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Senescent Cell SASP Induces CD38 in Non-Senescent Bystander Cells

cd38 sasp senescent cells nad+

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#1 Michael

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Posted 12 April 2019 - 02:52 PM


All:
 

The NADase CD38 is induced by factors secreted from senescent cells providing a potential link between senescence and age-related cellular NAD+ decline
Claudia Chini, Kelly A. Hogan, Gina M. Warner, Mariana G. Tarragó, Thais R.Peclat, Tamar Tchkoni, James L.Kirkland, Eduardo Chini
https://doi.org/10.1...brc.2019.03.199

Here we investigated if the cellular senescence phenotype is involved in the regulation of CD38 expression and its NADase activity. We observed that senescent cells do not have high expression of CD38. ...

Next, we investigated whether components of the SASP were able to regulate the expression of CD38 in non-senescent cells. M1 macrophages are the prototype CD38-expressing cells, and it has been demonstrated that induction of the M1 phenotype by LPS, TNF-α, and activators of the LXR receptor leads to increased CD38 expression in these cells. In fact, CD38 is proposed to be one of the main markers of induction of the M1 phenotype in macrophages. Here we show that representative SASP factors (TNFα, IL-6, CXCL1, CXCL2) had small or no significant effects on CD38 activity or protein expression when given individually, but when combined promoted a synergistic effect that led to a strong increase in CD38 activity (Fig. 2B) and CD38 protein levels (Fig. 2C) in murine bone marrow-derived macrophages (BMDM).

3.3. Conditioned media from senescent cells induces CD38 expression in macrophages and endothelial cells.
We next tested whether or not conditioned media derived from senescent cells could induce CD38 expression in both inflammatory (BMDM) and non-inflammatory (HUVEC) cells (scheme Fig. 3A). We focused on BMDM and HUVECs because previous reports demonstrate that CD38 in vivo is preferentially expressed in inflammatory and endothelial cells [9,33]. In support of our hypothesis, we observed that exposure to conditioned media from x-ray- or [gamma-radiation]-induced senescent HUVECs leads to increases in CD38 mRNA expression and NADase activity in mouse BMDMs compared to control condioned media (Fig. 3B). [This was later confirmed at the protein level -MR].

It has been previously demonstrated that pre-adipocytes are one of the main cells that become senescent in vivo. ... In support of our hypothesis we observed that conditioned media from senescent preadipocytes derived from two independent [middle-aged obese patients undergoing kidney transplant or gastric bypass surgery] induced CD38 expression and CD38 NADase activity in BMDM, although media from one of the patients caused a much stronger induction of CD38 than the other (Fig. 3C and D). We also observed that the SASP from senescent cells also induced CD38 expression in endothelial cells [again, later confirmed at the protein level, and via] expression of other cellular markers of the M1 phenotype such as IL-6, IL-8, and iNOS. ...
 

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Furthermore, it has also been observed that clearance of senescent cells in vivo can decrease the expression of several components of the SASP including TNF-α, IFNγ, IL-1b, IL-8 and IL-6. This may indicate that senescent cells in vivo may modulate CD38 expression via changes in tissue cytokines and chemokines (Fig. 4C). This hypothesis will be further tested in our laboratory using senolytic agents.

 


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#2 Harkijn

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Posted 03 April 2021 - 03:43 PM

I was not aware of the fact that CD38 basically is a SASP,  and this new review has  a lot more interesting statements about NMN and NR. I wonder what posters here think about it:


Edited by Harkijn, 03 April 2021 - 03:44 PM.

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#3 Phoebus

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Posted 03 April 2021 - 04:06 PM

Interesting vid 

 

He claims that raising NAD levels causes an increase in senescent inflammation, and a decrease in something called the acinar area (new concept to me) which is a precancerous condition. 

 

He quotes this study here 

 

https://pubmed.ncbi....h.gov/31140365/

 

 

 

A recent report links these processes, such that decreased NAD+ levels associated with aging may attenuate the SASP potentially reducing its pathological effect. Conversely, increasing NAD+ levels by supplementation or genetic manipulation, which may benefit tissue homeostasis, also may worsen SASP and encourage tumorigenesis at least in mouse models of cancer. Taken together, these findings suggest a fundamental trade-off in treating aging-related diseases with drugs or supplements that increase NAD+.

 

So its a chinese fingercuff issue. Lowering NAD -> lower senescent inflammation -> less cancer, but it accelerates again. Whereas raising NAD -> slowing aging process, BUT also increases senescent inflammation and therefore cancer risk. 

 

 

Eliminating senescent cells FIRST, then boosting NAD levels is the way to go, he say. But then he suggests using quercetin and fisetin to clear away S. cells, and quite frankly the evidence for that is weak so far. Interesting vid 


Edited by Phoebus, 03 April 2021 - 04:33 PM.

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#4 Harkijn

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Posted 04 April 2021 - 06:39 AM

Having watched the video again I see now that I was not fully accurate before. He does not say that CD38 is a SASP but that it is a reaction to SASPs.

However , we know that CD38 has many more functions, some detrimental but some also positive. The Wikipedia article on CD38 neatly sums them up.



#5 Mind

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Posted 04 April 2021 - 10:07 AM

Agreed that getting rid of a certain percentage of senescent cells first is probably the best way to go, considering the evidence thus far.


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#6 Phoebus

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Posted 04 April 2021 - 03:43 PM

Agreed that getting rid of a certain percentage of senescent cells first is probably the best way to go, considering the evidence thus far.

 

And do you think the evidence for fisetin/quercetin actually reducing S. cells in the human body is strong? 

 

Seems so so to me


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#7 Mind

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Posted 05 April 2021 - 08:12 PM

And do you think the evidence for fisetin/quercetin actually reducing S. cells in the human body is strong? 

 

Seems so so to me

 

I think the evidence is quite good for fisetin. Dozens of studies have been conducted in animals and humans, all coming out positive, as far as I am aware.

 

The only odd result is one company finding that they could not reliably measure a change in senescent cells or SASP markers, when conducting tests in vitro. But that is in vitro, as far I am aware. All of the in vivo work has been quite positive.


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