#83

Not to sound overly simplistic, but doesnt vigorous exercise not only get the vascular system in gear but also the lymph network, having functions to clear aged, senescent, and failing cells?

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#84

I think one needs to be careful when defining senescent cells here. It’s like autophagy. It ends up being a relatively meaningless, imprecise buzzword to describe highly complex process(es) involved in a vastly oversimplified story. Different papers use different markers in different parts of the body. A lot of heterogeneity. If you ask yourself “how to compare senescent cell burden between individuals?" and put on your thinking cap, you’ll quickly see the issues.

People get carried away without really reading papers and start using buzzwords without fully understanding the deeper parts. I reserve really layman-simplified explanations for any of the patients I see that are deeply health illiterate and/or have minimal to no biology background. But I’m not sure those people should be trying whatever drug that some influencer is claiming or implying they should take until they are patient enough to get quality resources to educate themselves without illusory knowledge or have some way to reliably determine advisory from a highly trustworthy and highly competent source. Unfortunately, generally this space is littered with the opposite.

I prefer to use SASP to describe the more precise phenotype. Rapamycin appears to suppress SASP in mice.

I think a slightly more robust way is to start with p16 levels in aging mice stem cells that suggest “accumulating senescent stem cells“ which appears to be evolution working to prevent neoplasias. So we aren’t really sure what to make of the potentially negative effects of “removing” these cells will do. It kind of seems similar to the situation of telomerase activators. p16 accumulation does lead to diminished function in multiple organs and we have tried reducing levels of p16 in engineered mice but they are in fact more cancer-prone. So it’s enough to be quite wary to do something irreversible like “senolytic”

In humans, we look at the p16/INK4a gene. There’s some associations with T2D, CAD, and other aging related conditions in some SNPs. The main issue is balancing the potential for increased cancer risk. Considering rapa does seem to have the potential for reducing several types of cancer risks and not actually removing any so-called “zombie cells” where we already know have potentially positive functions that seem to be robust enough - I don’t see why one would jump to senolytics just yet over the strategy of potentially buying more time for more information. I suspect if senolytic therapy actually works as hypothesized, we’ll need to have some countermeasures as a combination therapy. Perhaps a few extra copies of TP53.

As for fisetin - it failed the ITP. Not only that, no sign of senolytic action in samples. The suggestion was actually by a highly prominent proponent of senolytic therapy with suggested dose, frequency and all. Kind of feels like a certain resveratrol person we are aware of. A pretty damning outcome where people should probably dial down whatever hyperbole they may have heard. “Zombie cells” are such a wild term that implies way more negativity than justified.

So it’s not quite clear whether proposed senolytics will do what is intended. And if it does, then we have quite a few real reasons to be wary.

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#85

I use the lowest level of CRP as a proxy for SASP. Not all the IL-6 will get to the liver, but it does give some indication of SASP levels. That is perhaps not a particularly inclusive solution, but it is I think the best as at today.

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#86

Senescent cells and SASP have a clear and proven role in wound healing. Not a small matter. Unfortunately, they then hang around and are very inflammatory.

As you say, they may also play a role in cancer prevention, but the inflammation is probably cancer inducing,so it’s complicated.

If you try to just shotgun this and kill them off, then you better know what you’re doing and have the timing down so you don’t interfere with wound healing and potentially promote cancer.

Rapamycin, on the other hand, interferes with geroconversion of arrested cells to senescent cells, but it appears to be a more limp effect.

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#87

A bit related - regeneration versus fibrosis.

Source papers of the presentation, below:

https://www.nature.com/articles/nature07039

I have no access to the other papers.

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#88

It depends on the person but way too many people are overtesting when they go on their own. Some people might even be able to use inflammatory predominant moderate to severe acne vulgaris responsive to sub-antibacterial doses of doxycycline (assuming relatively stable levels of other contributors in pathology) as a proxy for hs-CRP as well as mild erectile dysfunction as a proxy for subclinical atherosclerosis if psychogenic/drug induced is ruled out. :slight_smile:

I don’t bother too much with IL-6 levels. Long story. Albumin is a far cheaper lab to run with CMP, depending on context. But the idea is even the slightest of subtle clinical symptoms can often be way better.

BTW, CRP has both proinflammatory and antiinflammatory actions. People often don’t realize what is a very much oversimplified view of “inflammation”

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#89

Related to this general topic of conversation:

and a new paper:

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#90

They might be available through Sci-Hub. If you can get the DOI or the exact title (it’s case, character, and whitespace sensitive), you can run it through Sci-Hub to see if anyone uploaded the papers for free.

It’s a website that many, including myself, upload papers to in order to remove paywalls/institutional blocks. Basically piracy, but science.

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#91

Originally, I was in the camp of removing senescent cells by using treatments such as Dasatinib, Quercetin, Fisetin, grape seed extract, etc… But then, others mentioned it could negatively affect cells that are good such as endothelial cardiovascular cells.

I have slanted my efforts more toward senomorphics to prevent cells from becoming senescent in the first place. Some famous senomorphics are Rapamycin and either carnosine or beta-alanine. Can anyone recommend some other good senomorphics?

Also, I do believe purging senescent cells using senolytics may be beneficial, but instead of doing it once a month like current protocols dictate, I think it may be better to do it every 3-6 months. Thoughts?

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#92

If anyone can provide a PDF of the second paper listed, please post.

#93
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#94

As far as I know we don’t understand the dynamics of the senescent cell population in humans at all, which would be necessary to answer questions about treatment frequency. What makes most sense from a theoretical perspective to me is to target some populations of long lived, immune-evading, cells. With this goal frequent dosing becomes hard to justify.

Actually, we know very little about s.c.'s in the organism in general. Senescence isn’t just one thing, but a diversity of them, so it’s really very empirical how a specific “senolytic” will effect health. Even in mice we don’t yet have a really high quality demonstration that they extend lifespan at all.

So I recommend against experimenting. If one ignores this, my recommendation would be D+Q every 6 months (maybe with a closer series to start out).

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#95

Given the large number of senescent cells in body fat (esp. visceral) Could anything that reduces body fat (even temporarily) be considered a senolytic? Wegovy?Rapa? Exercise??
That would seem a low risk set of senescent cells to remove.
Is there evidence on the lifespan impact of short term calorie restriction or body fat reduction in later life?

“Exercise can reduce the markers of senescent cells in healthy humans, while it lowered the markers of senescent cells in obese but not healthy animals”
Is exercise a senolytic medicine? A systematic review - PubMed.

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#96

DeStrider, I take Dasatinib (100 mg) + Quercetin (1 gram) 3 days in a row in the morning with coffee (blended with a tablespoon of olive oil) an hour before any food every 3 months. It does not upset my stomach and I don’t notice anything different or unusual during those 3 days or afterword. But, I also have not noticed anything from Rapamycin either, except mild periodic spots of rash.

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#97

Generally I think senolytics look extremely interesting so I’m optimistic. But I also keep track of the negative things some people are writing about senolytics so I have a more complete picture… here is one on the other side of the scale…

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#98

I’m 66 and taking Dasatnib, 50mg + (extra)Quercetin 1 x mo; 4 mg Sirolimus 1 x wk, per Dr. Green for 1 year. So far, so good. Unfortunately, we won’t really know until my autopsy, though.

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#99

How did you decide on the once a month schedule?

#100

Cool, and now I know where the expression “snake oil” came from :wink:

#101

Seems like a brief overview of a few anti-aging techniques from Metformin to resveratrol to antioxidants. Not sure if it’s on the topic as many of the topics mentioned do not appear to be senolytics. Also, not a lot of in-depth analysis. Seems like something generated by ChatGPT. In the end, it recommends the Mediterranean diet and exercise. Not that useful IMHO.

It is a reminder though of all the past “successes” that turned out to be failures.

1 Like
#102

Does anyone have an opinion on senolytic resistance of populations of senescent cells, which can develop as a response to senolytics? Is it possible to reverse this resistance by pausing the senolytic or by rotation of the senolytic agents? Or use fasting or hyperbaric oxygen against resistant senescent cells?