Klotho gene and epigenetic age in the brain

Klotho

Methylation is a chemical reaction that involves the addition of methyl groups to specific regions of DNA. This process is one of the mechanisms for controlling gene activity in the cell. When we start to age, certain regions of our genes accumulate more methyl tags than usual. This fact can be used to calculate the so-called epigenetic age. To read more about epigenetic clock click here.

The epigenetic age does not always correspond to the real biological age of a person. Numerous factors can influence epigenetic age, such as chronic illness, environmental changes, the development of cancer, or even dietary preferences. Scientists at Boston University School of Medicine have demonstrated that mental illness can also affect epigenetic age.

These changes are associated with a gene called Klotho. Named after Greek goddess of fate. According to Greek mythology Klotho and her two sisters, controlled the thread of life of each human being and Klotho was responsible for spinning the thread of life. This gene is linked to the aging process. It has been shown that mice with a mutation in the Klotho gene age significantly faster than normal mice. Therefore, this gene is considered an aging suppressor.

Klotho also plays an important role in the functioning of the brain. For example, mice with a missing or poorly functioning Klotho gene were unable to perform certain cognitive tasks. In another experiment studying brain development in rats, Klotho protein levels changed with growth stages in animals. Another rodent experiment showed that the presence of the Klotho protein prevents brain inflammation. Taken together, these studies show that the Klotho gene is critical to normal brain function.

Unfortunately, levels of this important protein can be depleted in various mental illnesses. For example, the Klotho protein is significantly reduced in women with chronic stress.

Soldier
PTSD is common among war veterans

Another type of mental illness associated with changes in Klotho protein levels is post-traumatic stress disorder – PTSD. This disorder is common among survivors of violent attacks and war veterans. PTSD is a disorder in which patients experience intense anxiety and fear in response to certain things. In the most severe cases, PTSD patients are unable to carry out daily activities properly due to the strength of negative emotions and fear that the disorder causes.

According to current theories, PTSD is caused by an absence of a blockage in the amygdala, the part of the brain responsible for memory and the “fight-or-flight response”. A number of areas in the anterior regions of the brain, such as the ventromedial and dorsolateral prefrontal cortex, are implicated in the development of this disease. In particular, they are responsible for the regulation and suppression of fear, and PTSD is often associated with disorders in this area.

It was also recently discovered that veterans with PTSD symptoms have a faster epigenetic clock accelerating faster than people without the condition. Following this discovery, a group of researchers became interested in the link between epigenetic aging and PTSD. The researchers found that a particular variant of the Klotho gene, rs9315202, is often present in patients with severe PTSD. Moreover, the combination of the rs92315202 gene variant and PTSD has also been associated with other aging symptoms such as rapid epigenetic aging in patients’ cells.

The next stage of the study was to analyze the changes in the brain caused by mental illness and their possible connection with some variants of the Klotho gene. In this study, the researchers decided to study the brain that was donated after death of the patients with several types of mental disorders, including PTSD, depression, and alcohol-related disorders. The experiments involved analyzing specific areas of the brain: the dorsolateral and prefrontal cortex, which are often affected by PTSD, and the so-called motor cortex, which controls movement.

Researchers found that:

  • The presence of rs92315202 variant of the Klotho gene and the diagnosis of PTSD was associated with increased epigenetic aging in the motor cortex;
  • The only other medical condition that causes a similar acceleration of aging in the area of the brain responsible for movement was chronic alcohol use;
  • If rs92315202 variant of the Klotho gene was inserted into a cell line derived from human kidney, the protein produced by that gene functioned differently from the “normal” version of the protein and affected other genes.

It is important to be aware of the influence of certain gene variants, because this may help in personalized treatment in the future. Thus, given a variant of a gene that could expose a particular person to significant risk of pathological changes and could accelerate aging in the event of severe stress or mental illness such as PTSD, the worst-case scenario could be prevented by choosing the appropriate therapy. This is why research like this is important for the correct treatment of patients with severe mental illness, especially those with PTSD.

Literature.

  1. Clinton, S. M. et al.  [August 2013] Expression of klotho mRNA and protein in rat brain parenchyma from early postnatal development into adulthood. Brain. Res., V. 1527,pp. 1-14.
  2. Zhu, L. et al. [November 27, 2018]. Klotho controls the brain–immune system interface in the choroid plexus. PNAS, V. 115, №48.
  3. Prather, A. A. et al.[June, 2015].  Longevity factor klotho and chronic psychological stress. Transl. Psychiatry., V.5, № 6, p. e585. Retrieved December 1, 2020 from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4490291/
  4. Wimalawansa, S. J. [2014]. Mechanisms of developing post-traumatic stress disorder: new targets for drug development and other potential interventions. CNS Neurol. Disord.Drug Targets, V. 13, №5, pp. 807-16
  5. Lobo, I. et al. [2011]. The neurobiology of posttraumatic stress disorder: dysfunction in the prefrontal-amygdala circuit? Psychol. Neurosci., V. 4, № 2. Retrieved December 1, 2020 from: https://www.scielo.br/scielo.php?script=sci_arttext&pid=S1983-32882011000200004
  6. Pennington, Z. T., A. S. Anderson, M. S. Fanselow [2017]. The ventromedial prefrontal cortex in a model of traumatic stress: fear inhibition or contextual processing? Learn Mem., V. 24, pp. 400-406
  7. Wolf E. J., et al. [June 13, 2018] Posttraumatic psychopathology and the pace of the epigenetic clock: a longitudinal investigation. Psychological medicine, V. 49, Issue 5, pp. 791-800
  8. Wolf, E. J. et al. [August, 2019]. The Goddess Who Spins the Thread of Life: Klotho, Psychiatric Stress, and Accelerated Aging. Brain. Behav. Immun., V. 80, pp. 193-203

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