Replicative Senescence of Microglia as an Important Contributing Cause of Alzheimer's Disease

Somatic cells become senescent after reaching the Hayflick limit on replication. In the case of immune cells, that occurs more often in scenarios of infection or tissue damage that provoke an immune response and hence faster pace of replication. The central nervous system immune cells known as microglia are known to exhibit senescence in later life and neurodegenerative conditions, and the targeted elimination of these cells via senolytic therapies has been shown to reverse symptoms in animal models of these conditions.

Senescent cells secrete a mix of signals that produces chronic inflammation and disrupts tissue function; their presence is an important contributing cause of many age-related declines. Researchers here propose that replicative senescence of microglia is the connects forms of molecular damage and infection linked to Alzheimer's disease and the presence of senescent microglia that accelerate the condition. In other words that the immune response and increased pace of replication of microglia is an important factor in neurodegeneration.

The re-activation of microglial proliferative programs is the earliest response to pre-pathological events in chronic neurodegenerative diseases, with microglial proliferation increased in Alzheimer's disease (AD). Microglia have a very rapid proliferative response to the incipient accumulation of amyloid-β, during the onset of tau pathology, and in several other related models of neurodegeneration. We and others have demonstrated that the proliferation of microglia is a central contributor to disease progression. The inhibition of microglial proliferation, using CSF1R inhibitors, ameliorates amyloid and tau pathology, and has emerged as a promising target for clinical investigation.

Integrating our knowledge of microglial population dynamics renders an interesting hypothesis. When combined, the cycling events accumulated in microglia from development to disease would put these cells on a trajectory toward cellular senescence. Replicative senescence, the loss of mitotic potential accompanied by significant telomere shortening, occurs once a cell has undergone ∼50 replications, the so-called Hayflick limit. Thus, we hypothesized that the developmental setup of the population, combined with microglial turnover, would pre-condition these cells to undergo replicative senescence when challenged with additional proliferative events (i.e., as a consequence of brain pathology).

Some reports suggest that microglia show telomere shortening and decreased telomerase activity in both aging and end-stage AD. However, to date, no formal evidence has been provided supporting the idea that these progressive changes in the dynamics of microglia are driving the shift of the microglial response from beneficial to detrimental and therefore contributing to the initiation of AD.

Here, we provide evidence that microglia undergo replicative senescence in a model of AD-like pathology and in human AD. We demonstrate that microglia display a senescence-associated profile and that this is dependent on proliferation. Our data support that the early generation of senescent microglia contributes to the subsequent onset and progression of amyloidosis, as well as the associated neuritic damage that is observed in the early stages of AD.



I am interested in researchers and organizations who focus specifically on brain rejuvenation and the aging brain. It's likely to be the hardest organ to truly rejuvenate, and the one most central to our survival as functioning individuals with an unbroken identity... I have just run across a Stanford Brain Rejuvenation Project; are there others I should know about?

Posted by: Mitchell Porter at June 16th, 2021 8:53 PM

@Mitchell Porter .. Dr Dale Bredesen is reversing Alzheimer's Disease. in patients with full blown Alzheimer's. There are numerous intervues with him online. I recently watched a presentation that he did at the Cleveland Clinic. It's on youtube.I am rejuvenation my own brain through fasting (5 days per month), eating a whole food plant based diet with some fish, exercise, meditation, and several supplements. The results have been far better than I could have imagined. I'm thinking that the brain may be the easiest organ to rejuvenate with the right protocol.

Posted by: Chuck at June 20th, 2021 4:42 PM
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