Gauging Interest in a Trial with Valter Longo, PhD

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Julie G
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Gauging Interest in a Trial with Valter Longo, PhD

Post by Julie G »

I recently had a fascinating discussion with Dr. Longo re. both his Fasting Mimicking Diet (FMD) his Longevity Diet (LD). He wondered if we could get a group of homozygotes together for a year-long clinical trial with two arms — an intervention and a control, with both ultimately receiving the intervention. Those participating would use the FMD every two months (6 total) with the LD to be used in between. FYI, the the LD is low fat/high carb with at least 200g of whole grains daily.

If we gather a large enough group, Dr. Longo would try to get a grant to cover the cost of the trial. This is very much in the planning stages. Please let me know if you’re interested in this thread. Also, I’m curious to hear your thoughts about this approach.
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Re: Gauging Interest in a Trial with Valter Longo, PhD

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FYI, Gundry has instructions for DIY FMD in Chapter 9 of his Longevity Paradox and Chapter 10 of his Plant Paradox books, as well as extending his 3 day cleanse in the PP book to 5 days. Essentially his version is vegan and low calorie (as well with Longo's), but with foods from his approved list (which excludes most grains). There is a group of Gundry followers that have been doing this monthly for at least 6 or 7 months. They report they are happy with the results.

Here is a search on posts I previously made on the topic of the Gundry version of the FMD a number of years ago.

During one consult, I asked Gundry if he'd tested some of the markers Longo looked at in his studies (for example Igf-1) with Gundry's FMD version. He said he had.

From memory, when I looked at some of Longo's FMD studies years ago, his subjects had a beginning Igf-1 of ~195 and were ~150 after. Just following Gundry's normal plan, my Igf-1 is ~120 and my 4/4 wife's is ~80 (from memory),. So we do a lot better on an ongoing basis than Longo's participants do after his FMD. This assumes you buy into the assumption that a low Igf-1 better (certainly that is Longo's position from his work with people with Laron's syndrome {dwarfism} in Ecuador).

My two cents...
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Re: Gauging Interest in a Trial with Valter Longo, PhD

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Julie G wrote: Sun Mar 20, 2022 2:19 pm I recently had a fascinating discussion with Dr. Longo re. both his Fasting Mimicking Diet (FMD) his Longevity Diet (LD). He wondered if we could get a group of homozygotes together for a year-long clinical trial with two arms — an intervention and a control, with both ultimately receiving the intervention. Those participating would use the FMD every two months (6 total) with the LD to be used in between. FYI, the the LD is low fat/high carb with at least 200g of whole grains daily.
I’m a homozygote but NO WAY am I interested in this study. I realize ApoEε4/4s are associated with shortened longevity, but I’m more concerned with my risk of Alzheimer’s than longevity, I feel that if I lower my Alzheimer’s risk I will, by default, elongate my healthspan.

If this involved just the Fasting Mimicking Diet I’d be interested since that enhances autophagy, but I don’t believe autophagy alone can overcome the vulnerabilities of being a 4/4.

If there are homozygotes out there interested in participating, that’s fine, I just hope they offer their interest with eyes wide open. Therefore I feel the need to express my opinion on this matter.

My sticking point is low fat/high carb with at least 200g of whole grains daily, NO WAY!

1. This ignores our evolutionary history, the APOE4 allele is the ancestral human allele. We've been around far longer than the other alleles. A deep, deep history that does not include grains. So why is this part of the study? Makes no sense.

2. Grains (gluten and the glyphosate they're treated with) cause leaky gut and leaky gut causes leaky brain/neuroinflammation. From our wiki Gut-Brain Connection: Leaky Gut/Leaky Brain, Microbiome (gut bugs) :
Even without celiac disease, “It is known that gluten has a direct action on the mucosal barrier of the intestine [36]” [Source: Undigested Food and Gut Microbiota May Cooperate in the Pathogenesis of Neuroinflammatory Diseases: A Matter of Barriers and a Proposal on the Origin of Organ Specificity(Paolo Riccio and Rocco Rossano, 9 Nov 2019)]
Gluten activates the protein zonulin. Zonulin is a protein that modulates the permeability of tight junctions between cells of the wall of the digestive tract. Thus zonulin loosens the tight junctions and makes the intestinal barrier more permeable. “The increased permeability of the intestinal barrier caused by gluten is particularly evident in individuals with non-celiac gluten sensitivity [36].” [Source: Undigested Food and Gut Microbiota May Cooperate in the Pathogenesis of Neuroinflammatory Diseases: A Matter of Barriers and a Proposal on the Origin of Organ Specificity(Paolo Riccio and Rocco Rossano, 9 Nov 2019)]
“Gluten is resistant to digestion. Fragments of not completely digested gluten may be mistaken for a microbial molecule [36]” [Source: Undigested Food and Gut Microbiota May Cooperate in the Pathogenesis of Neuroinflammatory Diseases: A Matter of Barriers and a Proposal on the Origin of Organ Specificity(Paolo Riccio and Rocco Rossano, 9 Nov 2019)] “For this reason gluten fragments cause the release of zonulin and the opening of the tight junctions. In a similar way, when in the blood stream, gluten opens another barrier equipped with tight junctions: the blood-brain barrier (BBB). As gluten fragments pass through the intestinal wall, they are recognized as a foreign molecule, similar to a viral protein. Following the opening of the barrier, other undigested dietary molecules and microbes also pass through the barrier. All the invaders trigger an immune response. Antibodies against gluten and gliadin can cross react with some brain proteins and can promote neurodegenerative diseases [39,40]." [Source: Undigested Food and Gut Microbiota May Cooperate in the Pathogenesis of Neuroinflammatory Diseases: A Matter of Barriers and a Proposal on the Origin of Organ Specificity(Paolo Riccio and Rocco Rossano, 9 Nov 2019)]
3. Insisting that the grains be whole grains is even worse! Whole grains have Wheat Germ Agglutinin (WGA), a very tiny protein that can penetrate even the tight junctures of a healthy, non-leaky gut. WGA binds to the insulin receptors of our muscles and brains blocking them. Our brain needs these insulin receptors to utilize glucose, the brain cannot run on ketones alone and we, APOE4s already have issues with cerebral glucose utilization (next point).

4. Lots of grains (carbs) and low Fat? Really? Is Dr Longo ignorant that our genotype demonstrates greater glucose hypometabolism than non-carriers and that this begins decades before the onset of AD? One thing that rings clear to me after all the reading I’ve done on our genetics over the past 8 years regarding diet is: eat real food to mimic the diet of our ancestors, maintain insulin sensitivity, and maintain metabolic flexibility for the ability to generate ketones. We need fat. The brain is nearly 60% fat.

From APOE Alleles and Diet in Brain Aging and Alzheimer's Disease, (Hussein N Yassine , and Caleb E Finch, 2020):
The lower brain glucose metabolism and the increased mitochondrial oxidation of PUFAs in older APOE4 carriers suggest a role for dietary fat as brain fuel. In a small pilot trial, older APOE4 carriers with cognitive impairment (CI) appeared to respond to an increase in dietary fat intake for cognitive functions. In this study, 46 older adults with either CI or normal cognition (NC) ingested a LOW (25% total fat) and a HIGH-fat meal (50% total fat) in an acute and blinded random fashion. Acute high-fat feeding improved measures of cognition and plasma AD biomarkers in E4 carriers, but worsened these biomarkers in E4 noncarriers (Hanson et al., 2015).
Carbs are counterproductive to maintaining insulin sensitivity and metabolic flexibility. When the US government changed the nutrition guidelines to reduce fat and increase grains in the 70s, there was no scientific basis for this and since then obesity, Type 2 Diabetes (the extreme opposite of insulin sensitivity) and chronic disease rates have increased. Whatever dietary practices that are bad for the general population seems to be extra bad for ApoEε4/4s. It seems unethical to me to ask ApoE4/4s follow this type of diet.
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Re: Gauging Interest in a Trial with Valter Longo, PhD

Post by Julie G »

Thanks for weighing in, Tincup and Theresa. In Dr. Longo's defense, he acknowledges that aging is the greatest risk factor for Alzheimer's disease and epidemiological evidence suggests that the diet he is proposing leads to longevity. That said, if you examine the APOE genotype of the eldest people in the Blue Zones, there are very few E4 carriers... so perhaps this approach isn't working as well for us (?)

I also suspect that Dr. Longo is unaware of the N=1 experimentation that many of us have done to arrive at our current diets. For instance, I've done the Cyrex Lab testing (3X) for gluten reactivity and learned I was very sensitive to gliadin and WGA. Giving up wheat (and other grains) has ultimately resulted in a major health turnaround for me; my widespread body pain disappeared and my inflammatory and glycemic markers have dramatically improved. I would be very hesitant to adopt this approach based on epidemiological evidence alone.

I think a much more interesting trial would be to compare our current dietary approach to the Longevity Diet. Like Theresa and Tincup, I'm also a fan of the FMD and think it would be very beneficial for our population.
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Re: Gauging Interest in a Trial with Valter Longo, PhD

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Julie G wrote: Sun Mar 20, 2022 2:19 pm Also, I’m curious to hear your thoughts about this approach.
While I'm 3/4 and not eligible, I would be interested in better understanding Dr. Longo's specific research aim here. What endpoints does Dr. Longo plan to examine: chronological age, biological age, development of MCI/AD, brain imaging, specific biomarkers … ?

While his diet is really high carb, and I'm completely sympathetic with Theresa's concerns and n=1 success stories, I think it may be a stretch to characterize Dr. Longo's research as unethical. Someone (not me) might even say that of encouraging 4/4's to eat a ketogenic diet for life when there are no long-term studies (that I know of) showing that it will independently slow or prevent 4/4 incidence of AD (although my bet is that it will?).

I wonder if Dr. Longo is, maybe in part, digging deeper into questions about how regular use of the FMD might alter the 4/4's handling of the higher carb LD. If I were eligible, I would personally focus more on the very wholistic incorporation of net carbs in the context of a high, whole plant phytochemical load, very high fiber, daily fasting (if that's part of the LD), exercise (if that's part of LD), stress reduction (if that's part of LD), along with—perhaps crucially—regular use of the FMD.

Lately I've continued my 12-14 hour daily fasts but lower fat and increased my carbs with unprocessed, gluten free oatmeal, lentils, brown rice, occassionally quinoa and other grains/seeds, and fruit. I've also added pastured low fat cottage cheese to my other animal proteins (two eggs and one serving of fish, seafood, or lean poultry and very occasional red meat, an shot glass or two of goat milk keifer). I replaced dinnertime animal protein with beans and grains. For now I feel a lot better than I've felt eating more ketogenically for years. I'm not currently testing ketones at the end of my fast, but my glucose stays in what I think is respectable territory, with two hour post-prandial glucose 120 or usuall well below that, often below 100. (I realize this doesn't tell me how much insulin currently keeps it there.) These days I tend to think that—perhaps especially for 3/4 (and sorry to muddy this thread's waters with that)—one diet for too long might be like doing the exact same exercise program for too long and lead to imbalances. It takes a toll. Switching up is good.

I noticed that Dr. Fitzgerald's "Younger You" diet that slowed biological age in a small group omits grains, legumes, and dairy. I suspect this is to ensure a low inflammatory environment that must be important to healthy methylation, but I wonder whether the same diet including these foods also would be effective. How big a part did the low carb, low lectin variables play in the results compared with the inclusion of dietary methylation promoters and adaptogens? If you include enough of the latter, can you afford more of the former?

Theoretically adding to the Blue Zone epidemiological data that provides some support for the Mediterranean diet but in populations with lower levels of APOE 4, Being Patient just reported about some research into Chinese centenarians (not published?) done by a traditional Chinese medicine practitioner (38th generation). What's needed is more information about the centenarians' genetics:
From 1985 to 2005, Mao researched the habits of over a hundred centenarians in China, focusing extensively on what foods they ate…

[The] meals should be composed of primarily organic, plant based foods like vegetables, fruits, grains, beans, legumes, seaweeds, nuts and seeds, with fish and poultry playing a supplementary role…

Mao recommended eliminating fast foods, refined sugar and [refined] carbohydrates, because they can “stimulate the production of toxins in the body, leading to inflammation and the build-up of plaques in the brain.”
Assuming these centenarians all had decent cognition (an assumption that probably shouldn't be made!), he must have found that, as with the Blue Zone populations, in these 100 Chinese centenarians unprocessed carbs were safe. Unfortunately, I doubt there was any APOE genetic testing, but I'm curious whether his group of centenarians share the low level of APOE4 found in the Blue Zones. The article doesn't mention whether the 100 people were from across China and genetically heterogenous or shared sub-population, lower levels of APOE 4 from the south.

Does the geographical gradient of ApoE4 ... opulations (2010) concludes:
Systemic comparison among multiple Chinese populations revealed that positive correlation existed between the e4 allele frequency distribution and latitude north (r = 0.586, P = 0.008), but no correlation of the e4 allele frequency distribution with longitude east was found (r = −0.018, P = 0.942). We conclude that there is a south-to-north, but not an east-to-west gradient for the apoE4 allele in China.
How might the (perhaps optional) addition of ketone salts or esters influence some prospective participants' decisions whether to join Dr. Longo's 4/4 research?

I wonder why he fixes carbs at 200/day rather than using macro percentages that could accomodate individual caloric needs better.

I offer these thoughts humbly, since you three are all far more versed in the literature than I am. I appear to be better at asking questions and editing my posts than drawing firm conclusions.
ApoE 3/4 > Thanks in advance for any responses made to my posts.
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Re: Gauging Interest in a Trial with Valter Longo, PhD

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circular wrote: Mon Mar 21, 2022 11:31 am While I'm 3/4 and not eligible, I would be interested in better understanding Dr. Longo's specific research aim here. What endpoints does Dr. Longo plan to examine: chronological age, biological age, development of MCI/AD, brain imaging, specific biomarkers … ?
For a much better idea of Longo's thoughts, suggest reading his book. Here is the Kindle link.

A cursory review of my copy (which I read when it first came out) looks like a lot of Longo's criticism of keto comes from some mice studies he did. I did not dig in and read those papers.

This is from the book (see end of post):
Image
What is interesting is his "low protein group" has IGF-1 values in the 190's. When Dr. Gundry interviewed Dr. Paul Saladino, Saladino, who eats a carnivore diet, mentioned that his IGF-1 was 120, as well his carnivore patients. In general concept, Gundry's mostly plant based approach with limited animal protein isn't far from Longo's. Where they differ is what plants to eat & Gundry would propose a higher fat approach (from nuts & EVOO).

A week or two ago, Gundry released a book, "Unlocking the Keto Code", the point of the book is that ketones signal mitochondrial uncoupling. That is the objective. There are other ways to signal uncoupling including heat & cold stress, increased serum CO2 from breathing techniques, intermittent hypoxia, red light, melatonin & polyphenols. It is like a unified field theory for hormetic stressors.

From the book: "Consider this: What do the following items have in common? Ketones, fermented foods, a 12-plus-hour fast, coffee or tea, MCT oil, vinegar, red wine, turmeric, goat cheese, plunges in ice-cold water, dietary fiber, hot saunas, soybeans, selenium, vitamin D, exposure to red light, vitamin K2. All these items make, or are themselves, signaling molecules that instruct your mitochondria to uncouple. Ketones tell your mitochondria to go into repair mode and keep themselves healthy and functional—as do red wine and infrared light. All these very different influences and substances can activate mitochondrial uncoupling." Gundry, MD, Steven R.. Unlocking the Keto Code (The Plant Paradox) (pp. 50-51). HarperCollins. Kindle Edition.

Gundry's takeaway is there are many ways to signal uncoupling and it doesn't just have to be a hard core keto diet. The benefits of uncoupling are myriad.

I think there is a lot to take away from Longo's work. Minimizing IGF-1 is part of that. However, there is more than one path to that objective.
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Re: Gauging Interest in a Trial with Valter Longo, PhD

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Yes, I'm a big fan of his work and qualify. I would be totally interested.
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Re: Gauging Interest in a Trial with Valter Longo, PhD

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alina wrote: Tue Mar 22, 2022 1:54 pm Yes, I'm a big fan of his work and qualify. I would be totally interested.
Welcome Alina,

Thanks for voicing your interest in Dr Longo's trial. I am also a big fan of his.

I wanted to reach out to you as a welcome intern and direct you to some links that might be helpful for you as you explore the site. You may already be aware of these if you have spent much time here, but if not you should check out
the Primer. It includes researched-based prevention strategies.

Some helpful tips and tricks to navigate the site include the How-to Guide. This guide is a great resource I found helpful when I started posting. It includes topics such as navigating the forum, private messaging, and searching. One great tip is using the quote (") button when replying to a post. Using the button will automatically alert the member of your response. It really helps to keep the conversation going.

If you would like to tell us more about yourself or interested in learning more about other members check out Our Stories. We would love to hear more about you.

I hope you find this helpful and that the trial works out for you. I look forward to hearing from you in the future.

Be well,
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Re: Gauging Interest in a Trial with Valter Longo, PhD

Post by Brian4 »

Julie, this is a great initiative!

I wonder whether one could add a separate arm: FMD but with a low-carb diet in the intervening periods.

Do you know what markers he's looking at?

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Re: Gauging Interest in a Trial with Valter Longo, PhD

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Brian4 wrote: Tue Mar 22, 2022 10:39 pm I wonder whether one could add a separate arm: FMD but with a low-carb diet in the intervening periods.
A great suggestion! However Julie mentioned that many of our members weren't keen on grains, or high carb. His response, he thinks low carb/keto is very bad! Hence a non- starter with him. Perhaps bootstrapping one ourselves...
Do you know what markers he's looking at?
When I read some of his papers years ago, it was primarily IGF-1. Here is a search on his FMD papers. Here is a 2017 paper "Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease"

"Three FMD cycles reduced body weight, trunk, and total body fat; lowered blood pressure; and decreased insulin-like growth factor 1 (IGF-1). No serious adverse effects were reported."

This figure from the paper gives an idea of what he looks at:
Longo FMD metrics.jpeg
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