RESEARCH ARTICLE

Age as a limiting factor for effectiveness of photostimulation of brain drainage and cognitive functions  

Terskov Andrey, Shirokov Alexander, Blokhina Inna, Zlatogorskaya Daria, Adushkina Viktoria, Semiachkina-Glushkovskaia Anastasiia, Atul Kumar, Fedosov Ivan, Evsukova Arina, Semyachkina-Glushkovskaya Oxana

2025, 18(2): 6.https://doi.org/10.1007/s12200-025-00149-3

Abstract：The progressive number of old adults with cognitive impairment worldwide and the lack of effective pharmacologic therapies require the development of non-pharmacologic strategies. The photobiomodulation (PBM) is a promising method in prevention of early or mild age-related cognitive impairments. However, it remains unclear the efficacy of PBM for old patients with significant age-related cognitive dysfunction. In our study on male mice, we show a gradual increase in the brain amyloid beta (Aβ) levels and a decrease in brain drainage with age, which, however, is associated with a decline in cognitive function only in old (24 months of age) mice but not in middle-aged (12 months of age) and young (3 month of age) animals. These age-related features are accompanied by the development of hyperplasia of the meningeal lymphatic vessels (MLVs) in old mice underlying the decrease in brain drainage. PBM improves cognitive training exercises and Aβ clearance only in young and middle-aged mice, while old animals are not sensitive to PBM. These results clearly demonstrate that the PBM effects on cognitive function are correlated with age-mediated changes in the MLV network and may be effective if the MLV function is preserved. These findings expand fundamental knowledge about age differences in the effectiveness of PBM for improvement of cognitive functions and Aβ clearance as well as about the lymphatic mechanisms responsible for age decline in sensitivity to the therapeutic PBM effects.

研究背景​：随着全球老年人口认知障碍问题的日益严重，以及缺乏有效的药物治疗方法，非药物策略的开发变得尤为重要。光生物调节（Photobiomodulation, PBM）作为一种有前景的方法，已被证明对中年和轻度认知障碍患者的认知功能改善有效。然而，PBM对老年患者（尤其是认知障碍和大脑衰老进程显著的患者）的效果尚不清楚。本研究旨在探讨PBM对不同年龄小鼠（年轻、中年和老年）认知功能和大脑引流的影响。

​主要内容​：研究发现，随着年龄的增长，小鼠大脑中的β-淀粉样蛋白（amyloid β，Aβ）水平逐渐增加，大脑引流能力下降，但这种下降仅与老年（24个月大）小鼠的认知功能下降相关，而与中年（12个月大）和年轻（3个月大）小鼠无关。老年小鼠的脑膜淋巴管（Meningeal Lymphatic Vessels, MLVs）出现增生，导致大脑引流减少。PBM能够改善年轻和中年小鼠的认知训练和Aβ清除，但对老年小鼠无效。这些结果表明，PBM对认知功能的影响与年龄相关的MLV网络变化相关，且仅在MLV功能得到保留时才有效。

​创新点​：本研究首次系统地探讨了PBM对不同年龄小鼠认知功能和大脑引流的影响，并揭示了年龄相关的MLV网络变化对PBM效果的影响。研究结果为理解PBM在改善认知功能和Aβ清除方面的年龄差异提供了新的见解，并为开发针对老年认知障碍的非药物治疗策略提供了理论依据。

​方法​：研究使用了3个月、12个月和24个月大的雄性C57BL/6小鼠，分别对应人类的25岁、42.5岁和69岁。通过免疫组化分析和共聚焦成像技术研究MLV网络的变化；通过注射荧光素异硫氰酸酯-葡聚糖（fluorescein isothiocyanate-dextran）研究大脑引流；通过PBM（10天疗程，1050 nm，30 J/cm²）处理后的小鼠进行认知功能测试；通过酶联免疫吸附试验（ELISA）分析Aβ水平。

​结果​：

• 认知功能​：老年小鼠在形成条件反射（Pavlov’s conditioned reflex, PCR）测试中表现更差，而PBM能够显著改善年轻和中年小鼠的认知训练，但对老年小鼠无效。

• ​MLV网络变化​：老年小鼠的MLV网络出现淋巴管增生，而年轻和中年小鼠未观察到显著变化。

• 大脑引流和Aβ水平​：老年小鼠的大脑引流能力下降，Aβ水平显著增加。PBM能够降低中年小鼠的Aβ水平，但对老年小鼠无效。

• ​PBM效果​：PBM对认知功能和Aβ清除的效果与MLV功能的保留相关。老年小鼠由于MLV功能下降，对PBM不敏感。

​结论​：PBM是一种有前景的非药物方法，能够改善中年小鼠的认知功能和Aβ清除，但对老年小鼠无效。MLV功能的保留是PBM效果的关键因素。未来的研究需要进一步探索如何提高PBM在老年小鼠中的有效性，例如通过结合睡眠控制的PBM技术来增强大脑引流和认知功能的改善。