Reviewing the Role of Klotho in Aging and Kidney Disease
When people talk about the klotho gene, they usually mean α-klotho, one of the better documented longevity-associated genes. It encodes a transmembrane protein, is expressed in a number of organs that sheds a portion of its structure to circulate in blood and tissues, interacting with other cells. In animal models artificially increased klotho expression improves late life health and life span while artificially diminished klotho expression worsens late life health and reduces life span. Interestingly, increased levels of klotho can improve cognitive function even in young animals. In humans, data shows the same correlation between circulating levels of klotho and age-related health and longevity.
The mechanisms by which klotho affects health on an organ by organ basis are far from fully understood, particularly when it comes to effects on the brain. It is best understood in the kidney, where it is protective against damage and diminished function with age. One hypothesis is that its body-wide effects are secondary to to kidney function, that loss of kidney function is an important contribution to age-related issues throughout the body. It does seem likely that it has direct effects on other organs as well, however.
The usual challenge in mechanisms relating to aging is that many processes are underway at the same time, interacting with one another. It is somewhere between hard and impossible to determine the relative size of each contribution to the end result of pathology and disease. The fastest path to that goal is to produce a therapy that only affects one contribution and observe the outcomes, but that is not always possible or practical.
Klotho antiaging protein: molecular mechanisms and therapeutic potential in diseases
Aging is not only a compilation of ailments that occur in the later stages of life; it is a dynamic process that unfolds throughout the lifespan. The escalating issue of an aging population is a significant economic, social, and medical concern of modern society. Over time, aging causes a segmental and gradual loss of strength and biological function, which leads to a decline in resistance and increasing physiological weakness. Multiple biochemical pathways actively control aging. It is distinguished by a number of molecular and cellular features, including abnormal nutrient sensing, mitochondrial dysfunction, cellular senescence, epigenetic imbalance, and loss of connectivity between cells. Globally, chronic illnesses tend to be more common in the aging population. Chronic illnesses need lengthy therapy, which alters the character of healthcare facilities and raises demand for them.
On the other hand, Klotho is an anti-aging protein with diverse therapeutic roles in the pathophysiology of different organs, such as the kidneys and skeletal muscle. Numerous pathways implicated in aging processes are regulated by Klotho, including Wnt signaling, insulin signaling, and phosphate homeostasis. It also impacts intracellular signaling pathways, including TGF-β, p53/p21, cAMP, and protein kinase C (PKC). Klotho expression and circulation levels decrease with increasing age. Klotho-deficient mice have excessive phosphate levels because of phosphate excretion imbalance in the urine. However, they also exhibit a complicated phenotype that includes stunted development, atrophy of several organs, hypercalcemia, kidney fibrosis, cardiac hypertrophy, and reduced lifespans. Given that supplementation or Klotho gene expression has been shown to suppress and repair Klotho-deficient phenotypes, it is likely that Klotho might have a protective impact against aging illness.
Recent cross-sectional cohort research with 346 healthy individuals aged 18 to 85 years showed that serum Klotho levels are negatively correlated with age and that older individuals (ages 55 to 85) exhibited the lowest serum α-Klotho levels. Another observational cohort research, which had around 804 adults over 65 years old, was conducted in Italy and found a negative correlation between serum Klotho levels and all-cause mortality. Furthermore, those with decreased serum Klotho levels had a comparable increased risk for all-cause death, according to a meta-analysis of six cohort studies that included adult chronic kidney disease (CKD) patients. Additionally, preclinical research has demonstrated that overexpressing the Klotho gene in transgenic mice can postpone or reverse aging. Therefore, increasing Klotho levels emerges as a promising strategy in diabetic kidney disease, CKD, and aging disorders.