79 replies to this topic

[Zarathrustra]

I have just come to realise that there is no empirical basis for any of the various theories and proposed solutions to ageing using the ideas of senescence and senolutics.

 

There is, at present, no way to assess the senescent burden in a human body. Hence there is no way to know if any proposed way to reduce such a burden is working.

 

It gets worse: there is no empirical evidence that mortality, frailty, illnesses are due to the supposed senescent burden. So even if one did reduce the amount of senescence, there is no guarantee this would improve one's health or increase one's lifespan.

[johnhemming]

There are ways of identifying Senescent cells, but as they produce SASP you can do a test for elements of SASP.  I am trying to test for Interleukin-10 (getting a quote on costs at the moment) which may IMO be the key part of SASP that causes Stem cells not to differentiate properly.

[Zarathrustra]

But that does not address the central issue: if there is no evidence that links the burden of senescent cells with illnesses or mortality, methinks you are not doing science, you are doing belief. Which may turn out to be true; but may not.

 

Given the centrality of senescence as the supposed root of ageing, it is odd that this untested (and maybe untestable) is being used to then try to find nostrums that may or may not reduce it - which we cannot know, as we have no measure of senescence. Not only that, but (a) the aforementioned nostrums may have deleterious side effects whilst perhaps not doing what is claimed (as its unmeasurable); (b) even if the senescence is reduced, it may have no effect on longevity or illnesses.

[johnhemming]

Interleukin-10 is quite expensive for blood tests and has to be frozen at the time so I am going to leave that for now.

 

There is very clear evidence that the failure of stem cells to differentiate causes a number of diseases of aging (or is a major cause) viz Sarcopenia, Osteoporosis, Artherosclerosis and slow nail growth.  There is evidence consistent with my hypothesis:

https://johnhemming....nd-gradual.html

 

Also Naked Mole Rats have very few senescent cells.

 

Hence it is IMO science. It is easily falsifiable.

[Zarathrustra]

I understand that the theory of the burden of senescent cells as an underlying cause of illness and lower mortality is plausible. My point is that it is just a theory; and that this theory needs proving before we go off on a hydra of research projects and applications based on it. It may be wrong.

 

The paper you quote essentially admits such "it is my view that when Stem Cells fail to differentiate they turn into Senescent Cells. (If it quacks its probably a duck) Hence we now have a feedback loop. I think there is a good chance that this is the feedback loop that drives a lot of deterioration of health." That is, it is proposed/thought likely - not proven or even shown.

 

The references supplied do make the important point that, in effect, inflammation is the main problem - it is posited that the burden of senescent cells is both known by and causes deleterious effects via raising inflammation. This being so, then I cannot see any point (especially when the supposed underlying cause cannot be measured and is only implied from the amount of inflammation) why one doesn't solely concentrate on inflammation as being the central target metric for both illness and longevity research.

 

My main point remains: there is no direct metric for senescence. So no proof that lowering this theoretical cause of problems can achieve anything; nor that any proposed intervention bent on reducing senescence can be shown to work. This is not science. This is speculation based on unproven assumptions, perhaps leading to unnecessary and costly and time-wasted and potentially deleterious interventions.

 

At the moment I am bewildered that so much has been made of this theory when there is no proven evidence that it is true.

[johnhemming]

Anything may be wrong. What you can say about David Sinclairs "information theory of aging" is that Heterochronic Parabiosis proves that it is wrong.  If it were true Heterochronic Parabiosis would not have any effect.  

 

In fact Interleukin-10 is anti-inflammatory.

 

The big issue is that stem cells don't differentiate.  The reason for that became quite clear in a paper in September 2021.

 

As to what happens when Stem Cells don't differentiate properly.   Given that Senescent cells appear mainly in renewable tissue there is no real alternative to the hypothesis that they are mainly Stem Cells that have failed to differentiate.  What else happens with the Stem Cells.  We know badly differentiated Stem Cells hang around at times being a nuisance.

 

Ideally the body would kill them.

Edited by johnhemming, 02 March 2022 - 05:10 PM.

[Mind]

No one has said that senescence is the ROOT cause of aging, only that it plays a significant role in the aging process. There is plenty of evidence chronic inflammation plays a part in many illnesses and produces poor health out comes - and senescent cells produce much of this inflammation. In addition, senescent cell removal has produced dramatic health improvements in animal models for many years now. Considering this, I don't see the reason to NOT pursue this line of research.

[johnhemming]

I am not saying it is the root cause.  I think the failure to differentiate is.   However, the cells that fail to differentiate end up potentially as senescent.

[Zarathrustra]

But how do you know that senescent cells have any effect on ageing or illnesses when you cannot measure them?

 

Why not just stick to inflammation?

 

Senolytics is a major field of research, based on the assumption that any such stuff would reduce senescence. But if you cannot measure senescence, how would you know?

 

I'm not against the theory of senescence being an important part of ageing and illnesses - just that it is an unproven theory. A theory that seems to be taken for granted as being true. Not good science. In fact, not science at all.

[johnhemming]

You can, however, work out which cells are Senescent.

 

I decided today not to spend about GBP 350 at time to do a 4 weekly Interleukin-10 test because 

a) I thought it was quite a bit to spend

b) I had to go to the lab to get my blood sample frozen

c) I am aiming to measure the rate at which my nails grow  (which save the hassle of measuring Interleukin-10

 

I don't know for certain that it is Interleukin-10 that does this, but the circumstantial evidence is pretty strong.

[Zarathrustra]

Thanks for the response. 

 

How do you work out which cells are senescent. More importantly, how does one get a measure of the amount? I could not find anything, only a statement that such a metric was not possible at the moment.

[johnhemming]

This is an article that talks about it.

 

https://www.frontier...2018.00247/full

 

I have decided not to go through the hassle and cost of testing for Interleukin-10.   It is research that needs to be done, but it needs to be done on a number of people in the same way.  I am working on the assumption that my hypothesis is true.  What I am trying to measure is the speed at which my nails grow.  That is linked to the health of stem cells.  

[Zarathrustra]

Thank you.

 

However, this paper only confirms my assertion: it nowhere addresses or measure the total senescence burden. It only shows that senescent cells are part  or the whole of the problem of the ageing problem in skin. The authors themselves implicitly confirm that there is no metric for the senescent burden: “However, a significant hurdle in the aging field has been the identification of a universal biomarker that facilitates the unequivocal detection and quantification of senescent cell types in vitro and in vivo.”; “The identification of unique markers that unequivocally detect and quantify senescent cells, particularly in vivo, remains challenging (Sharpless and Sherr, 2015)” “it remains difficult to multiplex the conventional detection method for SA-β-gal with other senescence-associated or cell-type specific markers, hence limiting the ability to identify senescent cell types or populations within a complex tissue or organ.” “Improved methodologies to detect senescent cells and a better understanding how senescence affects cellular function will [my emphasis]  enable us to determine how they contribute to various age-related skin changes and pathologies, including impaired wound healing and tumorigenesis.”

Until we have a metric for the amount of senescent cells in a body, we cannot know whether the accumulation of such cells even happens. It may be there is always a certain amount of senescent cells in a person's body. 

 

I suspect it is true that there is an increasing amount of senescent cells as we age, and that such an accumulation is a major part of the problems of ageing and of the degenerative diseases of ageing. But at the moment this is not proven - such changes may be a result of the ageing and not a cause. Until we have a senescence metric, we cannot know if the burden increases with age; ebbs and flow with changes of degenerative illnesses; etc.

 

The history of science is replete with failed but plausible theories.

 

Given this uncertainty, the precautionary principle of not then proceeding on the assumption that presumed increases of the senescent burden as a cause of degenerative illnesses be used to be the foundation for processes to reducing such an unmeasurable burden. Doing so, even if successful (how would we know?) may not have the effect sort. Meanwhile there are the unknown side-effects of any such processes, plus maybe squandered effort better spent elsewhere to more effect.

 

Having said all that, I suspect the idea of the increase in the senescent cellular burden is a sound one. I just urge caution in taking from granted that it is true and ploughing ahead with uncertain 'cures' for this. We need a proven metric of the senescent burden, so that we can know for certain that it is a problem, and can measure any process designed to alter it.

[Mind]

We will not know the degree to which senescent cells cause ageing unless research is conducted. The research in animals thus far has been positive for health and longevity. That is the starting point for figuring out if it is positive for humans.

 

If no one ever pursued a line of research because "it is just a theory", there would never be any progress.

[Zarathrustra]

I think you may have misunderstood my point.

 

All research starts with an idea, usually based on plausible explanations for known events. So no issue there.

 

My point is that at the moment we do not have any measure of the amount of senescence in a human. Without this, there is no way to know whether the idea that the (a) this amount changes with time (b) whether it is amenable to being changed by any action we may take; © whether it correlates with longevity or illness; (d) whether it is causative.

 

To then do, as much research is now directed towards, as well as actions being taking, specific actions supposedly to reduce senescence when it cannot be known if it matters or can be altered seems not just pointless but maybe harmful. No-one will know if such interventions alter the amount of senescence, or whether it matters to any supposed links in an unknown causal chain.

 

However, we are each at liberty to do what we want in this regards.

 

I will watch with interest.

[johnhemming]

Looking at this paper

https://pubmed.ncbi....h.gov/34728189/

(which I have had to get the actual pdf paper for as it is not available just as a link and the conditions it is provided under mean I should not publish it)

"However, at higher concentrations (10–100 ng/ml) IL-10 inhibited p38/MAPK signaling, by activating NF-κB with this response being blocked by the NF-κB inhibitor BAY11-7082."

 

This relates to Osteoporosis.

[Zarathrustra]

Thanks John.

 

If I understand correctly, this paper reports that various things give a biphasic relationship to inflammation and thus to osteoporosis and stem cells relating to that.

 

However, the very idea of the hormesis model of dose response is debatable, tho' it seems reasonable to me. But how much is enough and how much is too much? At present I tend to think more of, say curcumin is a good thing. Maybe not? 

 

My main metric for this is my inflammation levels - presently reasonably good.

 

I presume your post was not connected to my doubts about senolytics without any metric for senescence?

[johnhemming]

My post relates to my comments about IL-10

[Mind]

Here is a study (wish i had the full paper) which reviews many senolytic agents, but focuses on Fisetin. Markers of senescence were reduced and health was dramatically improved. Did they measure the actual number of senescent cells that were removed? How would one even do that? https://pubmed.ncbi....h.gov/30279143/

 

Even so, when you find therapeutics that reduce the damaging inflammatory markers of senescence AND dramatically increase the health and longevity of mice, it is well worth investigating further. I am unsure why one would NOT support further research.

[johnhemming]

There is a link to the full paper on the page you linked to:

https://www.ncbi.nlm...les/PMC6197652/

 

There are also ways of getting papers that are otherwise payable.

[Zarathrustra]

John, your paper has this statement: “Senescent cells have been demonstrated to play a causal role in driving aging and age-related diseases using genetic and pharmacologic approaches” I cannot find any papers that support this statement. If you have them, I would appreciate the references.

 

This statement “We previously demonstrated that the combination of dasatinib and the flavonoid quercetin is a potent senolytic improving numerous age-related conditions including frailty, osteoporosis and cardiovascular disease.” Indicates to me that dasatinib and quercetin have therapeutic properties, and the authors assume it is because they act on senescent cells, which, if true, fulfils the definition of them being senolytics – the paper itself does not prove that senescent cells have been cleared away and that the amount of clearance corresponds with the therapeutic improvements. There is no causal chain proven here. This does not detract from the efficacy of the therapeutics, only of a perhaps unnecessary underlying theory (cf. the ether).

 

Thanks Mind for taking the trouble to continue to discuss what I find a major problem with this branch of ageing research.

 

The paper you kindly brought my attention to highlight the very problem I am addressing. It says “Senescent cells have been demonstrated to play a causal role in driving aging and age-related diseases using genetic and pharmacologic approaches”. If this is true, then some of my concerns are laid to rest. But to be certain that this statement is correct, I have now read many of the various links. But let me first note one of my secondary concerns about senolytics: this might have serious side effects. In chasing through the links your paper led me to, it is clear that senescence is thought to be an anti-cancer process – that is, cells going into senescence is both a natural and an oncological goal to prevent cancer; so preventing/reversing senescence may increase cancer.

 

Bear in mind my earlier post from John’s blog “it is my view that when Stem Cells fail to differentiate they turn into Senescent Cells.” This is a view, not empirical evidence. And relates to stem cells, not normal cells.

 

The main links are indicated in the statement “One key mechanism demonstrated to drive aging is cellular senescence, whereby accumulation of DNA damage and/or other cellular stressors [[1], [2], [3], [4]] cause proliferating [8,9] or terminally differentiated non-dividing cells [[10], [11], [12], [13]] to enter a state characterized by profound chromatin and secretome changes, increased expression of the cell cycle inhibitor p16^Ink4a, replicative arrest, and resistance to apoptosis [1,14].

 

1. Tchkonia T., Zhu Y., van Deursen J., Campisi J., Kirkland J.L. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest. 2013;123(3):966–972. [PMC free article] [PubMed] [Google Scholar] refers to stopping cancer cells by making them senescent. Itself does not prove that the amount of senescent cells causes ageing or illnesses.

 

2. Lebrasseur N.K., Tchkonia T., Kirkland J.L. Cellular senescence and the biology of aging, disease, and frailty. Nestle Nutr Inst Workshop Ser. 2015;83:11–18. [PMC free article] [PubMed] [Google Scholar] This paper in turn refers to earlier works: “The abundance of senescent cells increases in multiple tissues with chronological aging [10, 11]”

 

10. Waaijer ME, Parish WE, Strongitharm BH, et al. The number of p16INK4a positive cells in human skin reflects biological age. Aging Cell. 2012;11:722–5. [PMC free article] [PubMed] [Google Scholar] This leads to further quoted links: “In tissues, the prevalence of senescent cells, that is, cells with a permanently arrested cell cycle, has been shown to increase with chronological age, both in animal models (Herbig et al., 2006; Janzen et al., 2006; Krishnamurthy et al., 2006; Molofsky et al., 2006) and in humans (Dimri et al., 1995; Ressler et al., 2006). Furthermore, increased numbers of senescent cells were found to associate with age-related pathologies such as atherosclerotic lesions (Minamino et al., 2002), diabetes (Sone & Kagawa, 2005), and renal disease (Melk et al., 2005; Sis et al., 2007). Higher levels of p16INK4a were associated as well with higher serum creatinine after renal transplantation (Koppelstaetter et al., 2008; McGlynn et al., 2009).”

 

Waaijer ME, Parish WE, Strongitharm BH, et al. The number of p16INK4a positive cells in human skin reflects biological age. Aging Cell. 2012;11:722–5. [PMC free article] [PubMed] [Google Scholar]  Therein states: “Increasing experimental evidence indicates that the accumulation of molecular damage underlies the aging process and age-related pathologies (Hamilton et al., 2001; Stadtman, 2001; Pamplona, 2008).” 

 

1. Hamilton ML, Van Remmen H, Drake JA, Yang H, Guo ZM, Kewitt K, Walter CA, Richardson A. Does oxidative damage to DNA increase with age? Proc. Natl. Acad. Sci. U.S.A. 2001;98:10469–10474. [PMC free article] [PubMed] [Google Scholar] Note: This paper refers to oxidative damage, NOT senescence.
2. Stadtman ER. Protein oxidation in aging and age-related diseases. Ann N. Y. Acad. Sci. 2001;928:22–38. [PubMed] [Google Scholar] Again, this relates to oxidation, not senescence.
3. Pamplona R. Membrane phospholipids, lipoxidative damage and molecular integrity: a causal role in aging and longevity. Biochim. Biophys. Acta. 2008;1777:1249–1262. [PubMed] [Google Scholar] Another paper only concerned with oxidation, not senescence.

“In tissues, the prevalence of senescent cells, that is, cells with a permanently arrested cell cycle, has been shown to increase with chronological age, both in animal models (Herbig et al., 2006; Janzen et al., 2006; Krishnamurthy et al., 2006; Molofsky et al., 2006) and in humans (Dimri et al., 1995; Ressler et al., 2006). Furthermore, increased numbers of senescent cells were found to associate with age-related pathologies such as atherosclerotic lesions (Minamino et al., 2002), diabetes (Sone & Kagawa, 2005), and renal disease (Melk et al., 2005; Sis et al., 2007)

1. Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl. Acad. Sci. U.S.A. 1995;92:9363–9367. [PMC free article] [PubMed] [Google Scholar] “evidence that senescent cells exist and accumulate with age in vivo is lacking. We show that several human cells express a beta-galactosidase, histochemically detectable at pH 6, upon senescence in culture [my emphasis; note this is not in vivo]. This marker was expressed by senescent, but not presenescent, fibroblasts and keratinocytes but was absent from quiescent fibroblasts and terminally differentiated keratinocytes. It was also absent from immortal cells but was induced by genetic manipulations that reversed immortality. In skin samples from human donors of different age, there was an age-dependent increase in this marker in dermal fibroblasts and epidermal keratinocytes. This marker provides in situ evidence that senescent cells may [my emphasis] exist and accumulate with age in vivo.” [Note: this a one-time assessment; no determination of whether the amount of senescent cells increase with age]
2. Ressler S, Bartkova J, Niederegger H, Bartek J, Scharffetter-Kochanek K, Jansen-Durr P, Wlaschek M. p16INK4A is a robust in vivo biomarker of cellular aging in human skin. Aging Cell. 2006;5:379–389. [PubMed] [Google Scholar]  “We therefore conclude that p16^INK4A is a true and robust biomarker of intrinsic cellular aging in vivo” [Note: this is a biomarker of a cell ageing; not whether it is senescent or not]

My main problem with the idea of senescent burden being one of the main drivers of ageing is that the only supporting evidence is weak and inferential, not empirically causal. A marker of skin ageing, p16^INK4A , is more prevalent in aged skin than young skin. This is thought to indicate a greater amount of senescent cells. Perhaps. Perhaps not.

 

Let us assume it is indeed true that p16^INK4A is an unambiguous biomarker for senescent cells. Where is the research that shows that there is a correlation for the quantity of such p16^INK4A and age in general, and various illnesses? In the absence of this base research, why use substances/processes that claim to reduce this biomarker? As noted above, just targeting inflammation may be adequate without the danger of accidentally enhancing the risk of collateral damage.

“A prime suspected cause of these prominent age-related disorders is the chronic, nonmicrobial inflammation that develops in multiple tissues” That is, it is inflammation that is the direct cause of problems. No need to proliferate more entities it seems (Occam’s Razor).

 

[johnhemming]

That's not my paper.  That's this one:

https://pubmed.ncbi....h.gov/30279143/

 

Background: Senescence is a tumor suppressor mechanism activated in stressed cells to prevent replication of damaged DNA. Senescent cells have been demonstrated to play a causal role in driving aging and age-related diseases using genetic and pharmacologic approaches. We previously demonstrated that the combination of dasatinib and the flavonoid quercetin is a potent senolytic improving numerous age-related conditions including frailty, osteoporosis and cardiovascular disease. The goal of this study was to identify flavonoids with more potent senolytic activity.

 

https://www.ncbi.nlm...les/PMC6197652/

[Mind]

 

 

But let me first note one of my secondary concerns about senolytics: this might have serious side effects. In chasing through the links your paper led me to, it is clear that senescence is thought to be an anti-cancer process – that is, cells going into senescence is both a natural and an oncological goal to prevent cancer; so preventing/reversing senescence may increase cancer.

 

The process of cells becoming senescent is thought to be the body's way of suppressing cancer. Once cells are senescent, they increase damaging types of inflammation throughout the body which is not good for health.

 

The idea with senolytic therapy is not to interfere with the body's process of senescence, only to remove some of the cells after they have already gone through this process. The current research is exploring brief therapies to remove some senescent cells, then allow the body to continue its natural processes with less of the damaging inflammation.

[Phoebus]

John, your paper has this statement: “Senescent cells have been demonstrated to play a causal role in driving aging and age-related diseases using genetic and pharmacologic approaches” I cannot find any papers that support this statement. If you have them, I would appreciate the references.

 

 

 

 

If you go to the full study, footnotes 19, 20, and 21 are studies which support this 

 

https://www.ncbi.nlm...les/PMC6197652/

[johnhemming]

The idea with senolytic therapy is not to interfere with the body's process of senescence, only to remove some of the cells after they have already gone through this process. The current research is exploring brief therapies to remove some senescent cells, then allow the body to continue its natural processes with less of the damaging inflammation.

 

There is an interesting thought if one starts with the assumption that a goodly proportion of senescent cells are cells which have not properly differentiated.  That thought is that it is possible to get the cells to properly differentiate.

 

There is an issue with that and senolytics when you have artherosclerosis at a substantial amount as killing off the senescent cells could cause blood to leak followed by clotting.  There may be other situations where just getting rid of the senescent cells quickly is not helpful, but doing it gradually is probably not an issue.

 

What you need, however, is sufficient stem cells that do differentiate property to maintain bodily functions.

 

In essence this means that reversing this process really needs to be quite slow.

[LeeYa]

@Zarathrusta

 

Indeed, chronic inflammation (SASP) is the main culprit in senescent tissues. Targeting inflammation is beneficial.

BUT- if you target inflammation, you will just target the symptoms, not the root causes of inflammation?

 

I think it is proven that senescent cells produce chronic inflammation.

 

My suggestion is that you can use your baseline inflammation biomarkers ( IL-6, hsCRP) as a surrogate parameter for senescence burden.

 

If chronic inflammation is absent, there is no need for Senolytics.

If inflammation is present, you have to rule out other specific diseases first.

 

If chronic inflammation persist after a senolytic trial, the treatment apparently failed.

 

Edited by LeeYa, 08 March 2022 - 12:15 PM.

[johnhemming]

My hypothesis is essentially that the primary cause of aging is the failure of the body's systems of renewal.  Those fail because of differentiation problems and the cells become senescent which drives more differentiation problems. Hence I would argue dealing with this process is key. It may be that a bit of lemon juice helps with the problems with the citrate carrier, but failure to renew is so obviously behind so many of the key disease of aging and it could be behind more of them.  That still leaves things like oxidative stress (which probably exacerbates renewal problems) and glycation of proteins as issues to deal with, but if the renewal systems break in a self-reinforcing manner then we get the exponentially increasing mortality rate behind Gompertz.

[Zarathrustra]

Re John Hemming Yesterday, 03:15 PM and his ref

 

Apologies John for referencing the incorrect paper. I have now done so, with the following results. Which are the same as earlier:

 

Fisetin is a senotherapeutic that extends health and lifespan

Therein is stated: “One key mechanism demonstrated to drive aging is cellular senescence, whereby accumulation of DNA damage and/or other cellular stressors [[1], [2], [3], [4]]”

 

1. Tchkonia T., Zhu Y., van Deursen J., Campisi J., Kirkland J.L. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest. 2013;123(3):966–972. [PMC free article] [PubMed] [Google Scholar]  This paper in turn states: “The abundance of senescent cells increases in multiple tissues with chronological aging and in progeroid syndromes (43, 47, 50, 52–55)”
   1. 43. Burton DG. Cellular senescence, ageing and disease. Age (Dordr). 2009;31(1):1–9. doi: 10.1007/s11357-008-9075-y. [PMC free article] [PubMed] [CrossRef] [Google Scholar] “his review therefore brings together and discusses recent findings which suggest that cellular senescence does contribute to ageing and the development/progression of disease. [Note: It does not prove that such exists]
   2. 47. Baker DJ, et al. Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nat Cell Biol. 2008;10(7):825–836. doi: 10.1038/ncb1744. [PMC free article] [PubMed] [CrossRef] [Google Scholar] “we identify BubR1 insufficiency as a trigger for activation of the Cdkn2a locus in certain mouse tissues, and demonstrate that p16^Ink4a is an effector and p19^Arf an attenuator of senescence and ageing in these tissues.” [Note: this says nothing about whether the amount of senescence increases with age, only that “p19^Arf an attenuator of senescence and ageing”, not that this is evidence of increases of senescent cells]
   3. 50. Waaijer ME, et al. The number of p16INK4a positive cells in human skin reflects biological age. Aging Cell. 2012;11(4):722–725. doi: 10.1111/j.1474-9726.2012.00837.x. [PMC free article] [PubMed] [CrossRef] [Google Scholar] This paper refers to two papers as evidence that an increasing amount of senescent cells underlies ageing. However, I have addressed this previously:
      1. Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl. Acad. Sci. U.S.A. 1995;92:9363–9367. [PMC free article] [PubMed] [Google Scholar] “evidence that senescent cells exist and accumulate with age in vivo is lacking. We show that several human cells express a beta-galactosidase, histochemically detectable at pH 6, upon senescence in culture [my emphasis; note this is not in vivo]. This marker was expressed by senescent, but not presenescent, fibroblasts and keratinocytes but was absent from quiescent fibroblasts and terminally differentiated keratinocytes. It was also absent from immortal cells but was induced by genetic manipulations that reversed immortality. In skin samples from human donors of different age, there was an age-dependent increase in this marker in dermal fibroblasts and epidermal keratinocytes. This marker provides in situ evidence that senescent cells may [my emphasis] exist and accumulate with age in vivo.” [Note: this a one-time assessment; no determination of whether the amount of senescent cells increase with age]
      2. Ressler S, Bartkova J, Niederegger H, Bartek J, Scharffetter-Kochanek K, Jansen-Durr P, Wlaschek M. p16INK4A is a robust in vivo biomarker of cellular aging in human skin. Aging Cell. 2006;5:379–389. [PubMed] [Google Scholar]  “We therefore conclude that p16^INK4A is a true and robust biomarker of intrinsic cellular aging in vivo” [Note: this is a biomarker of a cell ageing; not whether it is senescent or not]

I’m afraid this is me done with chasing references that fail to empirically show that there is an increase of senescent cells with age in humans.

 

I believe this is an important idea. That there well may be an increase of senescent cells with age. But I have yet to find an empirically based paper that shows this is so. I cannot find any metric that measure the amount of senescent cells in a human – such as, say, CRP does for the amount of inflammation.

 

Without such a metric, as I said at the start of my post, all that follows is based on conjecture, not science.

 

Someone needs to do the first step: produce a metric that measures the amount of senescent cells (if this exist, please provide the reference to the paper that does this, not endless linkages papers stating that it is so but not the paper that does so).

 

Once we have this metric, then we can test on the metric on different age groups and different illness to see whether this metric correlates with age and illnesses. If so, then we need to do a causal study – which will take years – to confirm that this correlation is causal.

 

Having done that, then we can explore whether altering the amount of senescent cells has any effect on ageing and/or illnesses.

 

Meanwhile, inflammation appears a better metric – it is well established.

 

The point that inflammation itself has an underlying, unknown, causation, is irrelevant as the same argument applies to any prior cause – there is an infinite chain of causation, right back to the Big Bang or God. What causes the Hayflick limit on cellular division, etc.

 

[Zarathrustra]

Thanks Mind (yesterday at 08:54

 

"The idea with senolytic therapy is not to interfere with the body's process of senescence, only to remove some of the cells after they have already gone through this process. The current research is exploring brief therapies to remove some senescent cells, then allow the body to continue its natural processes with less of the damaging inflammation." Laudable. I take your point about not interfering with the process of becoming senescent, but as always, good intentions need watching carefully. Any messing with cellular processes inevitably may indeed interfere with the senescent process.

[johnhemming]

Looking at this paper:

https://www.ncbi.nlm...les/PMC7607511/

 

Senescence is being measured by cells being p16Ink4a-positive.

 

It is also possible to measure elements of SASP

https://en.wikipedia...etory_phenotype

 

This paper looks at 

Techniques to Induce and Quantify Cellular Senescence

https://www.ncbi.nlm...les/PMC5565152/

Edited by johnhemming, 09 March 2022 - 02:08 AM.