Evidence for Earlier Life Use of Some Senolytics to be Detrimental in Female Mice
Senescent cell accumulation is an important contributing cause of aging. Senescent cells secrete a mix of signals that provokes growth and inflammation, useful in the short term in circumstances such as wound healing and cancer suppression, but damaging to tissue function and health when sustained over the long term. Senolytic drugs that can selectively destroy senescent cells have produced impressive displays of rejuvenation when used in aged mice. Some are in human trials, while many others are in development.
The most studied of present senolytic treatments are navitoclax, the dasatinib and quercetin combination, and fisetin, a mix of small molecule chemotherapeutics and plant extract supplements. Navitoclax has side-effects that make it undesirable. Administration of dasatinib and qercetin is the most proven of senolytic therapies, with data in human patients showing a similar reduction in senescent cells to that observed in mice. Fisetin is undergoing human trials, but results have yet to be reported.
Researchers here report on a study of earlier life intermittent administration of dasatinib and quercetin, and fisetin: monthly administration from 4 months to 13 months of age in mice. Mouse age does not correspond linearly to human age, if going by the usual exterior manifestations of aging. A 3 month old mouse is equivalent to a mid-20s human. A 12 month old mouse is equivalent to a 60 year old human. A 24 month old mouse is equivalent to a 70 year old human. The results here suggest that earlier life administration of current senolytics can have long term downsides that vary by gender and treatment, at least at the frequency used here.
This caution is aimed at those who would like to use senolytic therapies as a preventative approach to aging, starting earlier to stop the senescent cell burden from increasing at all - or at least to slow its progession considerably. To do so, senolytic therapies with better side-effect profiles are needed. Highly targeted small molecule approaches such as the prodrugs that only take effect in cells expressing high levels of β-galactosidase are one possible path towards achieving this goal.
Fisetin and quercetin (Q) are plant-derived flavonoids that offer cytoprotection against cellular stress and act as anti-inflammatory, chemopreventive, chemotherapeutic, and senotherapeutic agents. Dasatinib (D) is a tyrosine kinase inhibitor used to treat leukemia and is routinely used in combination with Q to improve the senotherapeutic potency. Fisetin and D+Q selectively clear senescent cells, thereby delaying aging-associated disorders and improving healthspan and lifespan. This has been observed after reducing senescent cell burden in progeroid mice or in 22-24 month old C57BL/6 mice. Moreover, deletion of senescent cells from the brain genetically or pharmacologically with senolytic drugs led to functional improvements in mouse models of neurodegenerative diseases such as Parkinson's and Alzheimer's=. These studies have shown senolytics can reduce senescent cell burden and have positive impacts on animals with accelerated aging, advanced age, or neurodegenerative disorders. Accordingly, senotherapeutics are currently marketed as anti-aging therapies where young, healthy adults can take these products as dietary supplements.
However, less is known regarding their anti-aging effects of these compounds when administered prior to significant senescent cell accumulation. Thus, the experiments were designed to examine the long-term effects of monthly oral treatment with Fisetin or a D+Q cocktail when administered to C57BL/6 mice starting at 4 months age. Since aging alters numerous biological functions, we examined morphological, metabolic, and cognitive components that are known to be affected by senescent cell accumulation. The results presented here indicate that monthly administration of Fisetin or D+Q had sexually dimorphic effects which also depended on treatment type in C57BL/6 mice.
Our study indicates that both age and sex may also determine the therapeutic outcomes of senolytic treatment. When the treatment was started at 4 months of age, before the reported senescent cell accumulation, Fisetin had beneficial effects in male mice while a D+Q cocktail had adverse consequences in female mice. Fisetin treated male mice had reduced senescence-associated secretory phenotype (SASP), enhanced glucose and energy metabolism, improved cognitive performance, and increased hippocampal expression of adiponectin 1 receptor and glucose transporter 4. D+Q treated females had increased SASP expression along with accumulation of white adipose tissue, reduced energy metabolism, and cognitive performance.
These observations provide novel information with translational relevance. First, senolytic drugs can be taken at an age before significant senescent cell burden to reduce or prevent their prevalence later in life. Second, males and females have differential responses to the same senolytic treatment when initiated at younger ages. Third, a particular senolytic treatment may have beneficial, negligible or detrimental effects depending on the age, sex, or disease. These observations should serve as a note of caution in this rapidly evolving and expanding field of investigation.
Hmm... I would have expected that it does not matter if fisetin or D+Q is used to kill senescent cells. According to the sutdy: 'Fisetin and D+Q selectively clear senescent cells'.
The fact that it does matter and also allegedly has a gender specific component hints that it's not (only) senescent cell clearance that causes significant changes.
My first thought when I read the summary was: 'That's completely absurd.' After reading the study I still think it is.
Wow, good to know. I'm 35, and was considering taking fisetin in large doses to "get a head start" on clearing senescent cells. After reading this, I think I'll wait a while...
It DOES seem unusual that there would be different reactions depending on gender...
@GREGORY S SCHULTE
35 is still quite young. Under normal circumstances you don't have that much ScC at this age. I am 45, and apart of some tendon and back pain i dind't see much improvement after taking fisetin.
So if you are young, don't have radiation,chemical, or other carcinogenic exposure nor you have a genetic disorder I see no benefit of taking senolytics. Not yet. not you. At least not until we have generation II-III senolytic therapies with conclusive human trials.
Anyone have any thoughts of most effective ways to reduce senescent cells at this point, fasting or fisetin?
Perhaps this is related?
https://www.nature.com/articles/s42255-021-00481-w
Sex-specific genetic regulation of adipose mitochondria and metabolic syndrome by Ndufv2
@Cuberat
What dosage did you use with fisetin? How did you get it? Would you recomend it to people 70 years old? Which is better, fisetin or D + Q?
Thanks!
@Josep
Here is some info, in the comments, about people taking fisetin:
https://www.fightaging.org/archives/2021/09/long-term-weekly-dosage-of-senolytic-dasatinib-and-quercetin-reduces-disc-degeneration-in-mice/#comments
Reason also has a post somewhere about taking D + Q... but it's pretty compicated/expensive/maybeDangerous
The Fisetin, at least from people I've actually heard on this site say "yes, i did that.." seems more tested.
Honestly, despite Reason's very well drawn out plans to take D + Q if you wanted to, I haven't heard of ANYONE who's actually done this.
@gregory
thanks!
@Josep
Here on FA there was a human equivalent to be about 20mg per kg human weight. I rounded it up and a bit more. The fisetin powder i have is 50% fisetin. I chose to have a tablespoon with a bit of top.
One problem is that flavonoids have poor water solubility. Alcohol is only 4 times better. You can mix the fisetin powder with olive oil and vodka. It goes in a bit smoother, but I doubt it improves the solubility much.
If using different solvents like DMSO you might dissolve it completely and get much more potent action. So there the quantity has to be reduced. Also small quantities can be easily digested, while the larger ones probably mostly just pass trough.
I got my fisetin from pure bulk. https://purebulk.com/products/fisetin-50 . It is reasonably priced and they have different supplements.
I didn't get Dasatinib ( I have ordered a bag of quercetine , which is quite cheap, though) since it is expensive, would require being quite creative with the doctors you know and on top it has side effects too. So for now, I am too young to die, I mean to try D+Q :)
For the 70 years old people, for sure( like 3 sigma confidence ) they have a high ScC load. So removing /reducing those would be beneficial, at least according to the bleeding edge animal studies. However, being old makes you frail and every treatment and intervention becomes more dangerous. A side effect that even a 65 years old could brush away might easily kill somebody at 75. And we have no conclusive human studies. So somebody over 65 could consider senolytics. The problem is that the older you are the less you can afford to ignore your doctors recommendations and no sane doctor would recommend an untested treatment without serious reasons.
So the usual disclaimer applies. (this is no tax,investment,medical, blah-blah advise) . I am not an a medical doctor(not even a phd in drama studies), i don't work for any medical institution, and for sure, my employer would't approve me (publicly?) advising such things.
@GREGORY S SCHULTE
To make such an undertaking one should be able to do a good lab testing too. Otherwise all will be just a fancy entertainment and placebo.
For example, unless you get a prescription D. You would need to be sure it is the real thing. Then you need to do blood work and other tests. And ideally have to do double blind study. All this requires money, dedication and, possibly a pact of like-minded people.
I guess it would be a smaller bar to pass with a grass root study for dogs. Ordering D+Q from a chinese lab over alibaba for old dogs would be easier. There might be some hurdles with ethical commissions and PETA and paperwork. If you are connected to a veterinary clinic and a university , probably they might do the paperwork if you supply the materials and recruit dog owners. Probably the whole study can be done for under 100K.
@cuberat
thanks!
I can comment on some of this information on an anecdotal level. 34yo female, taking a weekly senolytic combo (D+Q+Fisetin) on Sundays, plus daily resveratrol with a micro dose Fisetin. Started about 2 years ago? I've noticed I don't get aches and pains after pushing it, and I am not stiff in the mornings after lifting weights, no joints popping or wrinkles at my eyes... for all intents, I haven't felt any aging. But my energy levels are curious. Good strength, good stamina, but... slow? I can spend hours and hours doing hard labor, as long as I pace myself. Maybe a better way of saying it is that I simply can't go hard at anything, but I can go all day. The metabolic effects noted on female mice seem like they may be related to what's happening with my system. Hmm. Very loose connection, but now I have a jumping point for more reading.