The identification and validation of drugs that promote health during aging (“geroprotectors”) are key to the retardation or prevention of chronic age-related diseases. Here, we found that most of the established pro-longevity compounds shown to extend lifespan in model organisms also alter extracellular matrix gene expression (i.e., matrisome) in human cell lines. To harness this observation, we used age-stratified human transcriptomes to define the age-related matreotype, which represents the matrisome gene expression pattern associated with age. Using a “youthful” matreotype, we screened in silico for geroprotective drug candidates. To validate drug candidates, we developed a novel tool using prolonged collagen expression as a non-invasive and in-vivo surrogate marker for Caenorhabditis elegans longevity. With this reporter, we were able to eliminate false-positive drug candidates and determine the appropriate dose for extending the lifespan of C. elegans. We improved drug uptake for one of our predicted compounds, genistein, and reconciled previous contradictory reports of its effects on longevity. We identified and validated new compounds, tretinoin, chondroitin sulfate, and hyaluronic acid, for their ability to restore age-related decline of collagen homeostasis and increase lifespan. Thus, our innovative drug screening approach—employing extracellular matrix homeostasis—facilitates the discovery of pharmacological interventions promoting healthy aging.

中文翻译：

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年轻和与年龄相关的母体型预测药物可以延年益寿

识别和验证促进衰老期间健康的药物（“老年保护剂”）是延缓或预防与年龄相关的慢性疾病的关键。在这里，我们发现大多数已证实的延长模型生物体寿命的长寿化合物也会改变人类细胞系中的细胞外基质基因表达（即基质体）。为了利用这一观察结果，我们使用年龄分层的人类转录组来定义与年龄相关的基质型，它代表与年龄相关的基质体基因表达模式。使用“年轻”基质型，我们通过计算机筛选了老年保护候选药物。为了验证候选药物，我们开发了一种新工具，使用延长的胶原蛋白表达作为秀丽隐杆线虫寿命的非侵入性体内替代标记。有了这个报告器，我们能够消除假阳性候选药物，并确定延长线虫寿命的适当剂量。我们提高了我们预测的化合物之一金雀异黄酮的药物摄取，并调和了之前关于其对长寿影响的相互矛盾的报告。我们鉴定并验证了新化合物、维甲酸、硫酸软骨素和透明质酸，它们能够恢复与年龄相关的胶原蛋白稳态下降并延长寿命。因此，我们的创新药物筛选方法（利用细胞外基质稳态）有助于发现促进健康衰老的药物干预措施。