How Can a Single Gene Extend Human Life? — The O3 Protein Story
People who live over 100 years all have one thing in common: a variation of the gene called Forkhead box protein O3 (FOXO3)
By Izabela Ninu
In this case, the G-allele in this FOXO3 DNA strand is replicated and expresses some longevity factors. Here, we will focus on neurodegeneration (the loss of brain cells).
One of the main functions of the FOXO3 gene is to act as a switch for apoptosis, which is the programmed cell death that occurs when cells are damaged or no longer needed. Apoptosis helps to prevent diseases such as cancer and neurodegeneration, by eliminating abnormal or harmful cells.
The FOXO3 gene is also involved in the response to oxidative stress, which is the imbalance between the production and removal of reactive oxygen species (ROS). ROS are molecules that can damage DNA, proteins, and lipids, and cause cellular dysfunction and aging.
So, if our brain stem cells (which have the potential to replace specialized cells — such as muscle cells, blood cells, and brain cells — that have been damaged by injury or disease) are subject to a lot of oxidative stress, new neurons will be unable to be replaced, under those stress conditions.
FOXO3 is a double-edged sword: it can kill damaged cells by apoptosis, or it can protect healthy cells from being destroyed by external factors.
When we talk about oxidative stress, what happens is that harmful types of oxygen build up in the body, so it affects the response of the FOXO3 gene which is directly modified by oxidative stress. This modification sends the protein into the nucleus of the stem cell, where it turns on the stress response genes.
The genes that are activated use up a substance called SAM. This substance is needed to help another protein called lamin make a strong layer around the DNA in the center of the stem cell, to protect it from this stress.
Without SAM, lamin can’t make this layer and DNA will leak out of it, which will destroy the cell. If it happens, the cell thinks this DNA is from a virus that has infected it, which makes the cell start an immune reaction called the type-I interferon reaction. This makes the stem cells destroy themselves if the FOXO3 gene is not present.
“This reaction is actually good for the stem cells because the outside environment is not good for new brain cells” Dr. Paik explained their experience.
If new stem cells were growing in such bad conditions, they would automatically die. It’s better for stem cells to stop in a protected stable state (with the lamin layer), and not start producing new neuronal cells.
If the gene expression of the FOXO3 gene can preserve brain stem cells in a stable state in stressful conditions, this would explain the extraordinarily long and healthy lives of some individuals, because their neuronal activity and cell protection (not just stem neuronal cells) would be increased by this protein.
As such, while FOXO3 is a convincing longevity gene, the mechanism by which FOXO3 determines longevity remains unknown. Maybe if we can understand how to activate this gene, we would know how to better protect certain cells and, as such, help promote the longevity of the human body.
Photo: https://en.wikipedia.org/wiki/FOXO3
https://www.frontiersin.org/articles/10.3389/fcvm.2021.778674/full#B1
https://pubmed.ncbi.nlm.nih.gov/27071935/
https://pubmed.ncbi.nlm.nih.gov/36939886/#:~:text=Forkhead%20box%20O3%20is%20a,disease%2C%20glioblastoma%2C%20and%20stroke.
https://www.sciencedirect.com/topics/medicine-and-dentistry/oxidative-stress
https://www.sciencedirect.com/topics/neuroscience/foxo3
