Hijacking the epigenetic clock paradigm

This 2018 German human study’s last sentence was:

“Additionally we found an association between DNAm [DNA methylation] age acceleration and rLTL [relative leukocyte telomere length], suggesting that this epigenetic clock, at least partially and possibly better than other epigenetic clocks, reflects biological age.”

Statements in the study that contradicted, qualified, and limited the concluding sentence included:

“The epigenetic clock seems to be mostly independent from the mitotic clock as measured by the rLTL.

It could be possible that associations are confounded due to short age ranges or non-continuous age distribution, as displayed in the BASE-II cohort (no participants between the age of 38 and 59 years). [see the below graphic]

The BASE-II is a convenience sample and participants have been shown to be positively selected with respect to education, health and cognition.

Samples in which DNAm age and chronological age differed more than three standard deviations from the mean were excluded (N=19).

While the original publication employed eight CpG sites for DNAm age estimation, we found that one of these sites did not significantly improve chronological age prediction in BASE-II. Thus, we reduced the number of sites considered to seven in the present study and adapted the algorithm to calculate DNAm age.

  • Horvath described a subset of 353 methylation sites predicting an individual’s chronological age with high accuracy..
  • Even though the available methods using more CpG sites to estimate DNAm age predict chronological age with higher accuracy..
  • It is not clear how much of the deviation between chronological age and DNAm age reflects measurement error/low number of methylation sites and which proportion can be attributed to biological age.

Due to the statistical method employed, we encountered a systematic deviation of DNAm age in our dataset.”


Findings that aren’t warranted by the data is an all-too-common problem with published research. This study illustrated how researcher hypothesis-seeking behavior – that disregarded what they knew or should have known – can combine with a statistics package to produce almost any finding.

It reminded me of A skin study that could have benefited from preregistration that made a similar methodological blunder:

The barbell shape of the subjects’ age distribution wouldn’t make sense if the researchers knew they were going to later use the epigenetic clock method.

The researchers did so, although the method’s instructive study noted:

“The standard deviation of age has a strong relationship with age correlation”

and provided further details in “The age correlation in a data set is determined by the standard deviation of age” section.

Didn’t the researchers, their organizations, and their sponsors realize that this study’s problematic design and performance could misdirect readers away from the valid epigenetic clock evidence they referenced? What purposes did it serve for them to publish this study?

https://academic.oup.com/biomedgerontology/advance-article-abstract/doi/10.1093/gerona/gly184/5076188 “Epigenetic clock and relative telomere length represent largely different aspects of aging in the Berlin Aging Study II (BASE-II)” (not freely available)

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3 thoughts on “Hijacking the epigenetic clock paradigm

  1. Dear gettingwell4. Do you have any information on how long it epigenetic changes last? In other words, how many generations must pass before those changes are removed? Or are they ever removed?

    Bruce

    Liked by 1 person

  2. Hi Bruce! This researcher’s blog post (I subscribe to his blog but often don’t agree) while explaining the Horvath epigenetic clock, also explained how long epigenetic changes within an individual last:
    “Some change rapidly during youth and then remain constant. Some change continually over a lifetime. Some don’t change much at all until aging sets in.”
    https://joshmitteldorf.scienceblog.com/2018/04/17/the-mother-of-all-clinical-trials-part-ii/

    As far as epigenetic changes extending past the first generation, I’ve curated two studies from Washington State University’s Michael Skinner, the latest being:
    https://surfaceyourrealself.com/2018/05/15/a-self-referencing-study-of-transgenerational-epigenetic-inheritance/
    This study and two others I mentioned in:
    https://surfaceyourrealself.com/2018/06/07/a-disturbance-in-the-paradigm-of-child-abuse/
    found that:
    – Epigenetic effects often skip a generation or two; and
    – These effects can be different in different generations and sexes.

    Michael Skinner’s group has done the most work in rodent studies with transgenerational epigenetic inheritance. They usually go from the F0 to F3 generation and stop there, because it isn’t until the F3 great-grandchildren that there’s complete isolation from the original cause of the epigenetic effects.

    They and other research groups haven’t discovered the inheritance mechanisms that transmit these effects. Maybe they’ll continue past the F3 great-grandchildren once they’ve found evidence of the transmission mechanisms?

    Science is a long way away from adequately demonstrating transgenerational epigenetic inheritance in humans.

    Like

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