What is Klotho and its role in the body?
Klotho is a protein, often called a "longevity gene," that plays a protective role in the body by helping to regulate multiple processes, including the management of phosphate and calcium levels and the reduction of oxidative stress. It exists in both a membrane-bound form, primarily found in the kidneys, and a soluble form that circulates in the blood.
The crucial functions of Klotho
Klotho's primary functions include:
- Regulating phosphate and calcium: In the kidneys, Klotho works with fibroblast growth factor 23 (FGF23) to regulate the body's phosphate levels, preventing hyperphosphatemia.
- Inhibiting aging pathways: It suppresses signaling pathways like insulin/IGF-1 (insulin-like growth factor 1) and WNT, which are associated with accelerated aging.
- Reducing oxidative stress and inflammation: Klotho helps combat inflammation and oxidative stress, protecting against cellular damage and injury.
- Protecting the cardiovascular system: It guards against vascular damage by inhibiting inflammation, improving endothelial function, and preventing vascular calcification.
Chronic kidney disease and low Klotho
One of the most significant consequences of low klotho levels is its impact on kidney function. The kidneys are a major source of klotho, and a vicious cycle can occur where declining kidney health leads to lower klotho production, and lower klotho levels further exacerbate kidney damage.
Mechanisms of kidney damage
Klotho deficiency promotes kidney damage in several ways:
- Hyperphosphatemia: When klotho is low, the body's ability to excrete phosphate is impaired, leading to high phosphate levels in the blood. This contributes to kidney mineral and bone disorders.
- Increased oxidative stress: Without klotho's protective effects, oxidative stress and inflammation increase in renal tubular and vascular cells, accelerating senescence and cell death.
- Renal fibrosis: Low klotho levels can promote renal fibrosis, or the scarring of kidney tissue, further diminishing kidney function over time.
Cardiovascular complications from Klotho deficiency
Klotho's protective role extends to the cardiovascular system, and its deficiency is a known risk factor for heart and vascular disease, especially in chronic kidney disease patients. Low klotho is associated with accelerated vascular aging, leading to stiffening of the arteries.
Cardiovascular consequences
- Vascular calcification: Klotho deficiency promotes the accumulation of calcium in blood vessels, leading to arterial stiffness and hypertension.
- Cardiac dysfunction: Low klotho can lead to cardiac aging and heart failure. It impairs the Nrf2-GR pathway, which normally protects heart tissue from oxidative stress.
- Endothelial dysfunction: The lining of the blood vessels, the endothelium, becomes less functional, contributing to conditions like hypertension.
Cognitive decline and neurodegeneration
Low klotho levels are also linked to cognitive impairment and a higher risk of neurodegenerative diseases, such as Alzheimer's disease. Studies in mice have shown that klotho deficiency can alter brain transcriptomics and neuronal function.
Brain-related effects
- Impaired neuroprotection: Klotho provides neuroprotection, and its decline can leave the brain more vulnerable to age-related damage.
- Worse cognitive function: In nursing home residents, low klotho levels have been associated with poor cognition, increased frailty, and a higher risk of falls.
- Synaptic function: Klotho influences synaptic plasticity, and its deficiency can impair communication between neurons.
The link between low Klotho and other aging-related issues
Beyond the kidneys, heart, and brain, low klotho contributes to other signs of accelerated aging.
- Musculoskeletal issues: Low klotho is associated with sarcopenia, or the loss of muscle mass and strength, and frailty. It can impair muscle repair and counter the effects of growth-inhibiting factors.
- Bone health: By affecting calcium and phosphate regulation, low klotho can impact bone mineral density and increase the risk of bone disease.
- Cellular senescence: Klotho deficiency promotes cell senescence, the irreversible cessation of cell division, contributing to organ atrophy and other age-related changes.
Low Klotho vs. Normal Klotho Effects
| Feature | Low Klotho | Normal/Elevated Klotho |
|---|---|---|
| Aging | Accelerated aging and increased frailty. | Promotes longevity and healthy aging. |
| Kidney Function | Promotes chronic kidney disease, fibrosis, and hyperphosphatemia. | Protects against kidney damage and helps regulate phosphate. |
| Cardiovascular Health | Increases risk of vascular calcification, hypertension, and heart failure. | Protects blood vessels and reduces cardiovascular risk. |
| Cognitive Function | Linked to cognitive impairment, poor memory, and neurodegeneration. | Supports cognitive function and neural resilience. |
| Inflammation | Counteracts inflammation and cellular stress, leading to a pro-inflammatory state. | Acts as an anti-inflammatory agent. |
| Physical Performance | Contributes to sarcopenia, muscle weakness, and frailty. | Supports muscle function and repair. |
| Mortality Risk | Associated with increased all-cause mortality. | Associated with a reduced risk of mortality. |
What can be done to address low Klotho?
While klotho levels naturally decline with age, certain lifestyle changes can help support healthy levels and mitigate the risks associated with deficiency.
- Exercise regularly: Physical activity is known to boost klotho production.
- Maintain a healthy diet: A diet rich in antioxidants and vitamin D can support klotho levels. Some studies also point to curcumin from turmeric as a potential booster.
- Manage stress: Chronic stress can negatively impact hormone balance, including klotho.
- Get quality sleep: Sufficient, restful sleep is essential for overall hormone regulation and health.
- Consider potential therapies: Ongoing research explores therapies to supplement or increase klotho levels, such as recombinant protein administration or gene therapy.
Conclusion
Low klotho is far from a benign condition; it is a significant factor in the acceleration of aging and the development of numerous chronic diseases. The consequences of klotho deficiency are widespread, affecting the kidneys, cardiovascular system, brain, and musculoskeletal system. While klotho levels tend to decrease with age, lifestyle interventions like regular exercise, a healthy diet, and stress management may help support healthy levels. Emerging therapies also offer hope for addressing this crucial aspect of longevity and health. Understanding the multifaceted role of klotho is key to recognizing the interconnectedness of aging and chronic disease.
