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.

Comments

Navitoclax' main side effect seems to be thrombocytopenia

so if you took it for a short time, seems like you could recover from that.

Input/thoughts on the risks of a healthy person taking this drug for a short time?

Posted by: Phoebus at September 24th, 2018 4:41 PM

@Pheobus: Dasatinib will murder a bunch of immune cells as well. If you're young loss of 30% of any given population of immune cells is a lark and you'll get it back in a few days. That happens after three days of fasting, for example. If you are much older then that side-effect increasingly becomes a matter to think about carefully, and with reference to a physician.

See this report for an example of losing 25-50% of different immune cells during short term senolytic treatment, with no ill effects.

https://www.fightaging.org/archives/2018/02/reporting-on-an-attempted-study-of-one-with-candidate-senolytic-pharmaceuticals/

The subject there isn't old, of course. The challenge with age is frailty, in that many things that a younger person can just waltz through might turn into a risky proposition. That said, studies of dasatinib and quercetin in 65+ year old people are ongoing. At the end of the day, one has to make an informed decision on risk for oneself, and not take the word of others.

Posted by: Reason at September 24th, 2018 5:31 PM

Reason,
Do you happen to have links to those studies in humans 65+ .( I might not be ready for an extreme self experimentation but my parents are 70-75 plus, and I am over the hill, but probably not that old to see drastic improvements.)

For the older people, probably , a gradual increase in the dose and slowly training the body over several sessions to tolerate better the medication could reduce the risks. And probably , the immune cells to die first are already, if not outright cenessent , definitely subprime...

Posted by: Cuberat at September 24th, 2018 6:25 PM

Btw, I am skeptical of the mouse model of AD, since it takes 2 or 3 decades to develop in humans.. senolitics can reduce the inflammation and that should help with AD a lot, but I am afraid that that's not the whole story.

Posted by: Cuberat at September 24th, 2018 6:28 PM

@Cuberat: Nothing interesting is published yet. The Betterhumans trial ( http://betterhumans.com/projects.html ) has been going for a while and results should be published later this year or early next.

Posted by: Reason at September 24th, 2018 8:47 PM

We are living in interesting times indeed. If the senolitics work, then we have a good shot at reaching the LEV. And from a personal point of view that could be the most important development...

Posted by: Cuberat at September 24th, 2018 9:21 PM

Given the already enormous cost to society of Alzheimer's, they need to get this into clinical trials ASAP.

On the other hand, it is well known that mouse models of Alzheimer's are fairly useless.

Posted by: Jim at September 25th, 2018 6:00 AM

@Jim
And since AD is worse than a death sentence I would rather experiment with a possible cure or die trying, than rather bestow this tall to my relatives to see me slowly degrade to oblivion....

Posted by: Cuberat at September 25th, 2018 7:38 AM

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