Health Last Updated: 07 June 2025 - 03:19 AM

https://www.pnas.org/doi/10.1073/pnas.2416433122

Brain aging shows nonlinear transitions, suggesting a midlife “critical window” for metabolic intervention

 

Age-related cognitive decline is associated with metabolic, vascular, and inflammatory changes, making it challenging to distinguish primary causes from secondary (downstream) effects. This study demonstrates that brain aging follows a specific progression, with the first stage occurring in middle age and coinciding with increased insulin resistance. Moreover, we show that brain areas that age fastest are also those most vulnerable to neuronal insulin resistance. Importantly, we find that administering ketones, which can fuel neurons while bypassing insulin resistance, reverses brain aging effects. However, this intervention is only effective when provided early enough for neurons to remain viable. These findings contribute to our understanding of brain aging mechanisms and suggest neurometabolic strategies for targeted early intervention in preventing age-related cognitive decline.

Abstract
Understanding the key drivers of brain aging is essential for effective prevention and treatment of neurodegenerative diseases. Here, we integrate human brain and physiological data to investigate underlying mechanisms. Functional MRI analyses across four large datasets (totaling 19,300 participants) show that brain networks not only destabilize throughout the lifetime but do so along a nonlinear trajectory, with consistent temporal “landmarks” of brain aging starting in midlife (40s). Comparison of metabolic, vascular, and inflammatory biomarkers implicate dysregulated glucose homeostasis as the driver mechanism for these transitions. Correlation between the brain’s regionally heterogeneous patterns of aging and gene expression further supports these findings, selectively implicating GLUT4 (insulin-dependent glucose transporter) and APOE (lipid transport protein). Notably, MCT2 (a neuronal, but not glial, ketone transporter) emerges as a potential counteracting factor by facilitating neurons’ energy uptake independently of insulin. Consistent with these results, an interventional study of 101 participants shows that ketones exhibit robust effects in restabilizing brain networks, maximized from ages 40 to 60, suggesting a midlife “critical window” for early metabolic intervention.

 

One problem with this is that they used pure ( R )-3-hydroxybutyl-( R )-3-hydroxybutyrate monoester (ΔG ketone monoester, HVMN Inc., Miami, FL) dosed at 395 mg per kg of body weight and diluted with water (volume ratio 1:1.6).

This is important because if you tried to take that dose of any of the available Beta-Hydroxybutyrate (BHB) salts, it would result in a highly toxic if not fatal dose of potassium and possibly magnesium, and at least a very excessive dose of calcium or sodium. The monoester avoids this, but it's very very expensive (about $30 per dose from what I could find).

On the other hand, I found a Japanese supplier of the acid which may require refrigeration but has no metal in the compound. They sell only wholesale, so a group buy may be a possibility. It will still probably not be at all cheap.

Or we can always just do a keto diet.

1. Myers Cocktail IM - 10 ml 3 times / week

2. CITOPRIM ONCOLOGY STEM - 3 caps daily

3. Amygdaline (Vitamin B17) - 3 to 5 caps daily

4. ONCO DETOX - SOD Natural ( 2 ampoules daily)

5. Ringer Solution IV

source: gerovitalcosmetic.com

There are only a handful of places to get it, and some of them have suspicious "lab reports."

It's a in a couple products, like Novos and Bryan Johnson's.

I just unboxed my new order.

Hello everybody: I know a few GlyNAC anti-aging threads appeared years back, but I want to refresh the subject. I have been taking GlyNAC now for over two years at fairly high doses (3 grams of each per day, religiously), and this week I upped my dose to 5.5 grams of each, to more closely follow one of the Baylor dosing protocols and hopefully achieve bigger benefits (122lb/55 kg woman taking 100 mg per kg of body weight each of Glycine & NAC). 

Is anybody else here trying in the same high dosages they administored at Baylor? 

I have never had any adverse effects from these extreme amounts and it definitely "feels" as if this combo works well for me.

This post would be a lot more helpful to others if I had blood work results to cite, so please accept my apologies for being unable to even supply a baseline, as I haven't seen a doctor for three years.  _{(Explanation: I would love to seek healthcare but my  providers will not permit me to bring my very senior dogs to appointments and the dogs have too many special needs for dog sitters. One pup was recently euthanized at 16.5 when her cancer returned. The other is going strong at nearly 17, despite being paralyzed from the waist down by canine degenerative myelopathy; he still enjoys at least a 2-mi  walk each day on his front legs, supported by a harness, and swims for hours when weather permits).} 

I guess I am lucky given my age haven't had a recent health crisis, but perhaps that is partially due to the GlyNAC. For your convenience, here is Baylor's 2022 press release on their studies and here is a non-paywalled full-text link of one of their research papers. (There was also a Nestle study using GlyNAC in quite high but much lower amounts with mediocre results). 

I thought by now, there might be a community on this forum, home-trialing GlyNAC. There are a few people who tried it in the Reddit supplements sub, including one sixty-something guy and his wife who had been following the Baylor protocol pretty exactingly for over two years when they last posted.   There is also a Reddit GlyNAC sub, but it's dead.

Here is what I think GlyNAC is doing for me:

• immune effects (no colds or viruses since I started),
• better mental focus (no brain fog at all despite severe ADHD),
• respiratory improvements (no congestion and almost no post-nasal drip, which used to be a constant),
• no aches or pains (I used to have mild arthritis),
• slightly better mood
• better skin? (it's hard to say because even though I am 67, my skin texture has always been pretty dewey and free of discoloration, skin tags, etc., and it's not as if I look radically younger -- I don't notice increased collagen or diminished wrinkles). 
• stamina (but I only feel increased energy since I raised my GlyNAC from 6g to 11g daily, and that was only four days ago). 

I should also add that I take a lot of stuff besides GlyNAC. My supplements include CoEnzyme q10 (400mg), niacinamide (1200mg), biotin, Vitamin D/K combo, Vitron c iron supplement, hair gummies (to arrest telogen effluvium), 80% per cent silymarin extract (450mg), 18% oleuropein Olive leaf extract (800 mg), Echinacia extract, 4% (200mg), Acacia gum fiber (two heaping tablespoons), a generic multivitamin, three grams of Magnesium Citrate (DIY version made from mag oxide and citric acid), d-ribose (4.5g), methlyene blue (11mg). Note: I will be eliminating both d-ribose and methylene blue when I run out since they don't seem to do squat, at which point I'l reintroduce high DHA fish oil and MSM.  

I am taking the GlyNAC in bulk powder form. I usually order direct from Nutricost whenever they have a 40% off sale because their NAC is less ass-smelling than some other brands. I have also ordered a Capsule It machine so I can make GlyNAC capsules for travelling, because ready-made pre-capsuled GlyNAC is crazy expensive. 

Some of the people doing GlyNAC on Reddit buy separately capsuled NAC and Glycine (much less costly) and take them together in a 50/50 ratio by weight, but I don't have sufficient confidence in my sluggish digestion to believe it will mix fully in my gut (I've had three gut operations due to a genetic abnormality.  

Bulk powders aren't so bad. I weigh them out on a mg scale, mix in 20 ounces of cold water, add a few ounces of juice (grapefruit or cherry) and some plain dried monk fruit powdered extract as a sweetener. It doesn't taste horrible. And if I split the dose and kept to the same rate of dilution, I'd have a semi-pleasant fruit flavored beverage, however, I read that taking the whole dose in one go enables better absorption (something about the first pass of the liver? I'd love it if somebody smart would weigh in here). 

Okay. That's it. Thank you very kindly for your forbearance if you have gotten through this long post. Please share your thoughts!

Note: not sure why my head says "Guest" -- I have been a member here for very well over a decade, maybe twenty years (mostly lurking though so maybe that is why.