked studies aren't about humans... Unsure of relevance for that reason...

 

p65, p50, IL-6

 

=============================

 

 

 

F2.large.jpg?width=800&height=600&carous

 

Edited by HighDesertWizard, 22 May 2018 - 07:47 AM.

  • Informative x 1

#35 HighDesertWizard

  • Guest
  • 812 posts
  • 773
  • Location:Bend, Oregon, USA

Posted 22 May 2018 - 07:21 AM

In addition to the study summarized above, there are a good many more showing that NF-kB Expression and inhibition turns genes on and off... Links to follow within a few days...

 

I'll also provide study evidence links for every supposition I wrote out above within a few days...

 

Let's get clear about the key supposition now...

 

Can NF-kB Expression, does NF-kB Expression, or Inhibition, have an impact on Survival Probability?

 

https://www.longecit...urvival-curves/


Edited by HighDesertWizard, 22 May 2018 - 08:17 AM.


#36 Nate-2004

  • Guest
  • 2,339 posts
  • 324
  • Location:Philadelphia
  • NO

Posted 22 May 2018 - 03:26 PM

@HighDesertWizard 

 

I haven't read too far back on your posts about NF-kB and honestly I'm still a little spotty on my understanding. However, I wanted to ask a question. I've been using the sauna at around 82c for 20 mins 4 times per week for at least a year now. You mention body temperature as something that may affect NF-kB by "speeding up the clock" at high temps. What do you think about how sauna use might affect NF-kB and would this be perhaps a mechanism for why sauna use improves longevity in a number of studies?



#37 QuestforLife

  • Member
  • 817 posts
  • 399
  • Location:UK

Posted 24 May 2018 - 08:55 AM

This may be of interest to you HighDesertWizard

 

www.ncbi.nlm.nih.gov/pubmed/18442324

 

'Do mitochondrial DNA and metabolic rate complement each other in determination of the mammalian maximum longevity?'

 

The short answer is yes!

 

Metabolic rate is related to body temperature and mTOR - which is all about the rate of cellular and protein turnover, and the stability of mitochondrial DNA is basically a proxy for ROS and inflammation (possibly via DNA damage response). Both of these are going to have a big impact on the preservation or reduction of telomere length in a given species during their lifetime. Rats and mice for example have long telomeres and active telomerase in most cell types, but this is not enough to stop telomere shortening due to sky high metabolism and ROS (leading to inflammation) levels. Humans have relatively short telomeres without compensating telomerase in most cell types, but with a much lower metabolism and inflammation attrition is much reduced.

 

Evidence of the mitochondrial connection to the inflammatory cascade and apoptosis in tissues, via the immune response to pieces of mtDNA in the blood:

 

'BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis'

 

www.ncbi.nlm.nih.gov/pubmed/29472455

 

A possible method of blocking the cascade with coffee consumption:

 

'Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states'

 

www.ncbi.nlm.nih.gov/pubmed/28092664

 

As for the effects of all this on Horvath's clock? I don't think that connection is clear yet and whether it's connected to, or independent of telomere attrition, but it seems clear there is a connection.

 

Apologies if you've already read these papers, but to me they seem pertinent to the discussion at hand.


Edited by QuestforLife, 24 May 2018 - 08:59 AM.

  • WellResearched x 1

#38 John250

  • Guest
  • 1,451 posts
  • 106
  • Location:Temecula
  • NO

Posted 06 June 2018 - 09:03 PM

I wouldn’t recommend DNP without extreme caution but it seems to exhibit some of these effects.

https://www.ncbi.nlm...ubmed/26010875/

Perhaps a different more mild uncoupler like UCP1 May be beneficial if cycled.
  • Informative x 1

⌛⇒ new years donation: support LE labs

#39 Nate-2004

  • Guest
  • 2,339 posts
  • 324
  • Location:Philadelphia
  • NO

Posted 01 September 2018 - 03:42 AM

I got my methylation test back from DNAge. Is it meaningful or does it make sense that we aim to reverse this number? 

 

 https://drive.google...ECNtnXOHPr/view



⌛⇒ new years donation: support LE labs




Also tagged with one or more of these keywords: horvath clock, epigenetic clock, telomeres

1 user(s) are reading this topic

0 members, 1 guests, 0 anonymous users