Predicting Alzheimers & Dementia (and minimizing risk)

[hamtaro]

@RapAdmin

At a time when including the word “women” in research grants has triggered special review at the NIH,

Oy vey, these people are so bitterly entrenched in a narrative, they can’t help themselves.

[hamtaro]

Sleep habits are so difficult to fix. For me, they’ve been the most difficult aspect of a healthy lifestyle. Not all of us are Bryan Johnson.

[RapAdmin]

Does good sleep insulate the brain against Alzheimer's? | Erin Gibson - From...

[Stiv]

Might explain why naproxen was on a list of ‘longevity’ compounds discussed by Matt Kaeberlein

[Deborah_Hall]

This sounds pretty terrifying (and I do have skin in this having taken estradiol/progesterone for about 26 years starting at age 42).

But no, is a confirmation of the “timing hypothesis” which has been known for some time: if you start early, at the time of menopause or not later than about 5 years after menopause, HRT (estradiol + natural progesterone, not premarin/ synthesized progesterone) it is generally a good thing. But if you start later, in your sixties, it can be a problem.

When I first saw this headline I could immediately feel my heart beating wildly. As readers of my posts may recall I am particularly freaked out by the prospect of AD.

But no, nothing to see here.

[Deborah_Hall]

Dale Bredesen has a very clear (with diagrams) explanation about APP splicing in his book The End of Alzheimers. He targets it as the fundamental cause and as I read more about AD I am more ad more inclined to see it this way – and that is also consistent with this bioRxiv publication.

[John_Hemming]

splicing, of course, lies behind pretty well all of the aging phenotype (although there are also issues with senescence which is more linked to a failure of differentiation).

There are two theories as to why splicing is an aging problem

a) That of Professor Lorna Harries of Exeter University, UK who argues it is linked to the availabilty of splicing factors.
b) My hypothesis that splicing decisions are driven by acetylation (not only of the histone, but of other things as well although the histone is important) and is part of the system whereby the efficiency of the mitochondria controls what proteins are produced.

Actually these two theories may be linked as the acetylation may drive splicing factors. My hypothesis is IMO better because it explains why it happens.

[John_Hemming]

Asking ChatGBP 4o

what are the links between cytosolic acetyl-CoA levels and mRNA splicing

ChatGPT said:

Cytosolic acetyl-CoA levels are linked to mRNA splicing through multiple mechanisms, primarily via histone acetylation and the regulation of splicing factors. Here’s how:

1. Histone Acetylation and Chromatin Structure

• Acetyl-CoA is a key donor for histone acetylation, a process that relaxes chromatin structure and promotes transcriptional activation.
• Changes in chromatin structure can influence co-transcriptional splicing, where splicing factors are recruited to nascent transcripts based on chromatin modifications.

2. Acetylation of Splicing Factors

• Acetyl-CoA is required for the acetylation of splicing factors, which can alter their activity, localization, or interactions with pre-mRNA.
• Example: hnRNPs and SR proteins, key regulators of alternative splicing, can be acetylated, affecting their function.

3. Energy and Metabolic Signaling

• High cytosolic acetyl-CoA levels are associated with active metabolic states, which can impact mRNA splicing patterns in response to cellular conditions.
• Metabolic sensors (e.g., SIRT1, AMPK) regulate splicing factor activity in response to acetyl-CoA availability.

4. Direct Impact on RNA Polymerase II (RNAPII)

• Acetylation marks on histones influence RNAPII elongation rates, which in turn affect exon inclusion or skipping in alternative splicing.

Conclusion

Changes in cytosolic acetyl-CoA levels can modulate histone acetylation, splicing factor function, and transcription elongation, ultimately influencing mRNA splicing outcomes. This highlights a key link between cellular metabolism and gene expression regulation.

[AinmRapaNui]

Stiv,
Could you say more about naproxen?
I am not familiar with Matt K.

[EverVital]

@Deborah_Hall

the “timing hypothesis” which has been known for some time

Hi Deborah, can you provide more info or sources on the timing hypothesis?

Also, how do you get that the charts above relate to timing? My reading is baseline age is the age at the start of the study, not the age at initiation of HT.

[RapAdmin]

New study uncovers unexpected activity that may keep brain sharp later in...

[Deborah_Hall]

You may want to read “The Estrogen Dilemma” by Cynthia Gorney in the New York Times, April 2010. Yes 2010. That’s how long we have known about estrogen and the “timing hypothesis”.

In 2020 I was diagnosed with a very tiny, very indolent hormone positive breast cancer. At the time I believed I had given myself cancer because I had taken estradiol and prometrium for so many years. Now at a distance of five years (and no recurrence) I no longer think that – I think the microscopic lesions might even have been iatrogenic --caused by the many, many biopsies.

I now believe that having taken the HRT for years was, on balance, more positive than negative. I eschewed most of the interventions that I was guided towards, and in this process learned a whole lot . . . . . and decided to write up my experience.

So, I self published a short book under a pen name: Dora Kiehl Miller. It’s on Amazon. The title is “Three Mastectomies: A Cancer / Not Cancer Memoir.” Spoiler alert-- I did not have a mastectomy but came very close a few times.

[Stiv]

It was on Matt’s Optispan podcast talking about this 2024 review of which prescription drugs (from UK Biobank data) were correlated with increased lifespan. Naproxen was one. I take it on rest days.

Association between prescription drugs and all-cause mortality risk in the UK...

Abstract

‘Although most drugs currently approved are meant to treat specific diseases or symptoms, it has been hypothesized that some might bear a beneficial effect on lifespan in healthy older individuals, outside of their specific disease indication. Such drugs include, among others, metformin, SGLT2 inhibitors and rapamycin. Since 2006, the UK biobank has recorded prescription medication and mortality data for over 500’000 participants, aged between 40 and 70 years old. In this work, we examined the impact of the top 406 prescribed medications on overall mortality rates within the general population of the UK. As expected, most drugs were linked to a shorter lifespan, likely due to the life-limiting nature of the diseases they are prescribed to treat. Importantly, a few drugs were associated with increased lifespans, including notably Sildenafil, Atorvastatin, Naproxen and Estradiol. These retrospective results warrant further investigation in randomized controlled trials’.

[RapAdmin]

Specific age window may be critical in slowing down cognitive decline

Study Reveals Critical Age When Your Thinking Begins to Decline

Research Paper Source: (open access)

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.

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

[RapAdmin]

Advanced glycation end products or AGEs?

Higher Dietary Intake of Advanced Glycation End Products Is Associated with Faster Cognitive Decline in Community-Dwelling Older Adults AGEs content of food consumed by older adults varies with the food type and methods employed for its preparation. Thus, the level of AGEs in daily food consumption may contribute to the level and rate of cognitive decline in older adults. AGEs are formed endogenously in the course of normal cellular metabolism and their levels tend to increase with age [5]. Exogenous sources such as pre-formed AGEs from food may also contribute significantly to the body’s pool of AGEs [6,7]. AGEs exist in most foods, but they are particularly abundant in animal-derived foods, such as meat, poultry, and fish, which are also rich in fats. Content of AGEs in these foods increases significantly when cooking at high temperatures using a dry cooking technique (e.g., grilling, broiling, roasting, searing), but less when using lower temperatures and a cooking technique with …

[medaura]

“The findings do support the hypothesis that a keto diet during mid-life may be an effective strategy for preventing cognitive decline in late life,” he said.

“A clinical trial of a keto diet that increases insulin resistance in the brain in middle-aged volunteers could lead to a whole new intervention strategy for preventing late-life cognitive decline,” he added.

Doesn’t he mean insulin sensitivity? Or has cognitive decline already set in?

[Shady]

@RapAdmin

Intriguing study. Ketone esters make me feel amazing. On Friday’s I fast, do Norwegian protocol HIIT, and take 10-15g of ketone ester. The mental clarity and energy on those days is impressive. Unlike any other day of the week including days I fast and do cardio, but no ketones. Unfortunately ketones are expensive especially at the dose they used in the study (~32g for an 80kg person). DeltaG is the best ketone I’ve used, but also the priciest. The study used DeltaG (patented by Oxford), but mentioned HVMN as the company. HVMN doesn’t have a ketone ester for consumers, so I found that odd. They use 1,3-butanediol in their product. I’ve tried it and much prefer DeltaG. I’m going to try ketones daily for a couple weeks to see how I feel, but without a huge drop in price it doesn’t seem sustainable long term.

[dicarlo2]

Does this mean a limited run of a keto diet, or starting a permanent keto diet in mid-life until death?

[Neo]

@Shady

I’m going to try ketones daily for a couple weeks to see how I feel, but without a huge drop in price it doesn’t seem sustainable long term.

Do report back - interested in learning from your experience

[RapAdmin]

@Shady

without a huge drop in price it doesn’t seem sustainable long term.

Yes - I think this is the fundamental problem right now with exogenous ketones as products, the price is way too high still to be a feasible option for most people to use on a regular basis. I’ll watch this space and hopefully the prices get more reasonable in a year or two as volumes ramp up.