Klotho is a longevity gene in that more of the protein it codes for acts to modestly extend life in mice. Levels of klotho protein decline with age, and increased amounts appear to produce beneficial outcomes in health and longevity in part via stem cell function. Klotho also influences cognition, and a number of research groups are working on approaches, such as gene therapies to upregulate klotho expression, or delivery of recombinant protein fragments of the full klotho molecule, that might at some point result in ways to enhance cognitive function in humans, old and young alike.
Klotho is known to be closely related to FGF23, and research into this relationship has uncovered roles for klotho throughout the body, in many organs. This popular science article focuses on the brain however, covering research results suggesting that the influence of klotho on cognitive function might be quite circuitous and indirect, involving other organs in the body. This isn't an unreasonable suggestion - it is certainly the case in other, better known systems of regulation.
The longevity gene klotho keeps memory keen, but how? New research raises the possibility that it might influence cognition through its signaling partners FGF23 and the fibroblast growth factor (FGF) receptor. Researchers recently reported that mice lacking FGF23 have memory problems similar to those seen in klotho knockouts. Meanwhile, another group reported that older people with high levels of FGF23 in their blood are at elevated risk of developing dementia. However, changes in circulating FGF23 levels are also known to impair kidney function. Kidney disease by itself can harm cognition, leaving it unclear if FGF23 acts directly in the brain or indirectly in the periphery.
Klotho levels dwindle with age, and drop off steeply with disease progression in mouse models of amyloidosis. Conversely, high levels of klotho boost cognitive performance in people, and memory in mice. Another recent study adds genetic evidence for klotho's protective effect in the brain. Researchers found that the klotho variant associated with high expression and longevity seemed to negate some effects of the ApoE4 allele. Among 82 people with this protective klotho variant, ApoE4 carriers accumulated no more brain amyloid than noncarriers. The mechanism is unclear.
Researchers have elucidated at least one signaling pathway through which klotho acts. Klotho spans the cell membrane, where it binds FGF receptors to form a pocket that captures extracellular FGF, triggering intracellular signaling. It is unknown what effect this has on the brain. In the kidney, the binding of klotho and FGF23 stimulates excretion of phosphate and vitamin D, hence functions in their homeostasis. FGF23 levels appear to be tightly regulated. Mice with too much of it develop the vitamin-D-deficient bone disease rickets. Those with too little accumulate mineral deposits throughout their bodies and age faster, as do klotho knockouts.
Were the learning defects of the FGF23 knockout mice due to FGF23 in the brain? Probably not. The authors searched intensively for FGF23 mRNA or protein in wild-type mouse brain, but were unable to find significant expression. Because of this, they believe that brain klotho acts via other mechanisms, independent of FGF23. The FGF23 knockouts develop kidney disease, grow slowly, and die by 9 weeks of age. Kidney problems are linked to cognitive deficits. In particular, high FGF23 levels predict progression of kidney disease and worse cognition. Researchers believe the take-home message from these studies is the importance of kidney function for cognition.