BUFFALO, NY — June 3, 2025 — A new #research paper was #published in  Aging (Aging-US) on May 1, 2025, as the #cover of Volume 17, Issue 5, titled “Defining the hypoxic thresholds that trigger blood-brain barrier disruption: the effect of age.”

In this study, researchers Arjun Sapkota, Sebok K. Halder, and Richard Milner from San Diego Biomedical Research Institute investigated how aging affects the brain’s vulnerability to low oxygen, or hypoxia. Using C57BL/6J mice ranging from 2 to 23 months of age, they identified specific oxygen levels that disrupt the blood-brain barrier (BBB)—a critical structure that protects brain tissue from harmful substances. The findings are important for understanding age-related cognitive decline and the potential risks faced by individuals with chronic oxygen-limiting conditions such as asthma, sleep apnea, emphysema, and heart disease.

The BBB is essential for maintaining brain health. In this study, mild and prolonged hypoxia—called chronic mild hypoxia—was found to compromise the BBB in mice. Older mice showed significantly more BBB disruption than younger ones. Notably, barrier weakening and blood vessel changes occurred at oxygen levels of just 15% in aged mice, compared to 13% in young mice. These data suggest that the aging brain is more sensitive to oxygen deprivation, even at levels that may be considered only mildly hypoxic.

The researchers also determined when this vulnerability emerged. The BBB showed increased sensitivity to low oxygen not only in aged mice but also in mice as young as 2 to 6 months, with a second spike occurring between 12 and 15 months—equivalent to middle age in mice. These findings may reflect age-dependent changes in brain vascular function and remodeling capacity.

“Hypoxia-induced endothelial proliferation was relatively constant across the age range, but advanced age strongly enhanced the degree of BBB disruption (4-6-fold greater in 23 months vs. 2 months old).”

Another key focus was microglial activation, a sign of brain inflammation. Aged mice exhibited higher microglial activation across all oxygen levels, including normal conditions. Chronic microglial activation is closely linked to neuroinflammation and has been implicated in diseases such as Alzheimer’s. While the rate of blood vessel formation was constant across ages, the degree of BBB disruption increased sharply with age, suggesting that repair mechanisms may weaken over time.

These results may help explain why older adults with chronic hypoxia-related diseases are at higher risk for neurodegeneration and cognitive decline. The study also draws attention to the risks of high-altitude exposure for aging populations, where oxygen levels naturally drop.

Altogether, these findings underscore the importance of protecting brain health in older individuals by managing oxygen exposure and reducing hypoxia-related risks. The researchers emphasize the need to develop new therapies that support blood-brain barrier integrity, particularly in aging populations exposed to chronic or intermittent low-oxygen conditions.

DOI - https://doi.org/10.18632/aging.206241

Corresponding author - Richard Milner - rmilner@sdbri.org

Video short - https://www.youtube.com/watch?v=Nr6rTm7aJRo

Keywords - aging, blood-brain barrier integrity, endothelial, proliferation, microglia, chronic mild hypoxia, hypoxic threshold

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Aging (Aging-US)

Aging Increases Brain’s Sensitivity to Hypoxia and Blood-Brain Barrier Damage in Mice

Aging-US is dedicated to advancing our understanding of the biological mechanisms that drive aging and the development of age-related diseases. Our mission is to serve as a platform for high-quality research that uncovers the cellular, molecular, and systemic processes underlying aging, and translates these insights into strategies to extend healthspan and delay the onset of chronic disease.

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Aging Increases Brain’s Sensitivity to Hypoxia and Blood-Brain Barrier Damage in Mice

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