Klotho, stem cells, and aging

Abstract

Aging is an inevitable and progressive biological process involving dysfunction and eventually destruction of every tissue and organ. This process is driven by a tightly regulated and complex interplay between genetic and acquired factors. Klotho is an antiaging gene encoding a single-pass transmembrane protein, klotho, which serves as an aging suppressor through a wide variety of mechanisms, such as antioxidation, antisenescence, antiautophagy, and modulation of many signaling pathways, including insulin-like growth factor and Wnt. Klotho deficiency activates Wnt expression and activity contributing to senescence and depletion of stem cells, which consequently triggers tissue atrophy and fibrosis. In contrast, the klotho protein was shown to suppress Wnt-signaling transduction, and inhibit cell senescence and preserve stem cells. A better understanding of the potential effects of klotho on stem cells could offer novel insights into the cellular and molecular mechanisms of klotho deficiency-related aging and disease. The klotho protein may be a promising therapeutic agent for aging and aging-related disorders.

Keywords: Wnt; aging; cell senescence; klotho; stem cells.

Figure 1

Schematic diagram of membrane klotho and secreted klotho. Notes: Membrane form of klotho transcript arises from the klotho gene. Secreted klotho arises from an alternative RNA splicing. The internal splice donor site is in exon 3 of the klotho gene. The resultant alternatively spliced transcript contains insertion of 50 bp after exon 3 (gray), with an in-frame translation stop codon at the end. The product is released into the blood circulation. On the other hand, membrane klotho protein encoded by the membrane form of klotho transcript is a single-pass transmembrane protein. The extracellular domain of membrane klotho containing KL1 and KL2 repeats is shed and cleaved by α/β-secretases, and released into the circulating stream. Therefore, there are two forms of klotho protein in the circulation. One is derived from cleavage of the extracellular domain of membrane klotho called soluble klotho, a well-known active form. The other is the secreted membrane protein, which is directly derived from an alternatively spliced klotho transcript, but its function is largely unknown. Abbreviation: mRNA, messenger RNA.

Figure 2

Potential effects of klotho deficiency on stem cell depletion and the aging process. Notes: Klotho deficiency stimulates the Wnt signaling pathway to directly accelerate aging or indirectly induce stem cell depletion. Klotho deficiency downregulates autophagy, and low autophagy consequently accelerates aging and induces stem cell senescence and depletion. Klotho deficiency also activates the Wnt signaling pathway, and the resulting excessive Wnt signal activity also induces stem cell senescence and depletion. Both low autophagy and high Wnt signaling activity may directly accelerate aging. Klotho deficiency in turn depresses insulin/IGF signaling activity, disrupts mineral-metabolism homeostasis, and amplifies oxidative stress. Klotho deficiency is also associated with higher levels of blood antidiuretic hormone (ADH) and aldosterone (Ald). All of these effects accelerate the aging process and trigger or exacerbate age-associated diseases. Conceivably, elevation of klotho can interrupt klotho deficiency-induced pathologic processes, slow down aging processes, and attenuate age-associated diseases.