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.