Abstract

Frailty is classically associated with advanced age but is also an important predictor of clinical outcomes in comparatively young adults with cirrhosis. We examined the association of biological aging with frailty and post-transplant outcomes in a pilot of adults with cirrhosis undergoing liver transplantation (LT). Frailty was measured via the Liver Frailty Index (LFI). The primary epigenetic clock DNA methylation (DNAm) PhenoAge was calculated from banked peripheral blood mononuclear cells; we secondarily explored two first-generation clocks (Hannum; Horvath) and two additional second-generation clocks (GrimAge; GrimAge2). Twelve adults were included: seven frail (LFI ≥ 4.4, mean age 55 years) and five robust (LFI < 3.2, mean age 55 years). Mean PhenoAge age acceleration (AgeAccel) was + 2.5 years (P = 0.23) for frail versus robust subjects. Mean PhenoAge AgeAccel was + 2.7 years (P = 0.19) for subjects who were readmitted or died within 30 days of discharge post-LT versus those without this outcome. When compared with first-generation clocks, the second-generation clocks demonstrated greater average AgeAccel for subjects with frailty or poor post-LT outcomes. Measuring biological age using DNAm-derived epigenetic clocks is feasible in adults undergoing LT. While frail and robust subjects had the same average chronological age, average biological age as measured by second-generation epigenetic clocks tended to be accelerated among those who were frail or experienced a poor post-LT outcome. These results suggest that frailty in these relatively young subjects with cirrhosis may involve similar aging mechanisms as frailty classically observed in chronologically older adults and warrant validation in a larger cohort.

中文翻译：

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成人肝硬化患者的生物衰老与虚弱和移植后结局的关系

摘要

虚弱通常与高龄相关，但也是相对年轻的肝硬化患者临床结果的重要预测因素。我们在一名接受肝移植（LT）的成人肝硬化飞行员中研究了生物衰老与虚弱和移植后结果的关系。虚弱程度通过肝脏虚弱指数（LFI）来衡量。主要表观遗传时钟 DNA 甲基化 (DNAm) PhenoAge 是根据储存的外周血单核细胞计算得出的；我们其次探索了两个第一代时钟（Hannum；Horvath）和另外两个第二代时钟（GrimAge；GrimAge2）。包括 12 名成年人：7 名体弱者（LFI ≥ 4.4，平均年龄 55 岁）和 5 名强壮者（LFI < 3.2，平均年龄 55 岁）。 与强壮受试者相比，虚弱受试者的平均 PhenoAge 年龄加速 (AgeAccel) 为 + 2.5 年 ( P = 0.23)。 与没有此结果的受试者相比，LT 后再次入院或出院 30 天内死亡的受试者的平均 PhenoAge AgeAccel 为 + 2.7 年（P = 0.19）。与第一代时钟相比，第二代时钟对于体弱或 LT 后结果较差的受试者表现出更高的平均 AgeAccel。对于接受 LT 的成年人来说，使用 DNAm 衍生的表观遗传时钟测量生物年龄是可行的。虽然虚弱和强壮的受试者具有相同的平均实际年龄，但通过第二代表观遗传时钟测量的平均生物年龄往往会在那些虚弱或经历过 LT 后不良结果的受试者中加速。这些结果表明，这些相对年轻的肝硬化受试者的虚弱可能涉及与按时间顺序排列的老年人中经典观察到的虚弱相似的衰老机制，并且需要在更大的队列中进行验证。