Clearance of Senescent Cells is a Promising Approach to the Treatment of Alzheimer's Disease

Today's open access review discusses the growing burden of cellular senescence with age in the context of brain tissue and neurodegenerative disease. Cells become senescent constantly throughout life, largely the result of ordinary somatic cells hitting the Hayflick limit on replication, but also, and increasingly with age, due to a stressful, damaging, inflammatory environment. Senescent cells serve a useful purpose when present for the short term, in the context of wound healing or cancer suppression for example, by rousing the immune system into action and changing the behavior of nearby cells. But the signaling of senescent cells becomes very harmful to tissue function when sustained for the long term.

Unfortunately, this long term inflammatory signaling by senescent cells is exactly what happens in later life. The pace of creation picks up and the pace of clearance of senescent cells, via programmed cell death or via immune system activities, declines. The result is a growing imbalance and increased burden of senescent cells in tissues throughout the body. In recent years ever more evidence points to a meaningful role for senescent cells in the brain, particularly microglia and astrocytes. Chronic inflammation in brain tissue is strongly implicated in the progression of neurodegenerative conditions, and it is becoming clear that senescent cells are likely a major contributing cause of that inflammation.

Clearance of senescent cells using first generation senolytic therapies, at least those capable of passing the blood-brain barrier to enter the brain, has shown promising results in animal models of Alzheimer's disease, and a clinical trial of the same therapeutics in Alzheimer's patients is getting underway. It will be some years before we know in certainty that senolytic treatments are a good approach to Alzheimer's disease, but it seems plausible.

Aging, Cellular Senescence, and Alzheimer's Disease

Alzheimer's disease (AD) is an aging-related neurodegenerative disease and a major cause of dementia in the elderly. It is estimated that the incidence of AD doubles every 5 years after age 65, and 50% of the population aged 85 or older suffer from AD. Therefore, aging is considered the greatest risk factor for AD, although the mechanism underlying the aging-related susceptibility to AD is unknown. Evidence from both human and animal studies indicates that cellular senescence plays a critical role in the development of many aging-related diseases, including AD.

Senile plaques, which are extracellular deposits of β-amyloid (Aβ) peptides, and neurofibrillary tangles (NFTs), which are intracellular accumulation/deposition of hyperphosphorylated tau proteins, are two neuropathological features of AD. Although it is still debatable whether and how Aβ and hyperphosphorylated tau lead to neurodegeneration, a foundation of memory loss in AD, accumulating evidence indicates that both Aβ and tau pathologies are potent inducers of cellular senescence.

Senescent cells have been detected in the brain of AD patients and AD model mice that overexpress Aβ or tau protein. Removal of senescent cells pharmacologically and genetically reduced brain Aβ load and tauopathy and improved memory in these AD model mice. These data strongly suggest that cell senescence mediates Aβ- and tauopathy-induced neuropathophysiology in AD. These data also suggest that cell senescence promotes Aβ and tau pathologies. Elucidation of the mechanisms underlying brain cell senescence during aging and in AD, as well as the mechanism by which senescent cells contribute to neurodegeneration in AD, will be key to the development of strategies for the prevention and treatment of this devastating disease.


Does anybody know when will the results of the Mayo Clinic clinical trial on Dasatinib + Quercitin be released?


Posted by: Josep at March 11th, 2022 5:34 AM

Liposomes/exosomes loaded with fisetin probably just as effective as anything that pharma can come up with, at least in this generation of drugs.

Also, vastly cheaper. Fisetin is produced from Japanese knotweed.

Posted by: JLH at March 14th, 2022 4:45 AM
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