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.
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.
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Stiv
#509
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.
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’.
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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
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medaura
#512
Doesn’t he mean insulin sensitivity? Or has cognitive decline already set in? 
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Shady
#513
@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.
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Does this mean a limited run of a keto diet, or starting a permanent keto diet in mid-life until death?
Neo
#515
Do report back - interested in learning from your experience
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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.
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“We did multiple different tests of memory, and they were all improved with the drug,” says neuroscientist Stuart Lipton, from the Scripps Research Institute.
“It didn’t just slow down the decline, it improved virtually back to normal.”
One of the main challenges faced by the researchers was getting carnosic acid into a stable form that would last long enough in the brain to have an effect. After extensive tests, they found a suitable di-acetylated form (diAcCA).
diAcCA, a Pro-Drug for Carnosic Acid That Activates the Nrf2 Transcriptional Pathway, Shows Efficacy in the 5xFAD Transgenic Mouse Model of Alzheimer’s Disease
The antioxidant/anti-inflammatory compound carnosic acid (CA) is a phenolic diterpene found in the herbs rosemary and sage. Upon activation, CA manifests electrophilic properties to stimulate the Nrf2 transcriptional pathway via reaction with Keap1. However, purified CA is readily oxidized and thus highly unstable. To develop CA as an Alzheimer’s disease (AD) therapeutic, we synthesized pro-drug derivatives, among which the di-acetylated form (diAcCA) showed excellent drug-like properties. diAcCA converted to CA in the stomach prior to absorption into the bloodstream, and exhibited improved stability and bioavailability as well as comparable pharmacokinetics (PK) and efficacy to CA. To test the efficacy of diAcCA in AD transgenic mice, 5xFAD mice (or littermate controls) received the drug for 3 months, followed by behavioral and immunohistochemical studies. Notably, in addition to amyloid plaques and tau tangles, a hallmark of human AD is synapse loss, a major correlate to cognitive decline. The 5xFAD animals receiving diAcCA displayed synaptic rescue on immunohistochemical analysis accompanied by improved learning and memory in the water maze test. Treatment with diAcCA reduced astrocytic and microglial inflammation, amyloid plaque formation, and phospho-tau neuritic aggregates. In toxicity studies, diAcCA was as safe or safer than CA, which is listed by the FDA as “generally regarded as safe”, indicating diAcCA is suitable for human clinical trials in AD.
https://www.mdpi.com/2076-3921/14/3/293
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Research links TDP-43 loss in blood vessels to neurodegeneration
- What happened? New research finds that endothelial TDP-43 loss disrupts the blood-brain barrier, linking vascular dysfunction to Alzheimer’s, ALS and FTD.
- What does it mean? The study’s findings on the role of endothelial TDP-43 depletion in disrupting key blood-brain barrier (BBB) pathways in neurodegenerative diseases offer a compelling contribution to the field of geroscience – highlighting the fundamental link between vascular integrity and cognitive longevity
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https://www.neuroagetx.com
and I got an email recently from NeuroAge:
NeuroAge is recruiting for our research study
We are recruiting people with Mild Cognitive Impairment (MCI) or early stage Alzheimer’s Disease for our research study
We are offering free NeuroAge testing with brain MRI, genetics, and blood biomarkers to study participants and will share their results with them. There is no intervention in the study, just testing. The study is funded by the Alzheimer’s Drug Discovery Foundation. If you or someone you know would like to participate, please fill out the survey to sign up for the waitlist.
Sign Up For The Waitlist
The NeuroAge Test for brain aging is now available.
Track your brain aging. Change your tomorrow.
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Neo
#522
The participants in the study had inherited genetic variants that lead to early-onset Alzheimer’s disease, and among those who received the drug the longest – an average of eight years – the treatment lowered the risk of developing symptoms from essentially 100% to about 50%, according to a preliminary analysis of the data.
@adssx @DrFraser - any thoughts these seems like it could be big if translated to general prevention?
I think the problem with these drugs include up to 20% intracranial hemorrhage rate, and I’m not entirely convinced that all AD is the same. Will what works in Knight Family Dementia - which is young onset AD work on standard AD or AD due to senescence or ApoE?
We have evidence of other items that will get us 50% rate reduction that don’t involve these risks or costs, which will inevitably be high.
I’m not jumping on this yet. More data, including in individuals with ApoE4’s with MCI would be welcome.
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Neo
#524
Thx for perspective
I spoke to a scientist very close this and who thought that those risks were largely driven by how much the drugs had to clear
So the risks are large when intervening late
But may be much smaller if done earlier and perhaps hardly at all if done preventably
Will be interesting to learn more as more data comes in
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This is a fair perspective - the more diseased your brain, the more likely you are to hemorrhage.
The problem has been the cost of these agents, and then secondarily identifying which individuals are at highest risk (and also if having a whole host of bad lifestyle choices - should society bare these costs?).
We need to understand who will benefit (and who will be harmed) by these interventions. There must be a computation of cost per additional year of quality of life - the system cannot sustain giving every last item to every individual. This will result in patients at risk being denied (as I see daily on many of my prescriptions) and then there is the option to pay for it or not. By necessity, we’ll see the affluent get these therapies and the poor get denied.
This however isn’t a new concept in our healthcare system.
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