Owen Brady M, Phie James, Huynh Jennifer, Needham Scott, Fraser Cameron
Systematic Medicine, Melbourne, VIC, Australia.
Front Aging. 2023 Sep 15;4:1260502. doi: 10.3389/fragi.2023.1260502. eCollection 2023.
Functional decline with age contributes significantly to the burden of disease in developed countries. There is growing interest in the development of therapeutic interventions which slow or even reverse aging. Time and cost constraints prohibit the testing of a large number of interventions for health and lifespan extension in model organisms. Cell-based models of aging could enable high throughput testing of potential interventions. Despite extensive reports in the literature of cell properties that correlate with donor age, few are robustly observed across different laboratories. This casts doubt on the extent that aging signatures are captured in cultured cells. We tested molecular changes previously reported to correlate with donor age in peripheral blood mononuclear cells (PBMCs) and evaluated their suitability for inclusion in a panel of functional aging measures. The tested measures spanned several pathways implicated in aging including epigenetic changes, apoptosis, proteostasis, and intracellular communication. Surprisingly, only two markers correlated with donor age. DNA methylation age accurately predicted donor age confirming this is a robust aging biomarker. Additionally, the apoptotic marker CD95 correlated with donor age but only within subsets of PBMCs. To demonstrate cellular rejuvenation in response to a treatment will require integration of multiple read-outs of cell function. However, building a panel of measures to detect aging in cells is challenging and further research is needed to identify robust predictors of age in humans.
在发达国家，随着年龄增长出现的功能衰退是疾病负担的重要因素。人们对开发延缓甚至逆转衰老的治疗干预措施的兴趣与日俱增。时间和成本限制使得无法在模式生物中对大量延长健康和寿命的干预措施进行测试。基于细胞的衰老模型能够对潜在干预措施进行高通量测试。尽管文献中有大量关于与供体年龄相关的细胞特性的报道，但很少有在不同实验室中都能得到有力验证的。这让人怀疑在培养细胞中捕捉到的衰老特征的程度。我们测试了先前报道的与外周血单个核细胞（PBMC）供体年龄相关的分子变化，并评估了它们是否适合纳入一组功能性衰老指标中。所测试的指标涵盖了与衰老相关的多个途径，包括表观遗传变化、细胞凋亡、蛋白质稳态和细胞内通讯。令人惊讶的是，只有两个标志物与供体年龄相关。DNA甲基化年龄准确预测了供体年龄，证实这是一个可靠的衰老生物标志物。此外，凋亡标志物CD95与供体年龄相关，但仅在PBMC亚群中相关。要证明细胞对治疗有年轻化反应，需要整合多种细胞功能读数。然而，构建一组检测细胞衰老的指标具有挑战性，还需要进一步研究以确定人类年龄的可靠预测指标。
