#389

Never heard of such thing? Is that where the spirit resides? :joy:

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#390

It’s the largest organ we have… probably home to my ego :slight_smile: not sure about the spirit LoL!

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#391

I did a poor job of communicating agreement with @Davin8r . I was trying to say that I see more mass as a prerequisite for getting stronger once you get to a certain level of training. So that’s one reason why I’m training for hypertrophy now. I also like looking good at the pool/beach and it’s important in my work environment. Too much strength training and I get pretty beat up.

Re: body comp, it looks like my Hologic DEXA results put my bone mineral content at 6.43 lbs, then there’s fat mass and lean. I guess bones don’t amount to much. We won’t get reliable estimates of skeletal muscle mass without CT or MRI, but if these data from 2000 are still relevant (but for fluffy people), we can get a rough idea of the ratio of SMM to total lean mass. The mean values are pretty much what @RapMet quoted (70 lbs).

Leaner people have less SMM, of course.

I’m fine with just tracking lean mass deltas, and I prefer the DEXA total LM to appendicular b/c appendicular doesn’t say anything about chest and back.

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#392

Great data!

One of the things I like about this forum.

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#393

Here’s a rather interesting article about ancient Japanese ancestry. When looking at extremely ancient genes, so ancient that humans got them from Denisovans and other hominids, we see that they can contribute to very different reactions to modern medications:

https://scitechdaily.com/who-are-the-japanese-new-dna-study-shocks-scientists/

Quote:

" For instance, other researchers have shown that people in Tibet have Denisovan-derived DNA within a gene called EPAS1, which is believed to have aided their colonization of high-altitude environments.[3] More recently, scientists discovered that a cluster of Neanderthal-inherited genes on chromosome 3—a trait that is present in roughly half of all south Asians—is linked to a higher risk of respiratory failure and other severe symptoms of Covid-19.[4]

The analysis by Terao’s team shed light on 44 ancient DNA regions present in Japanese people today, most of which are unique to East Asians. These include a Denisovan-derived one, located within the NKX6-1 gene, known to be associated with type 2 diabetes, which the researchers say could affect a person’s sensitivity to semaglutide, an oral medication used to treat the disease. They also identified 11 Neanderthal-derived segments linked to coronary artery disease, prostate cancer, rheumatoid arthritis, and four other conditions."

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#394

Is tadalafil the solution to muscle loss? See: Tadalafil For Longevity | How I Use It - #84 by LVareilles

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#395

GLP-1 programs the neurovascular landscape 2024

Readily available nutrient-rich foods exploit our inherent drive to overconsume, creating an environment of overnutrition. This transformative setting has led to persistent health issues, such as obesity and metabolic syndrome. The development of glucagon-like peptide-1 receptor (GLP-1R) agonists reveals our ability to pharmacologically manage weight and address metabolic conditions. Obesity is directly linked to chronic low-grade inflammation, connecting our metabolic environment to neurodegenerative diseases. GLP-1R agonism in curbing obesity, achieved by impacting appetite and addressing associated metabolic defects, is revealing additional benefits extending beyond weight loss. Whether GLP-1R agonism directly impacts brain health or does so indirectly through improved metabolic health remains to be elucidated. In exploring the intricate connection between obesity and neurological conditions, recent literature suggests that GLP-1R agonism may have the capacity to shape the neurovascular landscape. Thus, GLP-1R agonism emerges as a promising strategy for addressing the complex interplay between metabolic health and cognitive well-being.

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#396

This is the key sentence as I see it. Elsewhere I asked what do GLP-1 agonists bring to the table above and beyond SGLT2i for a specific kind of presentation: the subject (in this case myself) who never struggles with appetite or weight. I appreciate that for many curbing appetite is key, as is weight loss, and so GLP-1 agonists are vital.

But these are not my problems. I did eight years of pretty robust CR, with zero issues as far as appetite and hunger. Now I am on a set diet, eat my portions and don’t snack, so there isn’t even an opportunity to overeat. I’d have to go out of my way to take extra portions, which simply doesn’t happen. My bowl is of a certain size, and that’s it, there are no seconds; f.ex. I have a small cup I fill with a few peanuts, some walnuts and a fistful of almonds - I consume it daily, but that’s it, I don’t understand this concept of “can’t stop eating nuts”, the cup has a bottom and that’s it for the day. In other words, overeating and weight control does not apply to my situation.

Therefore if the sole benefit of suppressing GLP-1 is that appetite is suppressed and downstream of that weight is controlled, I need it as a fish needs a bicycle as a sage once said.

On the other hand if GLP-1 suppression provides other benefits than those mediated by appetite suppression and weight control, I’m all ears.

I’m looking to take SGLT2i (empa) soon, because my blood glucose is high despite a good diet and exercise, and metformin at 500mg doesn’t do jack for me and I’m unwilling to go higher. So if empa can dump excess blood sugar, that’s great, plus apparently it can provide benefits above and beyond just getting rid of excess serum glucose. All with an apparently good risk profile. That’s a win. What does a GLP-1 agonist do for me beyond what empa can?

I was very eager to read about the remodeling of the “neurovascular landscape”, but it all came to a screeching halt with that sentence, which in my mind is nothing more than taping your mouth shut so you don’t overeat and gain weight. If that’s all a GLP-1 agonist does, I’ll pass.

#397

Again: many GLP-1RAs barely suppress appetite (albiglutide, exenatide, dulaglutide?). That’s why it took so long to repurpose GLP-1RAs from diabetes to weight loss. On top of that, people with T2D lose way less weight on GLP-1RAs compared to overweight people without diabetes. In the PD trial of lixisenatide, patients didn’t lose weight. Obesity is protective against PD, and yet GLP-1RAs seem protective against PD.

“Whether GLP-1R agonism directly impacts brain health or does so indirectly through improved metabolic health remains to be elucidated.”: they say “metabolic health” and not “appetite suppression” or “weight loss”. Metabolic health is broader: BP, glycemic control, lipids, inflammation, liver enzymes, etc. See, for instance: Intermittent (oral) Rybelsus / Semaglutide use in healthy individuals? - #382 by adssx . For sure, the effect of GLP-1RAs goes beyond weight loss. But does it go beyond optimizing “everything”? Does it do something additional in the brain?

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#398

Pendulum is one of the few probiotics manufacturers that use a process that preserves live gut bacteria (primarily acarmancia) that can survive stomach acid. They seem legit with clinical trials to back up their claims. Attia has an informative interview with their CEO. Anyway, they have both a glucose control product and a GLP-1 product. I’m going to try the GLP-1.

#399

Thymus rejuvenation is possible, at least according to the TRIIM and TRIIM-X trials.

We’ve been doing a variation of that for about 9 months, hope to see “something” in our next TruD test results in the immune section.

Elasitin is a very complex problem. Much more so than the thymus.

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#400

I see, let us know when you do the TruD test if indeed your variation worked or did something good.

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#401

We sent in our samples last week, ETA on results is Nov 5.

I will post results, good or bad :slight_smile:

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#402

Tirzepatide leads to better outcomes than other GLP-1RAs with lower side effects:

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#403

Any studies showing effects of tirzepatide in non-diabetic nonobese (i.e. healthy) 65+ people? Sorry to ask such a specific question, but since you’ve done so juch research on this class of drugs, maybe you’d know off the top of your head if such studies even exist (I’m guessing - no).

#404

All approved drugs are fırst tested in healthy volunteers (phase 1) so the data exists on non diabetic non obese. But is it published? I don’t know and I haven’t checked.

#405

The focus has been primarily on diabetic and/or obese subjects as this is one of the larger (no pun intended) markets. But there are quite a few studies on non-diabetic obese subjects.

Will those results translate into non-diabetic, non-obese subjects? probably is my guess.

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#406

Great articles Steve. I agree these are wonder drugs.

For those that don’t know it Steve has excellent access to GLP’s. I’m interested in having a combo of dulaglutide with tirzepatide or retatrutide as hitting both penetration of the brain and potent GLP-1 agonism through the vagus nerve probably has additive effects. A blend of agents seems ideal for neuroprotection.

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#407

While we are talking about a blend of agents, I am wondering if there are thoughts on DPP-4 inhibitors being used in conjunction with with GLP-1 agonists. Can they for instance, extend the half-lifes of GLP-1 agonists, particularly those such as dulaglutide which have short half-lifes, or do they only inhibit the degradation of physiologically produced GLP-1?

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#408

Really good question!

2 points, in the comparison of DPP-4-i vs GLP’s health outcomes seem significantly worse with DPP-4’s, which may represent that the GLPs are just such awesome drugs that they provide a multiple of the benefit, or it could be that the DPP-4’s are deleterious. The problem with the study with looking at Alzheimer’s Dementia was no control group. However, there are multiple studies indicating that DPP-4’s are beneficial for neurocognitive decline, but the mechanism is likely through increasing GLP/GIP endogenously. I’m not sure if the addition of DPP-4s to GLPs helps if getting an adequate dose of GLP/GIP medication like Tirzepatide?

I was thinking if the DPP-4i’s ended up crossing the BBB it could be a good way to increase GLP activity in the brain. Sadly, they don’t significantly cross the BBB.

So Vera-Health.ai does a good job answering this question - and my conclusion is that I generally don’t see a reason to Rx these meds except as a 4th agent for difficult to control T2DM.

Dipeptidyl peptidase-4 (DPP-4) inhibitors do not directly prolong the half-life or increase the effect of GLP-1 receptor agonists (GLP-1 RAs). Instead, they work by inhibiting the DPP-4 enzyme, which is responsible for degrading endogenous GLP-1 and GIP (glucose-dependent insulinotropic polypeptide). This inhibition results in increased levels of endogenous GLP-1 by preventing its breakdown, leading to a modest increase in GLP-1 levels, typically 2-3 times the baseline 6.

GLP-1 RAs, such as exenatide and liraglutide, are synthetic analogs of GLP-1 that are designed to resist degradation by DPP-4, thus having an inherently longer half-life. These drugs are engineered to have prolonged action independently of DPP-4 activity, which means their pharmacokinetics and pharmacodynamics are not significantly altered by concurrent DPP-4 inhibitor use 2.

While DPP-4 inhibitors enhance the duration of action of endogenous GLP-1, they do not directly increase the pharmacological effect of GLP-1 RAs. The complementary mechanism of action between DPP-4 inhibitors and GLP-1 RAs can enhance the overall incretin effect, but this does not translate into a direct prolongation of the half-life or increased effect of GLP-1 RAs themselves 8.

In clinical practice, the combination of DPP-4 inhibitors and GLP-1 RAs is generally not recommended due to overlapping mechanisms and limited additional benefit. Most guidelines suggest using either a DPP-4 inhibitor or a GLP-1 RA, but not both simultaneously, to manage type 2 diabetes mellitus (T2DM) 1.

In summary, DPP-4 inhibitors extend the half-life of naturally occurring GLP-1 by blocking its degradation, thereby sustaining its beneficial effects on glucose regulation. They do not directly increase the pharmacological effect of GLP-1 drugs, which are already designed to have prolonged action independently of DPP-4 activity. This distinction is crucial for understanding the complementary roles of DPP-4 inhibitors and GLP-1 receptor agonists in the management of T2DM.

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