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Klotho is one of the few robustly longevity-associated genes discovered over the past few decades. Increased levels of the circulating α-klotho protein slows aging in mice and is associated with better late life health in humans. Additionally, more of this α-klotho appears to slow cognitive aging and also boost cognitive function in younger animals. While klotho is thought to be primarily active in the kidneys, and thus indicates the importance of declining kidney function in degenerative aging, researchers are discovering potentially relevant interactions in the brain. It remains an open question as to how exactly klotho produces its observed benefits, which potential mechanisms are most important, and whether there is more to be discovered yet.
This lack of knowledge hasn’t prevented the research and development community from working on therapies based on delivery of optimized α-klotho variants. That is a work in progress, however, currently led by Unity Biotechnology and at a comparatively early preclinical stage. Other groups will no doubt join them as the possibilities for klotho-based therapies continue to attract further interest. Such therapies do not have to be limited to delivery of α-klotho as a protein. An increase in the levels of specific circulating proteins is one of the easier, more feasible prospects for gene therapies, as all it requires is delivery of the treatment to a small volume of fat tissue, turning it into a factory for the desired proteins, the effects lasting for years or more.
Aging and neurodegenerative disorders are complex medical conditions with poorly understood underlying pathophysiology that may affect virtually all tissues and organs. A limited number of genes and their transcripts have been associated with either premature aging, as seen in progeria, or with longevity. The α-Klotho protein, first identified in mice studies in 1997, primarily functions as a co-receptor for fibroblast growth factor 23 (FGF23) in the kidneys and parathyroid gland and therefore has a crucial role in phosphate homeostasis, vitamin D metabolism, and vascular calcification. In addition, α-Klotho has been identified in a wide variety of tissues, consistent with its role in the aging process, including endocrine organs, arteries, and reproductive, epithelial, and neuronal tissue.
β-Klotho is primarily expressed in the liver, adipose tissue, and kidneys and plays a role in lipid and energy metabolism by acting as co-receptor for FGF15 and FGF21, while the γ-Klotho isoform is expressed in the brown adipose tissue, skin and kidneys with as yet poorly defined roles and by acting as co-receptor for FGF receptor 1b (FGFR1b), FGFR1c, FGFR2c and FGFR4 and are not discussed in the current review, which is focused on α-Klotho.
Nevertheless, preclinical studies conducted on Klotho knockout mice have revealed that Klotho deficiency is associated with impaired cognition, shorter lifespan, cardiac hypertrophy, vascular calcification, multi-organ atrophy, and fibrosis and growth retardation. Moreover, overexpression of the Klotho gene has been shown to lengthen lifespan in mice, which raises the potential question of whether Klotho may be utilized as a target to control or reverse aging and/or neurodegeneration. One drawback of such models is the lack of distinction between soluble and transmembrane Klotho molecules, which may potentially have distinct physiological roles in the human body. Whether such physiological and pathological outcomes of Klotho deficiency and/or overexpression may simply be attributable to the role of Klotho on phosphate metabolism is unclear and should be evaluated with caution with the discovery of multiple phosphate metabolism-independent functions of Klotho protein.
In this narrative review, our aim is to evaluate the potential pathophysiological and therapeutic role of Klotho protein in aging and neurodegenerative conditions. Emerging clinical and experimental insights suggest Klotho deficiency not only as a risk factor, but also a modifiable therapeutic target. Even though there is a clear need for future large-scale human studies in order to develop clinical and therapeutic strategies involving Klotho proteins in humans, this field appears to be promising.
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