Klotho is one of the few well-established longevity-associated genes that works in both directions in animal models: less klotho shortens life span, while more klotho extends life. Klotho also improves cognitive function. The mechanisms by which klotho produces these outcomes remain poorly understood: there is the usual grab-bag of identified mechanisms, and little idea as to which are more or less important than the others, or as to whether the list is even near complete. In recent years, research results have indicated that klotho likely undertakes its important functions in the kidneys rather than the brain, and its effects are a reflection of the importance of kidney function to the body as a whole. Meanwhile, delivery of soluble α-klotho has been shown to be beneficial in mice, and some groups are presently in the early stages of developing this approach as a therapy for neurodegenerative conditions.
Cognitive dysfunction is a key symptom of ageing and neurodegenerative disorders, such as Alzheimer's disease (AD). Strategies to enhance cognition would impact the quality of life for a significant proportion of the ageing population. The α-klotho protein may protect against cognitive decline through multiple mechanisms: such as promoting optimal synaptic function via activation of N-methyl-d-aspartate (NMDA) receptor signalling; stimulating the antioxidant defence system; reducing inflammation; promoting autophagy and enhancing clearance of amyloid-β.
However, the molecular and cellular pathways by which α-klotho mediates these neuroprotective functions have yet to be fully elucidated. Key questions remain unanswered: which form of α-klotho (transmembrane, soluble, or secreted) mediates its cognitive enhancing properties; what is the neuronal receptor for α-klotho and which signalling pathways are activated by α-klotho in the brain to enhance cognition; how does peripherally administered α-klotho mediate neuroprotection; and what is the molecular basis for the beneficial effect of the VS polymorphism of α-klotho?
In this review, we summarise the recent research on neuronal α-klotho and discuss how the neuroprotective properties of α-klotho could be exploited to tackle age- and neurodegeneration-associated cognitive dysfunction.