#208

I think the key issue, however, is the quality of the mitochondria. Even quiescent cells have some rate of metabolism and the mitochondrial bottleneck only operates once for each oocytes.

1 Like
#209

Dear RapAdmin,

Thank you for this article.

There is also research from 2022 where Pirfenidon was administrated to 15 months old mouse for 2 weeks orally and results were very good. Ovaries looked much younger with less fibrosis.
Reference: Female reproductive life span is extended by targeted removal of fibrotic collagen from the mouse ovary, Author: [Takashi Umehara] at all.(https://www.science.org/doi/10.1126/sciadv.abn4564#con1)

I was taking Rapamyicn for approx. 5-6 months and my period stopped. So I stopped taking Rapamycin one month ago and I am waiting to se what will happened. I was thinking that Rapamycin pushed me in starvation mode (because it promotes autophagy and I have only 52 kg and was taking 4 mg per week). During that period I was collecting eggs through IVF and at those eggs looked morphology good . So what I am guessing is that Rapamycin suppress number of antral follicles because it is giving information to the body that it is starvation mode and body blocs production of hormones but maybe during period of taking Rapamycin ovaries are rejuvenating because of deep autophagy. We will see.

Also, I know that a lot of people on this Forum are buying Rapamycin form India so they have experience with different Indian drug companies.
As I would like to try Pirfenidon for reduction of ovarian fibroses, I would like to know which Indian drug company is good so I could try to order it?

Thank you very much!

3 Likes
#210

I took higher doses than the 4mg per week you mention, weigh 41-42kg (on CRON), low BMI, and my periods have never stopped while taking Rapa. I haven’t heard females in another Rapa group mention this either.

#211

See this section of this thread where we discuss what Indian Pharma companies are likely the best ones for higher quality medications: Rapamycin etc., Purchase Price Comparison Spreadsheet, and Issues Discussion - #39 by adssx

1 Like
#212

Thank you for information!

#213

Hello community,

I’m 37F. I take 6mg/week primary to delay menopause and manage a few autoimmune conditions. For simplicity I plan to track AMH, FSH and Estradiol (E2) once a year (day 21 of MC) to identify where I’m on my menopausal journey. I haven’t had any fertility issues and not having more kids. So far I haven’t had any side effects.

I’m keeping an eye on this study Effect of Rapamycin in Ovarian Aging
They give participants 5mg/week of rapamycin orally for 12 weeks and measure AMH, FSH, Estradiol (E2), TVUs (follicle growth) and Klotho Level for up to a year.

5 Likes
#214

I also would like to share this article from Nature Ageing:

Molecular and genetic insights into human ovarian aging from single-nuclei multi-omics analyses
https://www.nature.com/articles/s43587-024-00762-5

Important findings:

mTOR signaling emerged as an ovary-specific aging-prevalent pathway, highlighting its unique and central role in ovarian aging. This finding is particularly intriguing given the evidence that mTOR inhibition extends lifespan more strongly in female mice than in male mice and that it can delay mouse ovarian aging.

Abstract:

The ovary is the first organ to age in the human body, affecting both fertility and overall health. However, the biological mechanisms underlying human ovarian aging remain poorly understood. Here we present a comprehensive single-nuclei multi-omics atlas of four young (ages 23–29 years) and four reproductively aged (ages 49–54 years) human ovaries. Our analyses reveal coordinated changes in transcriptomes and chromatin accessibilities across cell types in the ovary during aging, notably mTOR signaling being a prominent ovary-specific aging pathway. Cell-type-specific regulatory networks reveal enhanced activity of the transcription factor CEBPD across cell types in the aged ovary. Integration of our multi-omics data with genetic variants associated with age at natural menopause demonstrates a global impact of functional variants on gene regulatory networks across ovarian cell types. We nominate functional non-coding regulatory variants, their target genes and ovarian cell types and regulatory mechanisms. This atlas provides a valuable resource for understanding the cellular, molecular and genetic basis of human ovarian aging.

2 Likes
#215

Improving mitochondrial function and metabolism

Rapamycin and metformin, compounds that inhibit mammalian target of rapamycin (mTOR) signaling to regulate cellular metabolism, have been extensively investigated for their antiaging effects. Rapamycin treatment of 8-month-old mice for 2 weeks increased the number of follicles present at 14 months of age and improved mitochondrial function in ovulated eggs. Similarly, metformin treatment for 6 months increased the number of follicles present at 12 months. Mice treated with metformin for 2 weeks had reduced ovarian fibrosis, and postmenopausal individuals taking metformin had abrogated ovarian fibrosis.

Emerging therapeutic strategies to mitigate female and male reproductive aging

https://www.nature.com/articles/s43587-024-00771-4.epdf?sharing_token=CVVD0pWLTcC_FnaCOSwXxtRgN0jAjWel9jnR3ZoTv0MrsuCH8HqgN2RPjaOLASbYWKx5hQaXQ0kIASMjRWr6f5iSz8dAm37Ti2HmC3xQC2CROr8eli8kWEPWqUIAQ34Vx_TIAYdRHNepjsDwuryj5Qcj3GEtdpPOouu5pRmNXhA%3D

3 Likes
#216

Canagliflozin slows ovarian aging in mice

Ovarian aging is characterized by declines in follicular reserve and the emergence of mitochondrial dysfunction, reactive oxygen species production, inflammation, and fibrosis, which eventually results in menopause. Menopause is associated with increased systemic aging and the development of numerous comorbidities; therefore, the attenuation of ovarian aging could also delay systemic aging processes in women. Recent work has established that the anti-diabetic drug Canagliflozin (Cana), a sodium-glucose transporter 2 inhibitor, elicits benefits on aging-related outcomes, likely through the modulation of nutrient-sensing pathways and metabolic homeostasis. Given that nutrient-sensing pathways play a critical role in controlling primordial follicle activation, we sought to determine if chronic Cana administration would delay ovarian aging and curtail the emergence of pathological hallmarks associated with reproductive senescence. We found that mice receiving Cana maintained their ovarian reserve through 12 months of age, which was associated with declines in primordial follicles FoxO3a phosphorylation, a marker of activation, when compared to the age-matched controls. Furthermore, Cana treatment led to decreased collagen, lipofuscin, and T cell accumulation at 12 months of age. Whole ovary transcriptomic and proteomic analyses revealed subtle improvements, predominantly in mitochondrial function and the regulation of cellular proliferation. Pathway analyses of the transcriptomic data revealed a downregulation in cell proliferation and mitochondrial dysfunction signatures, with an upregulation of oxidative phosphorylation. Pathway analyses of the proteomic data revealed declines in signatures associated with PI3K/AKT activity and lymphocyte accumulation. Collectively, we demonstrate that Cana treatment can delay ovarian aging in mice and could potentially have efficacy for delaying ovarian aging in women.

Paywalled paper:

6 Likes
#217

Thank you for this paper.

Reading different papers on ovarian aging I come to conclusion that main regulator of aging and also ovarian aging is Hypothalamus.

I found very interesting paper about " groundbreaking discoveries of mTOR and NF-κB pathways in the aging hypothalamus, one of the casualties of an overactive NF-κB is the suppression of GnRH gene expression, and a reduction in GnRH synthesis and secretion. Since GnRH is the key regulator of FSH and LH and secondarily controls the gonadal production of estrogen and testosterone.
Many reproductive and non-reproductive targets controlled by these sex steroids are adversely affected. These include the cessation of the menstrual cycle with its associated menopausal symptoms, a loss of muscle tone and bone strength, a decline in the energy level, a weakening of the body’s ability to defend against infectious agents, a degeneration of cognitive ability, and an increase in body fat that could lead to heart diseases and cancer.
Administration of GnRH or rapamycin (an mTOR inhibitor) in animals improves many age-related symptoms, including skin atrophy, muscle weakness, and bone loss. Therefore, in addition to the reproductive role, GnRH is shown to act on the brain and peripheral organ systems to regulate systemic aging, albeit through a different signaling pathway from rapamycin. The finding that hypothalamic inflammation is responsible for the shutdown of GnRH and systemic aging provides an additional molecular mechanism supporting the neuroendocrine basis for aging."

Also they found that not only Rapamycin can regenerate Hypothalamus, but also through administration of Succinate which “stimulates the expression of the HIF-1α gene, stabilizes the HIF-1α protein, and mitigates the functional decline in both the stress adaptation/energy-balancing pathway and the GnRH loop. This helps to moderate age-related processes that lead to weight gain, menopausal symptoms, and other degenerative diseases. Since the succinate receptor is widely distributed throughout the body, succinate may play a central role in reversing the gradual but significant dysregulation of the hypothalamus as well as peripheral cellular senescence.”

I have 2 questions:

  1. Does Rapamycin cross blood - brain barrier and can oral Rapamycin administration impact Hypothalamus cells mTOR supersession and is it possible to take Rapamycin nasally to impact Hypothalamus directly (I am taking NAD Nasal Spray to impact NAD energy in Hypothalamus cells to try to revers aging of these cells)

  2. what is Sucinate? I found a lot of different names and I am not sure which one is correct.

Thank you very much!

This is the papier:

1 Like
#218

I was in the VIBRANT study! That’s actually what brought me here. I don’t know currently whether I received placebo or rapamycin, my understanding is they’ll unblind in fall 2025.

2 Likes
#219

Did you get to see your test results in terms of FSH, etc.? Did you get any “side effects”; the most common are mouth sores and small rashes…

#220

I did get my blood test results and the ultrasound scans - there was a noticeable difference, but it might have been confounded a bit by the fact that I was going off birth control for the first time in like two decades in order to be in the study. They only had me wait a month without bc before enrolling, and my understanding is that it can actually take 3 months or more for certain measures to fully normalize post-hormonal bc, so I’m not really sure what to attribute the differences to. So the same problem with detailing side effects - I hadn’t had my period without bc, which for me really masks any cramps and other symptoms, in a million years, so I’d think I was getting some “side effect” and then realize it was probably PMS-related. Haha. Also I reallllllllly wanted to be in the experimental group vs control, so I think I probably overdramatized any tiny little thing I was feeling. I’m still waiting for my pills to arrive, but once I have them I’ll know for sure I’m taking rapa and can compare that to my experience during the trial.

2 Likes
#221

I monitor my women who are seeing me for prolongation of fertility with an Anti-Mullerian Hormone Level and track this. It is a reliable measure of how many potential eggs someone has, and is a fairly inexpensive test.

Here is Vera-Health.ai’s take on this:
Anti-Müllerian Hormone (AMH) is a key marker used to assess ovarian reserve, which is crucial for evaluating fertility potential in women. However, its interpretation can be complex and context-dependent.

  1. Ovarian Reserve and Fertility: AMH is widely recognized as a reliable indicator of ovarian reserve, reflecting the remaining quantity of non-growing follicles in the ovaries. It is considered more accurate than age alone for this purpose 3. However, its role as a standalone predictor of IVF success is limited, as women with low AMH levels can still achieve high pregnancy rates 2.
  2. Cancer Treatment: In oncology patients, AMH levels can be affected by cancer treatments, which may lead to gonadotoxicity. The interpretation of AMH in this context is complex and requires further research to understand the impact of specific treatments 17.
  3. Age and Menopause Prediction: AMH levels generally peak in the mid-twenties and decline with age. While promising for predicting the time to menopause, routine AMH testing for this purpose is not recommended due to limited data 38.
  4. Surgical Impact: Minimally invasive surgeries like ovarian cystectomy can affect AMH levels, but studies show no significant difference in ovarian reserve protection between robotic and laparoscopic methods 4.
  5. Assay Variability: Different immunoassays for measuring AMH can yield varying results, necessitating careful interpretation alongside clinical findings 6.
  6. PCOS and BMI: In patients with polycystic ovarian syndrome (PCOS), AMH levels are typically higher and can be inversely related to body mass index (BMI), affecting the interpretation of AMH in these patients 13.

In summary, while AMH is a valuable tool for assessing ovarian reserve, its interpretation should consider the individual’s clinical context, including age, treatment history, and specific health conditions. It is crucial to integrate AMH results with other clinical parameters for a comprehensive evaluation.

3 Likes
#222

Dear RapAdmin,

Could you please tell me what was the mouse dose of Pirfenidone in this study? I can not find it in this text,
I am planning to take Pirfenidone for ovarian rejuvenation effects.
Thank you

#223

.

hi @Marye_adams …i’m late to find your post, but hope not too late -

did you give up on IVF/ART?

are you located in the u.s.?

if you are in the u.s., i would say KEEP TRYING to get a clinic to help you -

they “don’t” (or shouldn’t, anyway!) get a right to decide if you try, or not…

…if in the u.s., or, willing to travel here,

…i did IVF at a clinic called “new hope fertility” in new york -

i also did something called “Ovarian PRP Rejuvenation,” there,

where they take some of your blood, spin it in a centrifuge and concentrate the good stuff, and inject it into your ovaries,

and it DID

(in my case, where i had “diminished ovarian reserve,”

with low Anti-Mullerian hormone [AMH], which ranged from like .79 down to a low of .39,

and egg count - was getting only 1 egg per retrieval)

improve my Anti-Mullerian Hormone, up to 1.10,

and at one point I got Four eggs (for me, a huge deal),

…3-4 months after the PRP -

if you do it, make sure you monitor until you see your egg count start to go up,

before doing any retrievals again, to see the benefit.

Good luck to you!

.

#224

.

@Sirt6 i know i’m late to find your post, but,

see my post above, about Ovarian PRP Rejuvenation…

good luck to your friend - she is still young and shouldn’t give up! :slight_smile:

.

#225

.

hi @djs498 i know i’m late to find your post, but please look at mine, above, about Ovarian PRP Rejuvenation -

and also …i know it’s uncertain, but, maybe you could try Rapa first, for maybe 6 months (but during this time, maybe try to Not get pregnant, by using condoms?),

and then, wait a month or so, and start monitoring,

as i think/hope the effect of Rapamycin might improve even after treatment is finished?

you are so young, i am very hopeful for you!

good luck to you!

.