Cell-type specific impact of metformin on monocyte epigenetic age reversal in virally suppressed older people living with HIV.
Cell-type specific impact of metformin on monocyte epigenetic age reversal in virally suppressed older people living with HIV.
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抗糖尿病药物二甲双胍可能促进健康衰老。然而，二甲双胍评估衰老生物标志物的临床试验很少完成。在这篇文章中，我们回顾性地研究了二甲双胍对表观遗传年龄的影响，使用了基于主成分（PC）的表观遗传时钟、有丝分裂时钟和外周血单核细胞和CD8+ T细胞的衰老速度，这些细胞来自两项接受二甲双胍治疗的病毒学抑制的HIV感染者（PLWH）。在一项为期24周的小型临床试验中，随机分配参与者接受辅助二甲双胍或观察，我们观察到，从基线到第24周，仅二甲双胍组参与者的PCPhenoAge和PCGrimAge单核细胞估计值显着降低，平均减少3.53年和1.84年。相比之下，我们观察到24周内观察组参与者的所有PC时钟均无显著差异。值得注意的是，我们对表观遗传有丝分裂钟的分析显示，与第24周的基线相比，二甲双胍组的单核细胞显著增加，这表明二甲双胍对骨髓细胞动力学有影响。对8例PLWH患者单臂辅助二甲双胍临床试验的分析显示，CD8+ T细胞在4周和8周时间点评估的所有表观遗传时钟没有显著差异。我们的研究结果表明，基于PC的表观遗传时钟生物标志物捕获的二甲双胍具有细胞类型特异性的髓细胞效应。需要对二甲双胍进行更大规模的临床研究来验证这些观察结果，本报告强调需要在老年科学试验中进一步纳入PLWH，以评估二甲双胍对延长健康寿命和寿命的影响。艾滋病毒感染者表现出免疫功能障碍、慢性炎症和表观遗传时钟捕捉到的生物衰老迹象加剧。在这里，我们使用基于主成分的表观遗传时钟、表观遗传有丝分裂时钟和衰老速度的表观遗传时钟对HIV感染者的两个小型二甲双胍临床试验的单核细胞和CD8+ T细胞进行了事后细胞类型特异性表观遗传年龄分析。
The anti‐diabetic drug metformin may promote healthy aging. However, few clinical trials of metformin assessing biomarkers of aging have been completed. In this communication, we retrospectively examined the effect of metformin on epigenetic age using principal component (PC)‐based epigenetic clocks, mitotic clocks, and pace of aging in peripheral monocytes and CD8+ T cells from participants in two clinical trials of virologically‐suppressed people living with HIV (PLWH) with normal glucose receiving metformin. In a small 24‐week clinical trial that randomized participants to receive either adjunctive metformin or observation, we observed significantly decreased PCPhenoAge and PCGrimAge estimates of monocytes from only participants in the metformin arm by a mean decrease of 3.53 and 1.84 years from baseline to Week 24. In contrast, we observed no significant differences in all PC clocks for participants in the observation arm over 24 weeks. Notably, our analysis of epigenetic mitotic clocks revealed significant increases for monocytes in the metformin arm when comparing baseline to Week 24, suggesting an impact of metformin on myeloid cell kinetics. Analysis of a single‐arm clinical trial of adjunctive metformin in eight PLWH revealed no significant differences across all epigenetic clocks assessed in CD8+ T cells at 4‐ and 8‐week time points. Our results suggest cell‐type‐specific myeloid effects of metformin captured by PC‐based epigenetic clock biomarkers. Larger clinical studies of metformin are needed to validate these observations and this report highlights the need for further inclusion of PLWH in geroscience trials evaluating the effect of metformin on increasing healthspan and lifespan. People living with HIV exhibit immune dysfunction, chronic inflammation, and heightened signs of biological aging captured by epigenetic clocks. Here, we performed a post hoc cell‐type specific epigenetic age analysis of monocytes and CD8+ T cells using principal component‐based epigenetic clocks, epigenetic mitotic clocks, and a pace of aging epigenetic clock of two small metformin clinical trials in people living with HIV.
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影响因子：
16
作者：
Gross AM;Jaeger PA;Kreisberg JF;Licon K;Jepsen KL;Khosroheidari M;Morsey BM;Swindells S;Shen H;Ng CT;Flagg K;Chen D;Zhang K;Fox HS;Ideker T
通讯作者：
Ideker T
DOI：
10.1093/infdis/jiv277
发表时间：
2015-11-15
期刊：
The Journal of infectious diseases
影响因子：
--
作者：
Horvath S;Levine AJ
通讯作者：
Levine AJ
表观遗传有丝分裂时钟与癌症风险的相关性
影响因子：
12.3
作者：
Yang Z;Wong A;Kuh D;Paul DS;Rakyan VK;Leslie RD;Zheng SC;Widschwendter M;Beck S;Teschendorff AE
通讯作者：
Teschendorff AE
影响因子：
1.5
作者：
Chew, Glen M.;Padua, Ana Joy P.;Ndhlovu, Lishomwa C.
通讯作者：
Ndhlovu, Lishomwa C.
影响因子：
4.4
作者：
He, Ziyuan;Allers, Carolina;Kuroda, Marcelo J.
通讯作者：
Kuroda, Marcelo J.