Non-Dividing Neurons Do In Fact Become Senescent, Impairing Brain Function
Cellular senescence is generally thought of as a characteristic of replicating cells; it is an end state reached when telomeres, reduced in length with each cell division, become too short. This is followed by programmed cell death or destruction by immune cells. When senescent cells linger, as is increasingly the case with age, they contribute to degenerative aging via their pro-growth, pro-inflammatory signaling, disruptive of tissue structure and function. Researchers have suggested that non-dividing, post-mitotic cells such as neurons can also exhibit a form of senescence, and here evidence is provided for this to be the case. Senescence in supporting cells in the brain, such as microglia and astrocytes, is known to contribute to neurodegeneration. If some neurons are also senescent, producing similar harmful signaling, then these cells will also contribute to the aging of the brain.
As cells age, they can undergo cellular senescence, which contributes to tissue dysfunction and age-related disorders. Senescence is also thought to play a role in cellular stress, molecular damage, and cancer initiation. However, scientists previously believed that senescence primarily occurred in dividing cells, not in neurons. Little was known about the senescence-like state of aging human neurons.
In this study, researchers took skin samples from people with Alzheimer's disease and converted those cells directly into neurons in the lab. They tested these neurons to see if they undergo senescence and examined the mechanisms involved in the process. They also explored senescence markers and gene expression of post-mortem brains from 20 people with Alzheimer's disease and matched healthy controls. This allowed the team to confirm that their results from the lab held true in actual human brain tissue.
The team found that senescent neurons are a source of the late-life brain inflammation observed in Alzheimer's disease. As the neurons deteriorate, they release inflammatory factors that trigger a cascade of brain inflammation and cause other brain cells to run haywire. Additionally, the gene KRAS, which is commonly involved in cancer, could activate the senescent response. The consequences of even a small number of senescent neurons in the aging brain could have a significant impact on brain function. This is because a single neuron can make more than 1,000 connections with other neurons, affecting the brain's communication system.
In addition to these findings, the authors also administered a therapeutic (a cocktail of Dasatinib + Quercetin) to the patient neurons in a dish. Both drugs are used to remove senescent cells in the body in conditions such as osteoarthritis, so the authors wanted to see if they were effective in senescent cells in the central nervous system as well. They found that the drug cocktail reduced the number of senescent neurons to normal levels. Targeting senescent cells could thus be a useful approach for slowing neuroinflammation and neurodegeneration in Alzheimer's disease.
We know this and it is a major strike against telomere shortening theories of aging. I suspect the cause is largely mitochondrial.
"largely mitochondrial" and we still don't even know why and how much of this mitochondrial deterioration comes form genetic mutations, epigenetic drift/program, mitochondrial genes damage, lysosomal lipofuscin build up, and other causes.