Light Therapy Clears Brain Waste in Young and Middle-Aged Mice but Fails in Old Ones

A course of near-infrared light therapy that sharpens learning and flushes amyloid beta from the brains of young and middle-aged mice loses its effect almost entirely in old animals, according to a study published in Frontiers of Optoelectronics. The research, led by Oxana Semyachkina-Glushkovskaya of Saratov State University with colleagues in Russia and India, tested a ten-day regimen of transcranial photobiomodulation (PBM) delivered by a 1050-nanometer light-emitting diode in male mice aged 3, 12 and 24 months, ages the authors map to roughly 25, 42.5 and 69 human years. The central finding is stark: the same light protocol that accelerated the formation of a learned conditioned reflex in the two younger groups left the oldest animals untouched, and the difference tracked a measurable breakdown in the meningeal lymphatic vessels that drain waste from the brain.

The experiment was designed to probe a gap in the PBM literature. Most studies of light-mediated cognitive improvement have been carried out in young adults or in middle-aged subjects showing only the earliest signs of cognitive decline, and the authors note that some trials in very old patients, including 85-year-old individuals with idiopathic Parkinson’s disease and with mild and moderate Alzheimer’s disease, reported no therapeutic effects after twelve weeks of PBM. To test whether advanced age itself limits the therapy, the team trained mice in a two-stage task. First the animals learned to associate a light signal with food; once that reflex was stable, the task was made harder, requiring the mice to press a lever after responding to two consecutive conditioned signals before the reward arrived. Learning was scored automatically by counting the number of daily sessions needed to reach a stable reflex and the number of successful head entries at the food dispenser.

The behavioral results showed a clear age gradient. Performance on the conditioned reflex task did not differ between 3-month-old and 12-month-old mice, but 24-month-old animals needed many more sessions to complete both the initial training and the transfer of the learned experience to the harder version of the task. When the ten-day PBM course was applied, starting on the first day of training, it significantly increased the rate at which the young and middle-aged mice formed the complex light-lever-food reflex. In the old mice, however, the light course produced no measurable improvement in learning speed. The authors conclude that PBM can improve learning in young and middle-aged mice but is not effective at improving cognitive abilities in old ones.

To understand why, the researchers turned to the meningeal lymphatic vessels, or MLVs, a network of lymphatics running along the main venous sinuses of the dura that PBM is known to target. These vessels act as tunnels for the excretion of metabolic waste, including amyloid beta, the peptide that accumulates in Alzheimer’s disease. The team stained the meninges with an antibody against LYVE-1, a marker of lymphatic endothelium, and imaged the vessels around the transverse sinus and the confluence of sinuses with a confocal microscope. In 24-month-old mice they found a significantly higher coverage of LYVE-1-positive vessels than in the younger groups, with no significant difference between the 3-month and 12-month animals. The authors interpret this overgrowth as lymphatic hyperplasia, a change they describe as a compensatory response to valve dysfunction that reduces peristaltic lymph flow rather than enhancing drainage.

Functional measurements confirmed that drainage deteriorates with age. The team injected a fluorescent tracer, FITC-dextran, and tracked its spread through the ventral and dorsal surfaces of the brain and its lymphatic removal to the deep cervical lymph nodes. Tracer distribution in the ventral brain was 2.5-fold lower in 12-month-old mice and 6.2-fold lower in 24-month-old mice than in 3-month-old animals, with corresponding reductions of 1.5-fold and 5.2-fold on the dorsal surface, all statistically significant. Signal from the tracer in the deep cervical lymph nodes was 13-fold weaker in middle-aged and 17-fold weaker in old mice compared with the young group. The picture that emerges is a gradual, progressive decline in brain drainage across the lifespan, not a change confined to the oldest animals.

Amyloid beta levels told the same story from the opposite direction. Using an enzyme-linked immunosorbent assay for the soluble form of Aβ (1-42), the researchers measured brain concentrations of 2.21 ± 0.17 picograms per milligram in the young mice, 5.52 ± 0.21 in the middle-aged group and 8.49 ± 2.45 in the old group, with the middle-aged and old values both significantly higher than the young baseline. Because soluble Aβ in the brain reflects the efficiency of lymphatic regulation of drainage, the authors treat this accumulation as a direct readout of the failing clearance system, consistent with earlier reports of Aβ buildup in aged C57BL/6J mice.

The PBM intervention produced a strikingly age-dependent pattern in these biochemical measures. In middle-aged mice, the ten-day light course reduced soluble Aβ from 5.52 ± 0.21 to 2.32 ± 0.25 picograms per milligram, bringing it down to the level of the young animals, a highly significant change. In young mice the course did not alter Aβ levels, which the authors attribute to a floor effect, since the baseline content was already low. In old mice, PBM left the high Aβ burden essentially unchanged, moving from 8.49 ± 2.45 to 8.37 ± 2.04 picograms per milligram, a difference that was not statistically significant. The clearance benefit of light, in other words, exists in a therapeutic window that closes with advanced age.

The mechanistic account the authors offer centers on how light drives lymphatic pumping. PBM is thought to generate singlet oxygen in the mitochondria of the endothelial cells lining the MLVs, prompting the production of nitric oxide, much of it localized in the valves where a large share of endothelial nitric oxide synthase resides. Nitric oxide relaxes the vessel walls and increases their permeability, allowing them to fill with fluid; as they fill, wall shear stress falls, nitric oxide is degraded, and a contraction follows through calcium influx, closing upstream valves and opening downstream ones to push lymph forward. This peristaltic cycle is the basis of the vessels’ drainage and cleansing function, and it depends on valves and contractile machinery that aging is known to compromise, including reduced lymphangiogenic factor production, diminished regenerative capacity of the lymphatic endothelium and reduced smooth muscle actin coverage around valves.

The study has clear boundaries. It was conducted only in male mice, a choice the authors justify by prior evidence that MLV morphology and function do not differ by sex, and they note that sex differences in PBM effects were not examined. The cognitive test used is a conditioned reflex task in rodents, not a clinical outcome, and the mouse-to-human age mapping is an approximation. The authors also caution that the precise role of amyloid beta in age-related cognitive impairment remains debated, noting that only about 30 percent of cognitive deficits are associated with high Aβ deposits and that therapies targeting Aβ plaques have not improved cognition in late-stage Alzheimer’s disease. The findings are correlational with respect to the mechanism: the old mice showed both hyperplastic MLVs and PBM insensitivity, and the authors suggest rather than prove that preserving MLV function is the determining factor.

Practically, the work matters because the 1050-nanometer band used here comes from light-emitting diodes that are inexpensive, widely used in clinical PBM and recognized by the US Food and Drug Administration as safe, unlike the scarce and costly 1270-nanometer lasers used in earlier pioneering experiments, and because 1065-nanometer light suffers roughly tenfold less water absorption than 1270-nanometer light, preserving more therapeutic energy. The authors point to sleep as a possible route forward, since deep sleep naturally activates brain drainage and has been shown to enhance the drainage effects of PBM, and they describe a prototype device for delivering PBM under sleep control that has shown promise in preclinical tests. Whether such approaches can reopen the therapeutic window in old animals remains an open question that the authors say future studies must address.

Subject of Research: Age-related limits of photobiomodulation on brain drainage and cognition in mice

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

Article References: Andrey, T., Alexander, S., Inna, B., Daria, Z., Viktoria, A., Anastasiia, S.-G., Kumar, A., Ivan, F., Arina, E., & Oxana, S.-G. (2025). Age as a limiting factor for effectiveness of photostimulation of brain drainage and cognitive functions. Frontiers of Optoelectronics, 18(1), Article 6. https://doi.org/10.1007/s12200-025-00149-3

Image Credits: AI Generated

DOI: 10.1007/s12200-025-00149-3

Keywords: photobiomodulation, meningeal lymphatic vessels, amyloid beta, brain drainage, cognitive decline, aging, mice study, glymphatic clearance, LED light therapy, Alzheimer's disease, lymphatic hyperplasia, neuroscience