“The growing number of physiological roles of senescent cells raises challenges concerning the development of senolytics and other senotherapeutics that target them. Perhaps removing certain types of senescent cells in some tissues is beneficial, whereas removing other types of senescent cells or too many of them is detrimental.”
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That’s why I prefer senomorphics. They prevent the bad senescent cells from forming but leave the good ones intact.
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I think a lot of senescent cells are stem cells that have got stuck in the process of differentiation. They are actually needed for somatic function, but have insufficient cellular energy (measured in acetyl-CoA levels) to pass through the step of differentiation.
My approach to them is to provide the extra energy to get over that hurdle and/or inhibit HDAC. This seems to work well.
This could be called senomorphic.
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Good senescent cell versus bad? Long term senescent cells versus transient? Intermittently removed long term (SASP) cells versus permanently inhibited Senecent Responce Process(inhibit P16)?
I ask these 3 questions because I’m hoping to highlight a concept (woven through the linked Science Journal article). 1. Removing Senecent cells increase health and life spans. 2. Blocking the Senecence cellular responce decreases health and life spans.
Is this an enigma? No, I don’t think so. The Senescence Cellular Response is a vital immune response initiator. In response to injury or stress (examples, amputation or tumor) surviving, injured, and stressed cells, from the immediate area flip from mitotic to senescent and initiate a well understood immunogenic response. This reminds me of the “see something, say something” security phrase.
The really pertinent questions (mostly answered in mice and partially in Humans) does D+Q(F) Intermittent therapy reduce the Senecent Cell Burden? Yes it does. Does D+Q(F) Intermittent Therapy inhibit The Senescent Cell Response to injury or stress? No, or not enough to be harmful.
I posit that The Senecent Burden is one of the Primary ageing factors and as such it’s “all hands on deck” when it comes to mitigating it. Citrate therapy for Mitochondrial support and decreased senecence? Yes please. Senomorphs like Taurine and Rapa? Yes please. SASP removal with D+Q(F)? Yes please.
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A question about senolytics is whether they actually kill the cells or get them back into the cell cycle so they are no longer senescent.
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@Mouse_wont_die Can you report on your success in this effort? I am waiting for better science and treatments to emerge. Am I wrong?
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Is this your opinion or based on studies?
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I think we have to look in the round at all of the studies.
Inefficient mitochondria and senescent cells seem to be the key drivers of aging. I think that senescence is a bigger issue for Homo Sapiens than Mus Musculus.
Homo Sapiens does a reasonable job of getting rid of inefficient mitochondria and moving them around the body between cells to improve function.
However, this can be improved by taking rapamycin from time to time.
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Opinion based on studies. I think we know from references #2 in the article that @Joseph_Lavelle posted that removing senecent cells (SASP not injured response) has remarkable life extension effects in mice. 24-27%. Not too shabby, this has been repeated and beaten by other studies.
I speak to lots of people and only really get their attention when I reference skin aging, but D+Q(F) reduces senecence in human skin with positive effects.
D+Q(F) therapy removes senececent cells and their markers, systemically, in humans.
I believe that Senecent Cell Burden is a Primary aging model because robust scientific observations, clinical results, and logical analysis lead me to this conclusion.
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Here’s the formula for dose conversion:
Human Equivalent Dose (HED)=Animal Dose×(Animal KmHuman Km)\text{Human Equivalent Dose (HED)} = \text{Animal Dose} \times \left(\frac{\text{Animal Km}}{\text{Human Km}}\right)Human Equivalent Dose (HED)=Animal Dose×(Human KmAnimal Km)
For mice, the Km factor is 3, and for humans, it is 37. Therefore, the conversion factor is:
(337)\left(\frac{3}{37}\right)(373)
Dasatinib
For dasatinib, the mouse dose is 5 mg/kg body mass.
HED of dasatinib=5 mg/kg×(337)\text{HED of dasatinib} = 5 , \text{mg/kg} \times \left(\frac{3}{37}\right)HED of dasatinib=5mg/kg×(373) HED of dasatinib=5×0.081\text{HED of dasatinib} = 5 \times 0.081HED of dasatinib=5×0.081 HED of dasatinib≈0.405 mg/kg\text{HED of dasatinib} \approx 0.405 , \text{mg/kg}HED of dasatinib≈0.405mg/kg
Quercetin
For quercetin, the mouse dose is 50 mg/kg body mass.
HED of quercetin=50 mg/kg×(337)\text{HED of quercetin} = 50 , \text{mg/kg} \times \left(\frac{3}{37}\right)HED of quercetin=50mg/kg×(373) HED of quercetin=50×0.081\text{HED of quercetin} = 50 \times 0.081HED of quercetin=50×0.081 HED of quercetin≈4.05 mg/kg\text{HED of quercetin} \approx 4.05 , \text{mg/kg}HED of quercetin≈4.05mg/kg
Therefore, the equivalent doses for humans would be:
- Dasatinib: approximately 0.405 mg/kg body mass
- Quercetin: approximately 4.05 mg/kg body mass
Therefore, for a male weighing 175 pounds (approximately 79.38 kg) with a BMI of 22, the calculated dosages are:
Dasatinib: approximately 32.15 mg
Quercetin: approximately 321.78 mg
I can’t claim the veracity of this as it comes from Claude, but think it is correct.
Just tell Claude your weight and BMI.
This was my initial query:
“Male C57BL/6 mice were used in a study and given senolytic drugs dasatinib (5 mg/kg body mass) and quercetin (50 mg/kg body mass). What would be the equivalent dose for humans?”
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I see Tailormade Pharmacy has a Quercetin/Dasatinib 400mg/30mg tablet priced at $3.09 per tab.
A nice article about transplantation - age mismatch:
Older organs to younger recipients and the other way around.
Including thoughts about effect of senescent cells or in case of young donors possible rejuvenation of other organs.
apologies for the delayed response on the other thread. it’s been an insanely busy month. will respond there, hopefully this weekend
as someone whose company measures senescence in humans with an analytically- validated assay that took 6 years to develop and has now been performed on over 7000 human samples of people doing all sorts of interventions, there are two things i can say:
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senescence in blood is not physiologically good except for low levels needed for the tumor suppression
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there is no evidence that supplements sold as senolytics decrease senescent cells in blood in humans. that diabetic kidney study from Kirkland collected blood but reported changes in fat and skin. my conclusion is that data in blood was negative. if senescence in blood is unchanged, improving it in a fat pad will not likely give you any functional or certainly longevity benefits
i know we all want senolytics but currently, your best bet is either indirect senolytics (improving immune system function for natural senolytic effect) or preventing senescence by adopting a healthy lifestyle and taking care of your mitochondria (e.g. rapamycin, but senescence prevention is impossible to prove in a human trial)
be safe, everyone
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It is your assessment at this time the Dasatinib / Fisetin done similar to some of the trials, for 3 days (I know they mostly used Quercetin) are likely to yield no benefit in senescent cell burden?
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we have not seen dasatinib/fisetin combo. we see, Q, D+Q, or fisetin. in our experience, clinicians shy away from D, given it’s a cancer drug with unproven safety in healthy individuals
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What do you think of the new SapereX test for senescent cells?
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love it! 
Sapere Bio is the company I lead that developed the test. So clearly, i’m partial. But I used to be a pretty good, careful scientist back in my academic faculty days and we certainly apply that rigor to SapereX and set the bar for analytical and clinical validation where it needs to be and not where it currently is for DTC products on the market
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You had me at “unproven safety record”. Thanks. I’m certainly not that desperate yet. I’m going to the gym now to get rid of some senescent cells the safe way.
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Thanks, just reviewed all your posts. So have you seen anything - from rapamycin to senolytics or other interventions that appear to directly correlate with better SapereX test results?
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This is a medication with a safety record - but agreed unclear in the way often times used as a senolytic - and in healthy individuals.
I was doing a bit more research and found and article here from a few months back - not sure if others have read this. Has me more concerned about use of these agents given that in this limited study it seems like D+Q+F or D+Q might decrease telomere length and might accelerate aging.
The study was far from a diffinitive study - but raises a lot of concerns for me. Have others reviewed this already, and what is everyone’s conclusion on this.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10929829/
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