2255 replies to this topic

[tunt01]

Parp-1 activity is reduced by AMPK activation.  Telmisartan, Metformin and AICAR elicit this metabolic cascade.  Metoprolol, glipizide does not.

 

 

Cardiovascular Protective Effect of Metformin and Telmisartan: Reduction of PARP1 Activity via the AMPK-PARP1 Cascade.

 

Hyperglycemia and hypertension impair endothelial function in part through oxidative stress-activated poly (ADP-ribose) polymerase 1 (PARP1). Biguanides and angiotensin II receptor blockers (ARBs) such as metformin and telmisartan have a vascular protective effect. We used cultured vascular endothelial cells (ECs), diabetic and hypertensive rodent models, and AMPKα2-knockout mice to investigate whether metformin and telmisartan have a beneficial effect on the endothelium via AMP-activated protein kinase (AMPK) phosphorylation of PARP1 and thus inhibition of PARP1 activity. The results showed that metformin and telmisartan, but not glipizide and metoprolol, activated AMPK, which phosphorylated PARP1 Ser-177 in cultured ECs and the vascular wall of rodent models. Experiments using phosphorylated/de-phosphorylated PARP1 mutants show that AMPK phosphorylation of PARP1 leads to decreased PARP1 activity and attenuated protein poly(ADP-ribosyl)ation (PARylation), but increased endothelial nitric oxide synthase (eNOS) activity and silent mating type information regulation 2 homolog 1 (SIRT1) expression. Taken together, the data presented here suggest biguanides and ARBs have a beneficial effect on the vasculature by the cascade of AMPK phosphorylation of PARP1 to inhibit PARP1 activity and protein PARylation in ECs, thereby mitigating endothelial dysfunction.

 

 

 

 

 

 

 

Metformin and telmisartan enhance AMPK and PARP1 phosphorylation in HUVECs. (IN VITRO)

 

 

Western blot analysis of AMPK Thr-172 and PARP1 Ser-177 phosphorylation in HUVECs treated with concentrations of metformin (A), glipizide (B), telmisartan ©, and metoprolol (D) for 4 hr or (E-H) metformin (5 mM), glipizide (500 nM), telmisartan (5 μM), and metoprolol (500 μM) for the indicated times. Data are mean±SD ratio of phospho-PARP1 to total PARP1 and phospho-AMPK to total AMPK from 3 independent experiments. *p<0.05 compared to controls.

 

 

 

 

AMPK phosphorylates PARP1 Ser-177 in vitro and in vivo.   (IN VIVO)
 

 

 

 

Twelve week-old male C57BL6 mice were administered (A) metformin (200 mg/kg body weight), (B) glipizide (1.3 mg/kg body weight), © telmisartan (10 mg/kg body weight), or (D) metoprolol (30 mg/kg body weight) for the indicated times. Control mice received 0.5 ml saline. Western blot analysis of AMPK and PARP1 phosphorylation in aortic extracts from 2 mice pooled. Data are mean ± SD ratio of phospho-PARP1 to total PARP1 and phospho-AMPK to total AMPK (n = 8 mice per group). *p<0.05 compared to controls.

 

 

Edited by prophets, 10 August 2016 - 03:18 PM.

[Nate-2004]

It's looking more and more like working down the stream of what's causing NAD depletion, PARP, the rise in CD38 and other culprits, is going to be the ultimate solution to the NAD+ angle.  There are so many angles to the aging problem it seems.

 

Metformin is unavailable without a prescription in the U.S.  I'm not sure how I'd go about getting it as a preventative. I could just ask my GP I suppose.

 

The evidence so far, in doing searches around the board and elsewhere, is still spotty and hit or miss with Metformin.

 

Let's hope we get results on senolytics and other methods soon. 

 

The dosing might not need to be high as its not needed to recover NAD+. My own speculation is that the body start off with having an abundance of NAD+ and problems start when a certain threshold low value is achieved. So we may only need to boost till this threshold.

 

Stefan why did you conclude that?

Edited by Nate-2004, 10 August 2016 - 03:21 PM.

[Steve H]

It's looking more and more like working down the stream of what's causing NAD depletion, PARP, the rise in CD38 and other culprits, is going to be the ultimate solution to the NAD+ angle.

 

 

Indeed this is what I suggested weeks ago. It is my hope that in reducing SASP (which contains CD38) the availability of NAD will rise again as it is no longer being destroyed by CD38. This would then vindicate that the SENS approach to aging is valid and targetting the root of the problem should allow the body to recover somewhat. Of course there are various factors involved in aging and senescent cells and the resulting inflammaging cascade is only one of them but it is in my view a large part of why we age. I would go as far as suggesting that CD38 in SASP is responsible for the decline of NAD with age, indeed as SASP rises NAD declines and CD38 in particular (though other cytokines like TGF-beta, TNF-a from the NFKB pathway may also have a role) could be the key mechanism of that loss, indeed Sinclair eludes to this in his 2012 paper. It could also explain why we see improvement in healthspan from senolytics and is consistent with other tests with NAD upregulation which have shown improvements to healthspan also, so this could be one of the primary reasons for this result. 

It is one reason why the MMTP will monitor NAD levels and NAD ratio to see if this hypothesis pans out and there is every reason to suspect it might.

Edited by Steve H, 10 August 2016 - 04:03 PM.

[albedo]

While we wait for the Football study, from this article 

 

http://www.ncbi.nlm....pubmed/25361036

 

"Skeletal muscle from aged mice displays higher PARP-1 activity and lower SIRT-1 activity due to decreased intracellular NAD+ content, and as a result reduced muscle performance in response to exercise. Interestingly, injection of PJ34, a PARP-1 inhibitor, in aged mice increased SIRT-1 activity by preserving intracellular NAD+ content, which resulted in higher skeletal muscle mitochondrial biogenesis and performance."

 

Based on the results of this article it seems that preserving your NAD+ and increasing SIRT-1 activity with improve skeletal muscle performance.

 

As Resveratrol is supposed to increase SIRT1 activity, I wonder if the following study (pay-walled but will get access to it) also adds to the beneficial evidence of NR via a similar path. I also posted it on the sarcopenia thread:

 

Resveratrol primes the effects of physical activity in old mice

http://journals.camb...ne&aid=10458324

 

"Decrease in muscle mass and performance with ageing is one of the main factors of frailty in the elderly. Maintenance of muscle performance by involving in physical activities is essential to increase independence and quality of life among elderly. The use of natural compounds with ergogenic activity in old people would increase the effect of moderate exercises in the maintenance of physiological muscle capacity. Resveratrol (RSV), a polyphenol found in walnuts, berries and grapes, shows this ergogenic activity. By using young, mature and old mice as models, we have found that RSV improves muscle performance in mature and old animals but not in young animals. Without showing significant effect by itself, RSV primed the effect of exercise by increasing endurance, coordination and strength in old animals. This effect was accompanied by a higher protection against oxidative damage and an increase in mitochondrial mass. RSV increased catalase and superoxide dismutase protein levels in muscle and primed exercise to reverse the decrease in their activities during ageing. Furthermore, RSV increased the level of mitochondrial mass markers such as cytochrome C, mitochondrial transcription factor A and nuclear respiratory factor-1 in muscle in exercised animals. Our results indicate that RSV can be considered an ergogenic compound that helps maintain muscle performance during ageing and subsequently reduces frailty and increases muscle performance in old individuals practising moderate exercise." (bold mine)

 

[Nate-2004]

 

While we wait for the Football study, from this article 

 

http://www.ncbi.nlm....pubmed/25361036

 

"Skeletal muscle from aged mice displays higher PARP-1 activity and lower SIRT-1 activity due to decreased intracellular NAD+ content, and as a result reduced muscle performance in response to exercise. Interestingly, injection of PJ34, a PARP-1 inhibitor, in aged mice increased SIRT-1 activity by preserving intracellular NAD+ content, which resulted in higher skeletal muscle mitochondrial biogenesis and performance."

 

Based on the results of this article it seems that preserving your NAD+ and increasing SIRT-1 activity with improve skeletal muscle performance.

 

As Resveratrol is supposed to increase SIRT1 activity, I wonder if the following study (pay-walled but will get access to it) also adds to the beneficial evidence of NR via a similar path. I also posted it on the sarcopenia thread:

 

Resveratrol primes the effects of physical activity in old mice

http://journals.camb...ne&aid=10458324

 

"Decrease in muscle mass and performance with ageing is one of the main factors of frailty in the elderly. Maintenance of muscle performance by involving in physical activities is essential to increase independence and quality of life among elderly. The use of natural compounds with ergogenic activity in old people would increase the effect of moderate exercises in the maintenance of physiological muscle capacity. Resveratrol (RSV), a polyphenol found in walnuts, berries and grapes, shows this ergogenic activity. By using young, mature and old mice as models, we have found that RSV improves muscle performance in mature and old animals but not in young animals. Without showing significant effect by itself, RSV primed the effect of exercise by increasing endurance, coordination and strength in old animals. This effect was accompanied by a higher protection against oxidative damage and an increase in mitochondrial mass. RSV increased catalase and superoxide dismutase protein levels in muscle and primed exercise to reverse the decrease in their activities during ageing. Furthermore, RSV increased the level of mitochondrial mass markers such as cytochrome C, mitochondrial transcription factor A and nuclear respiratory factor-1 in muscle in exercised animals. Our results indicate that RSV can be considered an ergogenic compound that helps maintain muscle performance during ageing and subsequently reduces frailty and increases muscle performance in old individuals practising moderate exercise." (bold mine)

 

 

Two questions:

 

1: On the topic of adding SIRT activators with NR. Does pterostilbene in fact activate SIRT1 2 or 3? I see conflicting evidence about this amidst the tiny amount of research on pterostilbene.

2: Any suggestions on getting Metformin? I figure this may tide me over in the meantime. Would be great if my insurance covered it but how would one go about talking the doctor into prescribing it?

 

[Bryan_S]

 

I think the study shows 3 things:

1) NAD+ boosting recovers muscle

2) NR performs better than nicotinamide

3) The dosing might not need to be high as its not needed to recover NAD+. My own speculation is that the body start off with having an abundance of NAD+ and problems start when a certain threshold low value is achieved. So we may only need to boost till this threshold.

 

 

This study is making its rounds.

https://www.fightagi...pacity-in-mice/

[stefan_001]

 

It's looking more and more like working down the stream of what's causing NAD depletion, PARP, the rise in CD38 and other culprits, is going to be the ultimate solution to the NAD+ angle.

 

 

Indeed this is what I suggested weeks ago. It is my hope that in reducing SASP (which contains CD38) the availability of NAD will rise again as it is no longer being destroyed by CD38. This would then vindicate that the SENS approach to aging is valid and targetting the root of the problem should allow the body to recover somewhat. Of course there are various factors involved in aging and senescent cells and the resulting inflammaging cascade is only one of them but it is in my view a large part of why we age. I would go as far as suggesting that CD38 in SASP is responsible for the decline of NAD with age, indeed as SASP rises NAD declines and CD38 in particular (though other cytokines like TGF-beta, TNF-a from the NFKB pathway may also have a role) could be the key mechanism of that loss, indeed Sinclair eludes to this in his 2012 paper. It could also explain why we see improvement in healthspan from senolytics and is consistent with other tests with NAD upregulation which have shown improvements to healthspan also, so this could be one of the primary reasons for this result. 

It is one reason why the MMTP will monitor NAD levels and NAD ratio to see if this hypothesis pans out and there is every reason to suspect it might.

 

Hi Steve, I think there are ways to combat CD38 e.g.Quercetin and Apegenin.I have not gone all in with that because its unclear to me why the CD38 rises. You have any view on that?

[Nate-2004]

Hi Steve, I think there are ways to combat CD38 e.g.Quercetin and Apegenin.I have not gone all in with that because its unclear to me why the CD38 rises. You have any view on that?

 

Stefan see here post number 872: http://www.longecity...-30#entry780825

[tunt01]

del'd

 

del'd.  I need to write a more complete response later.

Edited by prophets, 11 August 2016 - 12:56 AM.

[stefan_001]

It's looking more and more like working down the stream of what's causing NAD depletion, PARP, the rise in CD38 and other culprits, is going to be the ultimate solution to the NAD+ angle.  There are so many angles to the aging problem it seems.

 

Metformin is unavailable without a prescription in the U.S.  I'm not sure how I'd go about getting it as a preventative. I could just ask my GP I suppose.

 

The evidence so far, in doing searches around the board and elsewhere, is still spotty and hit or miss with Metformin.

 

Let's hope we get results on senolytics and other methods soon. 

 

The dosing might not need to be high as its not needed to recover NAD+. My own speculation is that the body start off with having an abundance of NAD+ and problems start when a certain threshold low value is achieved. So we may only need to boost till this threshold.

 

Stefan why did you conclude that?

 

The article talks about this. Also in figure 4J you can see that there is a sort of threshold effect and increased dosing doesn't lead to much additional improvement. Ofcourse it remains to be seen then if the threshold value is reasonable....

[Nate-2004]

1.  This is on my list of things to do.

 

Pterostilbene is Resveratrol + a methyl group.  I know pterostilbene activates SIRT3, which is downstream from SIRT1.  I believe SIRT2 (human version) does not matter.  SIRT1, I am not 100% clear on, but I think a lot of the downstream targets of SIRT1 like SIRT3 and Ppar-alpha are targeted by Pterostilbene.

 

In the absence of complete information, I was thinking about maybe a "full" pterostilbene dose and maybe an additional 5-10 mg low dose resveratrol.  I'm not sure yet, and am working through this question you pose.

 

2.  Metformin can be purchased through doctor RX or alldaychemist, etc.  

 

The differences between Metformin and Resveratrol/Pterostilbene are another important question, because beyond any AMPK, SIRT1 activation and NAD+ sparing activity, there may be other significant differences such as significantly increased beta amyloid synthesis under metformin.

 

I don't know.

 

 

1. Things to do? You have any references for the SIRT3 downstream activation?

 

2. Doctor RX?

 

Metformin significantly *increases* beta amyloids?? That doesn't sound good.

[stefan_001]

 

Hi Steve, I think there are ways to combat CD38 e.g.Quercetin and Apegenin.I have not gone all in with that because its unclear to me why the CD38 rises. You have any view on that?

 

Stefan see here post number 872: http://www.longecity...-30#entry780825

 

 

Ok thanks. It still doesnt answer the question. CD38 does usefull things in the body. It has been linked to inflammatory processes which increase as we age. The question is what does the increased CD38 do? Nothing except comsuming NAD+? Combat inflamation? Other things?

[Nate-2004]

 

 

Hi Steve, I think there are ways to combat CD38 e.g.Quercetin and Apegenin.I have not gone all in with that because its unclear to me why the CD38 rises. You have any view on that?

 

Stefan see here post number 872: http://www.longecity...-30#entry780825

 

 

Ok thanks. It still doesnt answer the question. CD38 does usefull things in the body. It has been linked to inflammatory processes which increase as we age. The question is what does the increased CD38 do? Nothing except comsuming NAD+? Combat inflamation? Other things?

 

 

Is it not a byproduct of inflammation? Maybe it doesn't *do* anything beneficial in humans other than contribute to aging. Like AGE's or beta amyloids or lipofuscin. I think what Steve H is trying to do is tie it to inflammation caused by the increasing number of senescent cells.

Edited by Nate-2004, 10 August 2016 - 10:25 PM.

[Supierce]

Hi Steve, I think there are ways to combat CD38 e.g.Quercetin and Apegenin.I have not gone all in with that because its unclear to me why the CD38 rises. You have any view on that?

 
Stefan see here post number 872: http://www.longecity...-30#entry780825

 
Ok thanks. It still doesnt answer the question. CD38 does usefull things in the body. It has been linked to inflammatory processes which increase as we age. The question is what does the increased CD38 do? Nothing except comsuming NAD+? Combat inflamation? Other things?

From Wikipedia:

The loss of CD38 function is associated with impaired immune responses, metabolic disturbances, and behavioral modifications including social amnesia possibly related to autism.[7][8]

The CD38 protein is a marker of cell activation. It has been connected to HIV infection, leukemias, myelomas, solid tumors, type II diabetes mellitus and bone metabolism, as well as some genetically determined conditions.

CD38 produces an enzyme which regulates the release of oxytocin within the central nervous system.[8]

Disable it at your peril.

[Bryan_S]

 

1. Things to do? You have any references for the SIRT3 downstream activation?

 

2. Doctor RX?

 

Metformin significantly *increases* beta amyloids?? That doesn't sound good.

 

 

SIRT3, there is one such activator that is still making headlines. honokiol from this thread.

 

New studies:

Honokiol suppresses lung tumorigenesis by targeting EGFR and its downstream effectors.

Song JM1, Anandharaj A1, Upadhyaya P1, Kirtane AR2, Kim JH1,3, Hong KH4, Panyam J1,2, Kassie F1,3.

http://www.ncbi.nlm....pubmed/27458163

 

From Mitochondria to Meditation: An Integrative Approach to Enhancing Cognitive Function

http://www.naturopat...in Function.pdf

[Nate-2004]

 

 

1. Things to do? You have any references for the SIRT3 downstream activation?

 

2. Doctor RX?

 

Metformin significantly *increases* beta amyloids?? That doesn't sound good.

 

 

SIRT3, there is one such activator that is still making headlines. honokiol from this thread.

 

New studies:

Honokiol suppresses lung tumorigenesis by targeting EGFR and its downstream effectors.

Song JM1, Anandharaj A1, Upadhyaya P1, Kirtane AR2, Kim JH1,3, Hong KH4, Panyam J1,2, Kassie F1,3.

http://www.ncbi.nlm....pubmed/27458163

 

From Mitochondria to Meditation: An Integrative Approach to Enhancing Cognitive Function

http://www.naturopat...in Function.pdf

 

 

I haven't gone in search of the full text of the first one but did the rat experiments referenced administer the honokiol orally?

[Bryan_S]

 

 

 

1. Things to do? You have any references for the SIRT3 downstream activation?

 

2. Doctor RX?

 

Metformin significantly *increases* beta amyloids?? That doesn't sound good.

 

 

SIRT3, there is one such activator that is still making headlines. honokiol from this thread.

 

New studies:

Honokiol suppresses lung tumorigenesis by targeting EGFR and its downstream effectors.

Song JM1, Anandharaj A1, Upadhyaya P1, Kirtane AR2, Kim JH1,3, Hong KH4, Panyam J1,2, Kassie F1,3.

http://www.ncbi.nlm....pubmed/27458163

 

From Mitochondria to Meditation: An Integrative Approach to Enhancing Cognitive Function

http://www.naturopat...in Function.pdf

 

 

I haven't gone in search of the full text of the first one but did the rat experiments referenced administer the honokiol orally?

 

this compound has traditionally been orally administered. The article for the lung tumor, intraperitoneal injection.

The article is open access http://www.impactjou...59&path[]=34065

[Nate-2004]

 

From Wikipedia:

The loss of CD38 function is associated with impaired immune responses, metabolic disturbances, and behavioral modifications including social amnesia possibly related to autism.[7][8]

The CD38 protein is a marker of cell activation. It has been connected to HIV infection, leukemias, myelomas, solid tumors, type II diabetes mellitus and bone metabolism, as well as some genetically determined conditions.

CD38 produces an enzyme which regulates the release of oxytocin within the central nervous system.[8]

Disable it at your peril.

 

 

I don't think inhibition equals disabling. If CD38 sharply rises with age as NAD+ falls then all taking inhibitors (are inhibitors less effective than activators?) would accomplish (if they do much) is a reduction in CD38. Nobody's testing this theory in humans to my knowledge. Would be nice if they'd give it a try on a nice double blinded sample size of people. I'll volunteer.

 

I don't know what the mechanism of action is as far as the inhibition goes with Quercetin. Is it inhibiting CD38 by getting rid of senescent cells? What is apigenin doing?

Edited by Nate-2004, 11 August 2016 - 04:24 AM.

[Harkijn]

I don't want to 'clog the blog' by hitting the quote button, but anyone considering taking metformin for a longer time should read this first:

 

http://www.pcosnutri...pcos-metformin/

Don't mess with vitamin B12!

 

(BTW, Looking at the functions of Metformin, I notice many parallells with Glucosamine, a harmless substance, with a proven longevity record. For this see the Anti-aging Firewalls.)

Edited by harkijn, 11 August 2016 - 06:35 AM.

[Steve H]

Regards CD38. The idea of senolytics is not to "disable" CD38 completely as has been suggested above, the idea is to reduce it to a level that is not damaging the metabolism. Factors like TGF-beta also require calibration rather than simply blocking them completely as at youthful levels they are useful for wound healing, no doubt CD38 is the same and needs to be carefully calibrated. The danger of senolytics is in being too thorough and removing too many senescent cells at once which will effect wound healing so like all things in biology it is a matter of balance. 

 

As previously mentioned in this thread CD38 Destroys NAD shown here: 
Why NAD+ Declines during Aging: It’s Destroyed
http://www.cell.com/...(16)30244-3.pdf

Quercetin will be reducing CD38 by removing Senescent cells and the resulting SASP. This paper discusses this and shows in fact that NAD levels do return if you reduce CD38 levels.

Flavonoid apigenin is an inhibitor of the NAD+ ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome.
http://www.ncbi.nlm....pubmed/23172919
 

We also see further confirmation of CD38 and NAD and its role in Aging:

 

CD38 Dictates Age-Related NAD Decline andMitochondrial Dysfunction through an SIRT3-Dependent Mechanism
https://www.research...ndent_Mechanism

 

The next question is, does NAD bounce back in-vivo when senolytics are applied in normal Black 6 lab mice that are not engineered in any way? The MMTP is going to find out this. 

So really Senolytics has the big potential here to increase NAD levels and restore tissue and stem cell function through increase of NAD and reduction of cytokines. 

Edited by Steve H, 11 August 2016 - 01:56 PM.

[tunt01]

 

 

1. Things to do? You have any references for the SIRT3 downstream activation?

 

2. Doctor RX?

 

Metformin significantly *increases* beta amyloids?? That doesn't sound good.

 

 

 

1.  I read it in a James Watson article and it seemed to comport with everything I read thereafter, so I never wrote down further sources.  I can't recall it being incorrect, although SIRT3 activation probably doesn't require SIRT1, per se.  SIRT3 is in the mitochondria and SIRT1 is in the nucleus/cytoplasm, so it might make sense that there is some cross-talk going on between them, given their different locations and the needs of the mitochondria to convey to the nucleus energy status and required protein/gene expression.

 

 

 

 

It appears that the reason for this decline in SIRT3 expression may be due to the fact that SIRT1 regulates the gene expression of SIRT3. This is why many experts believe that the decline in SIRT1 activity is an “upstream event”, whereas the decline in SIRT3 is a “down stream events”.  The following possible causes for the decline in SIRT1 activity are illustrated in the diagrams above and listed in the table below:  SOURCE

 

 

 

 

 

2.  Don't need a Doctor Rx.  I have a pile of 500 mg XR Metformin from Alldaychemist sitting in my bathroom cabinet.

 

 

3.  There is some discussion of Metformin's role in beta amyloid generation is via activation of AMPK that leads to upregulation of BACE1 (one of the biggest problem in ALZ pathology).   SOURCE

 

I've seen literature and the sourced article suggesting to combine insulin + metformin to treat ALZ.  I'm not sure exactly of the pathway that is restored by insulin, such that BACE1 is inhibited.  I suspect it's something like PI3K/Akt, that a poor man's solution might be to take Lipoic Acid, which is a potential insulin mimetic.

[stefan_001]

Regards CD38. The idea of senolytics is not to "disable" CD38 completely as has been suggested above, the idea is to reduce it to a level that is not damaging the metabolism. Factors like TGF-beta also require calibration rather than simply blocking them completely as at youthful levels they are useful for wound healing, no doubt CD38 is the same and needs to be carefully calibrated. The danger of senolytics is in being too thorough and removing too many senescent cells at once which will effect wound healing so like all things in biology it is a matter of balance. 

Quercetin will be reducing CD38 by removing Senescent cells and the resulting SASP. This paper discusses this and shows in fact that NAD levels do return if you reduce CD38 levels.

http://www.ncbi.nlm....pubmed/23172919

The next question is, does NAD bounce back in-vivo when senolytics are applied in normal Black 6 lab mice that are not engineered in any way? The MMTP is going to find out this. 

 

Hi Steve, is there any reference that senescent cells drive CD38 to the high levels seen? Also my understanding of Quercetin is that it is a direct inhibitor of CD38. I guess it may have influence on senescent removal but I think that is secondary. So use of Quercetin would simply inhibit CD38 without adressing the actual cause. Now if CD38 is simply a runaway then inhibition may be just fine.

Edited by stefan_001, 11 August 2016 - 02:00 PM.

[Nate-2004]

3.  There is some discussion of Metformin's role in beta amyloid generation is via activation of AMPK that leads to upregulation of BACE1 (one of the biggest problem in ALZ pathology).   SOURCE

 

I've seen literature and the sourced article suggesting to combine insulin + metformin to treat ALZ.  I'm not sure exactly of the pathway that is restored by insulin, such that BACE1 is inhibited.  I suspect it's something like PI3K/Akt, that a poor man's solution might be to take Lipoic Acid, which is a potential insulin mimetic.

 

 

That is so not good. I may avoid it for now, I don't wanna mess with my memory or cognition or increase my chances of alzheimer's. NR has helped a bit I think with memory and cognition for me.

 

Someone said glucosamine was like Metformin. That's interesting. I take N-A-G for the microbiome angle.

[Steve H]

Stefan Quercetin reduces SASP by inducing Apoptosis in cells via the BCL2 family in certain cell types and this will be reducing the levels of SASP as a result. Of tbe BCL2 family the three most important in Senolytics are BCL-W, BCL-XL and BCL-2, the first two being more important and the last being more additive in effect by lowering the cells resistance to apoptosis and the other two primary paths. You can find a full explanation of this action here though in this case they use ABT199 and ABT737:

 

Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL
dx.doi.org/10.1038/ncomms11190

 

Quercetin specifically here:

Quercetin induces apoptosis via caspase activation, regulation of Bcl-2, and inhibition of PI-3-kinase/Akt and ERK pathways in a human hepatoma cell line (HepG2).

http://www.ncbi.nlm....pubmed/17056790

Again in cancer cells which are closely related to our work with Senolytics as shown by Campisi:

Quercetin induces apoptosis by activating caspase-3 and regulating Bcl-2 and cyclooxygenase-2 pathways in human HL-60 cells
https://www.research...man_HL-60_cells

CD38 is identified as being part of SASP and this absolutely rises with age as the senescent cell burden rises as high as 25% of cells in some tissues (shown in monkeys). As the immune system fails in particular Senescent associated macrophages (SAMS) become increasingly poor at keeping the senescent cell % down and as a result the cytokines and inflammation responses rise. Sinclair himself makes the connection between CD38 and Campisi et al show how SASP includes it and various other cytokines and inflammatory signals. 

Now the regulator of CD38 that would be NFKB and there is another excellent thread on Longecity all about that. In the short term attenuation of CD38 levels is very likely going to be via Senolytic agents capable of reducing SASP, of which Quercetin and apigenin may both be useful. If we can confirm that NAD levels bounce back in non engineered mice as they have in knockouts via reducing CD38 by removing SASP it makes the picture clearer and reason to be hopeful that Senolytics could increase lifespan as well as healthspan. Considering in NAD increasing tests most mice live longer except in the case on inhibiting PARP but they lived longer by inhibiting CD38 as Sinclair shows in 2013.

Just to be clear I am not suggesting Quercetin alone will be overly effective but the second generation of engineered small molecules capable of effecting cells systemically and of a wider serotype currently being created could be. The problem with Quercetin and the other current senolytics is they are all so far limited to particular cell populations when the need is a system wide effect which can effect all cells. Unity and Osiin biotechnology are both working on therapies that will effect a wide range of cells system wide, this will lead to systemic reduction of SASP and CD38 etc... then we shall see what we shall see....

Edited by Steve H, 11 August 2016 - 02:39 PM.

[stefan_001]

Stefan Quercetin reduces SASP by inducing Apoptosis in cells via the BCL2 family in certain cell types and this will be reducing the levels of SASP as a result. Of tbe BCL2 family the three most important in Senolytics are BCL-W, BCL-XL and BCL-2, the first two being more important and the last being more additive in effect by lowering the cells resistance to apoptosis and the other two primary paths. You can find a full explanation of this action here though in this case they use ABT199 and ABT737:

 

Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL
dx.doi.org/10.1038/ncomms11190

 

Quercetin specifically here:

Quercetin induces apoptosis via caspase activation, regulation of Bcl-2, and inhibition of PI-3-kinase/Akt and ERK pathways in a human hepatoma cell line (HepG2).

http://www.ncbi.nlm....pubmed/17056790

Again in cancer cells which are closely related to our work with Senolytics as shown by Campisi:

Quercetin induces apoptosis by activating caspase-3 and regulating Bcl-2 and cyclooxygenase-2 pathways in human HL-60 cells
https://www.research...man_HL-60_cells

CD38 is identified as being part of SASP and this absolutely rises with age as the senescent cell burden rises as high as 25% of cells in some tissues (shown in monkeys). As the immune system fails in particular Senescent associated macrophages (SAMS) become increasingly poor at keeping the senescent cell % down and as a result the cytokines and inflammation responses rise. Sinclair himself makes the connection between CD38 and Campisi et al show how SASP includes it and various other cytokines and inflammatory signals. 

Now the regulator of CD38 that would be NFKB and there is another excellent thread on Longecity all about that. In the short term attenuation of CD38 levels is very likely going to be via Senolytic agents capable of reducing SASP, of which Quercetin and apigenin may both be useful. If we can confirm that NAD levels bounce back in non engineered mice as they have in knockouts via reducing CD38 by removing SASP it makes the picture clearer and reason to be hopeful that Senolytics could increase lifespan as well as healthspan. Considering in NAD increasing tests most mice live longer except in the case on inhibiting PARP but they lived longer by inhibiting CD38 as Sinclair shows in 2013.

Just to be clear I am not suggesting Quercetin alone will be overly effective but the second generation of engineered small molecules capable of effecting cells systemically and of a wider serotype currently being created could be. The problem with Quercetin and the other current senolytics is they are all so far limited to particular cell populations when the need is a system wide effect which can effect all cells. Unity and Osiin biotechnology are both working on therapies that will effect a wide range of cells system wide, this will lead to systemic reduction of SASP and CD38 etc... then we shall see what we shall see....

 

Hi Steve,

 

Thanks for the explanations. I also believe that Quercetin helps via induction of apoptosis but my impression of this study is that the mechanism is different:

http://diabetes.diab...ntent/62/4/1084

You can see the inhibition in the in-vitro results, there is no mention of apoptosis. Hence my thinking that Q and A have fast effect via CD38 inhibition and a long term effect via the mechanisms you desribe. Whether the first one is good is what I wonder.

 

Stefan

[albedo]

 

Two questions:

 

1: On the topic of adding SIRT activators with NR. Does pterostilbene in fact activate SIRT1 2 or 3? I see conflicting evidence about this amidst the tiny amount of research on pterostilbene.

2: Any suggestions on getting Metformin? I figure this may tide me over in the meantime. Would be great if my insurance covered it but how would one go about talking the doctor into prescribing it?

 

 

I never really researched on this and suggest to continue interacting with more knowledgeable folks on this Board, Tom seems to know a deal about this and likely you already have in hands most of the relevant papers. I am just taking pTeroPure for what looks like a synergistic effect with resveratrol (admittedly only from the vendor sites, Chromadex and LEF). Btw, I just like to log here a paper giving a table with sirtuins reactions, cellular targets and biological effects, likely already know to everyone here, so it is mainly for me.

 

Wrt to metformin you would need to talk with your doctor.
 

[Harkijn]

 

 

Two questions:

 

1: On the topic of adding SIRT activators with NR. Does pterostilbene in fact activate SIRT1 2 or 3? I see conflicting evidence about this amidst the tiny amount of research on pterostilbene.

2: Any suggestions on getting Metformin? I figure this may tide me over in the meantime. Would be great if my insurance covered it but how would one go about talking the doctor into prescribing it?

 

 

I never really researched on this and suggest to continue interacting with more knowledgeable folks on this Board, Tom seems to know a deal about this and likely you already have in hands most of the relevant papers. I am just taking pTeroPure for what looks like a synergistic effect with resveratrol (admittedly only from the vendor sites, Chromadex and LEF). Btw, I just like to log here a paper giving a table with sirtuins reactions, cellular targets and biological effects, likely already know to everyone here, so it is mainly for me.

 

Wrt to metformin you would need to talk with your doctor.
 

 

About the paper: Thanks for this, Albedo. You overestimate some of us, in any case me :-) The list and the article as a whole will prove very useful for future reference. Additionally, this paper contains the first explanation of how a pathogenic bacterium reprogrammes a host cell that I can (sort of) understand.

[tunt01]

I spent a little time looking into this issue of direct / indirect SIRT1 activation.  I kept coming into articles saying that Resveratrol might be an indirect activator of SIRT1 or didn't even require SIRT1 for activation of AMPK (which occurred via CAMKKB).  (Vingtdeux 2010) 

 

Guarente briefly addressed this SIRT1 direct activation issue in this paper (Guarente 2013)

 

 

Three subsequent studies provide strong evidence that these compounds really work by directly activating SIRT1. First, activation can, in fact, be demonstrated using peptide substrates without any fluorescent conjugate (Dai et al. 2010). Importantly, the presence of aromatic amino acid side chains at residues positioned near the deacetylated lysine was required, suggesting a substrate specificity for activation foreshadowed by the earlier apparent requirement for the fluorescent tags. Second, acute deletion of SIRT1 in adult mice prevented many of the physiological effects of resveratrol and other STACs (Price et al. 2012). Third, a single mutation in SIRT1 abolished the ability of resveratrol and all 117 other STACs tested to activate the enzyme in vitro or promote the canonical physiological changes in cells (Hubbard et al. 2013). This mutation lies adjacent to but outside of the catalytic domain and is thought to define an allosteric site in the enzyme for activation by small molecules. At present, it is difficult to interpret all of these findings in any model other than direct activation of SIRT1 by resveratrol and other STACs. Of course, the dose of resveratrol or other STACs may affect whether additional targets are also engaged in vivo.

 

 

 

I don't really understand how mutation or blocking/deleting SIRT1 explains direct vs. indirect activation of SIRT1.  I didn't go any further than this, but you can probably look at those 3 references he points to and dig into it deeper.

 

 

Guarente, L. (2013). Calorie restriction and sirtuins revisited. Genes & Development,27(19), 2072-2085. doi:10.1101/gad.227439.113

 

Vingtdeux, V., Giliberto, L., Zhao, H., Chandakkar, P., Wu, Q., & Simon, J. et al. (2010). AMP-activated Protein Kinase Signaling Activation by Resveratrol Modulates Amyloid-  Peptide Metabolism. Journal Of Biological Chemistry, 285(12), 9100-9113. doi:10.1074/jbc.m109.060061

 

[Nate-2004]

Thanks prophets. Resveratrol is known to activate SIRT1. My question though was about the far more bioavailable pterostilbene that stays in the system a lot longer (and is less expensive). People keep claiming it activates SIRT1 and Elysium puts it in their Basis Nicotinamide Riboside for that very reason yet there is little evidence that it does and there's contradictory evidence at that.

Edited by Nate-2004, 12 August 2016 - 01:51 PM.

[Tom Andre F. (ex shinobi)]

 

 

This study seems really important. I only know just enough of the metabolic science to be able to tell that -- looks like evidence of oral NR making a big impact in exercise performance in older mouse models, even when concentration in the muscle tissue seems lower. There is differential absorption in different tissues, but yet still a strong impact. Intriguing implications for muscular dystrophies, as well. AND Cell is a highly prestigious journal. But I look forward to more insights from the rest of the group so you can help us understand the intricacies of the results.....seems the pace of results is increasing, as was hoped for....very interesting!!

 

Yes, still no football players yet,but this study on mice will probably assuage concerns about NR and skeletal muscle. Encouraging also that administration was oral.

http://www.cell.com/...4131(16)30350-3

 

Quote:

Mice beginning at age 5.5 months received the treatment continuously for 6 weeks. Intriguingly, this intervention appeared to completely prevent the development of exercise intolerance observed in 7-month-old mNKO mice and reversed lactic acidosis at the point of exhaustion

 

harken,

 

Thanks, I was running a search every day on their website. This was one of the articles I was waiting for from Cell.com 

I find this next paragraph very suggestive. It seems subtle changes in NAD can disproportionately modulate aerobic metabolism. So moving the needle a little bit can have larger downstream benefits. I'll be combing thru this article for days to come.

fx1_lrg.jpg

"In light of its potent phenotypic effects in mNKO mice, we were surprised to find that NR exerts only a subtle influence on the steady-state concentration of NAD in muscles. Our tracer studies suggest that this is largely attributable to breakdown of orally delivered NR into NAM prior to reaching the muscle. Nonetheless, our results indicate that NR is more effective than NAM for reversing mNKO phenotypes (Figure S5). The correlation between the NAD content and the respiratory capacity of isolated mitochondria, even in cultured myotubes (Figure 4), supports the model that subtle changes in NAD can disproportionately modulate aerobic metabolism. It is important to note that NAD turnover may vary independently from NAD concentration and that small changes in average tissue concentration might reflect larger changes in specific cells or subcellular compartments. It is also possible that intramuscular conversion of NAD into secondary messengers potently influences calcium homeostasis, which is both essential to muscle contraction and can independently modulate mitochondrial respiration (Cárdenas et al., 2010)."

 

 

 

 

 

I think the study shows 3 things:

1) NAD+ boosting recovers muscle

2) NR performs better than nicotinamide

3) The dosing might not need to be high as its not needed to recover NAD+. My own speculation is that the body start off with having an abundance of NAD+ and problems start when a certain threshold low value is achieved. So we may only need to boost till this threshold.

 

NR performs better than nicotinamide only in mNKO mice. Means they turned off Nampt : muscle-specific Nampt knockouts

 

They explain the small increase is due to the fact most NR is actually converted into Nicotinamide before it reach the muscle (targeted area).

 

Disproportion does not mean bad at all. They dont see negative result there. At least I dont see where after reading their graph

 

Actually what I see is: NR increase just a bit NAD+ when Nampt is turned off, the result looks clear to me. NR fail to recover mNKO mice from their state.

 

So Bryan and Stefan, you understood this not correctly: "NAD can disproportionately modulate aerobic metabolism". Why ? Because this just means that mitochondria isolated from C2C12 myotubes treated with FK866 and NR, you have NR that does not act proportionately in its ability to increase back complex I-dependent respiratory O2 consumption and NAD amount in mito. It seems at 10uM NR you reach the point where the respiratory is optimal and will remain stable while you increase more NAD with better dose. Thats all !

 

I dont mean the crash is not possible, but this study does not show us that. Its more a report for me of how important is Nampt once again, so this is my targeted area recently...

 

It also show NR in low dose can have positive effect