129 replies to this topic

[jamesagreen]

Examine:
Darren J. Baker, et al, (2011),
Clearance of P16INK4a-positive senescent cells delays aging-associated disorders, Nature Letters, 2011.
See associated Links , and the Article in Nature.
The associated Letter has a touch of black humor
about it, as photos show that the bigger mouse (an "INK-ATTAK 5" mouse) seems to have arse-whipped the little mouse
with P16INK4A senescent cells until its spine has curled up,
judging from the original communication in Nature Research Letters, which is not of today visible on Internet.
There is some question about what is actually being viewed and a possible shell game played with the mice.

[Mind]

How about this for a marker for senescent cells: http://www.longecity...enescent-cells/

Due to its role in aging and antitumor defense, cellular senescence has recently attracted increasing interest. However, there is currently no single specific marker that can unequivocally detect senescent cells. Here, we identified α-L-fucosidase (α-Fuc) as a novel sensitive biomarker for cellular senescence. Regardless of the stress stimulus and cell type, α-Fuc activity was induced in all canonical types of cellular senescence, including replicative, DNA damage- and oncogene-induced senescence. Strikingly, in most models the degree of α-Fuc upregulation was higher than the induction of senescence-associated β-galactosidase (SA-β-Gal), the current gold standard for senescence detection. As α-Fuc is convenient and easy to measure, we suggest its utility as a valuable marker, in particular in cells with low SA-β-Gal activity.

Edited by Mind, 17 May 2013 - 05:58 PM.

[Elus]

How about this for a marker for senescent cells: http://www.longecity...enescent-cells/

Due to its role in aging and antitumor defense, cellular senescence has recently attracted increasing interest. However, there is currently no single specific marker that can unequivocally detect senescent cells. Here, we identified α-L-fucosidase (α-Fuc) as a novel sensitive biomarker for cellular senescence. Regardless of the stress stimulus and cell type, α-Fuc activity was induced in all canonical types of cellular senescence, including replicative, DNA damage- and oncogene-induced senescence. Strikingly, in most models the degree of α-Fuc upregulation was higher than the induction of senescence-associated β-galactosidase (SA-β-Gal), the current gold standard for senescence detection. As α-Fuc is convenient and easy to measure, we suggest its utility as a valuable marker, in particular in cells with low SA-β-Gal activity.

Step 1. Obtain DNA nanobot developed by George Church et al. This bot opens via lock-and-key when exposed to tumor antigen, then delivers toxic payload for apoptosis induction.

Step 2. Rejigger nanobot to open in the presence of α-L-fucosidase, selectively inducing apoptosis in senescent cells. Inject bots into mouse.

Step 3. ?????

Step 4. Profit.

EDIT: Not sure if the above method would work if α-L-fucosidase was not exposed on the cell surface.

Edited by Elus, 18 May 2013 - 12:12 AM.

[Logic]

"...is now becoming evident
that cellular senescence is a robust physiological antitumor
response that is engaged by tissues to counteract oncogenic insults.
Not only does it appear to be one of the primary physiological
mechanisms which serve to inhibit tumorigenesis, but it is also now
evident that senescent cells can be cleared in vivo through an innate
immune response. In fact, senescent cells have been reported to
express ligands for cytotoxic immune cells, such as natural killer
cells, that may permit the immune system to specifically target
senescent cells and kill them in vivo...

...The anti-cancer potential of an organism over the life-span may
depend both on the integrity of molecules involved in tumor suppressor
pathways, and in particular of genes involved in apoptosis
and cellular senescence, and on the proper effectiveness of immune
functions, which are involved both in the killing of tumor cells and
in the elimination of senescent cells. Both these systems cooperate
in the prevention of tumorigenesis and cancer progression. The
good effectiveness of the mechanisms regulating this homeostasis,
generally associated with young age, gradually decline with age
because of the time-dependent accumulation of mutations in cells
and the degeneration of the immune system (i.e. Immunosenescence)..."
http://www.google.co...tdHiYfPsACK3vbA

"...The primary response to p53 was not apoptosis, but instead involved the induction of a cellular senescence program that was associated with differentiation and the upregulation of inflammatory cytokines. This program, although producing only cell cycle arrest in vitro, also triggered an innate immune response that targeted the tumour cells in vivo, thereby contributing to tumour clearance..."
http://www.ncbi.nlm....pubmed/17251933

"...senescent activated stellate cells exhibit gene expression profile consistent with cell-cycle exit, reduced secretion of extracellular matrix components, enhanced secretion of extracellular matrix-degrading enzymes, and enhanced immune surveillance. Accordingly natural killer cells preferentially kill senescent activated stellate cells in vitro and in vivo..."
http://www.ncbi.nlm....pubmed/18724938
 
So it would seem that we should be concentrating on avoiding Immunosenescence and cell/DNA mutations as a means to stay clear of senescent cells..?

 

There are practical methods of achieving this that are already being applied.

 

[HighDesertWizard]

"...is now becoming evident
that cellular senescence is a robust physiological antitumor
response that is engaged by tissues to counteract oncogenic insults.
Not only does it appear to be one of the primary physiological
mechanisms which serve to inhibit tumorigenesis, but it is also now
evident that senescent cells can be cleared in vivo through an innate
immune response. In fact, senescent cells have been reported to
express ligands for cytotoxic immune cells, such as natural killer
cells, that may permit the immune system to specifically target
senescent cells and kill them in vivo...
 

<< SNIP >>

 

So it would seem that we should be concentrating on avoiding Immunosenescence and cell/DNA mutations as a means to stay clear of senescent cells..?

 

There are practical methods of achieving this that are already being applied.

 

NF-kB has recently become a study focus for those thinking about Senescence and the Senescence Associated Secretory Phenotype, or SASP...

 

NF-κB inhibition delays DNA damage–induced senescence and aging in mice

 

Deciphering the role of Nuclear Factor-κB in cellular senescence

 

Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity

 

Emerging role of NF-κB signaling in the induction of senescence-associated secretory phenotype (SASP)

Edited by HighDesertWizard, 15 February 2015 - 08:08 PM.

[Logic]

NF-kB has recently become a study focus for those thinking about Senescence and the Senescence Associated Secretory Phenotype, or SASP...
 
NF-κB inhibition delays DNA damage–induced senescence and aging in mice
 
Deciphering the role of Nuclear Factor-κB in cellular senescence
 
Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity
 
Emerging role of NF-κB signaling in the induction of senescence-associated secretory phenotype (SASP)

If the cell already has DNA damage we want it taken out, not kept alive.
The best way to do so atm seems to be by keeping the immune system in peak condition.

[HighDesertWizard]

 

NF-kB has recently become a study focus for those thinking about Senescence and the Senescence Associated Secretory Phenotype, or SASP...
 
NF-κB inhibition delays DNA damage–induced senescence and aging in mice
 
Deciphering the role of Nuclear Factor-κB in cellular senescence
 
Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity
 
Emerging role of NF-κB signaling in the induction of senescence-associated secretory phenotype (SASP)

If the cell already has DNA damage we want it taken out, not kept alive.
The best way to do so atm seems to be by keeping the immune system in peak condition.

 

 

It's a commonplace to say that Immune System health is critical for longevity. And it makes sense that it is. And, yet....

 

AFAIK, there is much more profound evidence that a healthy and functioning Vagus-CAIP-HRV process is more critical for longevity. And that nexus of functions modulates the Immune System expression of NF-kB...

 

Here are several slides I've put together about that evidence...

 

I'm not clear, yet, about how the literature of the Vagus-CAIP-HRV nexus of processes fits in detail with the recent literature about the importance of NF-kB to Senescence and the SASP.

 

But I do notice that the title of that first study above is NF-κB inhibition delays DNA damage–induced senescence and aging in mice. I take it, then, that a focus on Activation of the Vagus-CAIP-HRV nexus is a high priority. That's why I created the thread below... To brainstorm means to do it...

 

Triggering the Cholinergic Antiinflammatory Pathway to Inhibit NF-kB

 

Thoughts?

Edited by HighDesertWizard, 15 February 2015 - 10:51 PM.

[Logic]

 

 

NF-kB has recently become a study focus for those thinking about Senescence and the Senescence Associated Secretory Phenotype, or SASP...
 
NF-κB inhibition delays DNA damage–induced senescence and aging in mice
 
Deciphering the role of Nuclear Factor-κB in cellular senescence
 
Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity
 
Emerging role of NF-κB signaling in the induction of senescence-associated secretory phenotype (SASP)

If the cell already has DNA damage we want it taken out, not kept alive.
The best way to do so atm seems to be by keeping the immune system in peak condition.

 

 

It's a commonplace to say that Immune System health is critical for longevity. And it makes sense that it is. And, yet....

 

AFAIK, there is much more profound evidence that a healthy and functioning Vagus-CAIP-HRV process is more critical for longevity. And that nexus of functions modulates the Immune System expression of NF-kB...

 

Here are several slides I've put together about that evidence...

 

I'm not clear, yet, about how the literature of the Vagus-CAIP-HRV nexus of processes fits in detail with the recent literature about the importance of NF-kB to Senescence and the SASP.

 

But I do notice that the title of that first study above is NF-κB inhibition delays DNA damage–induced senescence and aging in mice. I take it, then, that a focus on Activation of the Vagus-CAIP-HRV nexus is a high priority. That's why I created the thread below... To brainstorm means to do it...

 

Triggering the Cholinergic Antiinflammatory Pathway to Inhibit NF-kB

 

Thoughts?

 

 

I read your posts on the above:  Very interesting info and points to gut health being very important too.

 

I didn't notice the 1st study!  Thx for setting me straight!

yet more study reqd.  Sigh!

 

 

[tintinet]

http://www.cell.com/...65?showall=true

[eighthman]

Sorry but this removal of senescent cells subject looks to me like a highly marginal affair or a dead end.   If any of the reputed senolytics do their job, then I would expect someone would offer an anecdote of benefit ( as in "Woo Hoo ! My hair isn't gray" etc.)

 

In the context of SENS, perhaps it is just marginal and we need a bit of synergy to show dramatic effects.  Please prove me wrong (no, really ... I'd rather be wrong here)