@nym Thank you for your expert opinion on D+Q and senolytics! Coming from you, that is a srong argument we should pay attention to.
@Joseph_Lavelle I agree. Time for the gym to remove some senescent cells… Along with my weekly Rapamycin. 
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Most interesting. I tried and indefinitely paused D+Q after side effects. The article you linked to makes me inclined to abandon this definitely.
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On what science you based your speculative idea?
Please, more info on Citrate therapy for Mitochondrial support
This page gives a lot of information:
https://citrate.science/2025poster/poster2025.html
Specifically on senescence this paper gave me the basic principles:
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Thanks
But I meant your statement that senescence cells are (most of them) nondifferentiated stem cells. Which looks totally untrue and misleading. But I could be wrong and maybe do not know some RCTs
That’s what I thought you meant which is why I provided the 2021 paper which to me was the key paper, but I also went into the details on my 2025 poster as well as the 2024 poster. (which is on citrate.science)
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For me they are unrelated. Maybe because you have being thinking about this matter for many years, and for me its new info and conceptions, and they look isolated. Typical issue with novices)
I’m a novice in this topic as well but my understanding from years back was that the main problem with senescence was the senescent non differentiated stem cells which move around the body creating more widespread senescence. Differentiated stem cells and other cells remain local. Was this never true or has the science moved on?
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It was never true. It looks like a random set of “looks scientific” words.
Senescent cells are the cells which can not proliferate anymore. The end. Hayflick limit. Or damage. Stem cells are like toddlers-cells. Then they become differentiated, some fibroblasts or epitelial cells, or any other cells, then they start to proliferate, live their life, then they become old, and come to the ~50 steps of proliferation. And then - become senescent. So senescent cells are like old cells. Not toddlers. Its like using the word “senescent” to completely unrelated matter. And making very broad assumptions which goes very far. Like "You do not need to remove senescent cells, you just need to “help them differentiate”. No you don’t, because there is nothing to help to. Old fibroblast? Help it “to differentiate”?
And what do you mean by “cells move around the body”? How is it? With what mechanics? Stem cells can (or can not) move as all other cells. Most of them bound to their places in organs. If they are in the blood or lymph - they move. So as adult blood and lymph cells, so saying that “Differentiated stem cells and other cells remain local” - is not true. BTW, what is about this dichotomy “differentiated stem cells AND other cells”? DSC - ARE the other cells. In the end of differentiation process - stem cell become SOME cell.
When we speak about science, I suppose, we have to be extremely precise in terms.
Off course I therefore extremely oversimplified all of these. Stem cells can devide many times before differentiation. They can become senescent. Or not. The can create progenitor cell. Or - neurons can not be senescent but do not proliferate. There are many options. But - senescent cells are NOT stem cells that are not differentiated.
btw, thus “senolytics” can not “help nondifferentiated stem cells to differentiate”. By definition, a senolytic is the one who kills senescent cells.
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Perhaps ask more specific questions or use an LLM to read my web page and then answer questions on it.
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That is replicative senescence.
Senomorphics are a class of agents that can modulate the phenotypes of senescent cells to resemble those of young cells without inducing apoptosis [17].
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To clarify, the issue as I understood it was 2-fold: senescent undifferentiated stem cells resulted in SASP producing cells roaming about the body (causing more cells to become senescent) and they could no longer reproduce to make more undifferentiated stem cells (you start to run low: heal more slowly).
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SASP producing cells roaming about the body - causing more cells to become senescent.
Exactly 
.
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Sorry, but senescent cells do not “roaming”, “infecting” other cells. They can roam - if they are “roaming” cells, or they can be bound to their place, if they that kind of cells. Its just not relevant at all.
They spread SASP around. It is called “Paracrine signaling”. When some cell become senescent (through the natural way things going) it starts spreading paracrine signaling around, pushing neighbour cells to the same state. It doesn’t need to roam for this. Cells become senescent by themselves all around the body all the time. As a result of a lot of natural processes.
Why you constantly mentioned undifferentiatedd stem cells as a senescent cells? Its just not relevant. Two different themes, not connected at all.
It will be better if I will use AI, because he knows english better then me)
" He is still combining several different biological concepts into one fundamentally incorrect model.
The central problem is that he seems to think that senescent cells are mainly, or even essentially, undifferentiated stem cells that have failed to differentiate. In his model, stem cells “break,” remain undifferentiated, become senescent, lose the ability to reproduce properly, and then roam through the body spreading senescence to other cells.
That picture is wrong at several levels.
Senescent cells are not another name for undifferentiated stem cells
Cellular senescence is a cellular state, not a cell lineage or developmental identity.
Many different types of cells can become senescent, including:
- fibroblasts;
- endothelial cells;
- vascular smooth muscle cells;
- epithelial cells;
- adipocyte progenitors;
- immune cells;
- astrocytes;
- differentiated somatic cells;
- stem and progenitor cells.
A stem cell can become senescent, but senescent cells are not generally stem cells, and senescence is not simply “failed differentiation.”
These are separate dimensions:
- stemness versus differentiation describes what type of cell it is and what developmental potential it has;
- senescence versus proliferation describes its functional state.
A differentiated somatic cell can become senescent. A stem cell can remain quiescent without being senescent. A progenitor cell can fail to differentiate without being senescent. These categories cannot be collapsed into one another.
Stem cells do not generally roam through the body
Most adult stem cells are tissue-resident and remain in specialised local niches:
- intestinal stem cells remain in intestinal crypts;
- muscle satellite cells remain associated with muscle fibres;
- neural stem cells remain in restricted brain niches;
- epithelial stem cells remain within their respective tissues;
- haematopoietic stem cells are primarily maintained in the bone marrow.
Some haematopoietic stem or progenitor cells can transiently circulate, but this is not a general model for adult stem cells, and it does not mean that senescent stem cells wander around the body “infecting” other tissues.
What spreads is usually signalling, not the cells themselves
The relevant concept is paracrine senescence.
Senescent cells release SASP factors—cytokines, chemokines, growth factors, proteases and extracellular vesicles. These signals can act on nearby cells and may:
- induce secondary senescence;
- impair local stem-cell function;
- promote inflammation;
- alter extracellular matrix;
- disturb the tissue niche.
The senescent cell usually remains in its tissue. What spreads locally is the signal.
There can also be broader systemic effects when SASP-related mediators enter the circulation, but that is still very different from saying that senescent undifferentiated stem cells themselves roam throughout the body.
So the correct model is:
Cells of many different lineages can become senescent. Some of them produce SASP. SASP can act locally through paracrine signalling and sometimes contribute to systemic inflammation. Stem and progenitor cells may themselves become senescent, or they may be impaired by SASP produced by neighbouring senescent cells.
That is not the same as:
Undifferentiated stem cells fail to differentiate, become senescent, travel around the body, and spread senescence.
Stem-cell ageing is not simply “running out of stem cells”
His second assumption is also too simplistic.
Age-related regenerative decline does not always occur because the absolute number of stem cells falls. In some tissues, stem-cell numbers can remain stable or even increase while their function deteriorates.
For example, aged haematopoietic stem-cell populations may become numerically expanded while showing:
- reduced regenerative capacity;
- myeloid bias;
- impaired differentiation;
- clonal skewing;
- poorer quality of progeny.
So slower healing can result from:
- senescence of some stem or progenitor cells;
- impaired activation;
- altered differentiation;
- mitochondrial dysfunction;
- epigenetic dysregulation;
- inflammatory or fibrotic niches;
- SASP from neighbouring cells;
- defective communication between stem cells and their microenvironment.
It is not simply that a universal circulating pool of undifferentiated stem cells becomes depleted.
The most charitable scientifically accurate version of his idea
His statement could be rewritten as follows:
Some tissue-resident stem and progenitor cells can become senescent and lose self-renewal or differentiation capacity, which may impair regeneration. Separately, senescent cells from many different lineages can release SASP factors that act locally through paracrine signalling, disrupt stem-cell niches, and induce secondary senescence in neighbouring cells.
That formulation is scientifically defensible.
But his actual model—senescent cells being primarily malfunctioning undifferentiated stem cells that roam through the body—is not consistent with modern cell biology."
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I think this is AI arguing with me. I am not inclined to go through a lot of AI and identify where it is wrong.
I have not argued myself, for example, that stem cells roam.
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I thought, however, I would use chatGPT(5.5paid) to answer my question:
what is the evidence that a proportion of senescent cells are in that state because they were stem cells which started the process of differentiation in order to become tissue cells, but were arrested because the process of differentiation failed.
If you wish to read the detailed response it is here:
Conclusion
Your proposed category is biologically credible and has a particularly strong experimental foundation in the lung:
Some senescent or senescence-like cells are former stem/progenitor cells that entered a regenerative differentiation trajectory but became trapped at an intermediate stage because differentiation could not be completed.
The evidence is strongest where lineage tracing has demonstrated a progenitor origin and single-cell trajectories have demonstrated an incomplete transition, especially the AT2 → KRT8-high transitional cell → AT1 pathway.
What has not yet been demonstrated is that this accounts for a known proportion of the total senescent-cell burden in normal ageing. At present it should be regarded as an important, tissue-dependent route into senescence rather than a quantified universal mechanism.
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“Restored clearance of senescent neutrophils by tissue‑resident macrophages limits organ aging”
scientists switched off a single immune receptor in old mice, and the animals kept the memory, muscle, and heart function of younger mice
scientists switched off a single immune receptor i.pdf (958.1 KB)
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And that is why other types on known senescent cells are important to clear out. Why deal with something that may or may not be important, when there are known senescent targets that are important.
One example is senescent cell accumulation in damaged vertebral disks.
senescent cell accumulation in damaged vertebral d.pdf (538.9 KB)
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Thank all of you for participating in this discussion. As a complete novice, I am learning a lot. This is what the forum is all about. I really appreciate learning from people who are taking the time to advance our understanding of things that might increase our healthspan and possibly longevity.
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