The one protein in question is called the ferritin light chain 1 (FTL1). This protein has been observed in increased quantities in the brains of older mice. When researchers increased the amout ot FTL1 in young mice, they started showing qualities of aging. The FTL1 has been associated with cognitive decline by impairing the neurons in the hippocampus. The hippocampus plays a large role in memory consolidation, spatial mapping, and emotional regulation.
The ferritin light chain 1 protein is associated with iron, as the name suggests. Ferritin's normal function is to store and regulate iron, but when there is an increase in the FTL1, it changes the oxidation state of the free iron in the neurons. This causes an increase in oxidized iron, which in turn leads to a disruption in the iron balance and causes damage over prolonged periods of time.
This damage to the cells decreases the level at which the neurons can communicate. This increase in FTL1 reduces the synaptic communication, reducing synaptic density and dendritic complexity. In petri dishes, the nerve cells that were engineered to make lots of FTL1 only grew one arm neurites. Normal nerves grow lots of branching neurites. The light chain of ferritin and the heavy chain of ferritin are both involved in the maturation of oligodendrocytes. These oligodendrocytes play a crucial role in the myelination of neurons. Without this myelination, neurons have a hard time sending out action potentials to communicate with the surrounding neurons. This plays a large role in developing new memory storage and learning.
The knowledge of this increase in ferritin light chain 1, causing brain aging, helped steer researchers to try and reduce this protein. When the protein was reduced in the old mice, there were noticeable reversals in cognition, essentially regaining their youth. The FTL1 also slowed down the metabolism of the neurons, but treating the cells with something that stimulates metabolism reversed this.
This leads to the discussion about whether or not a type of therapy can be used to try and reduce brain aging in humans.
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This is fascinating! It's exciting to see how iron homeostasis in the brain could be a key target for aging interventions. One thing that really struck me is the link to myelination and oligodendrocytes. Could excel FTL1 be increasing demyelinating conditions in aging humans, like in multiple sclerosis, or even Alzheimer's and Parkinson's, where iron dysregulation is also involved? I dug into this a bit and found a 2015 study on a mouse model of neuroferritinopathy (a human disorder caused by FTL mutations), which shows that mutant FTL leads to iron overload, oxidative stress, and neurodegeneration with symptoms resembling Parkinson's. The paper suggests similar mechanisms might apply broadly to age-related cognitive decline! Here's the article:
ReplyDeleteMaccarinelli, F., Pagani, A., Cozzi, A., Codazzi, F., Di Giacomo, G., Capoccia, S., Rapino, S., Finazzi, D., Politi, L. S., Cirulli, F., Giorgio, M., Cremona, O., Grohovaz, F., & Levi, S. (2015). A novel neuroferritinopathy mouse model (FTL 498InsTC) shows progressive brain iron dysregulation, morphological signs of early neurodegeneration and motor coordination deficits. Neurobiology of disease, 81, 119–133. https://doi.org/10.1016/j.nbd.2014.10.023