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Clearing Senescent Cells Reduces Tau Aggregation and Cognitive Loss in Mouse Models of Alzheimer's Disease

Researchers have once again demonstrated that a senolytic therapy capable of selectively destroying senescent cells can reduce tau aggregation and consequent loss of cognitive function in a mouse model of Alzheimer’s disease. The research materials noted below report on the use of navitoclax, also known as ABT-263, in mice and follow very closely on the heels of two other studies that produced very similar results using different senolytic treatments, piperlongumine in one study and the dasatinib / quercetin combination in the other. This is very characteristic of research into the removal of senescent cells: any approach that succeeds in destroying a significant fraction of senescent cells produces significant gains in health; there is no shortage of different approaches; the treatments employed cost very little and are easily purchased in the global marketplace; and researchers can readily replicate the findings of other groups. This a very robust intervention in the aging process, producing data that is far more consistent than any other approach I am aware of.

Why does the removal of senescent cells work so well? Firstly, there are few of these cells, perhaps a few percent by number in aged tissues, so selective destruction is not particularly disruptive. It leaves little debris to clean up, and the few lost cells can be rapidly replaced. Secondly, these few senescent cells produce produce sizable harm through the continuous secretion of inflammatory and other harmful signals. A large fraction of that harm is in effect an altered, degraded state of tissue function that is actively maintained via signaling. The moment that this unwanted signaling is cut back, the environment shifts back to a more youthful, less inflammatory, less disrupted state. Regenerative capacity picks up, and many other forms of cellular function improve. This change is rapid. Near any age-related inflammatory condition is mostly likely significantly driven by the accumulation of senescent cells, whether that is arthritis, fibrosis, or Alzheimer’s disease. In animal models, removal of senescent cells has been demonstrated to reverse measures of aging in numerous diseases and near all major organs.

It is interesting to compare dosing strategies between the three studies that demonstrated reductions in tau aggregation and cognitive decline. They are illustrative of the behavior of different classes of senolytic drugs, as each of navitoclax, piperlongumine, and the dasatinib / quercetin combination use different mechanisms to kill senescent cells. The navitoclax study here used long-term intermittent administration, five days on and sixteen days off over the full lifetime of the mice. The piperlongumine study used a daily dose over eight weeks. The dastinib study used a bi-weekly schedule of administration over twelve weeks. This is consistent with other data from studies using these compounds, in which dasatinib appears to require far less frequent dosing to achieve more or less the same outcome.

Zombie cells found in brains of mice prior to cognitive loss

Zombie cells are the ones that can’t die but are equally unable to perform the functions of a normal cell. These zombie, or senescent, cells are implicated in a number of age-related diseases. In a mouse model of brain disease, scientists report that senescent cells accumulate in certain brain cells prior to cognitive loss. By preventing the accumulation of these cells, they were able to diminish tau protein aggregation, neuronal death, and memory loss.

In the current study, the team used a model that imitates aspects of Alzheimer’s disease. “We used a mouse model that produces sticky, cobweb like tangles of tau protein in neurons and has genetic modifications to allow for senescent cell elimination. When senescent cells were removed, we found that the diseased animals retained the ability to form memories, eliminated signs of inflammation, did not develop neurofibrillary tangles, and had maintained normal brain mass.” They also report that pharmacological intervention to remove senescent cells modulated the clumping of tau proteins.

“Two different brain cell types called microglia and astrocytes were found to be senescent when we looked at brain tissue under the microscope. These cells are important supporters of neuronal health and signaling, so it makes sense that senescence in either would negatively impact neuron health. We had no idea whether senescent cells actively contributed to disease pathology in the brain, and to find that it’s the astrocytes and microglia that are prone to senescence is somewhat of a surprise.”

Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline

Cellular senescence, which is characterized by an irreversible cell-cycle arrest accompanied by a distinctive secretory phenotype, can be induced through various intracellular and extracellular factors. Senescent cells that express the cell cycle inhibitory protein p16INK4A have been found to actively drive naturally occurring age-related tissue deterioration and contribute to several diseases associated with ageing, including atherosclerosis and osteoarthritis. Various markers of senescence have been observed in patients with neurodegenerative diseases; however, a role for senescent cells in the aetiology of these pathologies is unknown.

Here we show a causal link between the accumulation of senescent cells and cognition-associated neuronal loss. We found that the a mouse model of tau-dependent neurodegenerative disease accumulates p16INK4A-positive senescent astrocytes and microglia. Clearance of these cells as they arise using INK-ATTAC transgenic mice prevents gliosis, hyperphosphorylation of both soluble and insoluble tau leading to neurofibrillary tangle deposition, and degeneration of cortical and hippocampal neurons, thus preserving cognitive function. Pharmacological intervention with a first-generation senolytic modulates tau aggregation. Collectively, these results show that senescent cells have a role in the initiation and progression of tau-mediated disease, and suggest that targeting senescent cells may provide a therapeutic avenue for the treatment of these pathologies.

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