Analysis of Epigenetic Age Predictors in Pain-Related Conditions

Chronic pain prevalence is high worldwide and increases at older ages. Signs of premature aging have been associated with chronic pain, but few studies have investigated aging biomarkers in pain-related conditions. A set of DNA methylation (DNAm)-based estimates of age, called “epigenetic clocks”, have been proposed as biological measures of age-related adverse processes, morbidity and mortality. The aim of this study was to determine if different pain-related phenotypes show alterations in DNAm age. We considered in our analysis 3 cohorts for which whole blood DNAm data were available: heat pain sensitivity (HPS), including 20 monozygotic twin-pairs discordant for heat pain temperature threshold; fibromyalgia (FM), including 24 cases and 20 controls; and headache, including 22 chronic migraine and medication overuse headache patients (MOH), 17 episodic migraineurs (EM) and 13 healthy subjects. We used the Horvath’s epigenetic age calculator to obtain DNAm based estimates of epigenetic age, telomere(definition) length, levels of 7 proteins in plasma, number of smoked packs of cigarettes per year and blood cell counts. We did not find differences in epigenetic age acceleration, calculated using 5 different epigenetic clocks, between subjects discordant for pain-related phenotypes. Twins with high HPS had increased CD8+ T cell counts (p-value = 0.028). HPS thresholds were negatively associated with estimated levels of GDF15 (p-value = 0.008) and positively with estimated levels of leptin (p-value = 0.056). FM patients showed decreased naive CD4+ T cell counts compared to controls (p-value = 0.015). The severity of FM manifestations expressed through various evaluation tests was associated with decreased levels of leptin, shorter length of telomeres, reduced CD8+ T and natural killer cell counts (p-values < 0.05), while the duration of painful symptoms was positively associated with telomere length (p-value = 0.034). No difference in DNA methylation based estimates was detected for MOH or EM compared to controls. In summary, our study suggests that HPS, FM and MOH/EM do not show signs of epigenetic age acceleration in whole blood, while HPS and FM are associated with DNAm based estimates of immunological parameters, plasma proteins and telomere length. Future studies should extend these observations in larger cohorts.