Klotho Shields the Brain from the Peripheral Immune System, but Declines with Age

Klotho is one of a number of well-known longevity-associated genes. The amount of klotho observed in tissues declines steadily with advancing age. Interventions that increase levels of klotho have been shown to slow measures of aging to some degree in animal studies. Beyond life span, klotho is also strongly associated with cognitive function. More klotho is better in this case as well. Artificially raised levels of klotho might one day be used as a form of enhancement therapy, capable of improving cognitive function even in younger people.

In the research noted here, scientists uncover one of the mechanisms linking falling levels of klotho to the impact of aging on the brain. Klotho helps to protect the brain from the activities of the immune system in the rest of the body, and when that protection falters, chronic inflammation can result. Inflammation is important in near all forms of neurodegeneration. In the view of aging as an accumulation of molecular damage, loss of klotho is a downstream consequence of that damage. Finding ways to deliver klotho to older individuals, boosting the amount in circulation, may well help with this one narrow outcome resulting from rising levels of cell and tissue damage. It remains the case that it would be far more effective to repair the damage, and thus remove all of the varied downstream consequences.

Curiously, within the brain, one structure contains vastly higher levels of klotho than all the others. This structure is the choroid plexus, which comprises a complex assembly of cells that produce cerebrospinal fluid and form an important barrier between the central nervous system and the blood. In a new study, researchers showed that klotho functions as a gatekeeper that shields the brain from the peripheral immune system. "We discovered, in mouse models, that klotho levels in the choroid plexus naturally decrease with age. We then mimicked this aging process by reducing levels of klotho in this structure experimentally, and we found that depleting this molecule increases brain inflammation."

The researchers further investigated the impact of this phenomenon on other brain regions. They discovered that in mice with less klotho in the choroid plexus, innate immune cells in an important memory center reacted more aggressively when other parts of the body were exposed to immune challenges that mimic infections. "The barrier between the brain and the immune system seems to break down with low levels of klotho. Our findings indicate that klotho helps keep that barrier closed. When levels of this molecule are depleted in the choroid plexus, the barrier becomes more porous and allows immune cells and inflammatory molecules to get through more easily."

"The molecular changes we observed in our study suggest that klotho depletion from the choroid plexus might contribute to cognitive decline in elderly people through brain inflammaging. It could help explain, at least in part, why we often notice deteriorations in cognitive functions in hospitalized seniors when they have infections, such as pneumonia or urinary tract infections. This complication tends to be particularly prominent in patients with Alzheimer's disease, in which inflammation has emerged as a major driver of pathology."

Link: https://gladstone.org/about-us/press-releases/new-insights-aging-brain