NO-ergic mechanisms of age differences in photostimulation of lymphatic drainage, filtration, and clearance

Photobiomodulation (PBM) is recognized as a promising, noninvasive, and safe therapy for brain diseases. However, age is a limiting factor for effective phototherapy of brain pathology. The mechanisms of decreasing efficiency of therapeutic effects of PBM in the aging brain remain poorly understood. Recently, it has been shown that PBM of brain lymphatic drainage by stimulation of the nitric oxide (NO) production in the lymphatic endothelium plays a key role in the PBM-therapy of brain diseases. In this study, we clearly show that PBM increases the NO production in the lymphatic endothelial cells and the contractility of the afferent (drainage function) and efferent (filtration function) cervical lymphatic vessels (cLVs), which is significantly suppressed after the NO blockade in 3- and 12-month-old mice. However, 24-month-old mice are insensitive to both factors, PBM and its suppression by the NO blockade. In old mice, a decrease in sensitivity to PBM is associated with age-related lymphatic endothelium dysfunction, including changes in the cLV morphology (hyperplasia), a decrease in the NO production, and the contractility of cLVs, leading to reduced lymphatic removal of beta amyloid from the brain. These results suggest that the combined therapy, including PBM with an increase in NO production in the lymphatic endothelium, can substantially improve the effectiveness of the stimulating effects of PBM on brain drainage and the removal of toxic metabolites from its tissues, which might generally contribute to improving phototherapy of brain diseases in the elderly.