It is exciting to see animal data arrive for some of the potentially senolytic compounds that may turn out to destroy enough senescent cells in mammals to be worth using as first generation rejuvenation therapies. As a reminder, the accumulation of senescent cells is one of the causes of aging; countless cells become senescent every day in our bodies, but near all are destroyed. A tiny fraction linger to cause significant harm through the inflammatory signal molecules that they secrete. If these errant cells can be removed, then inflammatory diseases and numerous aspects of aging can be turned back to some degree. The results in mice stand head and shoulders above all of the other approaches to aging in terms of reliability and breadth of benefits.
Some senolytic compounds have been tested in animals, but a larger body of candidate senolytic drugs are presently only accompanied by cell study data. The ability to selectively destroy senescent cells in a petri dish does little more than indicate potential; there is a significant rate of failure in medical research and development for compounds with promising cell data, and any number of reasons as to why they may not work well enough in tissues or otherwise turn out to be infeasible for use in animals and humans. Fisetin was one such senolytic candidate with cell study data only, and I had not viewed it as a likely prospect. It is a flavonoid, and the one other well-known possibly senolytic flavonoid turned out not to be useful on its own - though it is helpful as a part of a combination treatment.
Given that, results from the recent animal study of fisetin noted here greatly exceed expectations, surprisingly so. Fisetin appears about as effective in mice as any of the current top senolytics, such as the chemotherapeutics dasatinib and navitoclax. Per the data in the open access paper below, dosing with fisetin destroys 25-50% of senescent cells depending on organ and method of measurement. The dose level is large in absolute terms, as one might expect for a flavonoid. For aged mice and a one-time treatment, the researchers used 100 mg/kg daily for five days. The usual approach to scale up estimated doses from mouse studies to initial human trials leads to 500 mg per day for five days for a 60kg human.
Given the wealth of new results emerging these days, it seems to me that people focused on self-experimentation, open human trials, and investigative mouse studies in this field should be moving to focus on combination therapies. Consider a combination of fisetin, dasatinib, quercetin, piperlongumine, and FOXO4-DRI - multiple different mechanisms to provoke apoptosis that are all hitting senescent cells at the same time. The goal would be to see if it is possible to engineer a significantly higher level of clearance of senescent cells than any of these senolytics can achieve on their own. This seems like a plausible goal, and may turn out to present meaningful competition to efforts such as those of Oisin Biotechnologies and other groups developing more sophisticated senolytic therapies that should have high rates of clearance.
As people age, they accumulate damaged cells. When the cells get to a certain level of damage they go through an aging process of their own, called cellular senescence. The cells also release inflammatory factors that tell the immune system to clear those damaged cells. A younger person's immune system is healthy and is able to clear the damaged cells. But as people age, they aren't cleared as effectively. Thus they begin to accumulate, cause low-level inflammation and release enzymes that can degrade the tissue.
Researchers found a natural product, called fisetin, reduces the level of these damaged cells in the body. They found this by treating mice towards the end of life with this compound and see improvement in health and lifespan. "These results suggest that we can extend the period of health, termed healthspan, even towards the end of life. But there are still many questions to address, including the right dosage, for example." One question they can now answer, however, is why haven't they done this before? There were always key limitations when it came to figuring out how a drug will act on different tissues, different cells in an aging body. Researchers didn't have a way to identify if a treatment was actually attacking the particular cells that are senescent, until now.
A panel of flavonoid polyphenols was screened for senolytic activity using senescent murine and human fibroblasts, driven by oxidative and genotoxic stress, respectively. The top senotherapeutic flavonoid was tested in mice modeling a progeroid syndrome carrying a p16INK4a-luciferase reporter and aged wild-type mice to determine the effects of fisetin on senescence markers, age-related histopathology, disease markers, health span and lifespan. Human adipose tissue explants were used to determine if results translated.
Of the 10 flavonoids tested, fisetin was the most potent senolytic. Acute or intermittent treatment of progeroid and old mice with fisetin reduced senescence markers in multiple tissues, consistent with a hit-and-run senolytic mechanism. Fisetin reduced senescence in a subset of cells in murine and human adipose tissue, demonstrating cell-type specificity. Administration of fisetin to wild-type mice late in life restored tissue homeostasis, reduced age-related pathology, and extended median and maximum lifespan.