"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

36replies Oldest first
  • Oldest first
  • Newest first
  • Active threads
  • Popular
    • Danmoderator
    • skipping my funeral
    • dantheman
    • 5 yrs ago
    • Reported - view

    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. 

    Like 2
      • adonoho
      • adonoho
      • 5 yrs ago
      • Reported - view

      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

      Like 1
      • Danmoderator
      • skipping my funeral
      • dantheman
      • 5 yrs ago
      • Reported - view

      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. 

      Like 1
      • BobM
      • BobM
      • 5 yrs ago
      • Reported - view

      DanMcL 

      Like
    • Suzanne
    • Suzanne
    • 5 yrs ago
    • Reported - view

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

    Like 1
      • Danmoderator
      • skipping my funeral
      • dantheman
      • 5 yrs ago
      • Reported - view

      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. 

      Like 3
      • adonoho
      • adonoho
      • 5 yrs 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.

      Like
    • Iðunn
    • Iunn
    • 5 yrs ago
    • Reported - view

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

    Like
      • Danmoderator
      • skipping my funeral
      • dantheman
      • 5 yrs ago
      • Reported - view

      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. 

      Like
    • albedo
    • albedo
    • 5 yrs ago
    • Reported - view
    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?

    Like 3
      • Danmoderator
      • skipping my funeral
      • dantheman
      • 5 yrs ago
      • Reported - view

      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. 

      Like 1
      • albedo
      • albedo
      • 5 yrs ago
      • Reported - view

      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.

      Like 1
      • Danmoderator
      • skipping my funeral
      • dantheman
      • 5 yrs ago
      • Reported - view

      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. 

      Like 2
      • albedo
      • albedo
      • 5 yrs ago
      • Reported - view

      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.

      Like 2
      • Danmoderator
      • skipping my funeral
      • dantheman
      • 5 yrs ago
      • Reported - view

      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.

      Like 1
      • adonoho
      • adonoho
      • 5 yrs ago
      • Reported - view

      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.

      Like 1
      • Danmoderator
      • skipping my funeral
      • dantheman
      • 5 yrs ago
      • Reported - view
      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. 

      Like 1
      • adonoho
      • adonoho
      • 5 yrs ago
      • Reported - view

      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.

      Like 2
      • adonoho
      • adonoho
      • 5 yrs ago
      • Reported - view

      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.

      Like 1
      • Danmoderator
      • skipping my funeral
      • dantheman
      • 5 yrs ago
      • Reported - view

      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 :)

      Like 2
      • Danmoderator
      • skipping my funeral
      • dantheman
      • 5 yrs ago
      • Reported - view

      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). 

      Like 3
    • Dan I am a 60YO type two diabetic on metformin, no insulin. After many years my dose is up to 1000mg twice a day, and it keeps my A1C in the low 6 range, but like you that is going up over time. My liver is healthy, and produces glucose from excess protein if given a chance. Multi-day fasting has been the only way that I have found to get my glucose down. 

      Like 1
    • BobM
    • BobM
    • 5 yrs ago
    • Reported - view

    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 

    Like 1
      • Danmoderator
      • skipping my funeral
      • dantheman
      • 5 yrs ago
      • Reported - view

      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). 

      Like 2
      • Danmoderator
      • skipping my funeral
      • dantheman
      • 5 yrs ago
      • Reported - view

       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.

      Like 2
Like6 Follow
  • 6 Likes
  • 2 yrs agoLast active
  • 36Replies
  • 1920Views
  • 14 Following