The Correlation Between Klotho and Age-Related Diseases

Klotho's protein has a small intracellular component, a transmembrane component and an extracellular component. The entire length of Klotho is a type I single-pass transmembrane protein, with two different glycosidase-like domains, KL1 and KL2. α- and β-cleavage sites can be attacked by ADAM10, ADAM17 and BACE1, which cleaves full-length Klotho into soluble 130 kDa Klotho and secreted 65 kDa Klotho, which get emitted into blood, cerebrospinal fluid and urine. KL1 and KL2 domains are sequence-identical to glycosidase, and they were shown to act like a glycosidase. However, compared to catalytically active glycosidases, both KL1 and KL2 domains lack key catalytic glutamic acid residues and show significant conformational differences in the loops surrounding the catalytic pocket. The substitution of key active site residues in β-Klotho also indicates that this protein cannot function as an active glycosidase. Therefore, it is unlikely that Klotho itself possesses glycosidase activity; rather, it is more probable that the KL domains bind to sugars on glycoproteins or glycolipids, thereby facilitating protein-protein or protein-lipid interactions.

Figure 2. Architecture of the human Klotho protein
(Source: Xu Y, et al. 2015)

The Klotho protein has various biological functions. Klotho gene knockout mice showed profound growth retardation, reduced longevity, vascular and soft tissue calcification, diminished bone mass, and atrophy of organs, according to research. When the Klotho gene is overexpressed, by contrast, mice become higher in Klotho protein, live longer and have fewer or no chronic frailty diseases – which indicates that Klotho has anti-ageing effects. It is also antioxidant and manages calcium and phosphorus metabolism. We know that low Klotho protein in humans can cause degenerative illness, weakness, dementia, kidney dysfunction and death.

Klotho Proteins and Aging Diseases

Frailty is the great manifestation of accelerated ageing and its cause can be diverse, including chronic inflammation, oxidative stress and cellular decline. The Klotho protein delays frailty by several mechanisms: anti-chronic inflammation, antioxidants, cell senescence and death.

Chronic physiological stimulation of the immune system can lead to inflammatory senescence, characterized by a persistent low-grade sterile inflammatory state. The cause of fatigue is also heightened pro-inflammatory cytokines like white blood cell count, C-reactive protein and tumour necrosis factor-alpha. Inflammation also brings on the signs of ageing such as atherosclerosis, diabetes and neurodegenerative diseases. Klotho protein was also an instructive indicator of inflammation: its level was negatively associated with inflammation markers such as CRP, white blood cell counts and interleukin-1. Klotho protein has been tested in animal models of age-related cardiac and renal failure in mice, by inhibiting inflammatory reactions.

During replication, the body also induces oxidative stress, accumulating reactive oxygen and nitrogen species (RONS), and then cells senescence and stop proliferating. Klotho protein is also shown to prevent oxidative stress. A deficiency of Klotho protein in muscle stem cells can lead to pathogenic changes in mitochondrial structure, mitochondrial DNA damage, and increased senescence. Additionally, Klotho protein can protect mitochondrial function by inhibiting the Wnt signaling pathway.

Aging cells exhibit impaired regenerative or proliferative capacity, reduced metabolic function, and dysregulated apoptosis, which closely correlates with the decline in physiological reserve capacity, diminished stress resistance, and increased vulnerability observed in frailty across multiple organs or systems. The rise of the senescent cells accelerates the decline. Klotho protein halts the cell's senescence and is an apoptotic and senescence inhibitor. It prevents senescence and apoptosis by suppressing the p53/p21 signaling system and shields cells from oxidative and cytotoxic stress.

In many studies, a decrease in circulating soluble Klotho protein is linked to the progression of several diseases. In mice of different endogenous soluble Klotho levels that had undergone ischemia-reperfusion injury, the plasma soluble Klotho levels correlated with the degree of AKI (as a measure of kidney damage). They show that plasma soluble Klotho concentrations could be used as biomarkers and targets for AKI. And soluble Klotho protein might cause coronary artery calcification by preventing the Wnt/signaling pathway. For example, when researchers compared the rate and risk factors of coronary artery calcification in hemodialysis patients, they found a strong decline in soluble Klotho levels from non-calcified to mildly and severely calcified groups, suggesting that higher levels of Klotho were partly protective against coronary artery calcification in the patients.

Figure 3. Overview of the functions of Klotho
(Source: Xu Y, et al. 2015)