Renewed interest in a protein called klotho is pervading the scientific world. Klotho is a known anti-inflammatory protein that also contains anti-aging properties. In this two-part series, we will explore what klotho is, how it might impact inflammatory brain diseases, and how it ultimately prevents aging.
The History of Klotho
The Klotho gene and protein were discovered in 1997 by a scientist named Makoto Kuro-o. The name Klotho refers to the Greek mythological story of the three Fates. Klotho spun the thread of human life. The two other fates, Lachesis and Atropos dispensed and cut the thread. Together, the three fates controlled the lives of each human being and had the power to choose who was saved and who passed away.
How does this story about a Greek mythological character relate to a small protein in our bodies?
Klotho was discovered when a team of scientists in Japan noticed an inbred variant of mice that aged more quickly and had a shortened lifespan. The mice exhibited symptoms of multiple organ degeneration and cardiovascular disease among other age-related difficulties. They tracked this trait to a single inactivated gene that they named klotho. Subsequent experiments have confirmed this observation in other mouse strains and have determined that higher levels of klotho protein in mice extend lifespan significantly.
Other studies have shown that levels of klotho diminished with age in humans. Lower levels of klotho are associated with other symptoms of aging at the cellular level. This prompts the question of whether klotho might be useful in the treatment of age-related diseases.
The Structure and Function of Klotho
Klotho is a protein encoded by the klotho gene (Figure 1). The klotho protein can exist in either a membrane-bound form or a secreted, soluble form. The membrane-bound form is produced when the entire klotho gene is transcribed and translated into protein. The soluble form is produced when the gene is spliced to remove the transmembrane portion (Figure 2).
There are three subfamilies of the klotho protein that are formed depending on how the klotho gene is spliced (Figure 1). These subfamilies are alpha, beta, and gamma. Within the brain, soluble alpha klotho is the most abundant form of the protein.
Klotho in Inflammation
One of the primary ways that klotho is suspected to increase longevity is by acting as an anti-inflammatory protein. Inflammation is part of the body’s defense against harmful stimuli such as viruses or damaged cells. Controlled inflammatory responses are necessary for protecting our bodies and keeping us healthy. However, when inflammatory responses are uncontrolled or chronic, they can hurt the body more than they help. Harmful inflammatory responses have been implicated in aging, neurodegenerative diseases, rheumatoid arthritis, autoimmune diseases, and atherosclerosis among other serious diseases.
A number of experiments have now shown that klotho inhibits two key players in the inflammation process. One of these is NF-kB which is a transcription factor critical for the activation of the entire inflammatory pathway. Transcription factors regulate the production of proteins from genes in the body. NF-kB plays a crucial role in regulating the production of inflammatory proteins.
The second is tumor necrosis factor-alpha (TNF-alpha). TNF-alpha is a cytokine and is also a major regulator of the inflammatory response. Cytokines act as messengers and send signals to other immune cells, recruiting them to areas of injury.
The details of how klotho inhibits these inflammatory players are currently under investigation.
Klotho in the Brain
Chronic inflammation in the brain has been linked to several diseases including Alzheimer’s disease and brain fog. Inflammation is also a common feature of aging and a risk factor for several age-related diseases. In 2000 a team of scientists (Franceschi et al.) coined the term inflammaging which refers to chronic, low-grade inflammation that develops with advanced age.
With its anti-inflammatory properties, there is recent suspicion that the klotho protein may play a role in protecting the brain against inflammatory neurological diseases and neurodegenerative diseases. Alpha-klotho is highly abundant in a central structure of the brain called the choroid plexus. The choroid plexus is a network of blood vessels that produce cerebrospinal fluid. The choroid plexus vasculature and cerebrospinal fluid are important for providing the brain with nutrients and protection.
With this, understanding the klotho protein and its anti-inflammatory properties is crucial to developing a deeper understanding of aging and new treatments for inflammation-based neurological diseases including neurodegenerative disorders.
Klotho is clearly a gene and protein that is going to require much more attention. It is evident that aging is a complex phenomenon that involves multiple pathways. However, the genetic and biochemical data regarding klotho indicates that it plays an important if not central role in many of these processes. We look forward to learning much more about the role of klotho in health, disease, and aging. In the next section of this short series, we describe a more recent study on the role of klotho in neurodegenerative diseases.