August 19, 2025 • 10 mins
In the aging brain, neurons begin to lose a hidden currency. Not just ATP, but GTP - that powers their ability to clear away toxic proteins. Without it, the cleanup crews stall, and amyloid builds up. A team at UC Irvine may have uncovered a way to recharge that system using two familiar compounds. In aged and Alzheimer’s model neurons, this pairing restored GTP, reactivated trafficking pathways, and swept away protein aggregates. In this episode, we follow the trail from dwindling cellular energy to revived cleanup machinery, and explore how these findings fit with human evidence.
00:00 Introduction: The Overlooked Clue in Aging Brains
00:47 The Energy Crisis in Aging Neurons
01:21 Natural Compounds to the Rescue
01:55 The UC Irvine Study: A Closer Look
03:05 Mechanisms Behind Nicotinamide and EGCG
04:37 Human Data: What Do We Know?
06:59 Comparing Strategies: Drugs vs. Natural Compounds
08:11 Challenges and Future Directions
09:27 Conclusion: A Promising but Unproven Strategy
PMID: 40661491
Mark as Played
Transcript
Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Speaker 1 (00:01):
Every detective story begins with a clue overlooked
In the aging brain.
It isn't just amyloid plaquesor tangled proteins.
It's a missing currency, anenergy form that powers the
cell's cleanup crews.
Without it, garbage builds up,neurons slow down and memory
begins to fray.
Recently, researchers uncoveredsomething surprising.
Two familiar natural compoundswere able to bring that currency
back, and with it the cell'sability to take out its own
(00:23):
trash.
In just 24 hours, worn downneurons regained energy, cleared
toxic proteins and reduced thestress that drives degeneration.
What are these compounds andwhat does this discovery mean
for how we think about cognitivedecline?
(00:47):
As the brain ages, energy beginsto run short.
Atp production drops,especially in a place like the
hippocampus, a region thatcarries the heaviest load for
memory and learning.
That deficit fuels oxidativestress, while the cleanup system
, autophagy, slows down.
And here's the twist Autophagyisn't powered by ATP alone.
It depends on another energycurrency GTP, to drive vesicle
(01:11):
trafficking and proteinclearance.
But with age, nad plus levelsfall, cutting off the very
precursors needed to keep GTPflowing.
Neurons become starved of theenergy they need to take out the
trash.
Now imagine if there weresimple natural molecules,
compounds you could find in avitamin or even in a cup of tea
that could recharge this hiddenenergy system.
(01:31):
Two such molecules have caughtscientists' attention in a very
recent finding.
One feeds the NAD plus pool,the other a green tea
antioxidant that flips on thebrain's antioxidant defenses.
Together they appear to dosomething very unique restore
lost GTP and give old neuronsback their ability to clean
(01:51):
house.
That's the story behind a newstudy from UC Irvine.
Before we go any further, it'simportant to be clear.
The study we're about to unpackwas done in neurons from aged
mice and in Alzheimer's modelmice.
This isn't a clinical trial andit doesn't prove that the same
effects occur in humans.
What it does provide is awindow into mechanisms we can
then compare against human data.
(02:12):
So in this episode we'll walkthrough what the researchers saw
in the lab and then we'll bringin findings from clinical
studies to see how it all linesup.
The UC Irvine team started witha simple question If declining
GTP is a bottleneck in agingneurons, can we restore it?
To test that, they culturedhippocampal neurons from aged
(02:33):
mice, tracked live GTP levelswith a fluorescent sensor and
asked what happens when you addback two natural compounds.
The results showed that freeGTP levels, which normally
collapse with age, reboundedwithin 24 hours when the cells
were treated with nicotinamide,the vitamin B3 amide, and EGCG,
(02:54):
the green tea antioxidant.
That recovery reactivatedvesicle trafficking, lowered
oxidative stress and clearedamyloid aggregates, essentially
giving old neurons back theircleanup function.
So why do these two compounds,nicotinamide and EGCG, make such
a difference in age neurons?
The answer lies in how they feedinto two complementary systems.
Nicotinamide is a form ofvitamin D3 that feeds the NAD
(03:21):
plus salvage pathway.
Nad plus is the gateway toguanine nucleotide synthesis.
Without it, neurons can'tefficiently make GMP and GTP.
By restoring NAD+ availability,nicotinamide reopens the supply
line for GTP, and that GTP iswhat fuels small GTPase enzymes
that drive vesicle trafficking,endocytosis and ultimately
(03:42):
autophagy.
Egcg works from a differentangle.
It's a polyphenol from greentea that very rapidly activates
Nrf2.
That's the transcription factorthat turns on antioxidant
defenses.
Importantly, first line ofdefense enzymes.
Within 30 minutes, EGCG drivesNrf2 into the nucleus and
increases expression of enzymeslike glutathione peroxidase,
(04:03):
superoxide dismutase and more,countering the oxidative stress
that otherwise paralyzestrafficking pathways.
Put together, nicotinamidesupplies missing fuel and EGCG
protects the machinery that usesit.
The result vesicles move again,lysosomes fuse and amyloid
cargo gets cleared.
In effect, the energy systemand the defense system come back
(04:25):
online at the same timerestoring a cleanup process that
had ground to a hull.
Now that was all neurons fromaged mice.
The real question is do we seeanything like this in people?
Let's start with the energyside.
In humans, brain imaging showsthat brain NAD plus levels
decline with age and thosereductions track directly with
(04:47):
ATP production.
In other words, the sameenergetic bottleneck seen in
mouse neurons shows up in livinghuman brains and there's proof
that you can move this system.
In Parkinson's patients, 30days of supplementation with
nicotinamide riboside at 1,000milligrams boosted brain NAD
(05:07):
plus levels and shifted cerebralmetabolism on PET scans.
That doesn't prove benefit forAlzheimer's, but it shows the
pathway can be engaged in people.
Nicotinamide itself has alsobeen tested in early Alzheimer's
.
In the phase two NEAT trial,patients received three grams
per day for 48 weeks.
It was safe, but it didn'tshift tau biomarkers, the likely
(05:29):
reason Most of the nicotinamidewas inactivated in the
bloodstream before it reachedthe brain.
That detail echoes exactly whatthe UC Irvine team warned about
Delivery matters.
What about the green teacompound?
In healthy adults, a singledose of green tea extract
containing 300 mg EGCG has beenshown to enhance parietal
(05:52):
frontal brain connectivityduring working memory tasks on
an fMRI In older adults withmild cognitive impairment, a
blend of green tea catechinsplus 60 milligrams of L-theanine
daily improve working memoryand attention span over 16 weeks
.
Other trials using one to twograms of green tea catechins
over 12 months have shown mixedresults, sometimes no clear
(06:14):
cognitive benefit, butconsistent reductions in
oxidative stress markers and, inan entirely different context,
cardiac amyloidosis.
Patients taking 450 mg of EDCGdaily from green tea extract
showed reductions in amyloidburden in the heart muscle over
a year.
It's not the brain, but it'scompelling evidence that
catechins can remodel proteinaggregates in humans.
(06:35):
Put together, the human datadoesn't yet confirm what UC
Irvine saw in a dish, but itpoints in the same direction.
Energy declines with age, b3derivatives can raise NAD plus
in the brain, and green teacatechins can alter connectivity
, memory and even amyloidbiology.
The pieces fit, thoughtranslation is going to depend
(06:55):
on dose formulation and morelong-term trials.
The UC Irvine work points in adifferent direction compared to
certain drugs on the market.
Instead of pulling amyloid outof the brain with an external
tool, the goal is to repower theneuron's own cleanup crew.
By restoring GTP and balancingredox status, neurons might be
able to take out their own trash.
(07:16):
This theme also lines up withother non-drug strategies that
have shown human signals.
Ketone therapies, for instanceoften in the form of
medium-chain triglycerides,provide around 20 to 30 grams
per day can bypass defectiveglucose metabolism in the
Alzheimer's brain, leading toimprovements on cognitive scales
in certain subgroups.
Synaptic support formulas likesovinade, which combine omega-3s
(07:39):
, uridine and choline, haveshown that supplying the right
metabolic precursors can slowD-kind in prodromal Alzheimer's
over several years.
What makes the UC Irvineapproach different is its
simplicity.
Both compounds are alreadyavailable as dietary supplements
.
Vitamin B3 derivatives canrestore NAD+.
Green tea catechins can flip onantioxidant defenses and, in
(08:00):
some contexts, remodel amyloid.
It's not proof yet, but itsketches out a path where
nutrition and energy metabolismaren't just supportive care,
they're part of the therapeuticequation.
Of course there are importantlimits to keep in mind.
The UC Irvine findings comefrom neurons in culture, not
from human brains.
What works in a dish doesn'talways translate to living
(08:21):
people.
On the supplementation side,nicotinamide at very high doses
3 grams per day, like in theMEAT trial was safe for most
participants, but it didn't moveAlzheimer's biomarkers and it
can stress the liver in someindividuals.
Newer NAD plus precursors likenicotinamide riboside show
better delivery to the brain butstill need long-term testing.
(08:41):
For green tea catechins, humantrials have used a wide range of
doses.
Lower daily amounts 300 to 600milligrams of EGCG are generally
well tolerated, but higherintakes, especially from
concentrated extracts, carry aknown risk of liver toxicity in
a fraction of people.
That's why clinical studiesmonitor liver enzymes closely.
(09:01):
Finally, while there are signalsin Parkinson's disease, mild
cognitive impairment and evencardiac amyloidosis, we don't
yet have strong randomized trialdata showing that these
compounds prevent or reverseAlzheimer's disease.
Translation will hinge onbioavailability, formulation and
long-term safety.
Until those studies are done,this remains a promising but
(09:23):
unproven strategy to maintaincognitive capacity as we age.
The takeaway is simple Agingneurons don't just lose energy,
they lose the very currency GTPthat powers their ability to
clean house In mice.
Restoring that fuel withnicotinamide and a green tea
antioxidant gave old neuronsback their ability to clear
(09:43):
toxic proteins.
In people the story is stillunfolding.
We know brain NAD plus fallswith age.
We know that B3 derivatives canraise it.
And we know green tea catechinscan alter brain connectivity
and even remodel amyloid inother tissues.
But the leap to Alzheimer'stherapy will depend on dose
delivery and long-term trials.
(10:04):
For now it's a compellingglimpse at how nutrition and
metabolism might one day jointhe front line in the fight
against cognitive decline.
Until next time, stay sharp andstay healthy.
Every detective story begins with a clue overlooked
In the aging brain.
It isn't just amyloid plaquesor tangled proteins.
It's a missing currency, anenergy form that powers the
cell's cleanup crews.
Without it, garbage builds up,neurons slow down and memory
begins to fray.
Recently, researchers uncoveredsomething surprising.
Two familiar natural compoundswere able to bring that currency
back, and with it the cell'sability to take out its own
(00:23):
trash.
In just 24 hours, worn downneurons regained energy, cleared
toxic proteins and reduced thestress that drives degeneration.
What are these compounds andwhat does this discovery mean
for how we think about cognitivedecline?
(00:47):
As the brain ages, energy beginsto run short.
Atp production drops,especially in a place like the
hippocampus, a region thatcarries the heaviest load for
memory and learning.
That deficit fuels oxidativestress, while the cleanup system
, autophagy, slows down.
And here's the twist Autophagyisn't powered by ATP alone.
It depends on another energycurrency GTP, to drive vesicle
(01:11):
trafficking and proteinclearance.
But with age, nad plus levelsfall, cutting off the very
precursors needed to keep GTPflowing.
Neurons become starved of theenergy they need to take out the
trash.
Now imagine if there weresimple natural molecules,
compounds you could find in avitamin or even in a cup of tea
that could recharge this hiddenenergy system.
(01:31):
Two such molecules have caughtscientists' attention in a very
recent finding.
One feeds the NAD plus pool,the other a green tea
antioxidant that flips on thebrain's antioxidant defenses.
Together they appear to dosomething very unique restore
lost GTP and give old neuronsback their ability to clean
(01:51):
house.
That's the story behind a newstudy from UC Irvine.
Before we go any further, it'simportant to be clear.
The study we're about to unpackwas done in neurons from aged
mice and in Alzheimer's modelmice.
This isn't a clinical trial andit doesn't prove that the same
effects occur in humans.
What it does provide is awindow into mechanisms we can
then compare against human data.
(02:12):
So in this episode we'll walkthrough what the researchers saw
in the lab and then we'll bringin findings from clinical
studies to see how it all linesup.
The UC Irvine team started witha simple question If declining
GTP is a bottleneck in agingneurons, can we restore it?
To test that, they culturedhippocampal neurons from aged
(02:33):
mice, tracked live GTP levelswith a fluorescent sensor and
asked what happens when you addback two natural compounds.
The results showed that freeGTP levels, which normally
collapse with age, reboundedwithin 24 hours when the cells
were treated with nicotinamide,the vitamin B3 amide, and EGCG,
(02:54):
the green tea antioxidant.
That recovery reactivatedvesicle trafficking, lowered
oxidative stress and clearedamyloid aggregates, essentially
giving old neurons back theircleanup function.
So why do these two compounds,nicotinamide and EGCG, make such
a difference in age neurons?
The answer lies in how they feedinto two complementary systems.
Nicotinamide is a form ofvitamin D3 that feeds the NAD
(03:21):
plus salvage pathway.
Nad plus is the gateway toguanine nucleotide synthesis.
Without it, neurons can'tefficiently make GMP and GTP.
By restoring NAD+ availability,nicotinamide reopens the supply
line for GTP, and that GTP iswhat fuels small GTPase enzymes
that drive vesicle trafficking,endocytosis and ultimately
(03:42):
autophagy.
Egcg works from a differentangle.
It's a polyphenol from greentea that very rapidly activates
Nrf2.
That's the transcription factorthat turns on antioxidant
defenses.
Importantly, first line ofdefense enzymes.
Within 30 minutes, EGCG drivesNrf2 into the nucleus and
increases expression of enzymeslike glutathione peroxidase,
(04:03):
superoxide dismutase and more,countering the oxidative stress
that otherwise paralyzestrafficking pathways.
Put together, nicotinamidesupplies missing fuel and EGCG
protects the machinery that usesit.
The result vesicles move again,lysosomes fuse and amyloid
cargo gets cleared.
In effect, the energy systemand the defense system come back
(04:25):
online at the same timerestoring a cleanup process that
had ground to a hull.
Now that was all neurons fromaged mice.
The real question is do we seeanything like this in people?
Let's start with the energyside.
In humans, brain imaging showsthat brain NAD plus levels
decline with age and thosereductions track directly with
(04:47):
ATP production.
In other words, the sameenergetic bottleneck seen in
mouse neurons shows up in livinghuman brains and there's proof
that you can move this system.
In Parkinson's patients, 30days of supplementation with
nicotinamide riboside at 1,000milligrams boosted brain NAD
(05:07):
plus levels and shifted cerebralmetabolism on PET scans.
That doesn't prove benefit forAlzheimer's, but it shows the
pathway can be engaged in people.
Nicotinamide itself has alsobeen tested in early Alzheimer's
.
In the phase two NEAT trial,patients received three grams
per day for 48 weeks.
It was safe, but it didn'tshift tau biomarkers, the likely
(05:29):
reason Most of the nicotinamidewas inactivated in the
bloodstream before it reachedthe brain.
That detail echoes exactly whatthe UC Irvine team warned about
Delivery matters.
What about the green teacompound?
In healthy adults, a singledose of green tea extract
containing 300 mg EGCG has beenshown to enhance parietal
(05:52):
frontal brain connectivityduring working memory tasks on
an fMRI In older adults withmild cognitive impairment, a
blend of green tea catechinsplus 60 milligrams of L-theanine
daily improve working memoryand attention span over 16 weeks
.
Other trials using one to twograms of green tea catechins
over 12 months have shown mixedresults, sometimes no clear
(06:14):
cognitive benefit, butconsistent reductions in
oxidative stress markers and, inan entirely different context,
cardiac amyloidosis.
Patients taking 450 mg of EDCGdaily from green tea extract
showed reductions in amyloidburden in the heart muscle over
a year.
It's not the brain, but it'scompelling evidence that
catechins can remodel proteinaggregates in humans.
(06:35):
Put together, the human datadoesn't yet confirm what UC
Irvine saw in a dish, but itpoints in the same direction.
Energy declines with age, b3derivatives can raise NAD plus
in the brain, and green teacatechins can alter connectivity
, memory and even amyloidbiology.
The pieces fit, thoughtranslation is going to depend
(06:55):
on dose formulation and morelong-term trials.
The UC Irvine work points in adifferent direction compared to
certain drugs on the market.
Instead of pulling amyloid outof the brain with an external
tool, the goal is to repower theneuron's own cleanup crew.
By restoring GTP and balancingredox status, neurons might be
able to take out their own trash.
(07:16):
This theme also lines up withother non-drug strategies that
have shown human signals.
Ketone therapies, for instanceoften in the form of
medium-chain triglycerides,provide around 20 to 30 grams
per day can bypass defectiveglucose metabolism in the
Alzheimer's brain, leading toimprovements on cognitive scales
in certain subgroups.
Synaptic support formulas likesovinade, which combine omega-3s
(07:39):
, uridine and choline, haveshown that supplying the right
metabolic precursors can slowD-kind in prodromal Alzheimer's
over several years.
What makes the UC Irvineapproach different is its
simplicity.
Both compounds are alreadyavailable as dietary supplements
.
Vitamin B3 derivatives canrestore NAD+.
Green tea catechins can flip onantioxidant defenses and, in
(08:00):
some contexts, remodel amyloid.
It's not proof yet, but itsketches out a path where
nutrition and energy metabolismaren't just supportive care,
they're part of the therapeuticequation.
Of course there are importantlimits to keep in mind.
The UC Irvine findings comefrom neurons in culture, not
from human brains.
What works in a dish doesn'talways translate to living
(08:21):
people.
On the supplementation side,nicotinamide at very high doses
3 grams per day, like in theMEAT trial was safe for most
participants, but it didn't moveAlzheimer's biomarkers and it
can stress the liver in someindividuals.
Newer NAD plus precursors likenicotinamide riboside show
better delivery to the brain butstill need long-term testing.
(08:41):
For green tea catechins, humantrials have used a wide range of
doses.
Lower daily amounts 300 to 600milligrams of EGCG are generally
well tolerated, but higherintakes, especially from
concentrated extracts, carry aknown risk of liver toxicity in
a fraction of people.
That's why clinical studiesmonitor liver enzymes closely.
(09:01):
Finally, while there are signalsin Parkinson's disease, mild
cognitive impairment and evencardiac amyloidosis, we don't
yet have strong randomized trialdata showing that these
compounds prevent or reverseAlzheimer's disease.
Translation will hinge onbioavailability, formulation and
long-term safety.
Until those studies are done,this remains a promising but
(09:23):
unproven strategy to maintaincognitive capacity as we age.
The takeaway is simple Agingneurons don't just lose energy,
they lose the very currency GTPthat powers their ability to
clean house In mice.
Restoring that fuel withnicotinamide and a green tea
antioxidant gave old neuronsback their ability to clear
(09:43):
toxic proteins.
In people the story is stillunfolding.
We know brain NAD plus fallswith age.
We know that B3 derivatives canraise it.
And we know green tea catechinscan alter brain connectivity
and even remodel amyloid inother tissues.
But the leap to Alzheimer'stherapy will depend on dose
delivery and long-term trials.
(10:04):
For now it's a compellingglimpse at how nutrition and
metabolism might one day jointhe front line in the fight
against cognitive decline.
Until next time, stay sharp andstay healthy.
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