303-A breakthrough in Alzheimer’s disease: potential of klotho for brain health & as a therapeutic
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- čas přidán 26. 06. 2024
- View show notes here: bit.ly/4bwwZVe
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Dena Dubal is a physician-scientist and professor of neurology at UCSF whose work focuses on mechanisms of longevity and brain resilience. In this episode, Dena delves into the intricacies of the longevity factor klotho: its formation and distribution in the body, the factors such as stress and exercise that impact its levels, and its profound impact on cognitive function and overall brain health. Dena shares insights from exciting research in animal models showing the potential of klotho in treating neurodegenerative diseases as well as its broader implications for organ health and disease prevention. She concludes with an optimistic outlook for future research in humans and the potential of klotho for the prevention and treatment of Alzheimer’s disease.
Disclosure: Peter is an investor in Jocasta Neuroscience, a company working to develop klotho as a therapy for people with Alzheimer’s disease.
We discuss:
0:00:00 - Intro
0:01:19 - Dena’s fascination with aging and how she came to study klotho
0:11:00 - Biological properties of klotho: production, regulation, decline with age, and factors influencing its levels
0:23:08 - Potential benefits of klotho on brain health
0:36:18 - The relationship between soluble klotho protein, platelet factors, and cognitive enhancement
0:52:31 - The role of platelet factor 4 (PF4) and it’s interaction with GluN2B in mediating cognitive enhancement
1:02:52 - Benefits of klotho observed in a mouse model of Parkinson’s disease
1:11:22 - Benefits of klotho observed in a mouse model of Alzheimer’s disease
1:17:18 - Promising results of klotho in primate models, and the importance of finding an appropriate therapeutic dose before moving to human trials
1:39:34 - Speculating why a single klotho injection has such long-lasting effects
1:42:45 - Potential cognitive benefits of klotho in humans, the impact of the KL-VS genetic variant on klotho levels, and the need for human trials to confirm these effects
1:50:10 - The interaction between the KL-VS genetic variant and APOE4 and how it impacts risk of Alzheimer’s disease
2:05:26 - The significance of klotho levels: studies linking lower levels to increased mortality and the broader implications for organ health and disease prevention
2:11:48 - Measuring klotho levels and determining an individual’s KL-VS status
2:18:32 - The promising potential of klotho for Alzheimer’s disease treatment, and the importance of philanthropy for funding research
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About:
The Peter Attia Drive is a deep-dive podcast focusing on maximizing longevity, and all that goes into that from physical to cognitive to emotional health. With over 90 million episodes downloaded, it features topics including exercise, nutritional biochemistry, cardiovascular disease, Alzheimer’s disease, cancer, mental health, and much more.
Peter Attia is the founder of Early Medical, a medical practice that applies the principles of Medicine 3.0 to patients with the goal of lengthening their lifespan and simultaneously improving their healthspan.
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![AGEs: The Surprising Link Between our Diet and Aging [Advanced Glycation End Products]](/img/n.gif)
In this episode, we discuss:
0:01:19 - Dena’s fascination with aging and how she came to study klotho
0:11:00 - Biological properties of klotho: production, regulation, decline with age, and factors influencing its levels
0:23:08 - Potential benefits of klotho on brain health
0:36:18 - The relationship between soluble klotho protein, platelet factors, and cognitive enhancement
0:52:31 - The role of platelet factor 4 (PF4) and it’s interaction with GluN2B in mediating cognitive enhancement
1:02:52 - Benefits of klotho observed in a mouse model of Parkinson’s disease
1:11:22 - Benefits of klotho observed in a mouse model of Alzheimer’s disease
1:17:18 - Promising results of klotho in primate models, and the importance of finding an appropriate therapeutic dose before moving to human trials
1:39:34 - Speculating why a single klotho injection has such long-lasting effects
1:42:45 - Potential cognitive benefits of klotho in humans, the impact of the KL-VS genetic variant on klotho levels, and the need for human trials to confirm these effects
1:50:10 - The interaction between the KL-VS genetic variant and APOE4 and how it impacts risk of Alzheimer’s disease
2:05:26 - The significance of klotho levels: studies linking lower levels to increased mortality and the broader implications for organ health and disease prevention
2:11:48 - Measuring klotho levels and determining an individual’s KL-VS status
2:18:32 - The promising potential of klotho for Alzheimer’s disease treatment, and the importance of philanthropy for funding research
Fascinating that Klotho can mitigate Apoe4. I wonder if it could also offset the LP(a) variant(I’d cheer out loud!). In regards to 23andme, I clicked Resources, then clicked Browse Data under Browse Raw Genotyping Data, then typed rs9536314 in the Chromosome Search Bar. (happily GT in my case). The other SNP(rs9527025) was not in the 23andme database, unfortunately. I used SelfDecode for that one, but I believe if one SNP is hetero then the other is as well..?
Dr. Dana, I express my sincere gratitude for your diligent research and especially for your decision to ensure that your findings can be transformed into treatments for people who suffer from Alzheimer’s. You are a caring and truly courageous physician . Thank you❤
My mom recently passed away from FTD at the very young age of 55. I pray that klotho proves to be a positive addition in improving and prolonging the onset of this disease, or even preventing it altogether. This disease is ruthless, and so many have suffered.
You inspire me each and every day, Peter. I hope to one day have the funds to be seen by you exclusively, as your approach is brilliant.
We need to develop a Cognitive Panel. Getting labs CBC, Chem 24, Lipid Panel and a COGNITIVE PANEL.
I love it! Honest conversation. I learned a lot today! Dr. Dena is very easy to listen, she has a wonderful smile, but most of all - she is passionate about her work...and that is priceless. Klotho - I hope human trials will begin soon. With such reach these days, Dr. Attia, Dr. Patrick, prof. Huberman etc - I bet you all could do trials, thousands would love to be part of, and raising money from the public must be much easier these days with all the social platforms. I'd love to see that happening!
Thanks for this episode. I learned something new today (Klotho, Platelet Factor 4 and their impacts to the cognitive functions).
It's great to hear about klotho again. Albeit, a bit discouraging at the same time. While it seems super promising, I remember listening to a podcast with Liz Parrish talking about it back in like 2019. 5 years later and we're still just talking about it with nothing on the horizon for people suffering. I just hate how slow progress is in these realms. I hope something eventually comes to fruition for people alive today. But, glad to see at least there's still people barking up this tree of potential! God speed Dr. Dubal! Lots of people could really benefit from your work should it progress on into human trials.
This was a masterclass on how to communicate complex science and make it extremely exciting!
Can I encourage Peter and the team to interview Dr Dale Bredesen who wrote the New York Times and Wall Street Journal bestseller, “The End of Alzheimer’s” back in 2017.
People are obtaining great results with his protocol while also conducting clinical trials demonstrating the benefits of the protocol. Definitely one to check and follow in the field of Alzheimer’s.
We tried his protocol to no avail.
It only helps those in very beginning of cognitive impairment. It's about the obvious for overall health, food/nutrition. It does not cure.
He now has published data to support his program. Dr Heather Sandison has also published improvements in MOCA with his protocol. He is currently doing a study comparing his protocol to the anti-amyloid meds. All saying the same thing- this is a multi factorial disease. Do you want to address the causative factors, or look for a drug to fix the problem. Time will tell.
@@jeffstrack1143any luck?
I am an Apoe4/4 and recovered from MCI using the Bredesen Protocol. 4 years symptom free. Obviously I’m a big fan. However the protocol was only effective in 84% of subjects and the amount of improvement was inversely related to the amount of pre-existing damage. The earlier you start, the better it works. To be honest, it is not an easy protocol and gets harder the older and more frail the subject. I highly recommend it as an early intervention but still look forward to a pharmaceutical to help those unable to perform the protocol.
This conversation is absolutely amazing
More bench science videos like this would be great. Really Enjoyed this episode thoroughly.
Looking at my 23andme report it looks like one of the two KL-VS SNPs are in there but not determined. I opted out of further testing of my sample so maybe it is available to more recent users. For those looking the two snips associated with the KL-VS mutations are rs9536314 and rs9527025.
I found it helpful to understand the nomenclature here. KL is klotho's gene name in humans. VS is shorthand for the two amino acid substitutions caused by the SNPs mentioned previously. rs9536314 is a F -> V mutation, and rs9527025 is a C -> S mutation.
Thank you covering the subject
It might be time to interview Liz Parrish. Her company Bioviva, has been delivering klotho into humans for several years.
Is there a lab in the US that currently offers testing for Klotho levels that is open to public?
I was going to test but it was expensive and I just decided to take it instead and see what happens and if I felt better
@ortcloud99 what did you take?
@@flash3047 klotho
@@flash3047Klotho, I assume
Thank you Peter. I am just a science fan, not a scientist. But I have intuition for breakthroughs. I believe this research is one major discovery for anti aging and disease prevention. Thank you for generating this content for the average citizen. God bless you.
I have one copy of the APOE4 variant (APOE3/4) Alzheimer's Gene but thankfully I also have one copy of the klotho-vs allele which reduces the impact of my APOE4 variant by 75%. I feel lucky!!
Congrats! I am APOE4/4 and looking to see what my KL-VS status is. Fingers crossed.
@@rachelrenfrow589 Good luck!! Fingers crossed for you!!
@@Judipops13 Unfortunately I just have normal KL-VS, but its better than the negative double copy!
@@rachelrenfrow589 Scientists are working so hard to help APOE4's at the moment so I guarantee they will find other beneficial SNPs that may help us :-) There will be a cure very soon too in addition to preventative medicine/supplements.
Toward the end, you mentioned that you have had trouble genotyping your patients to look for the KL-VS variant. One of the SNPs used to classify the KLOTHO KL-VS haplotype is available through 23andme. The G nucleotide and V residue at SNP rs9536314 (1062T->G; F352V) indicate KL-VS. I was genotyped ages ago (I believe using the v2 and v3 chips), so its possible that these SNPs are not included on their current chips.
Thanks. Would you interpret (1062T->G; F352V)? Is it favorable to have T?
@@peterz53 G is associated with the KL-VS haplotype (T is "normal"). As discussed toward the end of the podcast, being heterozygous (TG) at this locus is good; being homozygous (GG) is bad. The allele frequency is 0.13 (this varies quite a bit across different populations), so ~25% are heterozygous and ~1-2% are homozygous for the variant.
@@JakeSchroeder Thanks. Hadn't reached that point. Will check my 23andme.
@JakeSchroeder Was Peter saying "KL-VS" or "KL-DS"?
@@chandebrec5856 The name of the variant is KL-VS
Thanks to Peter I developed an incredibly healthy lifestyle but also a big fear of neurodegenerative illnesses.
This episode gives me hope there might be some medication for Alzheimers in the future!
Well now I even found out that Im E4 E4. tough pill to swallow
Fascinating listen! I look forward to hearing more from her and her colleagues on this worthwhile topic. Meanwhile, we must continue to pursue and promote the healthy lifestyle habits.
The problem with Klotho therapies is that it's unlikely that a daily injection is suitable for mass market. There are however researchers that are looking at oral compounds that stimulate natural Klotho production in the brain and the kidneys. This could be a game changer, and able to easily restore youthful Klotho levels in aging humans. With many benefits.
Easy to listen to someone with such a wonderful smile…thanks for sharing your knowledge 🙌🙌🙌
The question would be: how do we get Klotho naturally...? in addition to exercise.
Possibly time restricted eating. The 2020 Conboy study on plasma exchange, replacing 50% of plasma with saline, promoted many changes in gene expression, one of which was PF4. Higher PF4 seems to be related to Klotho. The same experiment increased BDNF. I started doing plasma donation about 2 years at my local blood bank. Mostly monthly. This involves a smaller amount than Conboy used, but still significant at 25% (800 mls).
Sugar and nuts promote it and calorie restriction plus, as always, exercise done consistently and a low end of healthy bmi. Carbs are the macro to focus on. I just googled it and read all the studies. I am no expert.
@@stargazerbirdi saw a study where sugar boosted Klotho. Everything I've ever read about sugar has been negative..save this. Am I interpreting correctly?
@@stargazerbird Do not eat sugar
to boost this protein, that is sawing off your leg to lose weight.
take senolytics like D&Q will boost it
I really enjoyed this podcast, especially the conversation about how human platelet factors and how they could play an amazing role unmasking how molecules, which don't cross the brain barrier, can still get their message to the brain.
I am a double apoe4. Father past away with pretty advanced Alzheimer’s at 90. Would love to have any info when human trials begin, I’ll volunteer!
Also, would like to hear about available testing for klotho levels and KL-VS status. Some folks have said they were able to get this information but, they did not say how or where.
When I asked 23andme about this they said that info was not available
Fascinating conversation! Thanks for sharing it!
How exciting! Looking forward to hearing more as Scientists further progress this research.
Absolutely fascinating.
As to the long term effects per dose, it sounds akin to how a single psychedelic dose can remodel neurons and last months.
This podcast is amazing
I would love to hear Peter's rating on this using the terms from his recent podcast: promising, fuzzy, noise, nonsense (those might not be all the exact terms). Feels like from his comments today, it may be promising or on the verge of promising, needing more human data.
Great episode! Love listening to your podcast and all of the incredible insights it offers! Dr. Dana is a real life hero doing big things to help those who suffer from Alzheimer's but also giving hope to the families that are walking through this battle with a loved one as well!
As a physician, I can’t tell you how many times a week patients tell me they have no time for exercise. How about starting with 10 min twice a week? Nope, no time for that. Give me a medication, doc.
On PF4 at 50 min. the Conboy Lab has also shown that PF4 increases with neutral plasma exchange in older animals without intervening with young plasma. They exchanged 50% of old plasma with saline. Have no idea if magnitude of change would be similar to exercise. We can donate ~25% of our plasma at local blood bank every 4 weeks in the US. I started this 2 years ago at age of 68. Also been exercising last 12 years and TRE for 10.
@peterz53 do you mean that be donating plasma, you get anti-Alzheimer benefits/prevention?
@@matreaus I can't say that. But if I recall correctly, plasma exchange experiments suggest so. Maybe best in early phase or preventative. Also, what I hear Dr. Dubal say, either here on Mark Mattson's channel, is that exercise is a potent promoter of klotho, and Pf4.
Great video, v interesting. We watch half of this video before he went missing and the remainer just now .. We of course are hoping Michael is found with enough time to help him.
thank you very interesting
This channel and it's exploratory teaching has been a major drive for me as I give back 50% of my weekly earning ($32,000) to the sick old ones in my neighborhood. God bless America 🇺🇸
God bless you more abundantly
Big thanks to Renee Marie Harrison
She's a licensed broker here in the states 🇺🇸
Her top notch guidance and expertise on digital market changed the game for me
Please how can I get connected with her?
Anyone know where we can buy klotho? I want to heal brain from partying in younger years memory and brain function definitely needs repair
Also what about possible gut brain effects via the vagus nerve to effect the brain from periphery?
When she said we needed a cocktail for preventing disease I was all in 😜
I think the solution to complex disease is a complex solution. An example is AIDS. It is not solved by one molecule. It is a COCKTAIL. I am going to predict that this will be the same situation with neurodegeneration. Bredesen is part, she is part, nutritional supplementation is part, light therapy is part, etc.
There is no letter C in the Greek alphabet. Only K for the k sound
Dr. Attia: what the hell is klotho???? Would you ask that question first?
I'd recommend researching yourself so no one asks these questions
Maybe we are supposed to go and Google for it during the ads?
Thank you for your videos Peter your work is more valuable than money.Some of the comments makes me think people didn't watch it or came to bash because they're part of the new anti-science ilk.
Intellix DNA does provide information on SNP’s for Klotho.
Fascinating.
Is this a coya theraputics trial?
Never heard of Klotho before? Might it be better than Rapamycin for anti-aging?
My mom in India can you suggest best doctor or treatment for Alzheimer’s
The accepted model of MS is that this is an autoimmune condition due to the immune system attacking myelin. Could it actually be a due to a failure of the klotho generation and deployment.
I have always wondered about the diurnal waxing and waning of various factors within the body, as most people in the US are night shift workers in whom the objective positioning of the sun may have little effect on things like klotho, cortisol or melatonin. If someone is not getting enough infrared wavelengths at the setting and rising sun and is rather say a night owl with a consistent nocturnal schedule, would klotho be rather be more effectively tested at the time they actually wake up?
Very, very cools stuff - looks like a promising avenue. I hope there is an angel investor out there willing to fund some clinical trial work in the near future...
Thank you ! We are fearfully and wonderfully MADE !
Fascinating!
25:58
Am I wrong in understanding the meaning of the word “facile”?
I thought it meant an only superficial understanding
Maybe Dr. Attia misspoke and meant another word?
The different understandings of a mouse’s daily metabolism seems to be a huge point to me, I could be wrong about that as well
Loved the podcast!
Any guess if Klotho would help a 65 year-old diseased brain to function like a healthy 65-year old brain.. or could it even make it function like a 25 year old?
Regarding the 21m mark on young blood transfusion.. I thought parabiosis mice experiments show that it's not so much that young blood is healthy, but that old blood contains inhibitory signals you don't want. The amount of hematopoietic cells in bone marrow declines, as does the amount of MANF in the blood.. yet donating blood a few times a year seems to be beneficial?
And of the 3 known ways of increasing brain-function (Exercise, Young Blood Transfusion, Klotho injection), are they all equal in strength (ex 800 pg/ml)?
People been saying there is breakthrough but doctors say NO
because it has not been through clinical trials...
.. what is klotho again?
Would love to be part of human trials.
Why wait? I have been taking Klotho protein subq for a few years now. Works great for anti-aging
Where do you buy this?
@@David-Longevity bucky
I wonder how Klotho levels are effected by the mouse being IN a learning environment. As in, if the mouse is in an environment where the mouse HAS to figure things out (at what it believes is its own peril) , are Klotho levels higher? By putting ourselves in to environments where we're out of our own comfort zone, does this increase/boost Klotho levels? An experiment to test this would be easy to set up as well. Some actual root cause types of information instead of just, "drug fixes this" would be good instead of just promising drug advert.
schizandra berries
what about TRONTINEMAB
I thought they debunked amyloid
What is Klotho??
Isnt it too early to tout the benefits of this drug---it is so typical of the pharma controlled med and dcocs, including ,sadly, Attia himself. WE were told that neurodegeneration is all genetic or protein based....when there is a lot more undiscovered.
Klotho is not a drug, it’s made naturally in our bodies. Not everything good to our health comes from the Pharma industry. Assuming so is purely bias.
Are you stupid, there is overwhelming evidence it could work but the next step is producing and giving this to patients
nobody is forcing you to listen to the podcast
I know CZcams is easy and probably gets a large audience, but the platform is failing. The ads are annoying and too plentiful, and the video stalls often.
I'm not sure what's going on?
is that useful for PARKINSONS?
Does Klotho make your teeth really fantastic too? Dr Dena has fantastic teeth!
Nice infomercial.
This is a deeply informative interview on the current state of the science on the klotho molecule. What would need to change for it not to trigger your infomercial characterization?
@@keithbyrd7566 I don't believe he watched it. If he did, and that's all he got well than bless his heart.
seems to have dodged the insulin resistance question
1:58:30 KLDS gene associated with metabolic benefit
Klotho barada nikto!
That crap is debunked.
3rd
too long, starting to skip
I so enjoyed nerding out on this topic!! As anyone who has spent time sciencing knows, there is a gamification in the process that amps the delight in the discoveries. She methodically pursues her life's work with joy and passion and has won the game! 🔬🧪🧬
Is it only me or she's basically saying nothing?
Can you be more specific?
It’s just you.
Omg. I feel the same way and am tuning out after 10 minutes. Lol!
Yeah she knows what it does but her research shows that she hasn’t gotten to far, Hence her not being able to answer the questions..
You need to work through the first part
Super annoying interviewee...
Unbelievably annoying interviewee