Levine Phenotypic Age Spreadsheet

[mccoy]

Another interesting piece is the role of methylation in aging; methylation according to horvath explains 50% of aging and he presents this plot, where we have log longevity on the Y axis and log velocity of methylation of the top 500 highest CpGs on the X axis.

[mccoy]

Greg Fahy shows in another TEDX presentation the results of the TRIIM experiment hinted at by Horvath. The trial involves subministration of a durg cocktail which regenerates the thymus. After 12 months the epigenetic clock (not specified which one) indicated a 2-3 years reversal of age, which ceased after the trial ceased.

The above together with other beneficial outcomes. The results are too good to be true and of course many replications are needed. They would imply that after 10 years of the treatment we may exhibit on average a rejuvenation of 25 years. Everything still very much hypothetical, but shows how the epigenetic clocks can be used as a detector of the possible outcome of a longevity trial.

Edited December 31, 2022 by mccoy

[Guest]

There is a quick summary of the state of aging clocks on the fightaging blog (see the links in that section for more details):

https://www.fightaging.org/archives/2022/12/a-look-back-at-2022-progress-towards-the-treatment-of-aging-as-a-medical-condition/

 

 

[mccoy]

A clip where Matt Kaberlain illustrate to Peter Attia his perplexities about epigenetic clocks. The first issue is that there are quite a few, not directly comparable.

Such issue of the not so comparable epigenetic clocks has been addressed by Morgan Levine in this presentation, she says the fact is actually disappointing and that each single clock is usually suited to different applications.

At 14:45 she projects this slide which compares various clocks, which give often opposite results (slowing versus accelerating aging). Please note that the uppermost group includes the DunedinPoAm clock, cited by Mike Lustgarten as a specific clock for CR practictioners. A real thorough work of standardization and classification should take place.

[mccoy]

I applied the Phenoage not to myself, but to my wife. Not withstanding her having high ApoB and moderately high Hba1c, she turned out to be 10-11 years younger according to the algorithm. As already cited, some parameters govern the result more than others. CRP is  one of these and my wife has zero CRP detected according to the lab results.

However, do we know the detection limit for CRP? In the spreadsheet zero is not an allowed value, so I tinkered with decimal figures, the result was the following:

• CRP 0.1 → Phenoage = -10.3
• CRP 0.01 → Phenoage = -12.7
• CRP 0.001 → Phenoage = -15.1

The above results show that probably the spreadsheet should have imposed a lower bound to the values.

High albumin also inordinately lowers Phenotypic age and my wife has a medium high value...

Anyway, Levine is a wizard and a bit of a genius, having become professor at Yale at a pretty young age and having left her position to be hired by Jeff Bezos' El Alto lab, together with Horvath and under the supervision of the nobel laureate Yamanaka.

My guess is that the correlation of phenoAge with the DNA-based test owned by Lumina (up until a little while ago) is pretty good and that the results may suggest the underlying trend of aging, beyond the contemporary metabolic health. That is, some biological setup may slow aging down even though some metabolic parameters suggest some disfunction, and this of course appears to be a contradictory statement.

It may be that age is slowing but the risk of cardiac events is nevertheless nontrivial, so the slow aging may be eventually interrupted by a fatal event (if countermeasures are not taken).

Edited May 25, 2023 by mccoy

[IgorF]

11 hours ago, mccoy said:

However, do we know the detection limit for CRP?

https://www.testing.com/tests/high-sensitivity-c-reactive-protein-hs-crp/

here 0.3-10mg/L mentioned, other sources googled giving similar ranges, e.g. 0.5-10 etc.

 

Here is a useful hint from "Therapeutic Lipidology" Second Edition https://link.springer.com/book/10.1007/978-3-030-56514-5

Quote

To be sure, hsCRP has been found to have
good repeatability with correlations ranging from
0.46 to 0.66.

 

https://books.google.com/books?id=cTMPEAAAQBAJ&pg=PA568&lpg=PA568&dq="To+be+sure,+hsCRP+has+been+found+to+have good+repeatability+with+correlations+ranging+from"&source=bl&ots=x6nNudNPO2&sig=ACfU3U3u9P6tNhgaXgLW2ssNufAJVAP_mA&hl=en&sa=X&redir_esc=y

 

I personally think that being so serious with these calcs is an overkill, they are rather pieces of tech art than real scientific tools, so even single variable calcs are questionable (e.g. they intentionally/unintentionally convincing the reader about the linearity of the process while in the real world there is a second order process - acceleration that is easily observable in most cases of the healthy aging, at some moment).

 

Br,

Igor

 

 

Edited May 26, 2023 by IgorF

[InquilineKea]

There is a difference between my blood PhenoAge and my DNAm Phenoage. It's consistent with my Phenoage DNAm being the lowest of any of the DNAm clocks, but there is a difference.

Suffices to say that there are many forms of aging that can take place even with almost no inflamma-aging (this is what you see in a lot of CRONites)... Many CRONites have perfect PhenoAge markers, but PhenoAge doesn't measure cystatin C (measured in Humanity) or GDF15 or any of the additional metabolites measured in GrimAge (which has much stronger p-values than PhenoAge). Idk if PhenoAge measures anything correlated with senescence (can senescence without inflammation occur?)

Edited May 26, 2023 by InquilineKea

[Mike Lustgarten]

Exactly Alex. PhenoAge (blood-based or epigenetic) is a part of the health/longevity story, but it doesn't cover all the bases. That's why I track BP, FEFV, physical function, oral microbiome, etc

[mccoy]

5 hours ago, InquilineKea said:

Idk if PhenoAge measures anything correlated with senescence (can senescence without inflammation occur?)

If I remember well, senescence is not a process included in epigenetic clocks

[IgorF]

Not the main topic but since there was here and in other places a discussion about slightly increased MCV and while I was looking for another thing I found IMHO a probable answer on this intriguing topic:

 

https://books.google.com/books?id=DCIVBQAAQBAJ&pg=PA93&lpg=PA93&dq="+storage+of+samples+for+too+long+a+time+or+at+an+inappropriate+temperature;+this+can+increase+the+MCV"&source=bl&ots=Db827VGaB4&sig=ACfU3U3DPb7KH9EBePn-RIEUkcopIRFIow&hl=en&sa=X&ved=2ahUKEwjx36nV1v__AhVi8bsIHVe-DuMQ6AF6BAgNEAM#v=onepage&q=" storage of samples for too long a time or at an inappropriate temperature%3B this can increase the MCV"&f=false

For the most machines in use today there is very low chance that they will do something improperly but there are many ways to feed them already altered specimen. So slight MCV swelling due to temperature regimen could be invisible in non-edge cases but in a specific edge case for people at CR could become more visible due to crossing the boundary.

I was curious to find what else could be suspicious and found this https://academic.oup.com/labmed/article-pdf/30/5/325/24957591/labmed30-0325.pdf

there are many more ways of MCV to increase and while osmolality change due to very high glucose or TG is not the case the generally spoken hyperosmolar state for the blood could probably have its place in some people if they have small stature (thus less body  fluids total) and in addition - without glass of water before the specimen acquisition (happens to me sometimes).

 

Thus, I would say - it is better to be very careful with wide generalizations based on MCV interpretation unless all the details of the analysis flow are known to be controlled.

 

Br,

Igor

Edited July 8, 2023 by IgorF

[IgorF]

While digging for other thing found a few words that could shed some light on RDW's weight in the calculator model:

Red Cell Distribution Width and the Risk of Death in Middle-aged and Older Adults
Kushang V. Patel, Ph.D., M.P.H.,1 Luigi Ferrucci, M.D., Ph.D.,2 William B. Ershler, M.D.,2 Dan L. Longo, M.D.,2 and Jack M. Guralnik, M.D., Ph.D.1

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2765040/

 

Quote

In this nationally representative study, RDW was a strong predictor of mortality in both middle-aged and older adults. Mortality rates were graded across the entire distribution of RDW and were particularly elevated in participants with RDW greater than 13.4%. Deaths from CVD, cancer, and other causes were all associated with RDW, although the effect was stronger for CVD mortality. Associations were independent of multiple potential confounding factors. Even when participants with high RDW values or nutritional deficiencies were excluded, RDW remained strongly associated with mortality. Importantly, RDW predicted mortality among participants who were clearly non-anemic. Summary measures of global model fit, model calibration, and model discrimination further showed that RDW significantly improved mortality risk prediction. The magnitude and robustness of these associations indicate that RDW is an age-associated biomarker that is prognostic in adults aged 45 and older.

 

There are two ways to report it - in % (rdw-cv) and in fl (rdw-sd). Sometimes labs do both, sometimes not. My cv usually is on the low side while sd on the high. Both sometimes are slightly out of ranges. The parameter is a secondary to help with anemia diagnostic but seems could also be a sign of some undernutrition (in colon deseases but for CR people it could be also "generic" perhaps).

IMHO this parameter is highly context-dependent and should not be interpreted without the context for an individual person/case but  model construction for mass assessments like these calculators perhaps was selected as useful for the reasons like an article above.

I personally wonder about such far going predictions based on indirect values, known to be skewed because of procedures, lab calibration and so on but well, it is not my statement that it is connected, thus, just posted here as a kind of 2 cents into the picture.

 

 

Br,

Igor

 

[IgorF]

And again RDW.

While playing with an occasion of common cold to learn from my tests during it I found an interesting piece of data, it is about covid19 but this does not really matter, it contains nicely presented data on some blood markers between several studied groups:

https://jag.journalagent.com/ijmb/pdfs/IJMB-03164-RESEARCH_ARTICLE-ALISIK.pdf

RDW has no difference between no covid / mild cases but is significantly increased in severe cases. I started to search additionally and it seems RDW was already known to be increased during systemic inflammation in e.g. within autoimmune reactions, cvds and so on.

From the author of https://jlpm.amegroups.org/article/view/3577/4289 :

Quote

Although many biomarkers have been used to estimate the disease activity of autoimmune diseases, such as CRP and ESR, RDW has some advantages. First, RDW can be obtained from routine hematological tests, without any additional cost. Second, traditional markers, such as CRP and ESR, are sensitive to infectious events, while RDW is only affected by the size of red blood cell. Because the half-life of red blood cell is approximately 130 days, RDW appears to be insensitive to infectious events. In my opinion, RDW represents long-term inflammatory status, while CRP and ESR represent short-term inflammatory status.

IMHO, RDW's weight in complex models could be tuned but it definitely is a candidate to be a part of them, for exactly these reasons - availability and disconnection of traditional infection-inflammation pair.

Br,

Igor

[Saul]

No comment.  I don't think much of any Guru's thoughts, no matter how many videos they make.

  --  Saul

[Ron Put]

On 1/9/2024 at 6:40 AM, IgorF said:

traditional markers, such as CRP and ESR, are sensitive to infectious events, while RDW is only affected by the size of red blood cell. Because the half-life of red blood cell is approximately 130 days, RDW appears to be insensitive to infectious events. In my opinion, RDW represents long-term inflammatory status, while

Very interesting and it makes sense. Thanks!

My CRP is usually very low, but my RDW varies between 12.2 and 12.4 in most tests, so maybe it should become the focus of my next dietary experiment, to see if I can drive it down. My folate intake is already fairly high, I supplement with B12, so I'll have to do some research on how to try and get it into the 11 range.