Clearing Senescent Cells from the Brain Reduces Tau Aggregation and Improves Function in Mouse Models of Alzheimer's Disease

Over the past few years researchers have demonstrated, numerous times, that using senolytic therapies to remove a significant fraction of senescent cells from old tissues in mice can reverse aspects of aging, successfully treat multiple age-related diseases that presently have no viable treatment options, and extend healthy life. In an exciting recent addition to this field of research, scientists used the dasatinib and quercetin combination in mouse models of Alzheimer's disease. The result is a restoration of function and a reduction of the characteristic tau aggregation that is a feature of this condition. The researchers in fact report that there is a two-way relationship between tau aggregation and cellular senescence: targeting either one reduces the other.

Even allowing for the fact that mouse models of Alzheimer's are highly artificial, as no such analogous condition naturally occurs in that species, this might be taken as good evidence for senescent cell accumulation to provide a meaningful contribution to neurodegeneration. Further, I think it important to note that the particular senolytics used here are very cheap. Dasatinib is a generic drug with years of human usage data resulting from the treatment of cancer, and can be obtained for $100-200 per senolytic dose from some sources. Add an equal amount to pay for validation of the identity of the ordered compound via mass spectroscopy. One dose every few years will probably be optimal for this class of drug; more frequent dosing likely wouldn't help much. These economics mean that self-experimentation with senolytics continues to look ever more like an interesting option, at least for those people willing to carefully think about the trade-off between risk and benefit, and accept responsibility for their actions.

In this context, here is an interesting question: given a working, first generation rejuvenation therapy that targets a fundamental cause of aging and is piling up considerable evidence for impressive across-the-board benefits in diseases of aging in animal studies, how long will it take the tens of millions of older people who could easily obtain and use dasatinib and quercetin to actually start obtaining and using these compounds in large numbers? I feel that the basis for some form of revolutionary change in the relationship between regulators and regulated is brewing. FDA functionaries are unlikely to allow widespread off-label use of dasatinib without a fight, but can any authority really stop a cheap, mass-produced compound from being widely available? History suggests no.

Stressed, toxic, zombie cells seen for 1st time in Alzheimer's

Cellular senescence is associated with harmful tau protein tangles that are a hallmark of 20 human brain diseases, including Alzheimer's and traumatic brain injury. Researchers have identified senescent cells in postmortem brain tissue from Alzheimer's patients and then found them in postmortem tissue from another brain disease, progressive supranuclear palsy. "When cells enter this stage, they change their genetic programming and become pro-inflammatory and toxic. Their existence means the death of surrounding tissue."

The team confirmed the discovery in four types of mice that model Alzheimer's disease. The researchers then used a combination of drugs to clear senescent cells from the brains of middle-aged Alzheimer's mice. The drugs are dasatinib, a chemotherapy medication that is U.S. Food and Drug Administration-approved to treat leukemia, and quercetin, a natural flavonoid compound found in fruits, vegetables, and some beverages such as tea.

After three months of treatment, the findings were exciting. "The mice were 20 months old and had advanced brain disease when we started the therapy. After clearing the senescent cells, we saw improvements in brain structure and function. This was observed on brain MRI studies and postmortem histology studies of cell structure. The treatment seems to have stopped the disease in its tracks. The fact we were able to treat very old mice and see improvement gives us hope that this treatment might work in human patients even after they exhibit symptoms of a brain disease."

In Alzheimer's disease, patient brain tissue accumulates tau protein tangles as well as another protein deposit called amyloid beta plaques. The team found that tau accumulation was responsible for cell senescence. Researchers compared Alzheimer's mice that had only tau tangles with mice that had only amyloid beta plaques. Senescence was identified only in the mice with tau tangles. In other studies to confirm this, reducing tau genetically also reduced senescence. The reverse also held true. Increasing tau genetically increased senescence. Importantly, the drug combination reduced not only cell senescence but also tau tangles in the Alzheimer's mice. This is a drug treatment that does not specifically target tau, but it effectively reduced the tangle pathology.

Tau protein aggregation is associated with cellular senescence in the brain

Tau protein accumulation is the most common pathology among degenerative brain diseases, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), traumatic brain injury (TBI) and over twenty others. Tau-containing neurofibrillary tangle (NFT) accumulation is the closest correlate with cognitive decline and cell loss, yet mechanisms mediating tau toxicity are poorly understood. NFT formation does not induce apoptosis, which suggests secondary mechanisms are driving toxicity. Transcriptomic analyses of NFT-containing neurons microdissected from postmortem AD brain revealed an expression profile consistent with cellular senescence. This complex stress response induces aberrant cell cycle activity, adaptations to maintain survival, cellular remodeling, and metabolic dysfunction.

Using four AD transgenic mouse models, we found that NFTs, but not amyloid-β plaques, display a senescence-like phenotype. Cdkn2a transcript level, a hallmark measure of senescence, directly correlated with brain atrophy and NFT burden in mice. This relationship extended to postmortem brain tissue from humans with PSP to indicate a phenomenon common to tau toxicity. Tau transgenic mice with late stage pathology were treated with senolytics to remove senescent cells. Despite the advanced age and disease progression, MRI brain imaging and histopathological analyses indicated a reduction in total NFT density, neuron loss, and ventricular enlargement. Collectively, these findings indicate a strong association between the presence of NFTs and cellular senescence in the brain, which contributes to neurodegeneration. Given the prevalence of tau protein deposition among neurodegenerative diseases, these findings have broad implications for understanding, and potentially treating, dozens of brain diseases.

Comments

Here is a question, what do senolytic treated animal models actually die from?

Posted by: Chris at August 23rd, 2018 2:12 PM

The autopsy proved that the subjects' dead was caused by the autopsy ...

On a more serous note, sensecent cells are only one of the many factors and even their cleanup is probably very incomplete and inefficient, so there are plenty morbidity causes.

Posted by: cuberat at August 23rd, 2018 2:51 PM

Hi Reason,
>Further, I think it important to note that the particular senolytics used here are very cheap. Dasatinib is a generic drug with years of human usage data resulting from the treatment of cancer, and can be obtained for $100-200 per senolytic dose from some sources. Add an equal amount to pay for validation of the identity of the ordered compound via mass spectroscopy.

I didn't try to do the whole chain and there might be quite a few surprised, but on Alibaba you can find offers for medical grade dasatinib, certified only for animal use, for less than a thousand dollars per KILO gram. So lab testing, shopping & handling , dose distribution, proper disposal and such are should be a higher cost than the chemical alone. The rest is royalties, markups and regulatory fees. Once the patents expire, in 2-4 years , the cost per dose shuold be a few dollars for a mass market medicine.

Actually it is perfectly feasible to obtain a few hundred doses worth of dasatinib and do an animal research, say in old dogs with volunteering owners. This probably would be ok with FDA, as long as there is an effort to pervert human use and no commercial enterprise...

Larger dogs are closer to the humans than the mice. And we, probably, have millions of old dogs in North America. I am not sure how that could work with the animal ethic approvals, but sounds pretty feasible. Actually, the chemical cost will be dwarfed by the human effort...

Posted by: Cuberat at August 23rd, 2018 6:51 PM

Remember, dasatinib is a chemotherapeutic so will kill stem sells as well.

Posted by: Ariel at August 24th, 2018 8:14 AM

The mice were treated with Dasatanib & Querecetin for 3 months, or they checked the results after three months?

Posted by: bmack500 at August 24th, 2018 8:44 AM

@bmack500 From the open access paper: "Control and auNFTMapt0/0 mice aged 19-20 months were randomized to receive DQ senolytic (5mg/kg dasatinib with 50mg/kg quercetin) or vehicle via oral gavage. Mice were weighed and fasted for 2 hours prior to treatment. One month after the first treatment, senolytic or vehicle gavage continued on a bi-weekly basis for a total of six treatment sessions over twelve weeks. Within two weeks of the final treatment, all mice underwent MRI analyses."

Which is more dasatinib and quercetin than earlier single-dose studies. It would be interesting to know whether and why they thought that extended dosing necessary.

Posted by: Reason at August 24th, 2018 10:58 AM

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