#299

The mechanism you describe is possible. But it seems unlikely to me that after just 30 days we would see a massive difference between two supposedly identical people: one on semaglutide and one on dulaglutide or dapagliflozin.

Some people say that some cases of delirium might be misdiagnosed as AD and that indeed lowering inflammation can stop delirium.

(That being said, I noticed some weird memory improvements a few days after starting semaglutide 3 mg, which is the non therapeutic starting dose… Just feeling mentally sharper and faster :thinking: So maybe the study is correct and semaglutide is that magical. I want to believe but I’m skeptical…)

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#300

100%. Just saying that guy on twitter did not have a strong argument.

(You know I have question marks about GLP being longevity helpful in metabolically, weight and exercised optimized individuals (not including eg average American or people with specific risks) even if there may be such longevity benefits/pathways from eg SGLTi, Acarbose and Rapa in such optimized individuals.)

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#301

Yes, Neo, from your lips to god’s ears. Wouldn’t it be wonderful to have rct studies of these drugs in healthy individuals whose lifestyles (diet, exercise, supplements etc.) are close to optimal. Won’t happen, even though it would enlarge the market for those drugs that pass the test :slight_smile:

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#302

Is there any pro-longevity intervention in “metabolically, weight and exercised optimized individuals”? Even calorie restriction doesn’t work in long-lived animals (from The impact of short-lived controls on the interpretation of lifespan experiments and progress in geroscience – Through the lens of the “900-day rule” 2024):

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Also: what does metabolically optimized mean?

So, everything has to be decided based on one’s particular situation (biomarkers and genetic background). Hopefully, in the future, you do a DNA methylation test, and you learn which genes to “tune,” and you take drugs accordingly.

There are 224 ongoing trials for semaglutide (as many for all other GLP-1RAs). Including some in healthy people such as: Semaglutide and Cognition in Healthy Volunteers (OxSENSE).

We’ll learn a lot from these trials. You should check the list, there’s a lot of interesting stuff.

But we can already learn from trials on sick people as “sick” is usually defined arbitrarily. For instance, CKD = eGFR < 60 mL/min/1.73m2 (or sometimes 75) and T2D = HbA1C > 6.5%. And, if I remember correctly, SGLT2is lower the speed of decline of eGFR in people with T2D but without CKD and in people with CKD but without T2D, in both cases, irrespective of their baseline eGFR. And according to MR studies, “SGLT2 inhibition also protects eGFR” (SGLT2 inhibition, high-density lipoprotein, and kidney function: a mendelian randomization study 2024). So, it’s reasonable to assume that SGLT2i might also protect eGFR in people without CKD and T2D (or, at the very least, in those with pre-CKD and/or pre-diabetes). On top of that, all approved drugs are first tested in healthy volunteers (short-term, normal dose) and on rodent and non-rodent animals (long-term, high doses), so they’re safe-ish. In the case of SGLT2i, we know that canagliflozin and empagliflozin extend lifespan in mice, so probably very safe. So, as eGFR declines from age 30 and lower eGFR is associated with higher all-cause mortality ( Optimal Blood Pressure we Should Target? Systolic Under 110 or 100? - #392 by adssx ), there might be a case for using SGLT2i in everyone above 30yo? Or everyone with eGFR that starts declining? Or everyone with eGFR below 90? I don’t know, but that was just an example of a potential reasoning triangulating RCTs on sick people + MR + association studies in the general population + animal studies.

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#303

Do you have a sense on what MR says at it pertains to GLP and longevity?

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#304

Above seems to be a way too black and white statement. At the minimum the jury is still out of think? Or do you feel that you actually know it does not work in long-lived animals (and I think you include humans in that)?

Personally think the evidence for CRON is at least as good as for any single FDA approved molecule

Below are some sources to start if you want to look at some of the literature:

And

And

And

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#305

Did you read the link I sent? I only mentioned CR in long-lived animals. Otherwise yes, CR is good. It increases longevity in animals on average. But are these animals “metabolically, weight and exercised optimized”? Or is the average animal like the “average American”? We always have this issue.

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#306

I couldn’t find any.

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#307

I can’t access more than the snippets when I click on the papers link above

You said:

Even calorie restriction doesn’t work in long-lived animals

The paper does not say it that strongly it says

• Caloric restriction works better in short-lived strains.

The papers seems to make the same point about medicines in short lived vs long lived animals

The second bullet in their summary is

• Most other longevity treatments work better in short-lived strains.

I don’t think we then conclude that we know there is no effect of those molecules in humans?

Do you mean long lived non/human animals or also humans? I was talking about humans and showing data in humans

#308

Risk mitigation begins at birth (or before birth with preimplantation genetic testing). We can model healthy diet and exercise for our children and encourage them to participate in sports that are relatively safer such as swimming or golf rather than more dangerous ones such as boxing or base jumping.

Eventually gene editing may provide one of the best ways to dramatically reduce the risk of Alzheimer’s. Until then, maintaining a healthy lifestyle and intermittent rapamycin use (in adults) seems like a great start.

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#309

I don’t want to argue about CR. My point was just that we don’t know anything that works in “metabolically, weight and exercised optimized individuals”. So it’s not only GLP1: it’s the same for every single intervention.

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#310

Ok, all good @adssx

The funny thing is that one and so far only reason I personally (while I’m still “optimized”) would consider a GLP med for longevity is to help me achieve a bit more calorie deficit/restriction in an easier way :slight_smile:

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#311

A new study, published in the journal GeroScience , highlights a promising link between nut consumption and a reduced risk of dementia. The findings suggest that middle-aged and older adults who regularly consume nuts have a 12% lower chance of developing dementia compared to non-consumers. This protective effect was particularly strong for those who consumed up to a handful of unsalted nuts daily, which appeared to yield the most significant cognitive benefits.

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#312

A new international study led by a team of scientists from Ben-Gurion University of the Negev showed controlling blood sugar levels is a significant key mechanism linking diet to slower brain aging.

“By tracking the volumes of dozens of different brain regions with MRI technology, we quantified the participants’ brain volumes before and after dietary intervention,” Shai added.

The original experiment, published about two years ago, demonstrated a 50% reduction in brain atrophy while consuming a green Mediterranean diet, which included the consumption of Mankai and green tea.

Now, the current study’s findings highlight blood sugar control as the primary link between diet and the brain regions vital for cognitive function (like the hippocampus, lateral ventricles, thalamus and cerebellum), motor control and sensory processing.

“These findings are crucial not only for people with high blood sugar but for everyone’s health at any age,” Shai explained. “We know that diabetics have a significantly higher risk of dementia, which isn’t a new finding. High blood sugar levels place strain on brain cells and lead to long-term damage, impairing brain function.”

“In this process, advanced glycation end-products (AGEs) form as sugars bind to cellular proteins like collagen and blood vessels, which reduces vascular elasticity and weakens blood supply to the brain.”

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Acarbose for healthy person? WHY?
#313

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See games here:

https://app.neuroagetx.com

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#314

Sometimes it feels like the whole field is one giant fraud:

https://www.science.org/content/article/top-alzheimer-s-researcher-goes-leave-amid-misconduct-concerns

“Berislav Zlokovic, a prominent Alzheimer’s disease and stroke researcher who has long headed a major neuroscience institute at the University of Southern California (USC), is now on an indefinite leave of absence, according to a school official. USC declined to clarify a reason for the leave, but Zlokovic has faced scrutiny since a 2023 Science investigation described evidence that he had engaged in scientific misconduct for decades. Science has also learned that a planned $30 million clinical trial of a stroke drug candidate Zlokovic helped develop has been formally called off by its company sponsor, and the National Institutes of Health (NIH) has required that USC return nearly $2 million in funding for the trial.”

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#315

I use CNS Vital Signs full panel to track neurocognition.

It is cheap, repeatable and trackable over time. Comprehensive and evidence based, also in 30+ languages and available worldwide.

My cost is $35 per test, I charge $50 as there is some administration to get it ordered.

Regards,

Grant

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#316

Physionic talks about Rapamycin, Alzheimer’s and autophagy

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#317

Frailty - A New and Early Predictor of Dementia?

Signs of frailty may signal future dementia more than a decade before cognitive symptoms occur, in new findings that may provide a potential opportunity to identify high-risk populations for targeted enrollment in clinical trials of dementia prevention and treatment.

Results of an international study assessing frailty trajectories showed frailty levels notably increased in the 4-9 years before dementia diagnosis. Even among study participants whose baseline frailty measurement was taken prior to that acceleration period, frailty was still positively associated with dementia risk, the investigators noted.

“We found that with every four to five additional health problems, there is on average a 40% higher risk of developing dementia, while the risk is lower for people who are more physically fit,” study investigator David Ward, PhD, of the Centre for Health Services Research, The University of Queensland, Brisbane, Australia, told Medscape Medical News.

https://www.medscape.com/viewarticle/new-and-early-predictor-future-dementia-2024a1000kuc

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#318

In Older People, Why Does a History of Oral Herpes Double the Risk of Dementia?

A 2024 study reported that an HSV infection may be indicative of doubled dementia risk in the older population (specifically, the participants included over 1,000 70-year-olds). The study found that people with antibodies for HSV-1 had a significantly higher risk of developing dementia. Specifically, being seropositive, or having antibodies in one’s blood, for HSV-1 nearly doubled the risk of dementia and Alzheimer’s disease.

Another study breaks it down this way: “Herpes simplex virus 1 (HSV1) is a neuroinvasive virus capable of entering the brain which makes it a candidate pathogen for increasing risk of dementia.” The virus can actually change the brain in a way that makes it susceptible to developing dementia.

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