Senolytics — opportunity and caution

Senolytics
Johnny Adams
http://www.AgingIntervention.org
JAdams@AgingInterventionFoundation.org
(949) 922-9786
https://www.aginginterventionfoundation.org/Senolytics.pdf

Constantly improved. Check for updates with the link above. You may not have the current version.
Last updated March 8 2020 10:35 am.

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Friendly Disclaimer: These are ideas that I use in my own age management program. It’s not my intention to provide specific medical advice, but rather to provide others with information to better understand their health. This is not medical advice including diagnosis and treatment. Always seek the advice of a trained health professional for medical advice, diagnosis or treatment.

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Several GRG members have thoughtfully taken the time to send information about dasatinib, sources, and testing.

This is a serious matter. If misused, senolytics can be dangerous.

READ AND UNDERSTAND EVERYTHING BELOW – AND MUCH MORE – BEFORE YOU PROCEED WITH SENOLYTICS

If you’re not going to take the time to read and understand everything below –
and further educate yourself beyond my inadequate information provided for your benefit here

THEN YOU HAVE NO BUSINESS MESSING WITH SENOLYTICS.

You will benefit from our learning curve, which has been substantial.

Members quotes from submitted messages are attributed to them.

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Definition 

Senescence is the condition or process of deterioration with age. Senescent cells release a variety of factors such as pro-inflammatory cytokines and chemokines, which contribute to the physical dysfunction of tissues and organs during aging. They change cellular behavior for the worse, and destructively remodel the structure of tissues. Programmed cell death (apoptosis) often doesn’t turn on.

Senolytic therapy is an emerging aging intervention therapy. Senolytic drugs and over the counter compounds are intended to specifically target and eliminate senescent cells. It appears senescent cells are necessarily the ONLY targets of senolytics.

In animal studies eliminating senescent cells improved some physical dysfunctions and increased the healthy life span of mice, even the elderly mice. In mice, senolytic therapies have been shown to slow the progression of numerous age-related diseases.

Research in humans is underway, and results from early human trials have shown some positive effects.

Educate yourself as to the potential risks and benefits before undertaking it.

PLEASE SEND ME your information and results on human studies – informal, pilot or formal studies.

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Warnings

I suggest these warnings apply not only to dasatinib, which is a cancer drug – but to all senolytics including:
quercetin,
fisetin,
FOXO4-DRI,
theaflavins,
piperlongumine,
Tocotrienols – alone or with quercetin
L-Carnosine – sometimes taken with ALCAR and/or DMAE,
BCL-2 family inhibitors navitoclax / ABT263 and ABT-737,
Some other BCL-2 inhibitors like TW-37 are reported not to be senolytic, though, so it isn’t just any old BCL-2 inhibition that works,
BCL-XL inhibitors A1331852 and A1155463,
17-DMAG,
ABT-737,
ABT263,
navitoclax,
isoquercetin,
venetoclax,
sulforaphane,
BCL-2 protein family inhibitors in general,
HSP90 inhibitors

to name a few.

I believe this was true at one time, but may have changed:
Unity Biotechnology is deriving from navitoclax and using in their current studies.
Oisin Biotechnologies (DNA construct) lipid nanoparticle/p16-promoter/caspase DNA “drug”
SIWA Therapeutics (antibody).

* SENOLYTICS WARNING — Caution is advised re. excessive senolytics.
Note: What’s excessive may be different between individuals
Vince Giuliano advises senolytic signaling is critical for cell renewal – you need enough inflammation and senescence to signal for regeneration factors — so if you go overboard in senolytics therapy it’s bad, you will miss out on cell renewal.
http://www.anti-agingfirewalls.com/2018/09/02/aging-cell-and-tissue-repair-renewal-and-regeneration-inflammation-and-the-sasp

More is often not better. Quote by Reason: All senolytics, so far, look like things you would take once every few years at most. More won’t be any more effective than that one dose – it will kill the senescent cells it can kill the first time, and won’t be helpful again until more senescent cells turn up in volume.
http://www.fightaging.org/archives/2018/03/how-to-plan-and-carry-out-a-simple-self-experiment-a-single-person-trial-of-senolytic-peptide-foxo4-dri#caveats-in-more-detail

Senescent cell researcher Dorota Skowronska-Krawczyk PhD personally discourages us from having long treatments with senolytic drugs. In fact she suggests they should only be taken for short periods interspaced with longer recovery times.

Stan Goldfarb has decades of applied nutritional supplement and aging intervention experience. He advises: I think even 2.5mg per KG is a higher than I want to take, especially when combining it with EMIQ (which in itself has no bad side effects till very high doses). I weigh 137 and am going to take 100mg once only. You should also be taking at least 10000iu of D3 to complete apoptosis and don’t take any blood thinners such as aspirin or omega supplements as it has been proven to go after fat cells for several days before and after. Without doing all of this a person is simply taking an unnecessary risk. When I did my first test of this in 2015, there were some really sharp people to say exactly what to do and when. I don’t see that now with the current crop of people and it concerns me. People have died from overdosing this drug! I also remember that several people who did take multiple doses experienced minor problems after the second dose (especially flu like syptoms but not after the first. One group is saying take what you’re doing twice one week apart. This is potentially risky. The effect Dasatinib has lasts longer than many people seem to think and that is why I think a second dose just one week later makes no sense.

James Kirkland MD PhD recommends not evaluating senolytics on our own at this early stage.

Similar cautions apply to other aging intervention therapies. There’s a lot we don’t know about this new frontier.

Everyone is different – some may be harmed from senolytics, some may benefit from more senolytic, others may need very little (and will be harmed by more).

Individuals may respond differently to combinations.

Retreatment interval may vary from individual to individual.

From the Age Reversal Network (formerly Rescue Elders) document presented at RAADfest 2018:
Possible side effects: Mild flu symptoms, diarrhea, headache, fatigue for 12-24 hours.
Note from Johnny: And for some people who knows what else, and for how long.
Read the product information.

Take in the presence of a qualified medical doctor in case of severe allergic reaction.
Do not engage in strenuous exercise during, or for one week after, the treatment period.

That said . . .

Dasatinib and Quercetin act on different paths and are often taken together.

Dasatinib
They usually come in tablets. I have heard of 20, 50 and 70 mg.
I get 20 mg because it’s easier to measure the exact dose I want to take.
Do not cut, crush, or chew the tablets

Brands I have heard of:
Sprycel brand from Bristol-Myers Squib
Others from offshore sources.

Research grade can be good and comes highly recommended by one of our skilled MD associates. But you would need a scale and measuring small amounts can be tricky. I bought a scale and other items needed for this, but decided against it.
I DO NOT recommend research grade. But if you have a lot of experience, here you go https://lclabs.com/products/d-3307-dasatinib-free-base

READ THIS: Useful Sprycel dasatinib info from Bristol-Myers Squib
www.sprycel.com
It says:
• Do not cut, crush, or chew the tablets
• Do not drink grapefruit juice during treatment with SPRYCEL
• Do not take St. John’s wort during treatment with SPRYCEL

Grapefruit juice competes for the clearance channel with metformin, probably the same for dasatinib.
Hence it may be bad to take dasatinib with metformin. It appears some more experienced members of our community take grapefruit juice along with therapies – presumably for increased effectiveness and to save money. This sounds really tricky and I do not think I’ll try it.

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Dosing
I’m kind of sensitive to drugs, also conservative. When initially naïve once I took too much so called “anti aging” therapies and it made me seriously ill.

So first time around I took about 1/3 of the usual. A new and innovative lab test we developed showed positive results. But that’s just me.

Stan Goldfarb has decades of applied nutritional supplement and aging intervention experience. He advises: I think even 2.5mg per KG is a higher than I want to take, especially when combining it with EMIQ (which in itself has no bad side effects till very high doses) . I weigh 137 and am going to take 100mg once only . You should also be taking at least 10000iu of D3 to complete apoptosis and don’t take any blood thinners such as aspirin for several days before and after. Without doing all of this a person is simply taking an unnecessary risk. When I did my first test of this in 2015, there were some really sharp people to say exactly what to do and when. I don’t see that now with the current crop of people and it concerns me. People have died from overdosing this drug!

One group is saying take what you’re doing twice one week apart. This is high risk and probably even irrational.

Here’s dosing recommendations from the Age Reversal Network (formerly Rescue Elders) document presented at RAADfest 2018. I do not know how this was arrived at.  I am not endorsing it, it’s presented for informational purposes only:
One quercetin + dasatinib dose once a week for two weeks only (two total doses)

Quercetin
25 mg per kilogram of body weight, which is approx.:
100 pounds = 1125 mg

Dasatinib
2.5 mg per kilogram of body weight is approx.:
100 pounds = 112 mg

Hopefully you can do the math to arrive at your personal dosage.
Example, I weigh 146 lb, so dasatinib would be
112 mg for first 100 lb
Plus 46/100 x 112 = 51.52 (or .46 x 112)
= 163.52
REMEMBER Do not cut, crush, or chew the tablets
So round down (or up).

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Testing Pharmaceuticals Purchased Offshore and Elsewhere for Safety and Efficacy

I do not trust drugs from sources other than licensed pharmacies (and even licensed pharmacies have been known to get it wrong). I’ve been burned.

Counterfeit products is a huge international problem. It’s not just jeans, Gucci bags, Barbie dolls and GI Joes — others include counterfeit airplane parts, pharmaceuticals and other mission-critical products. Whatever makes money. A doctor once told me about fake Lasix medicine made seriously ill patients even sicker because it had been mixed in a container that had previously been used to mix pesticide, and had traces of the pesticide in the “Lasix”.

Appearance and packaging are VERY convincing. I read that a phoney Apple store was opened in China with real looking “Apple” products.

So I do not automatically trust that offshore suppliers will provide pharmaceuticals that are pure or contain the specified content.

Pete Cooperider replied to John Cramer’s post:
John, I see that the Bon Hoa pharmacy has several brands of dasatinib like Lucidas, Dasanix, Dasanat. Kindly tell us which one you used that you refer to as having been tested?

My response
Pete —
I suggest that testing one pill is pretty good evidence the rest in the bottle is OK, and the entire lot or batch is probably OK I guess – but does not necessarily mean that all tablets from that source are OK now, or will be into the future.

This concept also applies to nutritional supplements. Some suppliers use cheap ingredients that do not contain the specified amounts, and may even contain toxins.

According to some of my sources: So-called “Canadian” pharmacies are usually not in Canada – they’re usually in Asia, India or somewhere else. It is illegal for a Canadian pharmacy to ship to the US, with or without a prescription. Unless the web address has a “.pharmacy” extension it is not legitimate. The legitimate way to get a Canadian pharmaceutical is to go to Canada and get it from a Canadian doctor, then go to the pharmacy.

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We recently had dasatinib and rapamycin tested at Echelon Biosciences. I was very satisfied with the service and value.

They now have the qualitative test data and reports for dasatinib and rapamycin. Our foundation covered the initial cost of development, and you will be able to send your tablets to them for testing at a much lower cost.

For dasatinib, they have data for samples tested against a sample from a US pharmacy.
For rapamycin they have data for samples tested against a generic (known) sample AND a sample from a US pharmacy.

However, the topic of quantitative versus qualitative has arisen. Qualitative testing evaluates for purity, and that it contains the indicated pharmaceutical. Quantitative evaluates for the amount of the pharmaceutical.

Qualitative analysis (like Echelon did) is easier than quantitative, or active pharmaceutical ingredient (API) analysis.
Quantitative involves building a calibration curve. That may take 1 day, then the test may take 1 day
Total cost quoted from Emory Pharma for one instance: $5K. Others may vary.

Upon further investigation a knowledgeable scientist advised that qualitative comparative analysis (the kind Echelon did) – is all that’s really needed and will tell if there’s the same response in height and peak area – so will tell if pretty much the same amount.

All is beyond my pay grade so I have yet to completely understand it.

We are seeking further details and a conclusive answer as to whether qualitative or quantitative testing are required for our purposes.
Who will take on the task of getting a definitive answer?

Other testing labs can be found on Science Exchange http://www.scienceexchange.com .

Qualitative uses high-performance liquid chromatography (HPLC) and other methods. The generic (known) sample of dasatinib, was acquired through Sigma-Aldrich: CAS: 302962-49-8.
http://www.sigmaaldrich.com/catalog/buildingblock/product/matrixscientific/mat370173661?lang=en&region=US

Qualitative testing:
Echelon Biosciences now has testing data for dasatinib and rapamycin. They are available to test samples from other members of our community. My group has covered the initial cost, which is greater than the cost of testing additional samples.
 Contact me if you plan to utilize Echelon’s services. Inefficiency and confusion may be eliminated if you have me in the loop.
Johnny Adams JAdams@grg.org (949) 922-9786
Echelon Biosciences Inc.
Mark Nelson, PhD
675 Arapeen Drive Suite 302
Salt Lake City, UT 84108
mnelson@frontiersci.com
801-588-0455 ex 308

Quantitative testing
Emory Pharma

Home


Neeku (Niki) Mahdavian
Business Development Manager
Tel: (510) 899-8825
neeku@emerypharma.com

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Biomarkers and objective measures to evaluate senolytic therapy effectiveness in subjects/patients

Some useful ones are in part 3:

Click to access AgingInterventionProgram.pdf

Everyone is different – some may be harmed from senolytics, some may benefit from more senolytic, others may need very little (and will be harmed by more).

Retreatment interval may vary from individual to individual.

How do you know whether it’s working, and how much to take, and how often?

Current lab tests for this are entirely inadequate. Beta Galactosidase is not practical in humans.

Who has information on effective lab tests to evaluate dose, interval, etc.?
Please send it to JAdams@grg.org or call 949 922 9786.

We have found DNA methylation age from blood increases (goes in the wrong direction) after dasatinib plus quercetin. It’s uncertain whether this is an undesirable effect on one part of the system that accompanies the supposedly positive effects on others, or some kind of artifact, or what.

I worked with some top scientists at a major university research lab to develop an innovative biomarker test that was initially developed to measure cell senescence for before and after senolytic therapy.
It also applies to:
virtually any aging intervention therapy
and gene therapy.

We are now bringing it from the research lab to production mode. I will let you know when it’s ready for use in our community.

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Finally: now that you are a little more educated about the hazards and how complicated senolytic therapy is, on to sources.

But FIRST – to show you how much I care about you and really don’t want you to hurt yourself –

and I took a lot of time out of MY OWN aging intervention program to write all this. So you better read and understand it.

So another friendly reminder:

READ AND UNDERSTAND EVERYTHING ABOVE BEFORE YOU PROCEED WITH SENOLYTICS

If you’re not going to take the time to read and understand everything below – and further educate yourself beyond my inadequate information provided for your benefit here

THEN YOU HAVE NO BUSINESS MESSING WITH SENOLYTICS.

About Johnny Adams

My full-time commitment is to slow and ultimately reverse biological aging and age related decline for more years of healthy living. I’ve been active in this area since the 1970s, steadily building skills and accomplishments. I have a good basic understanding of the science of aging, and have many skills that complement those of scientists so they can focus on science to advance our shared mission. Broad experience Top skills: administration, management, information technology (data and programming), communications, writing, marketing, market research and analysis, public speaking, forging ethical win-win outcomes among stakeholders (i.e. high level "selling"). Knowledge in grant writing, fundraising, finance. Like most skilled professionals, I’m best described as a guy who defines an end point, then figures out how to get there. I enjoy the conception, design, execution and successful completion of a grand plan. Executive Director Gerontology Research Group (GRG). Manages Email discussion forum, web site, meetings and oversees supercentenarian (oldest humans, 110+ years) research. CEO / Executive Director Aging Intervention Foundation (dba for Carl I. Bourhenne Medical Research Foundation), an IRS approved 501(c)(3) nonprofit. http://www.AgingIntervention.org Early contributor to Supercentenarian Research Foundation. Co-Founder Geroscience Healthspan Forum. Active contributor to numerous initiatives to increase healthy years of life. Co-authored book on conventional, practical methods available today to slow the processes of aging – nutrition, exercise, behavior modification and motivation, stress reduction, proper supplementation, damage caused by improper programs, risk reduction and others. Fundamental understanding of, and experience in the genomics of longevity (internship analyzing and curating longevity gene papers). Biological and technical includes information technology, software development and computer programming, bioinformatics and protein informatics, online education, training programs, regulatory, clinical trials software, medical devices (CAT scanners and related), hospital electrical equipment testing program. Interpersonal skills – good communication, honest, well liked, works well in teams or alone. Real world experience collaborating in interdisciplinary teams in fast paced organizations. Uses technology to advance our shared mission. Education: MBA 1985 University of Southern California -- Deans List, Albert Quon Community Service Award (for volunteering with the American Longevity Association and helping an elderly lady every other week), George S. May Scholarship, CA State Fellowship. BA psychology, psychobiology emphasis 1983 California State University Fullerton Physiological courses as well as core courses (developmental, abnormal etc). UCLA Psychobiology 1978, one brief but fast moving and fulfilling quarter. Main interest was the electrochemical basis of consciousness. Also seminars at the NeuroPsychiatric Institute. Other: Ongoing conferences, meetings and continuing education. Aging, computer software and information technology. Some molecular biology, biotech, bio and protein informatics, computer aided drug design, clinical medical devices, electronics, HIPAA, fundraising through the Assoc. of Fundraising Professionals. Previous careers include: Marketing Increasing skill set and successes in virtually all phases, with valuable experience in locating people and companies with the greatest need and interest in a product or service, and sitting across the table with decision makers and working out agreements favorable to all. Information Technology: Management, data analysis and programming in commercial and clinical trials systems, and bioinformatics and protein informatics. As IT Director at Newport Beach, CA based technology organization Success Family of Continuing Education Companies, provided online software solutions for insurance and financial professionals in small to Fortune 500 size companies. We were successful with lean team organization (the slower moving competition was unable to create similar software systems). Medical devices: At Omnimedical in Paramount CA developed and managed quality assurance dept. and training depts. for engineers, physicians and technicians. Designed hospital equipment testing program for hospital services division. In my early 20’s I was a musician, and studied psychology and music. Interned with the intention of becoming a music therapist. These experiences helped develop valuable skills used today to advance our shared mission of creating aging solutions.
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