BAAM Presentations - GLYLO, and Meclizine mTORC1 Inhibitor

[RapAdmin]

GLYLO Presentation - Lowering Methylglyoxal and associated Advanced Glycation End-products (AGEs) enhances physical activity and ameliorates aging-induced sarcopenia.

Human clinical trials have been (or are soon being) started at UCSF: Methylglyoxal (MGO) Lowering Cocktail to Reduce Appetite in Obese Individuals

A news story by the website Longevity Technology on the supplement is here: An antiaging supplement that also reduces appetite?

And, here is what is in GLYLO:

Additional Resources on GlyLo, and related research:

Presentation Overview

Excerpt From Cell Symposia: Metabolites in Signaling and Disease, April 2022

Glycation lowering combination therapy reduces caloric intake, improves glucose tolerance, and extends lifespan

Lauren Wimer1, Dr. Muniesh Shanmugam1, Jessica Ramirez1, Dr. Martin Valdearcos2, Dr. Kiyomi Kaneshiro1, Dr. Durai Sellegounder1, Dominique Gaffney3, Jennifer Beck1, Dr. Richmond Sarpong4, Dr. Soo-Jin Cho2, Dr. John Newman1, Dr. James Galligan3, Dr. Suneil Koliwad2, Dr. Pankaj Kapahi1
1Buck Institute for Research on Aging, Novato, CA, USA. 2University of California San Francisco, San Francisco, CA, USA. 3The University of Arizona, Tucson, AZ, USA. 4University of California Berkeley, Berkeley, CA, USA

Abstract

Obesity remains a leading risk factor for aging and age-related diseases, such as type II diabetes (T2D). The occurrence of obesity has been tied with an increase in caloric intake, enhancing glycolysis. A toxic byproduct of glycolysis is methylglyoxal (MGO), a reactive precursor for advanced glycation end-products (AGEs), which drives T2D and its complications. Here we show that MGO and MGO-derived AGE, MG-H1, affects hypothalamic regulation of food consumption parallel to the leptin pathway in wild-type mice. Conversely, glycation byproduct lowering compounds (Gly-Low), a combination therapy which reduces levels of MGO, reduced food consumption and body weights in wild-type mice while also extending lifespan as a late-life intervention. Furthermore, Gly-Low treatment in a leptin receptor deficient mouse model rescued diabetic phenotypes and lifespan. We highlight the potential of Gly-Low as an intervention to reduce the effects of glycation through the reduction of systemic MGO while downregulating novel FOXO1-associated feeding pathways.

Reducing Methylglyoxal Rescues Obesity Related Phenotypes and Lifespan in a Leptin Receptor Deficient Mouse Model

Reducing Methylglyoxal Rescues Obesity Related Phenotypes and Lifespan in a...

and

The role of advanced glycation end products in aging and metabolic diseases: bridging association and causality

nihms-1504270.pdf

The Role of Advanced Glycation End Products in Aging and Disease. Podcast with Pankaj Kapahi

Advanced Glycation End Products. Podcast w/ Pankaj Kapahi.

Pankaj Kapahi - Caloric Restriction and Glylo

Meclizine and More…

A Novel Piperazine Class of mTORC1 Inhibitors, One of Which Extends Lifespan in Mice

[LKB]

Quite a lot of information here, very interesting! I have a bottle of Glylo but haven’t used it yet.

The lifespan figure (Figure 5) was cut out of your pictures, do you have any images where that data is visible?

[RapAdmin]

Yes - will add it above in a second…

[LKB]

Much appreciated! The maximal (top 90 percentile) life extension is stronger than I would have anticipated.

[Krister_Kauppi]

Thans for sharing!

Regarding the image “Piperazines are specific mTORC1 inhibitors”. Can you explain little bit how the diagram should be interpretad? For example if we look at rapamycin does low mTORC1 value mean that is has an high mTORC1 inhibition?

If we look at insulin does it mean that insulin has a high stimulating effect on both mTORC1 and mTORC2?

Last question, why two diagrams in the image?

[Boldi]

Thank you for this! But I’m a bit puzzled as to what makes GLYLO work, given its ingredients. Peter Attia is pretty negative on niacin and I already take ALA and Piperine. That leaves high dose Vit B1 and B6.

[RapAdmin]

In the presentation the presenter went into great detail on the molecular pathways in the brain that they identified that were targeted by this combination of products, that they believe drove the results they were seeing. Sorry I didn’t photograph the entire presentation as that would have been helpful. But, read the text as much as you can in the Poster presentation above and perhaps you can get some insight. Plus, perhaps more has been published online - so perhaps search on google on some of the key words from the Poster above and you may find more in-depth information. Please post here if you do.

[RapAdmin]

@Krister_Kauppi

For example if we look at rapamycin does low mTORC1 value mean that is has an high mTORC1 inhibition?

If we look at insulin does it mean that insulin has a high stimulating effect on both mTORC1 and mTORC2?

Yes - your interpretation is correct. But keep in mind that this is a single assay done after a short term dose of the drugs (not after a long period of dosing…) You can see on the bar graph that rapamycin is quite specific and significantly inhibits mTORC1, where as Meclizine inhibits mTORC1 less significantly and has minimal impact on mTORC2 (at least in the short term).

The issue and unknown here is what happens with ongoing dosing of Meclizine - does it have any impact on mTORC2 with continual dosing? That is the unknown.

As we can see in this assay, rapamycin does not have any inhibition of mTORC2 in the short term - but we also know from previous studies that with continuous daily dosing eventually mTORC2 inhibition does occur at some significant level, and because of this (it is theorized) you get many of the negative side effects as well as immune system suppression.

I will have to look to see if there are longer term studies of people using Meclazine daily to see if there are side effects that arise from longer term use (as there is with rapamycin).

And yes - we would expect higher insulin levels to drive higher levels of mTOR, as is shown in this assay above.

[RapAdmin]

Here is a research paper that was done by the presenters of the above presentation on Piperazines and mTORC1 inhibition - if you want to learn more about this class of drugs. This paper was published in 2018, before the longevity study had begun for Meclizine.

MeclizinePaperCortopassi.pdf (795.5 KB)

[desertshores]

Personally, I see a lot of BS and hype surrounding this product. Still another group jumping on the longevity bandwagon.
(Sarcasm): Oh, let’s see what combinations of cheap ingredients we can find that already haven’t been patented. Then we will add some buzzwords like “Micronized”
(Don’t tell anybody that B vitamins are easily absorbed. And never mind it has been shown that we p-ss out any excess. But we will put in plenty of extra just in case. Oh, and we will put some Piperine because it has been shown to have some anti-oxidative properties with a little effect on brain aging. And, voila! We will have a patented product that is cheap to make and we can charge a lot for. For God’s sake don’t tell anybody they can take the ingredients themselves and let their stomach do the mixing.

I really think the secret ingredient is Piperazine which is relatively cheap.
I hadn’t realized what a potent mTORC1 inhibitor Piperazine is. Time to put some extra pepper on that steak.

I get first dibs on the right to patent and sell a Piperazine and Meclizine combo.

Novel mTORC1 Inhibitors Kill Glioblastoma Stem Cells

Novel mTORC1 Inhibitors Kill Glioblastoma Stem Cells

[RapAdmin]

@desertshores

I see a lot of BS and hype surrounding this product. Still another group jumping on the longevity bandwagon.

I wouldn’t be so negative. I think your criticism is in two areas: 1. hype/BS, and 2. Cost-effectiveness.

The research group behind this is some of the best in the world in aging - The Buck Institute, the founder of the company is the lead researcher is Pankaj Kapahi, PhD. So I suspect he knows his stuff and doesn’t just want to sell cheap vitamins at higher prices. Ultimately the research speaks for itself - its interesting, and somewhat compelling but as with all supplements, human clinical trials are lacking and are impossible to fund given the issue that at the core of the product the individual supplements are not patentable.

Kapahi Lab - BUCK

The second issue is the cost - which is a reasonable criticism. But, that is why I listed all the ingredients - I hope someone who is interested in this prices out the comparable supplements alone and in the GLYLO product and posts some analysis and pricing comparison.

[desertshores]

The research studies for the efficacy of this product are sparse indeed.
A Frenchman once said decades ago that Americans have the most expensive p-ss in the world.
Americans Have the ‘Most Expensive Urine’ in the World

Americans Have the 'Most Expensive Urine' in the World

[AlexKChen]

How about… just taking B vitamins + pepper? This is way too expensive for how common the ingredients are

[RapAdmin]

Guys - got some inside info from a researcher at Buck institute:

It’s very early days but our pilot combing rapa plus GLYLO shows promise that it maybe better than GLYLO alone. Starting a larger study … will keep you updated.

And, researchers at the Buck Institute are starting to take rapamycin personally :-). Good to see.

[EnrQay]

The Juvify company directions, with two capsules being twice the amounts posted above:

“Take one or two capsules every morning, before breakfast or lunch. For optimal results, we recommend overnight fasting of twelve to sixteen hours. GLYLO is designed for long-term use by healthy adults of all ages.”

GLYLO | The Anti-Aging Weight Loss Supplement

[desertshores]

I’m still not convinced this is not just another supplement money-making scheme.
“For optimal results, we recommend overnight fasting of twelve to sixteen hours”
That alone will result in weight loss and health benefits for many people.
I think fasting and piperine are the magic ingredients.
So, just use Google Scholar and Google “piperine benefits”
Just because Juvify has some academic scholars behind it is meaningless to me.
Even Nobel prize winners and Phds like Dr. David Sinclair have been known to promote and shill questionable products which they benefit from.
So, I challenge them to test Glylo against my anti-aging supplement:
1, B50 Daily
40 mg, generic piperine daily
12 to 16 hours fasting between supper and your first daily meal.
And, if you want to triple the benefits add in regular resistance training and exercise.

[desertshores]

Duh! Pray tell, rapamycin and almost any supplement will be better than the supplement alone.
(Sorry, I don’t mean to be rude.)

[RapAdmin]

Seen in another discussion forum:

[EnrQay]

You may be right, and there are some red flags here, but there are also some indicators of credibility: they do research with and publish with reputable institutions (Buck and UCSF), and they give the exact makeup of the intervention being used, not some “proprietary blend.”

[EnrQay]

Here is my cost analysis of Glylo vs DYI individual ingredients.

from the post above:

And, here is what is in GLYLO:

My cost estimate:

As you can see, Glylo doesn’t have a big mark-up: $0.47 vs $0.33, and it would be much closer if you bought pills of piperine. I chose P5P and Benfotiamine as the forms of B6 and B1 for their bioavailability. You might save $0.05 total with generics.