The effects of two different mitochondrial‐targeted drugs, SS‐31 and NMN, were tested on Old mouse hearts. After treatment with the drugs, individually or Combined, heart function was examined by echocardiography. SS‐31 partially reversed an age‐related decline in diastolic function while NMN fully reversed an age‐related deficiency in systolic function at a higher workload. Metabolomic analysis revealed that both NMN and the Combined treatment increased nicotinamide and 1‐methylnicotinamide levels, indicating greater NAD⁺ turnover, but only the Combined treatment resulted in significantly greater steady‐state NAD(H) levels. A novel magnetic resonance spectroscopy approach was used to assess how metabolite levels responded to changing cardiac workload. PCr/ATP decreased in response to increased workload in Old Control, but not Young, hearts, indicating an age‐related decline in energetic capacity. Both drugs were able to normalize the PCr/ATP dynamics. SS‐31 and NMN treatment also increased mitochondrial NAD(P)H production under the higher workload, while only NMN increased NAD⁺ in response to increased work. These measures did not shift in hearts given the Combined treatment, which may be owed to the enhanced NAD(H) levels in the resting state after this treatment. Overall, these results indicate that both drugs are effective at restoring different aspects of mitochondrial and heart health and that combining them results in a synergistic effect that rejuvenates Old hearts and best recapitulates the Young state.

中文翻译：

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SS-31 和 NMN：改善老年心脏新陈代谢和功能的两种途径。

在老年小鼠心脏上测试了两种不同的线粒体靶向药物 SS-31 和 NMN 的作用。单独或联合药物治疗后，通过超声心动图检查心脏功能。SS-31 部分逆转了与年龄相关的舒张功能下降，而 NMN 则完全逆转了在较高工作负荷下与年龄相关的收缩功能缺陷。代谢组学分析显示，NMN 和联合治疗均增加了烟酰胺和 1-甲基烟酰胺水平，表明 NAD ⁺周转率更高，但只有联合治疗导致稳态 NAD(H) 水平显着升高。使用一种新颖的磁共振波谱方法来评估代谢水平如何响应变化的心脏负荷。PCr/ATP 随老年对照心脏工作量的增加而下降，但年轻对照心脏则不然，这表明与年龄相关的能量能力下降。两种药物都能使 PCr/ATP 动态正常化。SS-31 和 NMN 治疗还在较高的工作负荷下增加了线粒体 NAD(P)H 的产生，而只有 NMN因工作负荷的增加而增加了 NAD ^{+ 。}接受联合治疗后，这些指标在心脏中没有发生变化，这可能是由于这种治疗后静息状态下 NAD(H) 水平的提高。总体而言，这些结果表明，这两种药物都能有效恢复线粒体和心脏健康的不同方面，并且将它们结合起来会产生协同效应，使老年心脏恢复活力并最好地重现年轻状态。