Department of Genetics, Harvard Medical School, Boston, MA, USA.
Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA, USA.
Hum Genet. 2023 Aug;142(8):1293-1302. doi: 10.1007/s00439-023-02529-1. Epub 2023 Apr 1.
Aging is a progressive multifaceted functional decline of a biological system. Chronic age-related conditions such as neurodegenerative diseases are leading causes of death worldwide, and they are becoming a pressing problem for our society. To address this global challenge, there is a need for novel, safe, and effective rejuvenation therapies aimed at reversing age-related phenotypes and improving human health. With gene expression being a key determinant of cell identity and function, and in light of recent studies reporting rejuvenation effects through genetic perturbations, we propose an age reversal strategy focused on reprogramming the cell transcriptome to a youthful state. To this end, we suggest using transcriptomic data from primary human cells to predict rejuvenation targets and develop high-throughput aging assays, which can be used in large perturbation screens. We propose neural cells as particularly relevant targets for rejuvenation due to substantial impact of neurodegeneration on human frailty. Of all cell types in the brain, we argue that glutamatergic neurons, neuronal stem cells, and oligodendrocytes represent the most impactful and tractable targets. Lastly, we provide experimental designs for anti-aging reprogramming screens that will likely enable the development of neuronal age reversal therapies, which hold promise for dramatically improving human health.
衰老是生物系统进行性多方面功能下降的过程。慢性与年龄相关的疾病（如神经退行性疾病）是全球主要死亡原因，它们正成为我们社会的紧迫问题。为了解决这一全球性挑战，我们需要新型、安全且有效的抗衰老疗法，旨在逆转与年龄相关的表型并改善人类健康。鉴于基因表达是细胞特性和功能的关键决定因素，并且最近有研究报告称通过遗传干扰可实现抗衰老效果，我们提出了一种专注于将细胞转录组重编程为年轻状态的抗衰老策略。为此，我们建议使用来自原代人类细胞的转录组数据来预测抗衰老靶点，并开发高通量的衰老测定法，可用于大规模的扰动筛选。我们建议将神经细胞作为抗衰老的特别相关靶点，因为神经退行性病变对人类脆弱性有重大影响。在大脑的所有细胞类型中，我们认为谷氨酸能神经元、神经元干细胞和少突胶质细胞是最具影响力和最具可操作性的靶点。最后，我们提供了抗衰老重编程筛选的实验设计，这可能会促进神经元抗衰老疗法的开发，从而有望显著改善人类健康。
