48 replies to this topic

[RWhigham]

I took apigenin + quercetin plus several Sirt1 increasers at bedtime. The next morning I was wiped out. I recovered later in the day. I suspect some senescent cell clearance may have occurred.

 

Theory:

Nuclear CD38 is the main consumer of NAD+ in the cell nucleus in old age.  Ref

Apigenin + quercetin blocks CD38 from entering the cell nucleus restoring nuclear NAD+ to youthful levels Ref

Youthful levels of nuclear NAD+ will allow Sirt1 production to increase  Ref 

(Sirt1 can be increased by supplements such as OPC_Grape Seed extract, gynostemma P., etc if not limited by nuclear NAD+ availability.)

Senescent cells are in the last stages of pre-apoptosis but blocked from finishing self-dismantlement by p53.  Ref

Sirt1 inhibits p53 Ref (like Fox04-DRI) allowing senescent cells to finish self-dismantlement.

[Nate-2004]

Why would clearing senescent cells lead to symptoms of feeling "wiped out"?

[RWhigham]

Why would clearing senescent cells lead to symptoms of feeling "wiped out"?

A lot of cells committing hari kari all at once would likely make one need to recuperate.  

Edited by RWhigham, 01 February 2018 - 04:15 PM.

[Rocket]

 

Why would clearing senescent cells lead to symptoms of feeling "wiped out"?

A lot of cells committing hari kari all at once would likely make one need to recuperate.  

 

 

That's how I felt after Dasatanib. Wiped out and ran over by a freight train. Not a cell biologist but when you kill a bunch of cells in the body, there simply must be lots of nasty chemical side effects that need to be removed from the body. I think that's why most people here say that Dasatanib doesn't work is because they never took a high enough dose to actually do anything significant. Go big or go home!

 

I'm going to start taking my megadoses of R again very soon. Maybe I will up the dosage to something crazy and see how that shakes out.

 

Would be awesome if liposomal resveratrol is as effective as the FOXO4 peptide.

Edited by Rocket, 01 February 2018 - 06:20 PM.

[Nate-2004]

 

Why would clearing senescent cells lead to symptoms of feeling "wiped out"?

A lot of cells committing hari kari all at once would likely make one need to recuperate.  

 

 

Yeah but, senescent cells, not functional cells, right?

[RWhigham]

 

Yeah but, senescent cells, not functional cells, right?  - Nate-2004

 

Senescent cells can no longer replicate, but are still functioning cells. They may be essential for development and wound repair.  The role of senescent cells in ageing Cellular senescence has historically been viewed as an irreversible cell-cycle arrest mechanism that acts to protect against cancer, but recent discoveries have extended its known role to complex biological processes such as development, tissue repair, ageing and age-related disorders.

 

Edited by RWhigham, 01 February 2018 - 08:10 PM.

[Daniel Cooper]

 

 

Why would clearing senescent cells lead to symptoms of feeling "wiped out"?

A lot of cells committing hari kari all at once would likely make one need to recuperate.  

 

 

Yeah but, senescent cells, not functional cells, right?

 

 

 

When senescent cells undergo apoptosis some of the products released are toxic/inflammatory.  You wouldn't normally notice this as some senescent cells are always undergoing apoptosis (just not enough). But when you have a coordinated trigger that causes a significant number of those cells to die off simultaneously, it can likely create a noticeable increase in inflammation and the like, albeit transitory and for a good cause.

[sthira]

Why would clearing senescent cells lead to symptoms of feeling "wiped out"?

A lot of cells committing hari kari all at once would likely make one need to recuperate.

That's how I felt after Dasatanib. Wiped out and ran over by a freight train. Not a cell biologist but when you kill a bunch of cells in the body, there simply must be lots of nasty chemical side effects that need to be removed from the body. I think that's why most people here say that Dasatanib doesn't work is because they never took a high enough dose to actually do anything significant. Go big or go home!

Define your "go big" numbers. I took three consecutive rounds of 140mg dasatinib combined with three rounds of 400mg EMIQ on days 5, 6, and 7 of a ten day water/coffee only fast. I felt nothing out of the ordinary of a usual ten day water fast. Maybe I didn't go big enough. Don't kill myself yet. My urine ketone lev measured >80. Who knows, I'm speculating blindly I was also in some magical mysterious states of macroautophagy; but since "we" can't measure cell death very well here in our consumer hell of self-experimental desert, wtf knows. One day we'll have some more mouse answers, I'm sure, just wait five more years as if, right. Tell us about your go big.

[ryukenden]

I took apigenin + quercetin plus several Sirt1 increasers at bedtime. The next morning I was wiped out. I recovered later in the day. I suspect some senescent cell clearance may have occurred.

Theory:
Nuclear CD38 is the main consumer of NAD+ in the cell nucleus in old age. Ref
Apigenin + quercetin blocks CD38 from entering the cell nucleus restoring nuclear NAD+ to youthful levels Ref
Youthful levels of nuclear NAD+ will allow Sirt1 production to increase Ref
(Sirt1 can be increased by supplements such as OPC_Grape Seed extract, gynostemma P., etc if not limited by nuclear NAD+ availability.)
Senescent cells are in the last stages of pre-apoptosis but blocked from finishing self-dismantlement by p53. Ref
Sirt1 inhibits p53 Ref (like Fox04-DRI) allowing senescent cells to finish self-dismantlement.

Following article implies quercetin may be harmful to non-senescent cells? They say it is not senolytic.

https://www.ncbi.nlm...26/#!po=9.15493

http://journals.plos...al.pone.0190374

Edited by ryukenden, 02 February 2018 - 12:22 AM.

[RWhigham]

Following article implies quercetin may be harmful to non-senescent cells? They say it is not senolytic. http://journals.plos...al.pone.0190374 

 

I did not attempt here to use quercetin as a senolytic.  Endogenous SIRT1 was the presumed senolytic.

 

I took quercetin with apigenin to block CD38 from the cell nucleus because nuclear CD38 triples in old age and causes a shortage of nuclear NAD+. (For references see the OP)

 

Details:

I took 50 mg of bioavailable quercetin (169 mg of EMIQ) nightly for a couple of weeks plus 50 mg of apigenin MWF - apigenin has a 90 hour half life, quercetin a short one. My serum apigenin likely increased over this time.

 

In theory this allowed my nuclear NAD+ to increase beyond any level my body has seen for many decades.  I then took various supplements to stimulate SIRT1. Being wiped out the next morning was unexpected.

 

SIRT1 can interfere with p53. I surmise that it did so, and allowed senescent cells being held in the last stage of apoptosis (by p53) to finish apoptosis. I have no way to verify this.

 

I'm hoping to see some effect on my body over the next few weeks (eg a darker beard or something).  Today on the 2nd day I have a greatly increased appetite and took an afternoon nap.

Edited by RWhigham, 02 February 2018 - 02:16 AM.

[Rocket]

Why would clearing senescent cells lead to symptoms of feeling "wiped out"?

A lot of cells committing hari kari all at once would likely make one need to recuperate.

That's how I felt after Dasatanib. Wiped out and ran over by a freight train. Not a cell biologist but when you kill a bunch of cells in the body, there simply must be lots of nasty chemical side effects that need to be removed from the body. I think that's why most people here say that Dasatanib doesn't work is because they never took a high enough dose to actually do anything significant. Go big or go home!

Define your "go big" numbers. I took three consecutive rounds of 140mg dasatinib combined with three rounds of 400mg EMIQ on days 5, 6, and 7 of a ten day water/coffee only fast. I felt nothing out of the ordinary of a usual ten day water fast. Maybe I didn't go big enough. Don't kill myself yet. My urine ketone lev measured >80. Who knows, I'm speculating blindly I was also in some magical mysterious states of macroautophagy; but since "we" can't measure cell death very well here in our consumer hell of self-experimental desert, wtf knows. One day we'll have some more mouse answers, I'm sure, just wait five more years as if, right. Tell us about your go big.

Its been a while but probably 2x your dosage.

Also keep in mind that with the research chemicals we have access to that the quality likely varies by A LOT.

Also having read enough pubmed articles, I've learned that not everyone reacts the same to like amount dosages of medicines. Why? Who knows... I am not biochemist.

Edited by Rocket, 02 February 2018 - 02:02 AM.

[ryukenden]

Following article implies quercetin may be harmful to non-senescent cells? They say it is not senolytic. http://journals.plos...al.pone.0190374

I did not attempt here to use quercetin as a senolytic. Endogenous SIRT1 was the presumed senolytic.

I took quercetin with apigenin to block CD38 from the cell nucleus because nuclear CD38 triples in old age and causes a shortage of nuclear NAD+. (For references see the OP)

Details:
I took 50 mg of bioavailable quercetin (169 mg of EMIQ) nightly for a couple of weeks plus 50 mg of apigenin MWF - apigenin has a 90 hour half life, quercetin a short one. My serum apigenin likely increased over this time.

In theory this allowed my nuclear NAD+ to increase beyond any level my body has seen for many decades. I then took various supplements to stimulate SIRT1. Being wiped out the next morning was unexpected.

SIRT1 can interfere with p53. I surmise that it did so, and allowed senescent cells being held in the last stage of apoptosis (by p53) to finish apoptosis. I have no way to verify this.

I'm hoping to see some effect on my body over the next few weeks (eg a darker beard or something). Today on the 2nd day I have a greatly increased appetite and took an afternoon nap.

Interesting. Keep us informed.

I wonder which Sirt1 increasers did you take?

[RWhigham]

I wonder which Sirt1 increasers did you take? 

 

Sirt1_Agonists

  Resveratrol 2 cap 200mg -BPPV/TSH/Cancer +SIRT1/NQO1/neurons/otoliths/T3

  Fisetin 1 cap 100 mg +SIRT1/memory/cog/senolytic -inflam/Alz/newfat/C/TOR1

  Pterostilbene 1 cap 50 mg +SIRT1/memory/autophagy/PPAR_a -Cancer w EMIQ

  Dynveo OPC_GSE 2 cap 200 mg +Sirt1-Sirt3-Foxo3-PINK1-PARKIN/NAMPT/NAD+ -Tau

  Olea25 1 cap 25 mg hydroxytyrosol +SIRT1/T3/telomerase -tau/P_cancer-w-Magnolia

  Metformin 875 mg +Sirt1/autophagy syn-Rap -inflam

  ActivAMP jiaogulan 1 cap 225 mg +T3/AMPK/NAD+ -LDL/Trig/BG/IR/TSH/vfat

  White-Willow-bark 1 cap 125 mg-salicin +AMPK/NAD+ -CRP/LPS/NF-kb/cancer

  Andrographis 400 mg 1 cap +Nrf2/NQO1/SOD -PARP/LPS/CRP/colitis/glioblastoma/BG

  Cocoa, raw, unsweetened, not Dutch process, multiple cups

  Leucine

  Niagen

 

I did not take resveratrol, fisetin, pterostilbene, leucine, or Niagen. I took the rest.

 

Edited by RWhigham, 02 February 2018 - 06:13 PM.

[ryukenden]

I wonder which Sirt1 increasers did you take?

Sirt1_Agonists
Resveratrol 2 cap 200mg -BPPV/TSH/Cancer +SIRT1/NQO1/neurons/otoliths/T3
Fisetin 1 cap 100 mg +SIRT1/memory/cog/senolytic -inflam/Alz/newfat/C/TOR1
Pterostilbene 1 cap 50 mg +SIRT1/memory/autophagy/PPAR_a -Cancer w EMIQ
Dynveo OPC_GSE 2 cap 200 mg +Sirt1-Sirt3-Foxo3-PINK1-PARKIN/NAMPT/NAD+ -Tau
Olea25 1 cap 25 mg hydroxytyrosol +SIRT1/T3/telomerase -tau/P_cancer-w-Magnolia
Metformin 875 mg +Sirt1/autophagy syn-Rap -inflam
ActivAMP jiaogulan 1 cap 225 mg +T3/AMPK/NAD+ -LDL/Trig/BG/IR/TSH/vfat
White-Willow-bark 1 cap 125 mg-salicin +AMPK/NAD+ -CRP/LPS/NF-kb/cancer

Andrographis 400 mg 1 cap +Nrf2/NQO1/SOD -PARP/LPS/CRP/colitis/glioblastoma/BG
Cocoa, raw, unsweetened, not Dutch process, multiple cups
Leucine
Niagen

I did not take resveratrol, fisetin, pterostilbene, leucine, or Niagen. I took the rest.

Thank you.

[QuestforLife]

I wonder which Sirt1 increasers did you take?

Sirt1_Agonists
Resveratrol 2 cap 200mg -BPPV/TSH/Cancer +SIRT1/NQO1/neurons/otoliths/T3
Fisetin 1 cap 100 mg +SIRT1/memory/cog/senolytic -inflam/Alz/newfat/C/TOR1
Pterostilbene 1 cap 50 mg +SIRT1/memory/autophagy/PPAR_a -Cancer w EMIQ
Dynveo OPC_GSE 2 cap 200 mg +Sirt1-Sirt3-Foxo3-PINK1-PARKIN/NAMPT/NAD+ -Tau
Olea25 1 cap 25 mg hydroxytyrosol +SIRT1/T3/telomerase -tau/P_cancer-w-Magnolia
Metformin 875 mg +Sirt1/autophagy syn-Rap -inflam
ActivAMP jiaogulan 1 cap 225 mg +T3/AMPK/NAD+ -LDL/Trig/BG/IR/TSH/vfat
White-Willow-bark 1 cap 125 mg-salicin +AMPK/NAD+ -CRP/LPS/NF-kb/cancer

Andrographis 400 mg 1 cap +Nrf2/NQO1/SOD -PARP/LPS/CRP/colitis/glioblastoma/BG
Cocoa, raw, unsweetened, not Dutch process, multiple cups
Leucine
Niagen

I did not take resveratrol, fisetin, pterostilbene, leucine, or Niagen. I took the rest.

Taking most of these would make you feel tired without any need for senescent cell clearance, just from the effects on mitophagy. Maybe not 'wiped out' but hell, a strong gynostemma tea can make you sleepy on its own!

Also it's not P53 is preventing apoptosis, it's FOXO4 that is preventing P53 from doing it's job (very generally speaking FOXO keeps old cells going).

https://www.ncbi.nlm...pubmed/28340339

[HaplogroupW]

  Cocoa, raw, unsweetened, not Dutch process, multiple cups

 

 

In one sitting?

[RWhigham]

Also it's not P53 is preventing apoptosis, it's FOXO4 that is preventing P53 from doing it's job (very generally speaking FOXO keeps old cells going).

Yes, that is usually correct. However, there is another scenario:

 

Senescent Cells: A Novel Therapeutic Target for Aging and Age-Related Diseases

"Apoptosis occurs when cells experience irreparable damage and p53 transcriptional activity is robust. Growth arrest is established through p53-mediated transcriptional activation of p21. This occurs in response to moderate stress-related damage in order to allow time for repair. In instances when repair is unsuccessful, p21 inhibits the formation of active cyclin E–Cdk2 complexes, imposing a more permanent cell-cycle arrest by keeping RB hypophosphorylated.5 This particular senescent state differs from p16Ink4a-mediated senescence in that it is reversible upon the deactivation of p53 or p21."  

Edited by RWhigham, 02 February 2018 - 11:42 PM.

[ryukenden]

Also it's not P53 is preventing apoptosis, it's FOXO4 that is preventing P53 from doing it's job (very generally speaking FOXO keeps old cells going).

Yes, that is usually correct. However, there is another scenario:

Senescent Cells: A Novel Therapeutic Target for Aging and Age-Related Diseases
"Apoptosis occurs when cells experience irreparable damage and p53 transcriptional activity is robust. Growth arrest is established through p53-mediated transcriptional activation of p21. This occurs in response to moderate stress-related damage in order to allow time for repair. In instances when repair is unsuccessful, p21 inhibits the formation of active cyclin E–Cdk2 complexes, imposing a more permanent cell-cycle arrest by keeping RB hypophosphorylated.5 This particular senescent state differs from p16Ink4a-mediated senescence in that it is reversible upon the deactivation of p53 or p21."

Are you aware of any animal studies applying the concept? For example, Foxo4dri did rejuvenate mice.

[BieraK]

I agree how not to wake up tired with all of these supplements

Jiaogulan+Metformin per se is able to give you a higher state of autophagy, mTOR inhibition, low glucose and so on

 

After all I think it is not unreasonable to raise the hypothesis you killed some senescent cells with all that huge stack. The interaction is just insane: Nrf2+Sirt1+AMPK+nFKB inhibition+Mitofission and mitofusion+NAD+ and the list goes on....what happens to BCL-2, BAX, WNT signaling, JAK/STAT3, HIF-1a

 

Just only read all the several things Andrographis can do in the body

 

What worries me most is the possible damage done by the consumption of Quercetin, a supplement considered highly safe in the 1, 2 or 3 grams.

Edited by BieraK, 03 February 2018 - 09:50 AM.

[HaplogroupW]

 

Apigenin + quercetin blocks CD38 from entering the cell nucleus restoring nuclear NAD+ to youthful levels Ref

 

This observation does beg the question: what about chronic apigenin + quercetin merely to keep NAD+ elevated. Like what people are trying to do with NR and NMN supplementation. Is there some reason this would be a bad idea?

[xEva]

Also having read enough pubmed articles, I've learned that not everyone reacts the same to like amount dosages of medicines. Why? Who knows... I am not biochemist.

I think it's mainly due to genetic variations in various enzymes (tho diet and some substances can also have effect on enzymes, by blocking or upregulating them).  

[Nate-2004]

 

 

Apigenin + quercetin blocks CD38 from entering the cell nucleus restoring nuclear NAD+ to youthful levels Ref

 

This observation does beg the question: what about chronic apigenin + quercetin merely to keep NAD+ elevated. Like what people are trying to do with NR and NMN supplementation. Is there some reason this would be a bad idea?

 

 

I think it's probably not a very good idea but I doubt there is any research for or against this approach. Apigenin has a very long half life but like quercetin is not very bioavailable. I do this once or twice a week with 100g parsley and 3 stalks of celery in a blender with 2 cups water, 3 tbsp ground flax, and 100g almonds and walnuts with a banana. I also drink 2 cups of chamomile that night, double bagged. Apparently the almonds and flax can help with apigenin bioavailability. I posted a link to that research in the thread on manipulating mitochondrial dynamics.

Edited by Nate-2004, 04 February 2018 - 02:27 PM.

[RWhigham]

Update--after 2 months have passed

• My beard and hair are not less grey than before.
• I no longer notice the subtle effect I thought I saw on my face.
• At the time I thought my face looked a bit better, so I submitted a photo to How-old do I look?
• The estimated age came back 22 younger than my correct age. It may have been how I took the photo.

I want to reduce nuclear CD38 to a more youthful level, but I have no idea how much apigenin is required, or how much is too much. Mice without CD38 (CD38 K O mice) are very sick.  But restoring youthful nuclear CD38 in myself to restore youthful nuclear NAD+ and youthful sirtuin levels is verry attractive.

 

I've decided for the time being to try a largish dose of apigenin (300 mg) once every two weeks.

• 300 mg of apigenin once every two weeks gives a steady-state peak of 324 mg post-dose and a trough of 24 mg pre-dose.
• For comparison, 50 mg of apigenin taken daily gives a steady-state peak of 296 mg post-dose and a trough of 246 mg pre-dose.
• (Calculated for 90 hr half-life)

I'm also taking EMIQ quercetin 50 mg once per day during the 1st week after the apigenin dose.

Quercetin is toxic when a therapeutic level is maintained continuously.  But with its short half-life, a single dose per day, every other week, will only produce transient pulses that should be acceptable.

Edited by RWhigham, 04 April 2018 - 10:21 PM.

[Phoebus]

 CD38 is inhibited at low micromolar concentrations by the flavanoid luteolin

 

https://www.ncbi.nlm...pubmed/21641214

 

 

so thats another option other than apigenin. I take it and love it, it also has anti cancer, anti inflammatory, anti depressive etc qualities. Good stuff 

 

https://www.selfhack...efits-luteolin/

[RWhigham]

On further consideration,

 

(1) Cells usually commit apoptosis after reaching replicative senescence, but they can  get stuck waiting for p53 from the nucleus to release cytochrome-c from mitochondria. When enough cytochrome-c is released the apoptosis proceeds. FOX04 puts the brakes on excess apoptosis by deactivating p53. In old age the "brakes" are applied too often and senescent cells build up.

 

(2) Cells can go into a senescent-like state when excessive DNA damage is detected.  In this state they are waiting for DNA repair. This state is maintained by p53. This senescent-like state can persist until DNA repair occurs and is recognized,  Inhibiting p53 with SIRT-1 (or resveratrol) appears to revert these cells to a normal non-senescent state, but if the DNA has not been repaired this may be risky from the viewpoint  of cancer genesis.

 

Hypotheses: (1) Enhancing DNA repair may be one of the better approaches toward life extension, since all cells are constantly doing DNA repair but seem to fall behind with age. (2) Senescent cells attract macrophages which contribute to or cause the SASP instead of or in addition to the senescent cells. Controlling inflammation from macrophages would reduce SASP.

Edited by RWhigham, 29 May 2018 - 03:45 PM.

[RWhigham]

 

Senescent Cells: A Novel Therapeutic Target for Aging and Age-Related Diseases

"Apoptosis occurs when cells experience irreparable damage and p53 transcriptional activity is robust. Growth arrest is established through p53-mediated transcriptional activation of p21. This occurs in response to moderate stress-related damage in order to allow time for repair. In instances when repair is unsuccessful, p21 inhibits the formation of active cyclin E–Cdk2 complexes, imposing a more permanent cell-cycle arrest by keeping RB hypophosphorylated.5 This particular senescent state differs from p16Ink4a-mediated senescence in that it is reversible upon the deactivation of p53 or p21." 

Note the word "reversible"   I confused the reversal of these "senescent" cells (or should be say semi-senescent cells} to a non senescence state with their actual removal by apoptosis.  My mistake

[Nate-2004]

I had the same thoughts about the whole bringing senescent cells back to life thing with resveratrol. If FOXO4 delays apoptosis in senescent cells by inhibiting P53 then why would inhibiting P53 further with SIRT1 induction be helpful? Especially where the DNA is irreparable or cell death and turn over would be preferable.

 

According to Steve H, DNA repair may fall behind because of SASP, which increases NAD consumers like CD38, leaving little for PPARP in repair efforts. It seems more useful to approach from 3 angles: Do away with as many senescent cells as possible (either via inhibiting FOXO4 or otherwise finding more effective candidates), inhibit CD38 to some safe degree (supposedly a new drug is out which targets this, hopefully in a surgical manner) giving PPARP plenty of SIRT to do its job, then later find some way to ramp up telomerase.. though this is probably better off done in just the stem cells.

Edited by Nate-2004, 29 May 2018 - 07:21 PM.

[Nate-2004]

 CD38 is inhibited at low micromolar concentrations by the flavanoid luteolin

 

https://www.ncbi.nlm...pubmed/21641214

 

 

so thats another option other than apigenin. I take it and love it, it also has anti cancer, anti inflammatory, anti depressive etc qualities. Good stuff 

 

https://www.selfhack...efits-luteolin/

 

It'd be great if they could find something more bioavailable and modular than these. They say CD38 rises due to SASP but I'm inclined to think that it's not just SASP, it's an aging immune system. We can stave this off with exercise and supposedly regrow it with HGH and DHEA but I dunno if that works as well as reported. I'm always more inclined to go with upstream solutions and tackling root causes. CD38 has important functions so inhibiting it can be problematic can could cause unwanted side effects. Since luteolin is only a mild inhibitor, it's worth taking, not sure of its bioavailability though.

 

There's definitely something to be said about keeping NAD+ levels too high for too long though, it can't always be good to do that, because of how mitochondria respond to it. You can end up with dysfunction on that end.

[Phoebus]

you want healthy cd38 levels? then control for inflammation. Thats the key. 

 

 

UCLA researchers investigated the CD38 gene, which is expressed by most (but not all) luminal cells in the human prostate. By comparing luminal cells that express CD38 with those that do not, they found that a greater proportion of luminal cells without CD38 had the potential to expand and grow. Results also showed that these CD38-negative luminal progenitor cells are rare in regions without inflammation but are significantly more common in regions of inflammation. 

 

https://www.scienced...61206125202.htm

 

 

instead of worrying about targeting cd38, worry about systemic inflammation and how to calm it, then cd38 levels will normalize. 

 

like I have said elsewhere its likely that substances like luteolin dont target cd38 directly, instead they have anti inflammatory and/or anti oxidant effects that cause cd38 levels to fall indirectly. 

 

even depression may be a result of neuro inflammation in the brain. 

 

also luteolin is moderately bio available, not sure why you are saying its not. 

 

 

[orion22]

somone knows how much exces quercetin is excreted true urin or a supliment like fisetin or Apigenin that gets moslty used and dosen t stress the kidneys