How, how do they not have other vaccines? Shingles being the one most studied and impactful.
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This was from UK Biobank and Shingles vaccine was only introduced into UK in 2013 for people over 70 years old.
(Buying it out of pocket is rather expensive).
Even now you donāt get it on the NHS until you are over 65.
I suspect they just didnāt have the numbers for statistical significance.
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Ah. Wow that is absolutely horrible. I suspect that shingles vaccine would financially pay off at age 50 by reduced lost work, medical and even long term care costs.
The cost in the UK is really high relative to income.
Score one for the US health care system. Have to take it when we can. Now only about 22% of adults over 50 have had 2 shots so we can take a negative 5 points on education and health literacy.
Estrogen is huge for women. Iām talking YUUUGE. But must be started early enough and can possibly backfire if started too late. Itās like restoring electricity to a house after it was just cut off or about to be vs when itās been so long in disrepair that the circuitry is fried ā then it can start a fire. It should be discussed more on this site but I bet the demographics are 90% male or women too old to benefit from starting it now.
SGLT2iās also sound like a no brainer. PDE5iās are probably beneficial but I suspect far less than the signal suggests, because of the healthy user bias.
And why on earth canāt the U.S. collect the equivalent of the UKās biobank? Even with a decentralized health insurance ecosystem, thereās drug registries that actuaries can always get their hands on. So whatās the holdup?
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100% on the estrogen. The lay media is mostly taking care of that. Both my wife and her sister on different coasts got on it independently without this forum. At 45 and 50.
Now there are shortages because of the rapid uptake.
It is like TRT for men with only positive effects.
Iām a huge proponent for testosterone for women also.
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Iāve started at 39 this year at the instigation of ChatGPT. No noticeable perimenopause symptoms yet but Iām sure theyāre around the corner so the sooner the better, especially since Iāve given birth to five children and breastfed them for almost two years each on averageā so Iāve undergone a big area under the curve with low esterogen. I do think I need a bit of testosterone too but too shy to pull the trigger. Can you share more about what your wife has done in that department and how itās worked for her?
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Medaura, I liked your description of restarting estrogen ātoo late.ā
I started the estradiol patch and prometrium in my early forties as I went through very early menopause and was diagnosed at around 42 with osteoporosis. After several years, my GYN said enough but I wanted to continue so began buying from Canada. (You didnāt need a script then). I kept using until I was diagnosed with a very tiny, indolent hormone positive breast cancer at age 70. At this distance in time I have come to believe that the ācancerā was actually iatrogenic ā caused by many many biopsy pokes into tissue that was a dense white cloud on the ultrasound, disturbing what was probably a bit of ductal carcinoma in situ, and poking the cells out through the basement membrane. No cancer cells were found until pathology at lumpectomy, and then the Ki67 was 1%. Anyway, long story but at that juncture, at age 70, I stopped using the estradiol and started raloxifene. Now I wish I had not ever stopped the estradiol, but glad I took it for about 16 years. Now I am using vaginal estradiol but keep thinking about systemic estradiol. But I guess I better not . . . .and your explanation helps explain . . why not.
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Iām always so confused about oestrogen. It seems like such a double-edged sword to me, but likely since I am not well-versed enough in the topic.
(At least in some situations, in some tissues) transdermally applied oestrogen stimulates mTOR, such as in vaginal tissues but also in liver tissues it increases IGF-1 levels and mTOR, and systemically. And in caloric restriction mTOR of course is suppressed systemically (to trigger autophagy) and LH, FSH and oestrogen levels tend to drop. That makes me wonder if taking oestrogen as a woman is really likely to increase lifespan?
Publications suggest oral versus transdermal oestrogen have different effects. Transdermal oestrogen would apparently increase circulating IGF-1 (as it bypasses first-pass metabolism) and activate mTOR, whereas that would not be the case for oral oestrogen. In fact some research suggests oral oestrogen decreases systemic mTOR. But oral oestrogen of course isnāt as effective in reducing for example bone loss in menopausal women or vaginal atrophy - osteoblast activation and vaginal wall ārepairmentā requires cell proliferation and mTOR activation after all.
Iād love to hear a better informed opinion on this. Unfortunately GPT seems to give me different answers on different days, and the sources I ask it to include in its answers are commonly random studies that have nothing to do with the citations it made up.
https://www.nature.com/articles/s41419-022-05293-8
āThe mouse vaginal epithelium cyclically exhibits cell proliferation and differentiation in response to estrogen. Estrogen acts as an activator of mTOR signaling but its role in vaginal epithelial homeostasis is unknown. We analyzed reproductive tract-specific Rptor or Rictor conditional knockout mice to reveal the role of mTOR signaling in estrogen-dependent vaginal epithelial cell proliferation and differentiation. Loss of Rptor but not Rictor in the vagina resulted in an aberrant proliferation of epithelial cells and failure of keratinized differentiation. As gene expression analysis indicated, several estrogen-mediated genes, including Pgr and Ereg (EGF-like growth factor) were not induced by estrogen in Rptor cKO mouse vagina. Moreover, supplementation of EREG could activate the proliferation and survival of vaginal epithelial cells through YAP1 in the absence of Rptor. Thus, mTORC1 signaling integrates estrogen and growth factor signaling to mediate vaginal epithelial cell proliferation and differentiation, providing new insights into vaginal atrophy treatment for post-menopausal women.ā
https://pubmed.ncbi.nlm.nih.gov/1991807/
āOral EE treatment increased mean 24-h serum GH (2.0 +/- 0.4 to 7.0 +/- 0.6 mIU/L, P less than 0.0005) and mean pulse amplitude (5.3 +/- 1.2 to 11.2 +/- 2.5 mIU/L, P less than 0.01) but significantly reduced circulating IGF-I (0.70 +/- 0.09 to 0.47 +/- 0.04 U/mL, P less than 0.02) levels. Oral EE increased the percent specific binding of [125I]GH (22.0 +/- 1.6 to 32.0 +/- 1.9%, P less than 0.0005), however the derived mean 24-h free serum GH concentrations were significantly higher (P less than 0.0005) after treatment. By contrast, transdermal E2 administration, which restored circulating E2 concentrations to the midfollicular range, increased circulating IGF-I (0.86 +/- 0.15 to 1.10 +/- 0.14 U/mL, P less than 0.005) to levels that were not significantly different from those of premenopausal women (1.41 +/- 0.21 U/mL). This was not accompanied by changes in 24-h GH secretion or the percent specific binding of [125I]GH in serum. The route of administration is a major determinant of the effects of exogenous estrogens on the GH/IGF-I axis. Oral estrogen administration inhibits hepatic IGF-I synthesis and increases GH secretion through reduced feedback inhibition. Reduced GH secretion in the menopause is not explained by estrogen deficiency since GH secretion is not restored by the attainment of physiological E2 concentrations using the transdermal route. The contrasting route dependent IGF-I responses have important implications for the long-term benefit of hormone replacement therapy in the menopause.ā
https://pubmed.ncbi.nlm.nih.gov/25001019/
āAfter 10 weeks of CR or high-fat diet, ovarian follicles at different developmental stages were examined by histological analysis. Plasma levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estrogen (ESG) were measured, and the levels of mammalian target of rapamycin (mTOR), p70S6 kinase (p70S6K), and phosphorylated p70S6K in the ovary were detected by Western blot. The results showed that the reserve of follicle pool in CR rats was increased, accompanied by decreased level of phosphorylated p70S6K in the ovary, and decreased serum LH, FSH, and ESG levels. Taken together, these results suggest that CR may suppress ovarian follicular development and enhance the follicle pool reserve by inhibiting mTOR signaling.ā
(That is all besides the ITP study that showed 17-alpha-estradiol significantly increased the median lifespan of male mice but had no significant effect on females. Albeit there is a lot to discuss about that also).
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17-alpha-estradiol got the attention because it was not feminizing and worked in males. Females already have their own version, the plain vanilla beta estradiol.
Caloric restriction is a double edged sword or rather a very steep U curve effect source for ovarian aging. Some dampening of mTOR preserves the follicle pool. More aggressive downturn of mTOR accompanied with other starvation signals from CR increase artesia and put the ovary in quickened recruitment mode. Evolutionarily the organism seems to be deciding that the living unit is starving and doesnāt have long to live so best give it NOW, presto, whatever chance at reproduction, like the losing basketball team taking crazy shots with a few seconds to go.
We donāt know exactly the crossover thresholds and I suspect that rapamycin started young can really backfire in women if the dose is high. Towards the end of the fertile years at least at roughly 5 mg a week it seems to preserve what ovarian reserve thereās left.
But understand that when the ovaries are done, the biggest loss is that of estrogen and thatās how the rapid acceleration trend towards decrepitude and death is orchestrated in human females. I think that life cycle reset mechanisms vary by species to ensure that the organism dies right at the most opportune time and for human females, because of the few decades of ovulation-free grandmothering time deemed optimal for our speciesā survival, a lot has been riding on our bodies breaking down at the right pace after the total shutdown of estrogen. Right until then we do pretty wonderful, really. So I think itās going to be a game changer for women to start esterogen replacement before it really tanks. It will do for us way more than HRT can do for she-mice and other mammals whose females only experience a gradual depletion of reproductive capacity and hormonal output, similar to the males of our species. For them, evolution has already found other ways to do them in. For us she-humans, it never foresaw weād invent the patch.
Yes it increases mTOR all things equal and thatās not a bad thing in every context. Its effects seem tied to all the positives of mTOR ā anabolism, tissue repair, bone density etc, and none of the negatives if you donāt count the minor signal in breast cancer and endometrial cancer (which can be countered by progesterone).
Transdermal is better than oral unless you start too late. At which point oral is the only plausible option for reasons too deep in the weeds to cover here.
And any mtor raising negatives can be countered byā¦ you guessed itā¦ rapamycin.
@Deborah_Hall I would consult with a menopause specialist obgyn if I were you, before writing off esterogen. What matters is how long youāve been without it, not how long since it naturally got switched off. So if you took it since 42 until very recently you might be ok to hop back on, provided your cancer is properly screened. I donāt know obviously but Iād talk to an expert before writing it off.
Iām not planning to watch this, so you can correct me if Iām wrong. But from the title, I am inferring that their criteria for inclusion was extension of life-span. If so, I believe it is a serious mistake to dismiss the value and impact of health-span.
I merged with the existing post about that 2024 paper: Association between prescription drugs and all-cause mortality risk in the UK population 2024
Not sure itās a high-quality paper btw when you look at the details of the data.