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Antihypertensive Use Correlates with Higher Epigenetic Age Despite Reduced Mortality

The best epigenetic clocks correlate well with chronological age, and when the measure departs from chronological age, that difference correlates well with risk or incidence of age-related disease. A higher epigenetic age is seen in people known to have higher age-related morbidity and mortality. The tantalizing potential offered by these clocks is the ability to quickly determine whether or not a putative rejuvenation therapy actually works, and to what degree it works. A true, rapidly assessed, cheap marker of biological age would greatly accelerate research and development. Unfortunately, this goal remains elusive because it is very unclear as what exactly the clocks are measuring. Yes, they measure changes in specific epigenetic markers, but which of the myriad processes involved in aging cause those epigenetic changes? If researchers cannot answer that question, then it is very hard to derive any useful information from epigenetic clocks.

The open access paper here is a good illustration of this point. Researchers checked the epigenetic age of hypertensive patients, both those using antihypertensive medication and those who did not use the medication. One would expect to see a reduction in epigenetic age, given that (a) the raised blood pressure that occurs with aging is highly damaging to delicate tissues, and (b) even blunt pharmaceutical means of reducing blood pressure, that fail to address the root causes and instead forcefully override cellular reactions, reduce mortality and incidence of age-related disease. Instead, researchers found that patients using antihypertensive medications had a higher epigenetic age. What are we to make of this result? The challenge, again, is that there is no good answer to that question.

DNA methylation, a major form of epigenetic modification, is known to play an important role in aging and the development of age-related health outcomes. Recently, a DNA methylation-based biological age predictor, "DNA methylation age (DNAmAge)", has been established and found to be highly associated with chronological age. The discrepancy between this epigenetic-based indicator and the chronological age has been termed age acceleration (AA), which was found to be heritable and has been used as an index of accelerated biological aging.

Several aging-related factors, including inflammation, neurohormonal disorder, and endothelial dysfunction, have been found to play key mechanistic roles in the development of hypertension, the most common long-term medical condition among older adults that could lead to various forms of age-related health outcomes, such as cardiovascular diseases (CVD), kidney failure, and dementia. Relationships of hypertension and blood pressure with biological aging have also been studied since the introduction of DNAmAge. In 2016 it was found that people with hypertension had a higher AA (0.5 - 1.2 years) in comparison to controls.

The use of antihypertension medication (AHM) reduces the risk of adverse age-related health outcomes caused by hypertension. Specifically, observational studies, clinical trials, and systematic reviews mostly suggested that effective antihypertensive therapy greatly reduces the risk of CVD in patients with hypertension, and may also be associated with a decreased risk of cognitive decline and incident dementia. As DNA methylation is a durable and reversible modification, we hypothesized that the use of AHMs might also be able to influence the biological aging reflected by the epigenetic AA. Therefore, we assessed the associations of AHM use with AA and further determined whether the change of AHM use could modify the change rate of AA (ΔAA).

After the fully adjusting for potential covariates including hypertension, any AHM use showed a cross-sectional significant association with higher AA at each visit, as well as a longitudinal association with increased ΔAA between visits. Particularly, relative to participants who never took any AHM, individuals with continuous AHM use had a higher ΔAA of 0.6 year/chronological year. This finding underlines that DNAmAge and AA may not be able to capture the preventive effects of AHMs that reduce cardiovascular risks and mortality.

Link: https://doi.org/10.18632/aging.101626

Comments

I saw the $ 100.000 donation from Jim Mellon to SRF. Hope now that he or any other invests in biolife4d to make heart transplantation with patients own cells available ASAP.

Posted by: thomasa at November 15th, 2018 8:41 AM

Epigenetic clocks primarily measure the intersection of stem cell turnover rate and epigenitic agedness of stem cells as passed on to somatic cells...

So, within a certain indefinite range, health measures can improve while epigenetic age goes up both absolutely and at an increased rate...

Posted by: Don at November 15th, 2018 10:50 AM

Very interesting. I had a DNAmAge test done on my urine in September. I got the results back last week, it says I'm 6 years biologically older then my age (late 50s). It makes no sense since I'm in excellent health. All my blood work is perfect. Low glucose, resting HR in the mid 40's, BP 110/62, great LDL/HDL ratio. My max HR is >190 which is outstanding for my age. I do HIIT, low impact distance and lift weights. I literally have no co-morbidity's at all. Even my chronic moderate low back pain has gone in the last couple of months. My mind is fairly sharp and I feel great yet I am biologically aging faster then >99% of the population! I have been on Rapamycin/Metformin for the last 21 months with nothing but good results. Is that doing something to my epigenetics? I just can't wrap my head around it.

Posted by: L at November 15th, 2018 1:56 PM

@L

While very important, all of those bio-markers of your health are measuring your "biologic fitness" - defined as your ability to survive with general health

But your biological age is technically a combined physiological measure over time of:

- 1) Fitness (as defined above),

- 2) Fertility (the ability to reproduce),

- 3) Robustness (the ability to prevent negative changes from occurring),

AND

- 4) Resilience (the ability to recover from negative changes when the do occur),

all of which are dictated by the constant biologic epigenetic symphony being performed across your genome

So of course these two items will not line up

(When I mention "epigentic" in this context I'm referring not just to the current molecular biology themes of covalent DNA modifications / histone modifications, etc., but to the broader Waddington "epigenetic landscape" concept of phenotype plasticity) -

https://www.biorxiv.org/content/biorxiv/early/2016/05/12/053009.full.pdf

Posted by: Ira S. Pastor at November 15th, 2018 4:36 PM

I have to disagree Ira. The study clearly showed that lower blood pressure due to medication raised the biological age compared to controls. That makes no sense. Dr. Horvath himself says he does not know why his test correlates with ageing so I still consider this a mystery. If it correctly measured (AA) the body's inability to react to stress I should start seeing some co-morbidity's by my age. Most people my age have at least one. It's not like I've been living a super clean or healthy lifestyle my whole life. If I'm not "robust" I should be falling apart at the seams. I did have testicular cancer in my 20's but caught it early and never had chemo or radiation. That's it for health problems. I don't even get colds. What is "robustness" if not that? We will slowly figure out what's going on when more people get epigentic aging measured but right now it's all conjecture since we don't know what these epigentic changes do.

Posted by: L at November 15th, 2018 8:13 PM

@L

I think it makes quite a lot of sense.

In 2018 we still have no idea about the broad toxicogenomic / pharmacogenomic dynamics of most drugs; even those created decades ago

I take an Angiotensin receptor blocker (ARB) - decreases my BP, but gives me a higher risk of cancer - who knows what other effects it is having across my genome - but that's the "Russian Roulette" of any small molecule drug / xenobiotic / etc.

And robustness is not your ability to recover from stuff (that's resilience)

It is the ability of your integrated biologic "architecture" to keep things from ever happening, like those cancerous transformations, etc. - read the papers - they go into all the other dynamics that are quietly happening within the background

Posted by: Ira S. Pastor at November 16th, 2018 4:02 AM

Don is right and it is not that complicated. Antihypertensive drugs will extend the life of endothelial cells in the artery walls, preserving their telomeres and potentially upregulating telomerase. This means a given cell line will last longer before having to be replaced by epigenetically younger progenitor cells.

Although leukocyte telomere length is a terrible measure of aging, Africans have longer LTL on average but also an older epigenetic age as measured by Horvath, which supports my hypothesis.

Posted by: Mark at November 16th, 2018 4:35 AM

@L: you might get a telomere length test to see if it correlates with your perceived biological age or with your epigenetic age.

Posted by: Biotechy Marcks at November 16th, 2018 9:17 AM

Telomere length only has a 0.55 correlation with mortality so I'm not sure what that would show. My parents went through some extremely difficult and stressful times during and after WWII so it's possible they passed down some deleterious epeigenetic changes. My sister died of cancer in her 40's with no risk factors but my brother is in his 70's and never gets sick and is rebuilding his house by himself. I assume that maybe I'm at a higher risk of cancer or perhaps the supplements I've been taking for years have done some sort of damage? I'm not too worried about it but it has pushed me to improve my diet. It's good to know you're not invulnerable.

Posted by: L at November 16th, 2018 10:31 AM

Reminds me what happened to Vioxx. I suspect the higher AA associated with AHM use is pointing to an unknown side effect(s) of the drug(s). No surprise, right? We don't have very good pharmaceutical drugs at this point. What am I missing?

Posted by: NY2LA at November 20th, 2018 11:56 PM

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