Kwiatkowska Katarzyna Malgorzata, Garagnani Paolo, Bonafé Massimiliano, Bacalini Maria Giulia, Calzari Luciano, Gentilini Davide, Ziegler Dan, Gerrits Monique M, Faber Catharina G, Malik Rayaz A, Marchi Margherita, Salvi Erika, Lauria Giuseppe, Pirazzini Chiara
Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy.
IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy.
Geroscience. 2025 Jan 23. doi: 10.1007/s11357-025-01516-w.
About one out of two diabetic patients develop diabetic neuropathy (DN), of these 20% experience neuropathic pain (NP) leading to individual, social, and health-economic burden. Risk factors for NP are largely unknown; however, premature aging was recently associated with several chronic pain disorders. DNA methylation-based biological age (DNAm) is associated with disease risk, morbidity, and mortality in different clinical settings. The purpose of this work was to study, for the first time, whether biological age is involved in pain development in a huge cohort of DN patients with neuropathy assessed by anatomopathological assay (99 painful (PDN), 132 painless (PLDN) patients, 84 controls (CTRL)). Six subsets of DNAm biomarkers were calculated to evaluate NP-associated changes in epigenetic aging, telomere shortening, blood cell count estimates, and plasma protein surrogates. We observed pain-related acceleration of epigenetic age (DNAmAgeHannum, DNAmGrimAgeBasedOnPredictedAge, DNAmAgeSkinBloodClock), pace of aging (DunedinPoAm), and shortening of telomeres between PDN and PLDN patients. PDN showed decreased predicted counts of B lymphocytes, naive and absolute CD8 T cells, and increased granulocyte counts. Several surrogates of plasma proteins were significantly different (GHR, MMP1, THBS2, PAPPA, TGF-α, GDF8, EDA, MPL, CCL21) in PDNs compared to PLDNs. These results provide the first evidence of an acceleration of biological aging in patients with painful compared to painless DN. This achievement has been possible thanks to the state of the art clinical phenotyping of the enrolled patients. Our findings indicate that the aging process may be directly involved in the PDN progression and in general health degeneration in the T2DM patients. Therefore, it is possible to hypothesize that the administration of effective antiaging drugs could slow down or even block the disease advancement.
约二分之一的糖尿病患者会发展为糖尿病神经病变（DN），其中20%会经历神经性疼痛（NP），这会导致个人、社会和健康经济负担。NP的风险因素在很大程度上尚不清楚；然而，早衰最近与几种慢性疼痛疾病相关。基于DNA甲基化的生物学年龄（DNAm）与不同临床环境中的疾病风险、发病率和死亡率相关。这项工作的目的是首次研究生物学年龄是否参与了通过解剖病理学检测评估的大量DN合并神经病变患者（99例疼痛性患者（PDN）、132例无痛性患者（PLDN）、84例对照（CTRL））的疼痛发展。计算了六个DNAm生物标志物子集，以评估与NP相关的表观遗传衰老、端粒缩短、血细胞计数估计和血浆蛋白替代物的变化。我们观察到PDN和PLDN患者之间，与疼痛相关的表观遗传年龄加速（DNAmAgeHannum、基于预测年龄的DNAmGrimAge、DNAmAgeSkinBloodClock）、衰老速度（达尼丁多组学加速衰老指标）以及端粒缩短。PDN患者的B淋巴细胞、幼稚和绝对CD8 T细胞预测计数减少，粒细胞计数增加。与PLDN患者相比，PDN患者的几种血浆蛋白替代物有显著差异（生长激素受体、基质金属蛋白酶1、血小板反应蛋白2、妊娠相关血浆蛋白A、转化生长因子-α、生长分化因子8、外胚层发育不良蛋白、血小板生成素受体、CC趋化因子配体21）。这些结果首次证明了与无痛性DN患者相比，疼痛性DN患者的生物衰老加速。由于所纳入患者的先进临床表型分析，才得以取得这一成果。我们的研究结果表明，衰老过程可能直接参与了PDN的进展以及2型糖尿病患者的整体健康衰退。因此，可以推测，使用有效的抗衰老药物可能会减缓甚至阻止疾病进展。
