Qualy #57 - A primer on NAD+⧸NADH, its effect on lifespan⧸healthspan, and a review of the supplements
Episode Stats
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Summary
In this episode of The Qualies, we discuss the role of nad in maintaining cell health, and why it may be declining as we age. In particular, what role does nad play in maintaining cellular health? And why does this matter?
Transcript
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welcome to the qualies a subscriber exclusive podcast qualies is just a shorthand slang for
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subscribe so without further delay i hope you enjoy today's quali so there's one more topic i just want
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to get to if we can spare a bit more time which is which is nad the precursors the whole shtick
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you've spent a lot of time thinking about this what is your current thinking on does having more nad to
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nadh matter the the thing about the nad i guess i should provide context for people why am i asking
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this question right so there's lots of supplements out there now that are you know either giving nr
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or nad and the claim is that these things can enhance longevity you could live longer and that
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also you live better you have more energy all of these other things and so in the mitochondria you
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have complex one which converts nadh to nad and the idea is we we do know that as you age that ratio of
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nad to nadh goes down and so part of the thinking is well and this is outside of the sirtuin pathway but
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this is upstream of that but if you give more of either the precursor nad you're basically fixing
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something that is getting worse as you age yeah so that i mean the the question is why does it go down
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and that's i think there's multiple reasons for that at least that's been shown in literature nad is a
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very important cofactor for mitochondria i mean obviously mitochondria are making nadh and the
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that hydrogen the proton is used and electrons are used to basically generate energy through the
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electron transport chain and it's also generating the mitochondrial membrane potential by kicking out
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the the proton so that that's really important for mitochondrial function respiratory function
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energy production which is like the key of everything right but in addition to that you have as you
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mentioned sirtuins which are histone deacetylases which have a whole host of functions that they're
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doing regulating tons and tons of different pathways they're also seem to be very important
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for healthspan and then in addition to that there's very important dna repair enzyme part that literally
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syncs up nad i mean it's like an nad sync i mean it you know so you know we're constantly having
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damage where does it reside that enzyme where in the cell yeah is it nuclear it must be right yeah and
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the reason i ask is how do we know that these supplements that we take orally are going to
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actually reach their bioavailability in the place we want them right okay but that said we'll come back
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to that after um i think it's in the nucleus i mean it would make sense to be there but yeah other ways
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it shuttles there but i think it is so it's very important for repairing you know dna damage and so
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that's one of the major syncs and actually inflammation all these things are kind of upstream of
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parp activation so the more that's happening the more parps being activated so you kind of have you
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have nad going there so one argument just to make sure i understand what you're saying is look if
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you're getting older you're going to have more dna damage that's just stochastic and if your little
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guy that repairs it requires nad as fuel right that would explain one reason potentially why nad would
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decline as we age yeah it's and it's certainly a sink for it yeah and the other so the other thing is
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well if your immune system's constantly you know activated too if more inflammation you have all
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that energy is required so nad is being consumed more for that as well so that's sort of another
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sink basically nad levels decline with age and it's probably because it's just getting used up more
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or the other the alternative is you know is there something else going on in terms of like this whole
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salvage pathway there's another pathway that you can do to regenerate nad and if that's kind of going
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wrong and i think there's some increasing evidence for that as well would that make metformin a bad
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idea from this standpoint because metformin inhibits complex one so metformin lowers the ratio of nad to
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nadh does it has that been shown so you're saying it should lower it it should lower it now of course
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that's counterintuitive because we know it activates ampk so i probably have to sit down and think about this
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but we do know metformin inhibits complex one and we know that complex one turns nad to nad
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which makes me wonder does is it possible that metformin would impair dna repair through that
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mechanism by reducing substrate i have no idea well i'm going to write that down that's something
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we're going to have to look into because i wasn't aware of the any i didn't understand that uh that
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link but yeah yeah exactly i think that's a major one i literally think that's a major sink for it i
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think that the parp is i think it's just like going there yeah so the animal evidence you mentioned some
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of the supplements you know precursors that can form nad i think that the animal evidence suggests
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that it can at least in rodents improve health span particularly uh in models with like that are
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heavily dependent on mitochondria like muscle myopathy models or something like that i think i think that
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was one and also the brain so i think those are the two the two organs i've seen like major positive
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effects with uh with nad supplementation and then there's some of course pilot clinical studies showing
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that yes you can take for example nicotinamide rice riboside and it does seem to increase
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nad levels and plasma in a dose dependent manner now again you raise no idea if it's getting in the
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is it getting in the cell is it getting in the now we do know in animal studies i think that has been
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shown because it's affecting the mitochondria like i said those animal models of myopathy and stuff and
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mitochondrial function was improved and all that stuff so so in animal models it obviously is affecting
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mitochondrial function so it must be getting to the right place i don't know why i have found
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myself kind of skeptical of this i think it's good to start with skepticism i'm i mean i think that
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nad levels are you can you can increase them with fasting so when you fast you know as you mentioned
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you convert nad into nadh in the presence of of energy because because that's basically what when
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you have a substrate like glucose or fatty acid that's when you produce nadh or fadh too so in the
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absence of those substrates then you start to make your nad starts to build up so back to your
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metformin question you said i know who to ask i definitely know i'm gonna ask nav chandel he will
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know the answer to this i follow a lot of his work when i was in grad him ralph de bardini's i did
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because i was doing a lot of cancer metabolism cancer metabolism mitochondrial function and stuff so i
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followed a lot of his work do you have nav's book navigating metabolism no i don't no i just used to
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read his papers back when i was a graduate school just yeah so nav and david sabatini were in town a
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couple of weeks ago and i was leaving town the day they were coming into town so we hung out for
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three hours near the airport and uh i was just reminded of how much fun it is to talk about
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mitochondria yeah for sure i hope you enjoyed today's quali now sit tight for that legal disclaimer
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