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.

Comments

Antonio,

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.

Robert

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

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