"Senolytic Activator" and Extended Fasting …

Gentlefolk,

 

Our fine friends at Life Extension have released a new product, Senolytic Activator. It is a combination of Quercertin and Theaflavins. They intend us to use it weekly as a non-prescription version of the Dasatanib + Quercertin senolytic therapy. To fix multiple metabolic issues, I fast. Weekly I have a 24-40 hour fast and monthly I implement a 5 day extended fast. I also implement a 16:8/2MAD time restricted feeding pattern.

My fasting patterns are intended to induce aggressive activation of SIRTuin repair pathways and apoptotic reactions. To that end I supplement with NR. In this context, when should I take the Senolytic Activator? The Life Extension folks formally have no opinion on this question.

This question devolves down to phasing. For example, your body enters a different metabolic regime when your liver depletes its local store of glycogen, between 18 and 24 hours from your last meal. Autophagy rates are postulated to increase; growth hormone starts increasing; a whole panoply of other endocrine systems start shifting. That seems to me to be the likely best time to introduce the Senolytic Activator. SA would provide just the slightest nudge to push senescent cells over into apoptosis. Unless, of course, it is the worst time to introduce SA.

When does this august group think I should take the Senolytic Activator? In phase or out of phase with my fasts?

Anon,

Andrew

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  • Hi Andrew,

       I also engage in 5 day fasts twice a year, with overnight 12++ hour fasts. I also have the LE Senolytic Activator you mention. Personally I wouldn't take a senolytic activator during a fast, for one reason it would likely kick you out of the fast! Or something to that degree, the activator is not zero calories I assume. Plus your digestive system shuts down and takes a rest, I doubt it would either feel good or effectively digest if you took some supplements. So I recommend using it while not fasting, as I'm doing now. 

     

    I'm not overly convinced of the value of the SA product, so I'm testing. At least it's cheap and easy. 

    Reply Like 2
      • adonoho
      • adonoho
      • 2 mths ago
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      Dan Mc Hi Dan,

      Thank you for your reply. I've already taken it on day 3 of a 5 day fast. If we judge by my ketone levels, it did nothing to my fasting process. My bigger question is whether we can help SA do its job of pushing senescent cells over the apoptosis threshold by fasting. As most of my inflammation markers are quite low, I doubt we could see a change due to SA. My current plan of record is to dose SA at hour 24 of my weekly 40 hour fast. I'll keep folks posted.

       

      Anon,

      Andrew

      Reply Like 1
    • adonoho OK good you've tested it's fine during a fast. It's an interesting approach.

      To answer you question I really don't know, and I'm not sure a hypothesis could be made. Fasting activates some alternate genetic pathways (epigenetic) which may respond more or less favorably to senolytics. Normal cells 'bunker down' and 'harden' themselves via this to deal with ketosis and famine. Cancer cells, being unstable, usually don't have this ability (some cancers adapt to fasting). So fasting and chemo is an excellent pair (see Voltor Longo's work on this). What about Senescent cells? Depends on how abnormal they are I guess, I could be that they, like cancer cells, are weakened by fasting. Or they could be strengthened just like normal cells. 

      Reply Like 1
      • BobM
      • BobM
      • 2 mths ago
      • Reported - view

      DanMcL 

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  • Directions for LEF Senolytic activator is 2 caps once a week for 12 weeks. Does this effectively replace dasatinib/quercetin protocol?

    Reply Like 1
    • Suzanne I think nobody knows the answer to that, we'd have to do a direct clinical trial on both. LE might have an estimate though, I've found if you send them a product query they're excellent at replying with what they think. Carefully worded of course. 

      FWIW, on the one hand plants are basically chemical factories, and most or many drugs come from distilled plants. Dr Peter Attila said when his patents tell him they'd rather have a more 'natural' approach via supplementation he asks why, when supplements are basically unregulated drugs? So in theory it could be as or more effective. 

      On the other hand the only work here is LE went through a database of parameters from plants and found a combination believed to be similar. So again no idea. 

      My approach is that the LE activator is cheap and easy so I'll give it a shot. The problem is none of us have any measure for senolytic activity, except possibly our hair might lose some grey. For that reason as part of my daily biometric I take a mug shot. 

      Reply Like 3
      • adonoho
      • adonoho
      • 2 mths ago
      • Reported - view

      Suzanne It is clearly less effective on a per dose basis than dasatanib+quercetin. Does the full course equal the dasatanib dose? Unknown but unlikely is my guess. Does it offer some benefit? Likely. How much? Unknown. Hence, my question about taking it during fasting, i.e. could I make it more effective by stressing the senescent cells. Basically, if it can induce some of my senescent cells over the edge, then it is probably a net win.

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  • This is kind of moot, since there's no evidence that the theaflavin + quercetin supplement actually kills senescent cells: see my post here.

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    • Iðunn Agree with your point here. Once you have the digestive tract interfering most (or many at least) compounds fail to have the same effect as they do when isolated. I got the Senolytic activator as a 'why not because it's cheap' experiment but probably won't continue it. 

      Otherwise I'm approaching my Winter solstice fast, probably a low key one this year of 4 days. I'm not planning on taking any supplements during it. 

      Reply Like
  • DanMcL said:
    My approach is that the LE activator is cheap and easy so I'll give it a shot. The problem is none of us have any measure for senolytic activity, except possibly our hair might lose some grey. For that reason as part of my daily biometric I take a mug shot.

    I am also looking at the LEF's new product (as well as fisetin) as I am not ready yet for D+Q. Shouldn't a DNA methylation and the Levine's Phenotype Age calculator give a tentative answer. The recent LEF article indicates senolytics acting on so many fronts that we might be able to see an activity on biological age?

    Reply Like 1
    • albedo Great thoughts. Unfortunately I don't think these tests will tell us specifically if senescent cells are being mitigated. 

      The calculators are population referenced, meaning that the markers fit models created models created from age specified input variables. Roughly this means that if your numbers look rather like those from some age bracket then you get that result. 

      On the physical DNAm test we don't get help either. I'm using myDNAage.com , which uses a method developed by Dr Steve Horvath. Horvath is a statistician, he simply ran an analysis of age versus various epigenetic markers, and took the ones most correlated. But if you look further into the method, while researchers are tremendously excited about it due to its accuracy in 'predicting' age (or better said maybe, correlating age) nobody knows why it works this way. We certainly don' know if it corresponds to senescent cells. 

      And finally, the really important question is does the calculated/measured biological age actually correspond to remaining lifespan? Simple example, suppose for a minute that NAD levels don't reflect in any of these tests, and suppose that a NAD level of zero does result in death, then these are only partial estimators. 

      Reply Like 1
      • albedo
      • albedo
      • 2 mths ago
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      DanMcL 

      Mhhh Dan, I am not sure and I am not convinced. I see the issue maybe more globally.  Assuming these clocks measure a rate of accelerated or decelerated aging in the sense that, as for Levine's one, the increased or decreased rate of mortality and morbidity and assuming reducing senescent cells reduces your biological age by a series of meditative effects (say inflammatory), then I think we must see some effect by using them. Or not? The good of these clocks is they might be capturing the multifaceted characteristic of aging not just one aspect. However, surely you might find, and I am sure somebody is working on it, a biomarker measuring the senescent cell density per se which of course is very valuable but I think we must get to the point of a biomarker or a composite set of them measuring the impact of our interventions being senolytics or others on our biological age.

      Reply Like 1
    • albedo We don't have causality, without that all we have is different variables conflating with each other and can't say a-priori that it's senescence specifically. Taking a step back, it doesn't really matter. If whatever we do drives our aging markers down then that's success, we can leave it to the lab rats to figure out what variable (senescence, mitochondria function, etc) was improved. 

      I think we're in agreement though. What I worry about sometimes is what important factors are being missed? For example, a person could have great biomarkers, be doing NAD, senolytics, etc, yet still have the apoe4 gene and develop dementia/alzheimer's in late life. Or just memory loss, or something else. We have a lot of systems that need to be kept running. Longevity escape velocity might be reached in a decade, but surely not for everything right away. 

      Reply Like 1
      • albedo
      • albedo
      • 2 mths ago
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      DanMcL 

      "We don't have causality, without that all we have ...." Yes I do stand with you Dan. Actually in my thinking about biomarkers integration probably also genotyping such as Apoe4 would need to be taken into account too. It is controversial, some do not really think a particular genotype could be qualified as a biomarker, maybe only for specific cases.

      Reply Like 2
    • albedo Yeah that young.ai site has coming all sorts of markers - pictures (work has been done by networks figuring age from a face photo), oh I forget but a bunch of stuff. I think these guys are on the right track, actual bio age should come from every marker we have (100+), including ones you might not think of. For example, the soles of your feet. Soles have a tissue that degrades over a lifetime of walking, this is why when we get old we tend to get plantar fasciitis and other feed ailments. I think this falls into Aubreys "cellular matrix' category. I started to get this, and some fancy expensive custom orthotics fixed the problem thankfully. But my feet are not the same as they were when I was 20. So even though I might have good blood markers, I should get dinged because of the age of my feet.

      Reply Like 1
      • adonoho
      • adonoho
      • 2 mths ago
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      DanMcL My view is pretty simple, the body is a set of complex interacting systems. In particular, we have taken it far outside its evolutionary/historic biochemical milieu. As a result, I think we see "diseases", such as senolytic cell accumulation, that our body could not afford to tolerate in earlier ages. Senolytic cells are a bug in the program; cells that should have died but didn't. Hence, returning to a dietary hormetic stressor pattern from voluntary fasting is important to managing the load from senolytic cells. They must be convinced to die from stress response and senolytic agents. As fasting also encourages the activation of the SIRTuin based repair pathways, this is a two-fer strategy. Does the LE SA product provide enough of a push for my existing senolytic cells to start apoptosis? Unknown but possible. In the context of other stressors? Unknown but more likely. I think it falls into the bin of inexpensive, safe, and possibly effective. I would be fasting and supplementing with NR/NMN before starting the hunt for senolytic cells.

      Reply Like 1
    • adonoho said:
      As a result, I think we see "diseases", such as senolytic cell accumulation, that our body could not afford to tolerate in earlier ages. Senolytic cells are a bug in the program; cells that should have died but didn't

       Yeah that's a hot topic of discussion. One the one side you have the evolutionists, who say aging is caused by DNA programming (somehow) or lack of DNA programming. On the other side you have the accumulated damage theory. I believe the latter theory appears to be winning. Something complicating the programming theory of senescent cells is that they actually provide a pro-immunity function later in life. So they do 'poison' the cells around them, but with aging elders who have impaired immune function, those same senescent cells become active during infection in a positive way. My takeaway from this is that as you age you want both low senescence and high immune function, thus not needing the senescent cells. As you say, periodic true fasting addresses both by recycling the senescent cells, and improving immune by recycling old T-cells, plus all the other bennies. 

      My wife has a hard time fasting, at least on her recent first one (first time is always the hardest). I'll put her on the LE activator and I'll discontinue it for myself. On Rapa I'm going back and forth, I have a aging management Dr who will probably prescribe it for me, but I'm waiting for more data on that front. Springtime in the earliest. 

      Reply Like 1
      • adonoho
      • adonoho
      • 2 mths ago
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      DanMcL As to your wife's difficulty fasting, it is made much easier by becoming fat adapted. This happens naturally from time restricted feeding, 12+ hour fasting window every day plus no snacking nor sugar sweetened beverages. It took me 4 months but it changed everything. You can force the transition faster with a ketogenic diet but it isn't for everybody.

      Reply Like 1
      • adonoho
      • adonoho
      • 2 mths ago
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      DanMcL As to the damage theory versus the genetic theory, I don't think it is that simple. Evolved systems don't factor nicely. Damage can trigger genetic pathways and vice versa. While the path of evolution is long, it does not test all corner cases -- witness type 2 diabetes, not an evolution tested process. Hence, I reserve judgement from that determination.

      Reply Like 1
    • adonoho Yes we practice time restricted feeding, thanks. FWIW I don't support the ketogenic diet approach, it seems clear to me that intermittent ketosis via periodic fasting works, but chronic ketosis is in the cateogry of a 'good thing taken too far'. Our bodies are designed to run on glucose, you need to alternate rest/repair with stress, and so alternating ketosis was normal feeding appears (to me at least) to be the right approach. This is the same pattern we se with exercise, an optimal approach is to alternate rest with exercise stress. 

      I had several stints at the True North Health Center where they've had tens of thousands of patients do medically supervised fasts. They're pretty much the experts AFAIK, their take is that fasting is just hard any way you take it. The head of the group, Dr Goldhammer, told me he does yearly maintenance fasts and still doesn't like it :)

      Reply Like 1
    • adonoho I think we also agree here. Taking your Type 2 example, yes it's both genetic and lifestyle. I have several defects for high fasting glucose, which by my 20's resulted in terrible health and blood work. Back then I addressed it purely by lifestyle, which led to me being such a health fanatic. I did fix the problem, but now in my 50's my glucose is creeping up again, despite all the work I'm doing! So now I'm on Metformin, plus daily intense aerobic exercise in the morning. The two are successfully managing the issue. This demonstrates your point I think, that there's a intersection between genetics (the coding) and epigenetics (lifestyle). 

      Reply Like 2
  • Hey Dan,

    for those fasting and doing the senolytic process, could they measure urine and see anything? As the body disposed of senolytic cells, wouldn’t they come out in the urine? What might one look for ?

    Thanks 

    Reply Like 1
    • BobM Senescent cells are recycled, your body literally reuses the golgi and other parts. The only way to measure senescence that I know is by taking a tissue sample and using dye to visually see the senescent cells in a microscope. This highlights the fasting mechanism; in the absence of energy (glucose) your body is both in a anabolic state (not catabolic digestion - sometimes I get these backwards) which is a repair state. Secondly, your body is looking for energy. So it goes on a shopping trip in your system. It clears out plaques from your arteries, clears out senescent cells, old T-cells and so forth. These are all recycled and turned into food. You literally start eating yourself, but your body is smart and is protein sparing. It does everything to preserve the heart and brain first, then muscles, so it goes after the baggage (old junk and fat stores). 

      Reply Like 2
    •  Well there might be one test, I don't know if anybody has looked at this (note I'm a physicist/engineer/musician/composer, not a biologist!) which is using the Ames test for broken DNA in the urine. I believe this is mainly used for mitochondrial function (since DNA repair (mostly?) occurs there), but I wouldn't be surprised to find that increasing senescent cells also increase broken DNA. OTOH that might be sufficiently mitigated by immune and mitochondrial function. 

      The DNAage test I took looks at methylation, not discarded broken DNA AFAIK. Your body can't recycle DNA apparently so just excretes it. n.b., except digestive DNA? I recall there's a step in digestion, after the stomach, where <something> pulls out all the foreign DNA in your food that made it through the hydrochloric acid in the stomach. I don't know what happens with that DNA, whether it's used or discarded.

      Reply Like 2
  • DanMcL said:
    My approach is that the LE activator is cheap and easy so I'll give it a shot. The problem is none of us have any measure for senolytic activity, except possibly our hair might lose some grey. For that reason as part of my daily biometric I take a mug shot.

     Hi Dan. Sorry ... continuing on the challenge you are putting on senolytics and biomarkers and my later reply on DNAm, PhenoAge, composite BMs etc ... :)

    I just pop into this (a bit old though):

    "... At the level of cells, a potential biomarker of aging may be the presence of  senescence. Senescence is a condition in which old or damaged cells remain alive but cease to reproduce. This is an important tool in the body’s ability to prevent cancerous tumors from developing. The older a person becomes, the more senescent cells he or she accumulates. Several markers of senescence in humans have been suggested as biomarkers of aging. On November 10, 2011, researchers at the Mayo Clinic published a study in the journal Nature showing that an accumulation of senescent cells may lead to age-related diseases, at least in animals. By removing most of these cells from several organs (body fat, eye, and skeletal tissue) of lab mice, the investigators were able to significantly delay the onset these diseases, or stop their progression if they had already become established. The study suggests what may prove fruitful areas for future researchers to explore in the search for true biomarkers of aging..."

    https://www.afar.org/docs/AFAR_BIOMARKERS_OF_AGING_2016.pdf

    Reply Like 1
      • albedo
      • albedo
      • 2 mths ago
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      DanMcL

      Just in case, as I understand you have also read Aubrey's book, I posted something I guess relevant for senolytics and biomarkers here, on the Loncecity Forum.

      Reply Like 2
  • Hi, I see this topic don’t have new entries. Anybody notice any changes taking LE senolytic activator? 

    Reply Like 1
      • adonoho
      • adonoho
      • 4 wk ago
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      LISBETH Prieto As I perform a long 5+ day fast per month, it was always going to be hard to see if this did anything. (The theory is that the senolytic would push a few more cells over the apoptotic threshold.) As it was inexpensive and quercetin has other benefits, I took the pills. There are no bad side effects to report. It doesn't interact in any visible fashion with me during fasting.

      Reply Like 2
  • Bizarrely positive initial experience with LEF's SA.

    I'm new to this group and not engaged in any particular program or mode of life extension.  No regular fasts or formal age-reduction protocols.  I am, however, a physician in active practice, 80 years old, in excellent though not perfect health for my age, and interested in extending my life provided the quality is good.  I'm also well versed in what data is valid and what isn't, at one time was on the editorial board of a respected medical journal.  In my personal and professional life I'm quite open minded to alternative therapies as well as knowledgeable about conventional ones.  

    I've used the SA product for just 2 weeks and experienced some surprising early consequences.

    A big issue, of course, is in self-experimentation how can one know if a strategy is or is not "working" -- or conversely, whether it is or is not doing harm.  The conventional answer, of course, is that research must be done with proper controls, replication and long term follow up.  Yet that takes time, and time is one thing we have in limited supply.  Which is why we self-experiment and don't wait -- especially as we near the end of our shelf-life  when it will be too late to reap benefit.

    Exciting thing about senolysis, however it is triggered, is that it's darn near never too late for it to have at least some benefit.  But still the same question: how do you know if it helps.  Pictures, physical tests, etc can only go so far.  Subjective experience may be best (am I still alive?  If so, how do I feel, function?) but it's also unreliable for many reasons I'm sure all of you know.

    And yet...   I've tried the LEF senolytic activator product for the past two weeks... expecting pretty much nothing, at least at first.  Also, I'm sure I'm probably an outlier in terms of my responses... yet results have been remarkable and unlikely to be by chance.  Within a few days of the first I noticed:

    (1) spontaneous thinning, lightening and shrinkage of a few small seborrheic keratoses on my face without any concurrent topical treatment, scraping, cleaning.  WTF??  Without treatment these nonmalignant buggers only get darker and thicker...

    (2) increase in energy, especially in the morning, every day, not just right after taking... the subjective experience of feeling as alert in the morning BEFORE my morning 2-3 cups of coffee as I had previously felt AFTER it... though the coffee still adds more.  To sure this is subjective, but it was both unexpected and compared to a baseline of many months...

    (3) quite noticeable improvement in perceived brightness of shadowed or dark areas, such as fading/poorly maintained white lines on roads at night.  Unlike many at my age I still have been comfortable driving at night, though a predictable age-associated change in vision -- independent of cataracts, macular degeneration, etc -- is simply less sensitivity to light.  Dim areas look darker, etc.   About a week after starting the SA these areas were perceived as brighter... an effect neither expected nor looked for...  e.g. areas in a bathroom lit by the same dim blue-blocked night light now look fairly bright instead of shadowed; and driving at night, it no longer seems most road markings are way past their time to be repainted... If I had expected such results I might have tried eye charts before and after to quantify any changes in vision.  But the subjective changes have not been subtle.

    I realize even if SA is working, such rapid changes are not expected.  if didn't experience them myself I might not believe them. Yet the combination of my spontaneous observations leaves me feeling no doubt that it is doing something pretty good for ME.  What does this mean for anyone else?  Who knows?   And there's still the question: should I follow LEF's recommended schedule?  Stop taking it sooner?  Continue indefinitely?  Increase the default interval of one week?  Add or substitute fisetin?  

    I know testimonials prove nothing, but thought I'd share this.  Lots of questions unanswered.   Yet in my personal experience, rather mind-boggling and improbable, I'm convinced LEF has stumbled on (or figured out?) something can work, at least for some.

    Jon Russ MD

    Reply Like 6
      • BobM
      • BobM
      • 2 wk ago
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      Jonathan Russ 

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    • Jonathan Russ 

      Thanks for sharing your experience, please continue as you use the LE SA, perhaps being older senolytics would have a greater effect/benefit. Given your background as a physician, with a working life of listening to anecdotal symptoms and testimonials, I think your results have some weight. 

      I wonder if there are some kinds of rough tests you could run to test this theory? For example, at day five of a water only fast the body starts it's own senolytic therapy. I think this is observed by the urine turning yellow from clear, with a distinct odor. The specific gravity can be measured to be, well off the measuring ability of my test strips. My hypothesis is that this is the waste product from senolytic activity, and I wonder if you would see a similar effect?

      Note it might be masked by your normal urination patterns, and is obviously influenced by your hydration levels, so I recommend measuring your ideal daily hydration and logging your values. I use an iPhone app/watch app for this which makes it easy, I drink 170oz daily as my normal amount. 

      On dosing the thinking is you want to pulse this. You don't want continual senolytic activity, think "tear down/build up". Now I think this is why LE has it as a once a week, so given that using it longer time might be OK. I think however taking breaks between package (1-3 mo?) might be a good idea. For comparison, we know fasting is a senolytic, and Longo recommends a monthly fast for most people with typical health, and 2/year for those in optimal health (basically an athlete and eat a perfect diet). I fall in the latter category so do a week long every six months. 

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  • Thanks for thoughts/advice... after the 2 month weekly use of LEF's SA I plan to take a break... perhaps do 3-4 courses/year though would depend on how well the perceived benefits sustain. 

    I am flummoxed if pleased with the rapidity of my response to the SA product, which is sustaining with further gradual progress -- regardless of how many senescence cells I may have accumulated in 80 years... I do take some other things that might be relevant including metformin 500-1000mg/day; I'd been diagnosed with borderline diabetes a few years ago and initially improved my blood sugars  with diet and lifestyle changes alone.  but added metformin a few months ago not because I had to but figuring the less glycation the better as well as metformin's possible life extending effects....   [FYI metformin did not result in anything noticeable, though I tolerate it well.]  Perhaps it has a synergistic effect in synergy with the components of the SA product.  

    Then again, I have had unusually robust and rapid responses in the past to some things that might have a hormetic effect such as brief but high intensity exercise regimens.  

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