Extending one’s life has fascinated people for centuries. Eternal life appears consistently in mythology and religion: as ambrosia, a gift from the gods or a philosopher’s stone. Today, the average human lifespan is around 80 years. However, we are finding that more and more age-related illness, such as Alzheimer’s Disease and Parkinson’s Disease, along with cancers, are exhibited more frequently. Both of my grandmothers have age-related diseases (Alzheimer’s and PSP). The subject strikes at home for me. As such, the paper we discussed in class for Neurochemistry sparked my interest. It reviewed known mechanisms of aging and how a certain receptor, IGF1-R, may play an important role in aging of the brain and Alzheimer’s disease.
IGF1-R, Alzheimer’s, Ceramide, oh my!
IGF1-R stands for insulin-like growth factor 1 receptor. This is considered a tyrosine kinase receptor, one of the types of receptors found in the brain. These kinds of receptors usually bind to growth factors like insulin. The receptors, after binding to signal molecules, or ligands, can start a chain reaction of other signals within the cell. The signal pathways that IGF1-R activates are the PKB/Akt or Ras/MEK/ERK pathways, both important in cell growth and reproduction. The Akt pathway also encourages cell death. This plays a role in aging.
The signal from IGF1-R is thought to contribute to the switch in the presence of two different receptors: TrkA and p75 neurotrophin receptors. TrkA is exhibited more in younger animals, while p75 is shown in greater amounts in older animals. Somehow, the expression of these receptors switches; the mechanism has yet to be discovered. But it is this switch that is thought to contribute to the aging of cells and eventual development of Alzheimer’s.
p75 receptor signaling is associated with the production of ceramide, a lipid (fat). This lipid stabilizes the enzyme that breaks up the precursor molecule to the amyloid-beta. Amyloid-beta is a molecule that builds up to form the plaques that are characteristic of Alzheimer’s.
So, let’s review! IGF1-R can help cell growth, but also encourages cellular death. Somehow, it can lead the switch to p75, which will result in more ceramide. More ceramide means more enzyme; more enzyme leads to more plaques. The mechanism for Alzheimer’s is more complicated, and becomes more so everyday.
The Practical Applications of Roundworms
One thing that caught my attention is how we discovered the possible aging pathway. It was first found in roundworms. Mutations in the gene age-1 extended the roundworms’ lifespans. This gene in the worms codes for the protein PI3K which is also found in humans. Then IGF1-R was implicated as important to aging when mutations that inactivated the gene product in the daf-2 gene resulted in a doubling of the maximum lifespan of the worms. daf-2 codes for the insulin/IGF1 receptor. These genes and proteins are essentially the same as those found in humans. Further research into the human pathway confirmed that IGF1-R affects those pathways. It is logical to conclude that human lifespan, much like the roundworm’s, could be extended with mutations in the genes that code for IGF1-R and PI3K. However, we would not be able to see results right away like in the roundworm.
The fact that this information was obtained from a roundworm, something that is completely different from humans, is amazing. A simple organism can represent the “more highly evolved” organisms. All cells are connected at their roots. So next time you hear about research on roundworms, seahorses, or yeast, and think money and resources are being wasted, consider our continuing quest for life. Research is a necessity if we want to find our own ambrosia.
Discovering Ambrosia
