Chemotherapy Accelerates Age-Related Tauopathy and Cognitive Decline in Mice

It is fair to say that the extended chemotherapy treatment that is provided to cancer patients has the side-effect of accelerating aging. On the one hand, we can look at the epidemiological data to see the reduction in life expectancy and increased risk of age-related disease suffered by cancer survivors who underwent chemotherapy. It is also possible to look at various aging-associated biomarkers and see that they indicate an older biological age in these former patients. With the modern acceptance of senescent cell accumulation as an important cause of aging, it has become clear that the generation of excess senescent cells by chemotherapeutics is most likely the primary cause of accelerated aging in chemotherapy patients.

Lingering senescent cells build up in tissues with age, and secrete a potent mix of inflammatory signals and other harmful molecules that rouse the immune system into chronic inflammation, disrupt tissue structure and function, and cause nearby cells to change their behavior for the worse as well. When treating cancer, forcing cancer cells into senescence is beneficial: they stop replicating, and most self-destruct. Chemotherapy is fairly indiscriminate, however, and adds to the burden of senescence throughout the body. These cells then go on to speed up the development of all of the common age-related diseases via chronic inflammation, fibrosis and other disruptions of tissue regeneration, and other mechanisms. This is better than dying of cancer, but certainly worse than having fewer senescent cells.

Today's open access study is just about the opposite of senolytic therapies to clear senescent glial cells in the brain could reverse neuroinflammation and tau protein aggregation in a mouse model of Alzheimer's disease. The late stages of this condition are marked by neurofibrillary tangles of hyperphosphorylated tau protein, and it seems likely that chronic inflammation, senescence, and dysfunction of other sorts in glial cells are an important mechanism bridging the gap between early accumulation of amyloid-β and later accumulation of tau protein in the progression of Alzheimer's. In the work reported here, researchers used a chemotherapeutic to general more senescent cells in mice, and showed that this accelerated aggregation of tau protein in the brain.

Chemotherapy accelerates age-related development of tauopathy and results in loss of synaptic integrity and cognitive impairment

More than 74% of the 15.5 million cancer survivors in the United States are 60 years old or older. Various reports suggest that 35%-85% of patients treated for cancer suffer from long term reductions in cognitive function, which include attention deficits, decreased executive functioning and multitasking, and decreased memory function. Neuroimaging data obtained in patients treated for cancer indicate that cognitive deficits in these patients are associated with changes in the functional connectome and in structure of the white matter. In at least a subset of cancer survivors, there is evidence for accelerated biological aging.

Aging increases neuronal vulnerability and is associated with buildup of damaged proteins that perturb neuronal circuits. During aging, conformational changes and post-translational modifications of tau protein, such as phosphorylation, result in dissociation of tau from axonal microtubules. These changes in tau lead to missorting and clustering of the protein, a process known as age-related tauopathy. Tauopathy is associated with the synapse loss and neuroinflammation that occur during aging, and is exaggerated in human Alzheimer's disease patients and in animal models of the disease.

Most studies on chemotherapy-induced cognitive impairment have been done in patients undergoing treatment for breast cancer. However, there is accumulating evidence that patients treated with platinum-based compounds for solid tumors including testicular, lung, bladder, and head and neck cancer also frequently develop cognitive deficiencies and structural abnormalities in the brain. Preclinical studies have shown that administration of chemotherapeutic agents, including cisplatin and doxorubicin to mice increases expression of cellular senescence markers. We and others showed that treatment of young adult rats or mice with these chemotherapeutics reduces their performance in cognitive function tasks and induces structural changes in the brain.

We hypothesized that chemotherapy-induced cognitive impairment is associated with accelerated development of tau clustering in the brain as a sign of accelerated aging. We show for the first time that treatment of adult (7-8 month-old) male C57BL/6 mice with cisplatin results in reduced cognitive function and a marked increase in the number of large endogenous tau clusters in the hippocampus when assessed 4 months later. In contrast, we detected only few small tau clusters in the hippocampus of age-matched 11-12 month-old control mice. Our current findings indicate that the chemotherapeutic cisplatin accelerates development of age-related tauopathy, identifying chemotherapy as one of the possible causes for the accelerated aging in cancer patients. Further studies should include additional chemotherapeutics and also investigate ways to prevent the development of tauopathy after chemotherapy in order to mitigate accelerated brain aging in patients treated for cancer.



That definitely seems like something worth watching. More data needed, of course... but anything that can help with degenerative issues, even slightly at this point is certainly welcome

Posted by: Ham at April 11th, 2019 5:35 PM

Slightly off topic, but I just purchased some bottles of "Doctors Best" Fisetin with novusetin.

Does anyone have any thoughts on how long one should take this. I assume no longer than one month per year or even one month (or less) for 2-5 years. My wife is going to Russia and I suggested she gives it to her mo who is 78 years old and is mostly good health but have bad joint problems.

My wife and I plan to also take this for a short time.

Thanks everyone.


Posted by: Robert at April 11th, 2019 10:54 PM

I took 2 courses of Fisetin recently. I took them as a senolytic, not as a supplement. My protocol was as follows:

1,000 mg Fisetin
1,000 mg Quercetin
1/4 teaspoon freshly ground black pepper
1 Tablespoon olive oil (or cooking oil, 1/2 ounce, the same as 1/2 shot of Vodka, as they might say in Russia) [Humor]

I emptied out the pills into a small bowl and dissolved the powder in the oil, also adding the black pepper, and ingested it on an empty stomach. This is all to increase absorption and bioavailability.

I would recommend taking at night, about 2 to 3 hours after supper so your stomach is empty and you can sleep it off if you have joint pain or feel unwell. I also took this for 3 consecutive days, which accounted for 1 bottle of Fisetin (10 pills a day, total quantity of pills was 30).

For the first try I had some joint and bone pain around the third to fifth day approx. and felt just slightly "off" for the whole time. I didn't want to do much. About the 6th day I was feeling fine. I tend to have arthritic or rheumatic symptoms but usually not enough to stop me from basic activities. After about 2 weeks I felt really great and was starting to consider starting an martial arts class or starting Parkour conditioning classes. (Your grandma might want to start a kettle bell class, in Russia...) I mean, my joints and muscles really felt fantastic.

After that I caught a cold from my grandson, and as soon as that was on the way out started the second course. I am just finished with that, but have not had enough time to recover from that, but am feeling fine. I think it takes a week or two to really recover from the course if it is effective. For the second course, I also added about 1,000 mg of curcumin and had a lot more pain than the first time. I wouldn't necessarily recommend that for your grandmother, but I think the Quercetin is good.

I think doing a course and then waiting a month to see the results before doing it again is wise. After the first two courses, from my experience, I would consider doing it again (either 1 or 2 courses) in 6 or 12 months.

I felt that the first course improved my joints and connective tissues around my joints, and also got rid of 80% to 90% of a nagging tendonitis or bursitis in my shoulders (the chiropractor said tendonitis...) I am 67 yrs old and about 77 kg.

I hope that helps.

Posted by: Dan Nave at May 7th, 2019 5:03 PM

Incidentally, my wife also did one course just now. She did not have the curcumin added, just F+Q+P in oil. She did not have any side effects to report and no pains. She does not have any arthritis to speak of, but she has Parkinson's Disease. It is too early to see if there are any beneficial results for her, just no side effects during treatment. Weight approx 72 kg and age 68.

Posted by: Dan Nave at May 7th, 2019 7:44 PM

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.