Age slows down brain detoxification, but there is a drug that can help

Researchers have reversed the age-related buildup of waste products in the brains of mice by using a clinically approved drug to boost waste elimination and potentially treat neurological disorders.

AlzheimerParkinson's and other neurological disorders are often referred to as “dirty brain” diseases, where the brain has difficulty eliminating harmful waste. As we age, the risk of these diseases increases significantly because our brain's ability to eliminate toxic buildup declines as we age. However, recent research in mice shows that it may be possible to reverse these age-related changes and restore the brain's waste elimination processes.

“This research shows that restoring cervical lymphatic function can significantly rescue the age-related slowing of waste clearance from the brain,” said Douglas Kelley, PhD, professor of mechanical engineering at the University of Rochester's Hajim School of Engineering and Applied Sciences. “Moreover, this was achieved with a drug that is already in clinical use and offers a potential treatment strategy.” Kelley is one of the lead authors of the study, which appears in the journal Natural Aging, together with Maiken Nedergaard, MD, DMSc, co-director of the university’s Center for Translational Neuromedicine.

First described by Nedergaard and her colleagues in 2012, the glymphatic system is a unique brain waste removal process that uses cerebrospinal fluid (CSF) to flush away excess proteins produced by energy-hungry neurons and other cells in the brain during normal activity.

This discovery paved the way for potential new approaches to treating diseases commonly associated with the accumulation of protein waste in the brain, such as Alzheimer's (beta-amyloid and tau) and Parkinson's (alpha-synuclein). In healthy and young brains, the glymphatic system does a good job of flushing these toxic proteins out of the brain, but as we age, this system slows down, setting the stage for these diseases.

A network of tiny pumps sucks waste products out of the brain

Once inside the skull, the protein-waste-laden cerebrospinal fluid makes its way to the lymphatic system and eventually to the kidneys, where it is processed along with the body's other waste. The new research combines advanced imaging and particle tracking techniques to detail for the first time the route, via the cervical lymph vessels in the neck, by which half of the dirty cerebrospinal fluid leaves the brain.

In addition to measuring CSF flow, the researchers were also able to observe and record the pulsation of the lymph vessels in the neck that help pump CSF out of the brain. “Unlike the cardiovascular system, which has one large pump, the heart, the lymphatic system instead moves fluid through a network of small pumps,” Kelley said. These microscopic pumps, called lymphangions, have valves that prevent backflow and are lined up one after the other to form lymph vessels.

The researchers found that as the mice aged, the frequency of contractions decreased and the valves failed. As a result, the rate of dirty cerebrospinal fluid draining from the brains of older mice was 63 percent slower than in younger animals.

Well-known drug restarts the flow of brain cleansing fluid

The team then wanted to see if they could revive the lymphangions. They came across a drug called prostaglandin F2α, a hormone-like compound often used in medicine to induce labor that promotes smooth muscle contractions. The lymphangions are lined with smooth muscle cells. When the researchers applied the drug to the cervical lymph vessels of older mice, both the frequency of contractions and the drainage of dirty cerebrospinal fluid from the brain increased, returning to the levels of efficiency seen in younger mice.

“These vessels are conveniently located close to the surface of the skin, we know they are important, and we now know how to accelerate their function,” Kelley said. “You can see how this approach, perhaps in combination with other interventions, could be the basis for future therapies for these diseases.”

Reference: “Restoring cervical lymphatic function in old age rescues cerebrospinal fluid outflow” by Ting Du, Aditya Raghunandan, Humberto Mestre, Virginia Plá, Guojun Liu, Antonio Ladrón-de-Guevara, Evan Newbold, Paul Tobin, Daniel Gahn-Martinez, Saurav Pattanayak, Qinwen Huang, Weiguo Peng, Maiken Nedergaard, and Douglas H. Kelley, August 15, 2024, Natural aging.
DOI: 10.1038/s43587-024-00691-3

Other contributors to the study include first authors Ting Du, Aditya Raghunandan and Humberto Mestre, and Virginia Plá, Guojun Liu, Antonio Ladrón-de-Guevara, Evan Newbold, Paul Tobin, Daniel Gahn-Martinez, Saurav Pattanayak, Qinwen Huang and Weiguo Peng of the University of Rochester. The research was supported by funding from the National Institute of Neurological Disorders and Stroke, the Lundbeck Foundation, the Novo Nordisk Foundation, the Human Frontier Science Program, the Miriam and Sheldon G. Adelson Medical Research Foundation, the Simons Foundation, the EU Joint Programme – Neurodegenerative Disease Research, the US Army Research Office, the National Center for Complementary and Integrative Health, and the BRAIN Initiative.