Also wanted to point out that there was so much i couldn't include in this video (for time reasons) but maybe will do a more in depth video at a later date?!?
I wanted to clarify something. Someone else said that a problem with senescent cells is they can release the apoptosis chemicals into neighboring cells without successfully triggering apoptosis in themselves and this is a partial explanation for the "everything starts failing at once" symptom of aging. Could you confirm that, and discuss targeted apoptosis as a treatment? Note that this is a hot idea in the whole plant food community. Eg. - Turmeric: ruclips.net/video/7KQE9bAYig4/видео.html
Thanks so much for this! My takeaway is that we should remove / decompose senescent cells for the added bonus of restoring NAD+ levels. Let's watch closely all the senolytics coming to maket this year!
But Fisetin is essentially bad, it depletes glutathione, it disrupts mitochondria, it increases the amount of misfolded proteins. As far as I understand, this pushes senescent cells over the edge and regular cells can then hopefully recover from the damage.
Lovely video! :-) If I understand this right, white adipose (fat) cells accumulate senescent cells which activate M1 macrophages (white blood cells) which activates CD38 which uses up NAD+. So to increase NAD+ levels, loose weight. I hope that's right.
It sounds like insulin resistance? You need more and more NAD to have the same effect that you had when you were younger. This was a little beyond my reach but really interesting! I'm looking forward to more on NAD and ageing studies! Thanks!
As always, Brilliant!!! and Thanks! as a side note: Yes NMN great supplement and it looks that could replenish the leaky sink.... but, would (a cheaper) Vitamin B3 (Nicin) do the same? do you know of any studies on this?
3:50 On Thanksgiving eve here in the USA, it’s delightful to see that tryptophan can help us make more NAD+. Maybe I will eat a little more turkey this year.
Do the work example..Buy fresh parsley,chop into small pieces add to majority of cooked meals, soups,stews,scrambled eggs..don't be obese,smoke,excess alcohol,eat junk and man made chemicals. Count your blessings to the Grand Maestro..Or stay mystified why there are more stars seen from one night succeeding the previous night. thank you brilliant lady for your hard work .Excellent presentation.
As your immune system declines with age, cd38 increases in response to viral/cancerous metabolic load. The real problem isn't cd38, it's the declining immune system and protein production mechanisms. CD38 is just the body trying to prevent Viruses and Bacteria from hijacking our NAD+, using it for their own replication; while safeguarding other viral like capsids in our bodies like Mitochondria and ARK proteins. We have three types of cells in the body. Underperforming cells, optimally performing cells, and super fit cells. Super fit cells are Virally/Bacteria high jacked cells, or cancerous cells that aberrantly express NQO1, to cause a flood of NAD+ into the cell, which is what makes it super fit and able to outcompete neighboring cells. Suppressing CD38 could boost NAD metabolism, but will further compromise your immune responses to super fit, infected/aberrant cells.
Hopefully it is safe to suppress CD38. I'm religiously shoving bundle of parsley into my mouth every day in hopes it suppresses CD38, I'm kind of sick and tired of it though.
Thanks for the thorough breakdown and analysis. I've been interested in this dance between NAD and CD38 for a while. From what I've read, CD38 seems to be part of the immune response to infection, I think it's likely that CD38 knock-out mice are at least somewhat immune compromised. As you discussed in your wrap-up, I think senolytics be preferable to taking CD38 inhibitors (like apigenin).
As your immune system declines with age, cd38 increases in response to viral/cancerous metabolic load. The real problem isn't cd38, it's the declining immune system and protein production mechanisms. CD38 is just the body trying to prevent Viruses and Bacteria from hijacking our NAD+, using it for their own replication; while safeguarding other viral like capsids in our bodies like Mitochondria and ARK proteins. We have three types of cells in the body. Underperforming cells, optimally performing cells, and super fit cells. Super fit cells are Virally/Bacteria high jacked cells, or cancerous cells that aberrantly express NQO1, to cause a flood of NAD+ into the cell, which is what makes it super fit and able to outcompete neighboring cells. Suppressing CD38 could boost NAD metabolism, but will further compromise your immune responses to super fit, infected/aberrant cells.
Better off fixing the declining immune system or boosting melatonin production to restore the Thymus, epigenetic drift/loss of epigenetic quality control, or aberrant clock gene expression. CD38 will take care of itself.
P.S CD38 also plays a role in Oxytocin production, and spatial intelligence. I have no idea why a cellular protection mechanism that guards us against Cancer and Viruses would make us 'more sociable' the more infected we get. Maybe seeking out social support? Seems like an ingredient for social chaos to me; the body driving us into situations we could spread the virus through craving more social contacts.
Quercetin inhibits cd38 but it also inhibits sirt6 and activates sirt1 but does not give an extended life so maybe sirt6 also important or not powerfull enough? I believe the sirt6 inhibition of quercetin is one of the reasons why quercetin is a senolytic because sirt6 keeps scenecent cells alive because of autophagy. Fisetin on the other hand look 99% identical and has different outcomes has life extending propreties. Maybe quercetin not biovailabel since both are senolytics and activate sirt1?
Are you familiar with any known (or suspected) negative effects of inhibiting CD38? I keep hearing about people supplementing with apigenin (including one of the other comments) to try to inhibit CD38. Just curious if you're aware of any potential side effects.
Is the function of CD38 to break down NAD+ (oxidised) or NADH (reduced)? It could be part of a recycling mechanism to retain the correct ratio of NAD+:NADH if excess NADH is being produced due to high cellular demand for NAD+. Therefore influencing this may actually make things worse - it would cause an accumulation of NADH and with low NAD+. It could be that the demand for NAD+ is higher as we age and therefore breakdown/recycling mechanisms are up-regulated to deal with this higher demand - due to greater proportion of NADH being converted from NAD+ in the cell.
So, I think you are saying that if you do something that reduces inflammation, then you reduce CD38 and will have more NAD+ available whether you supplement or not? I think AKG is anti-inflammatory for me, and I am beginning to think that any amount of carb is inflammatory.
At what point in average adults do NAD+ levels start their decline and at what point do senescent cells start accumulating? I feel like I started aging back in my late 30's but people say senescent cells don't accumulate till way later. So I can't imagine this being the issue with early aging as far as aches, pains and appearances go.
Honestly dont know/dont know if we even have an accurate answer for this in research! Would definitely be interesting to look into though, but likely differ between tissues! 😊
I wonder if this is the first time the cause of NAD+ decline with age was discovered because I remember hearing David Sinclair on a podcast say that we currently don't know if the cause of NAD+ decline is because of less production or more consumption (It was probably a few years ago and i'm really sorry if i'm mistaken 😬) But 9:59 is the first time i hear that it's actually more consumption. I also remember from your Resveretrol video that the proteins that regulate it also degrades with age, so i think the main objective should be fixing the leaky sinks when it comes to decline of something with age rather than just supplementing. This video was quite complicated for my level so i will probably watch it a few times to really grasp it xD
Thanks and no worries is definitely complicated! The study shows as you say that nad consumption may be a major driver but it diesnt mean that there is also issues with nad production. I didnt say but nampt levels have been suggested to decline with age! 😊
An estimate for humans based on animal research is about 600mg a day. There is 137 mg of it in a gram of dried parsley, so roughly 5 grams of dried parsley should be sufficient.
@@user-gd7mr5bx1l ah so this is where it gets complicated as it is thought that sirt1 activation is good for longevity and so that is one of the reasons to increase nad+, so that it is available for sirt1. But this is why i think understanding the dose of resverstrol is so important.
I understand you've got to try and make some money to pay you back for the obvious time that goes into making these videos, but could you use Patreon rather than shilling for supplements companies? Supplement companies damage the field of rejuvenation biotech by selling products that do not do anything (or have not been proven to have any clinically meaningful outcome in humans, or often even in animal models). This leads to the general public thinking the whole anti aging research area is bunk.
Thanks, appreciate your comment! Donotage have a good reputation so far which is why i have begun to partner with them and since many of my viewers use supplement sites thought the discount would be useful. But am always open to your opinions and if there is a general consensus to switch to a patreon instead of sponsors then i can do so. Am more just testing how things go at the moment. I really dont ever want to mislead my viewers, and want to generate a community who will be skeptical and appreciate the underlying science!!
@@TheSheekeyScienceShow On behalf of the pragmatists out there, let me say that we understand the limited amount and nature of research in this area. We understand that there is a requirement of evidence to come to scientific conclusions. However, we're not doing science. We're doing an upside/downside risk analysis to optimise aspects of our health. While the level of evidence is vastly insufficient to quantify risk to the upside, given the nature of the molecules we're interested in, we believe the downside risk to be trivial. People like me were already looking for good sources of these products long before we found your channel. We are adults who are taking into accounts our financial means and personal risk tolerance. So thank you for the discount. We don't need you to moderate your content or your business relationships because there are people out there who choose to remain scientifically illiterate. That said, the space is still very immature and although DoNotAge are trying to position themselves as the go-to retailer, there is still a lot they could do to improve their reputation. I do not trust them when I see their testing certs for NMN powder on their capsules page or when I see that they expect us to pay £500 for tests when they cannot cite the origin of these tests or any research that speaks to their efficacy/accuracy. Shilling for this brand is definitely happening though. Vince from My NMN Journey seems to be all about these guys right now and he's taken other companies to task for misreporting their purity tests. Why not these guys? Anyway sorry for the rant. I think you should be free to monetise your channel how you see fit, but as someone who is trying to build their reputation in this area, you could probably afford to be a bit more critical when choosing who to associate with given that your reputations will be somewhat linked. Either that or in the future use your growing influence to require that players in this market tidy up their game in areas where you as a scientist are not comfortable.
@@ashw6015 thanks and should update the info, i handed notice back in jan and officially end donotage next week. .. Have only updated more recent videos where i explain more in description
Also wanted to point out that there was so much i couldn't include in this video (for time reasons) but maybe will do a more in depth video at a later date?!?
Please do
yes plz
I wanted to clarify something. Someone else said that a problem with senescent cells is they can release the apoptosis chemicals into neighboring cells without successfully triggering apoptosis in themselves and this is a partial explanation for the "everything starts failing at once" symptom of aging. Could you confirm that, and discuss targeted apoptosis as a treatment?
Note that this is a hot idea in the whole plant food community. Eg. - Turmeric:
ruclips.net/video/7KQE9bAYig4/видео.html
This is one of the most informative and detail explanation yet on NAD+ and aging. Thank you!
Thanks so much for this!
My takeaway is that we should remove / decompose senescent cells for the added bonus of restoring NAD+ levels. Let's watch closely all the senolytics coming to maket this year!
Another excellent video - definitely a challenging one. You did a great job. Thank you!
Thanks!! 😊
Excellent!! It really supports the idea of using Senolytics like Fisetin in conjunction with an NAD booster like NMN.
But Fisetin is essentially bad, it depletes glutathione, it disrupts mitochondria, it increases the amount of misfolded proteins. As far as I understand, this pushes senescent cells over the edge and regular cells can then hopefully recover from the damage.
Lovely video! :-) If I understand this right, white adipose (fat) cells accumulate senescent cells which activate M1 macrophages (white blood cells) which activates CD38 which uses up NAD+. So to increase NAD+ levels, loose weight. I hope that's right.
To lose weight is important role in this case but it’s also important to consume high fat diet and low carbs
Great video. Thank you. Im researching this topic due to being a long Covid sufferer. Its been helpful.
Aw yea, loving this 2k energy
It sounds like insulin resistance? You need more and more NAD to have the same effect that you had when you were younger.
This was a little beyond my reach but really interesting! I'm looking forward to more on NAD and ageing studies! Thanks!
As always, Brilliant!!! and Thanks!
as a side note: Yes NMN great supplement and it looks that could replenish the leaky sink....
but, would (a cheaper) Vitamin B3 (Nicin) do the same? do you know of any studies on this?
Thanks! Spoke about niacin a while back ruclips.net/video/2oIPTvcs2GU/видео.html . would do another video if i see more studies!
Good one! Learned a lot. Thank you.
Brilliant as always!
I was just about to take a shower but just saw you uploaded so i'm instead here xD
3:50 On Thanksgiving eve here in the USA, it’s delightful to see that tryptophan can help us make more NAD+. Maybe I will eat a little more turkey this year.
Do the work example..Buy fresh parsley,chop into small pieces add to majority of cooked meals, soups,stews,scrambled eggs..don't be obese,smoke,excess alcohol,eat junk and man made chemicals. Count your blessings to the Grand Maestro..Or stay mystified why there are more stars seen from one night succeeding the previous night. thank you brilliant lady for your hard work .Excellent presentation.
From what little I read, it appears one can't just inhibit CD38 indiscriminately. It seems to be very important for the body.
As your immune system declines with age, cd38 increases in response to viral/cancerous metabolic load.
The real problem isn't cd38, it's the declining immune system and protein production mechanisms.
CD38 is just the body trying to prevent Viruses and Bacteria from hijacking our NAD+, using it for their own replication; while safeguarding other viral like capsids in our bodies like Mitochondria and ARK proteins.
We have three types of cells in the body. Underperforming cells, optimally performing cells, and super fit cells.
Super fit cells are Virally/Bacteria high jacked cells, or cancerous cells that aberrantly express NQO1, to cause a flood of NAD+ into the cell, which is what makes it super fit and able to outcompete neighboring cells.
Suppressing CD38 could boost NAD metabolism, but will further compromise your immune responses to super fit, infected/aberrant cells.
Hopefully it is safe to suppress CD38. I'm religiously shoving bundle of parsley into my mouth every day in hopes it suppresses CD38, I'm kind of sick and tired of it though.
Just get apigenin from Swanson.
Thanks for the thorough breakdown and analysis. I've been interested in this dance between NAD and CD38 for a while. From what I've read, CD38 seems to be part of the immune response to infection, I think it's likely that CD38 knock-out mice are at least somewhat immune compromised. As you discussed in your wrap-up, I think senolytics be preferable to taking CD38 inhibitors (like apigenin).
Yeah maybe, would be good for more studies to look into it! 😊
As your immune system declines with age, cd38 increases in response to viral/cancerous metabolic load.
The real problem isn't cd38, it's the declining immune system and protein production mechanisms.
CD38 is just the body trying to prevent Viruses and Bacteria from hijacking our NAD+, using it for their own replication; while safeguarding other viral like capsids in our bodies like Mitochondria and ARK proteins.
We have three types of cells in the body. Underperforming cells, optimally performing cells, and super fit cells.
Super fit cells are Virally/Bacteria high jacked cells, or cancerous cells that aberrantly express NQO1, to cause a flood of NAD+ into the cell, which is what makes it super fit and able to outcompete neighboring cells.
Suppressing CD38 could boost NAD metabolism, but will further compromise your immune responses to super fit, infected/aberrant cells.
Better off fixing the declining immune system or boosting melatonin production to restore the Thymus, epigenetic drift/loss of epigenetic quality control, or aberrant clock gene expression. CD38 will take care of itself.
P.S CD38 also plays a role in Oxytocin production, and spatial intelligence. I have no idea why a cellular protection mechanism that guards us against Cancer and Viruses would make us 'more sociable' the more infected we get.
Maybe seeking out social support? Seems like an ingredient for social chaos to me; the body driving us into situations we could spread the virus through craving more social contacts.
Quercetin inhibits cd38 but it also inhibits sirt6 and activates sirt1 but does not give an extended life so maybe sirt6 also important or not powerfull enough? I believe the sirt6 inhibition of quercetin is one of the reasons why quercetin is a senolytic because sirt6 keeps scenecent cells alive because of autophagy. Fisetin on the other hand look 99% identical and has different outcomes has life extending propreties. Maybe quercetin not biovailabel since both are senolytics and activate sirt1?
awesome as always!
Are you familiar with any known (or suspected) negative effects of inhibiting CD38? I keep hearing about people supplementing with apigenin (including one of the other comments) to try to inhibit CD38. Just curious if you're aware of any potential side effects.
Haven't looked into this yet! 😊
Inflammaging drives NAD+ decline.
Is the function of CD38 to break down NAD+ (oxidised) or NADH (reduced)? It could be part of a recycling mechanism to retain the correct ratio of NAD+:NADH if excess NADH is being produced due to high cellular demand for NAD+. Therefore influencing this may actually make things worse - it would cause an accumulation of NADH and with low NAD+. It could be that the demand for NAD+ is higher as we age and therefore breakdown/recycling mechanisms are up-regulated to deal with this higher demand - due to greater proportion of NADH being converted from NAD+ in the cell.
So, I think you are saying that if you do something that reduces inflammation, then you reduce CD38 and will have more NAD+ available whether you supplement or not? I think AKG is anti-inflammatory for me, and I am beginning to think that any amount of carb is inflammatory.
Yes, would say that is a good consensus based on the evidence
If i put 5grams of parsley powder in my morning shake to get 600mg apigenin.
Challenging but important
At what point in average adults do NAD+ levels start their decline and at what point do senescent cells start accumulating? I feel like I started aging back in my late 30's but people say senescent cells don't accumulate till way later. So I can't imagine this being the issue with early aging as far as aches, pains and appearances go.
Honestly dont know/dont know if we even have an accurate answer for this in research! Would definitely be interesting to look into though, but likely differ between tissues! 😊
I wonder if this is the first time the cause of NAD+ decline with age was discovered because I remember hearing David Sinclair on a podcast say that we currently don't know if the cause of NAD+ decline is because of less production or more consumption (It was probably a few years ago and i'm really sorry if i'm mistaken 😬) But 9:59 is the first time i hear that it's actually more consumption. I also remember from your Resveretrol video that the proteins that regulate it also degrades with age, so i think the main objective should be fixing the leaky sinks when it comes to decline of something with age rather than just supplementing. This video was quite complicated for my level so i will probably watch it a few times to really grasp it xD
Thanks and no worries is definitely complicated! The study shows as you say that nad consumption may be a major driver but it diesnt mean that there is also issues with nad production. I didnt say but nampt levels have been suggested to decline with age! 😊
What supps do you take? Are you still taking NMN?
I take a general multi-vit, mainly for the iron and yeah still take low dose nmn
How much apigenin is required to inhibit CD38?
An estimate for humans based on animal research is about 600mg a day. There is 137 mg of it in a gram of dried parsley, so roughly 5 grams of dried parsley should be sufficient.
How do I test my nad level
Good question ?
how to get Reduced Nicotinamide Mononucleotide
What program are you using to draw?
Microsoft whiteboard
Does Resveratrol impact NAD+?
So resverstrol activates sirt1 which consumes nad+
@@TheSheekeyScienceShow so resveratrol consumes NAD+...sounds like resveratrol is bad because to get anti aging, one would want NAD+ to go up
@@user-gd7mr5bx1l ah so this is where it gets complicated as it is thought that sirt1 activation is good for longevity and so that is one of the reasons to increase nad+, so that it is available for sirt1. But this is why i think understanding the dose of resverstrol is so important.
Why do nad levels decline with age? So we don't die earlier from cancer.
Apigenin inhibits CD38 and increases NAD
need more drawing
7:00
Your brain is aching? I will need to listen again later. Johnny
I understand you've got to try and make some money to pay you back for the obvious time that goes into making these videos, but could you use Patreon rather than shilling for supplements companies? Supplement companies damage the field of rejuvenation biotech by selling products that do not do anything (or have not been proven to have any clinically meaningful outcome in humans, or often even in animal models). This leads to the general public thinking the whole anti aging research area is bunk.
Thanks, appreciate your comment! Donotage have a good reputation so far which is why i have begun to partner with them and since many of my viewers use supplement sites thought the discount would be useful. But am always open to your opinions and if there is a general consensus to switch to a patreon instead of sponsors then i can do so. Am more just testing how things go at the moment. I really dont ever want to mislead my viewers, and want to generate a community who will be skeptical and appreciate the underlying science!!
@@TheSheekeyScienceShow On behalf of the pragmatists out there, let me say that we understand the limited amount and nature of research in this area. We understand that there is a requirement of evidence to come to scientific conclusions. However, we're not doing science. We're doing an upside/downside risk analysis to optimise aspects of our health. While the level of evidence is vastly insufficient to quantify risk to the upside, given the nature of the molecules we're interested in, we believe the downside risk to be trivial. People like me were already looking for good sources of these products long before we found your channel. We are adults who are taking into accounts our financial means and personal risk tolerance. So thank you for the discount.
We don't need you to moderate your content or your business relationships because there are people out there who choose to remain scientifically illiterate.
That said, the space is still very immature and although DoNotAge are trying to position themselves as the go-to retailer, there is still a lot they could do to improve their reputation. I do not trust them when I see their testing certs for NMN powder on their capsules page or when I see that they expect us to pay £500 for tests when they cannot cite the origin of these tests or any research that speaks to their efficacy/accuracy. Shilling for this brand is definitely happening though. Vince from My NMN Journey seems to be all about these guys right now and he's taken other companies to task for misreporting their purity tests. Why not these guys?
Anyway sorry for the rant. I think you should be free to monetise your channel how you see fit, but as someone who is trying to build their reputation in this area, you could probably afford to be a bit more critical when choosing who to associate with given that your reputations will be somewhat linked. Either that or in the future use your growing influence to require that players in this market tidy up their game in areas where you as a scientist are not comfortable.
@@ashw6015 thanks and should update the info, i handed notice back in jan and officially end donotage next week. .. Have only updated more recent videos where i explain more in description