Aging is associated with molecular and functional declines in multiple physiologic systems. We have previously reported age-related changes in spinal cord that included a decline in α-motor neuron numbers, axonal loss, and demyelination associated with increased inflammation and blood-spinal cord barrier (BSCB) permeability. These changes may influence other pathologies associated with aging, in particular loss of muscle mass and function (sarcopenia), which we and others have shown is accompanied by neuromuscular junction disruption and loss of innervation. Interventions to protect and maintain motor neuron viability and function in aging are currently lacking and could have a significant impact on improving healthspan. Here we tested a promising compound, OKN-007, that has known antioxidant, anti-inflammatory and neuroprotective properties, as a potential intervention in age-related changes in the spinal cord. OKN-007 is a low molecular weight disulfonyl derivative of (N-tert Butyl-α-phenylnitrone) (PBN) that can easily cross the blood–brain barrier. We treated middle age (16 month) wild-type male mice with OKN-007 in drinking water at a dose of 150 mg/kg/day until 25 months of age. OKN-007 treatment exerted a number of beneficial effects in the aging spinal cord, including a 35% increase in the number of lumbar α-motor neurons in OKN-treated old mice compared to age-matched controls. Brain spinal cord barrier permeability, which is increased in aging spinal cord, was also blunted by OKN-007 treatment. Age-related changes in microglia proliferation and activation are blunted by OKN-007, while we found no effect on astrocyte proliferation. Transcriptome analysis identified expression changes in a number of genes that are involved in neuronal structure and function and revealed a subset of genes whose changes in response to aging are reversed by OKN-007 treatment. Overall, our findings suggest that OKN-007 exerts neuroprotective and anti-inflammatory effects on the aging spinal cord and support OKN-007 as a potential therapeutic to improve α-motor neuron health.

衰老与多种生理系统的分子和功能下降有关。我们之前曾报道过与年龄相关的脊髓变化，包括 α 运动神经元数量减少、轴突丢失以及与炎症和血脊髓屏障 (BSCB) 通透性增加相关的脱髓鞘。这些变化可能会影响与衰老相关的其他病症，特别是肌肉质量和功能的丧失（肌肉减少症），我们和其他人已经证明这种情况伴随着神经肌肉接头的破坏和神经支配的丧失。目前缺乏保护和维持运动神经元活力和衰老功能的干预措施，可能对改善健康寿命产生重大影响。在这里，我们测试了一种很有前途的化合物 OKN-007，它具有已知的抗氧化、抗炎和神经保护特性，作为对与年龄相关的脊髓变化的潜在干预。OKN-007 是 (N-叔丁基-α-苯基硝酮 (PBN)，很容易穿过血脑屏障。我们用 OKN-007 在饮用水中以 150 mg/kg/天的剂量处理中年（16 个月）野生型雄性小鼠，直至 25 个月大。OKN-007 治疗对衰老的脊髓产生了许多有益影响，包括与年龄匹配的对照组相比，接受 OKN 治疗的老年小鼠的腰椎 α 运动神经元数量增加了 35%。OKN-007 治疗也削弱了在老化脊髓中增加的脑脊髓屏障通透性。OKN-007 减弱了小胶质细胞增殖和激活的年龄相关变化，而我们发现对星形胶质细胞增殖没有影响。转录组分析确定了许多与神经元结构和功能有关的基因的表达变化，并揭示了一部分基因，其对衰老反应的变化被 OKN-007 治疗逆转。总体而言，我们的研究结果表明 OKN-007 对老化的脊髓具有神经保护和抗炎作用，并支持 OKN-007 作为改善 α-运动神经元健康的潜在疗法。