Roles of autophagy in androgen‑induced benign prostatic hyperplasia in castrated rats
Gemini Pro Paper Analysis:
BPH Breakthrough: Rapamycin Reverses Prostate Enlargement by Reactivating Cellular “Clean-Up”
Context: Department of Urology, The First Affiliated Hospital of Xiamen University, China. Published in Experimental and Therapeutic Medicine (2018).
Impact Evaluation: The impact score of this journal is ~2.4 (Impact Factor), evaluated against a typical high-end range of 0–60+ for top general science, therefore this is a Low impact journal.
The Big Idea:
Benign Prostatic Hyperplasia (BPH) plagues aging men, often treated with slow-acting drugs like 5-alpha reductase inhibitors. This study identifies a rapid, potent alternative mechanism: mTOR inhibition. The researchers demonstrate that high testosterone levels drive prostate enlargement not just by fueling growth, but by shutting down autophagy—the cell’s internal recycling system. Without autophagy, prostate cells accumulate damage and refuse to die (apoptosis failure).
By administering Rapamycin (a well-known longevity drug and mTOR inhibitor) to rats with testosterone-induced BPH, the team successfully reactivated autophagy. This pharmacological switch dismantled the hyperplastic tissue, significantly reducing prostate weight and volume. The findings suggest that BPH is fundamentally a disease of stalled cellular turnover, and that unlocking the autophagy pathway could offer a faster, more direct treatment than current hormonal therapies.
Evaluation: This study was a short-term pathology assessment (28 days) and did not evaluate lifespan.
Reference Note: The user-provided reference Interventions Testing Program (ITP) applies to HET3 Genetically Heterogeneous Mice. As this study utilized Sprague Dawley Rats, a direct lifespan curve comparison is not applicable.
Mechanistic Deep Dive
The study delineates a clear signaling cascade for androgen-driven hyperplasia:
The Driver (Testosterone): Activates the PI3K/Akt/mTOR pathway.
The Blockade (mTOR): Hyperactive mTOR suppresses autophagy (evidenced by reduced LC3-II and Beclin-1) and inhibits apoptosis (increased Bcl-2, decreased Caspase-3).
The Result: Prostate epithelial cells proliferate unchecked and do not undergo programmed cell death, leading to hyperplasia.
The Intervention (Rapamycin):
mTOR Inhibition: Rapamycin effectively blocked the PI3K/Akt pathway.
Autophagy Restoration: Treatment significantly elevated LC3-II and Beclin-1 levels. Electron microscopy confirmed the presence of autophagolysosomes digesting cellular debris.
Biohacker Takeaway: This reinforces the “Hyperfunction Theory of Aging” in the prostate. The organ isn’t just “growing”; it is failing to turn over due to nutrient-sensing overactivation (mTOR).
Novelty
Direct Autophagy Link: While the link between androgens and mTOR is known, this paper explicitly connects autophagy suppression as a primary driver of BPH tissue accumulation, rather than just proliferation.
Comparative Inhibition: It contrasts Rapamycin (autophagy inducer) with 3-MA (autophagy inhibitor), providing a nuanced view of how different disruptions to cellular cleaning affect tissue mass.
Critical Limitations
Translational Gap: The study uses a castrated rat model supplemented with exogenous testosterone. This mimics “hormone replacement” dynamics rather than the natural, complex hormonal aging of a human male (where BPH often occurs despite falling testosterone levels, driven by DHT/Estrogen balance).
Dosing Regimen: The Rapamycin dose (1 mg/kg/day) is extremely high for a chronic longevity protocol (roughly equivalent to ~10mg/day human equivalent dose, HED). This is an acute therapeutic dose, not a “longevity” micro-dose.
Short Duration: 28 days is insufficient to observe potential side effects of such high-dose Rapamycin, such as glucose dysregulation or immunosuppression.
Conflicting 3-MA Data: The results for 3-MA (autophagy inhibitor) are messy. The paper claims 3-MA increased apoptosis and reduced hyperplasia compared to testosterone, which contradicts the hypothesis that autophagy protects cells. This suggests 3-MA might have caused tissue reduction via toxicity/necrosis rather than healthy regulation.
Claims & Verification
Hierarchy of Evidence Key:
Level A: Human Meta-analyses / Systematic Reviews
Level B: Human RCTs
Level C: Human Observational / Cohort Studies
Level D: Pre-clinical (Animal/In vitro)
Level E: Expert Opinion / Anecdote
Extracted Claims & Verification Status
Claim 1: Rapamycin reduces prostate hyperplasia and volume in BPH models.
Evidence Level:Level D (Pre-clinical)
Verification: Validated in multiple rodent models.
Translational Uncertainty:High. Human clinical trials for Rapamycin specifically for BPH are lacking. Most human data on mTOR inhibitors in prostate focuses on Prostate Cancer (CRPC), not BPH.
Claim 2: Androgens (Testosterone) inhibit autophagy in prostate tissue.
Evidence Level:Level D (Pre-clinical) / Conflicting Consensus
Verification: The relationship is complex. While this paper claims T inhibits autophagy, other research suggests androgen deprivation (5-ARI therapy) induces autophagy as a survival stress response.
We included 32 604 kidney transplants (5687 sirolimus-exposed). Overall, cancer incidence was suggestively lower during sirolimus use (hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.70–1.11). Prostate cancer incidence was higher during sirolimus use (HR = 1.86, 95% CI = 1.15–3.02). Incidence of other cancers was similar or lower with sirolimus use, with a 26% decrease overall (HR = 0.74, 95% CI = 0.57–0.96, excluding prostate cancer).
They find that for people who take Sirolimus after an organ transplant, all the cancer types that they looked at had hazard ratios less than 1. The sole exception was prostate cancer, with a hazard ratio of 1.7
I personally (not a doctor) am not concerned about the increased risk of prostate cancer seen in this study. Some key points:
The dosing used in organ transplant patients (as studies in most clinical studies) is much, much higher than what we dose. Most people using rapamycin for longevity are dosing once per week, at between 4mg and 8mg once per week. See the full range of dosing used here: What is the Rapamycin Dose / Dosage for Anti-Aging or Longevity?
The Dosing used in transplant patients is as follows:
Standard Regimen (The “2mg” & “5mg” Per Day Arms):
Loading Dose: 6 mg (for the 2mg group) or 15 mg (for the 5mg group).
Daily Maintenance Dose: Fixed daily doses of 2 mg/day or 5 mg/day.
Median Exposure: ~2–5 mg daily (chronic).
Max Dosing Tested: Up to 40 mg/day was allowed for loading in specific high-risk scenarios, though rarely sustained. The 5 mg/day maintenance arm was the “high dose” comparator in major Phase III trials. Max Dosing: Clinicians rarely exceed 5–10 mg/day for maintenance because side effects (mouth ulcers, hyperlipidemia) become intolerable, and TDM shows that higher doses don’t necessarily improve graft survival.
Part 5: The Strategic FAQ
1. The “Detection Bias” vs. “Biological Aggression” Probe
Q: “You attribute the 70–86% spike in prostate cancer diagnoses to ‘detection bias,’ but did you stratify by Gleason score to see if Sirolimus users actually had more aggressive high-grade tumors?”
A: The study noted that the excess cases were mostly localized/low-grade. If Sirolimus promoted aggression, we would expect a shift toward advanced/metastatic stages, which was not observed.
2. The PSA Confounder
Q: “Since Sirolimus can reduce vascular inflammation, could it artificially lower PSA thresholds in healthy tissue, making any slight PSA bump from a tumor more statistically conspicuous to a urologist?”
A: This is plausible. If Sirolimus changes the baseline “noise” of PSA readings, the signal-to-noise ratio for tumor detection might change, leading to more biopsies.
3. The Missing Skin Cancer Data
Q: “You excluded non-melanoma skin cancer (NMSC) due to registry limitations, but isn’t NMSC the primarycancer type Sirolimus is proven to prevent? Doesn’t this exclusion massively under-represent the drug’s total anti-cancer benefit?”
A: Yes. RCTs confirm Sirolimus dramatically reduces NMSC. By excluding it, this study underestimates the total “Net Cancer Benefit” of the drug.
4. The “Healthy User” Bias
Q: “Were Sirolimus patients screened more frequently for cancer simply because they were on a ‘newer/second-line’ drug, triggering a surveillance bias?”
A: Likely. Patients switched to Sirolimus often have complications with other drugs, leading to closer medical scrutiny (and thus more cancer diagnoses).
5. Immunosuppression vs. Immuno-rejuvenation
Q: “At these transplant doses, the drug is immunosuppressive. Do you believe the cancer reduction is due to directtumor inhibition, or simply ‘less carcinogenesis’ compared to the highly carcinogenic Calcineurin Inhibitors (CNIs) they replaced?”
A: The study compared Sirolimus against other immunosuppressants. It is likely a mix of both: Sirolimus has intrinsic anti-tumor properties and lacks the direct carcinogenic DNA damage mechanisms of some CNIs.
6. Prostate Mechanism Speculation
Q: “Is it possible that mTOR inhibition in the prostate leads to a compensatory upregulation of Androgen Receptor (AR) signaling, driving tumor visibility?”
A: Cross-talk between mTOR and AR is documented. Inhibiting mTOR can sometimes lead to feedback activation of upstream or parallel growth pathways (like AR or MAPK), potentially fueling specific tumor subtypes.
7. The Washout Period
Q: “Given the 62-hour half-life, your daily dosing schedule ensures permanent mTOR occupancy. Would you expect the same prostate risk in a weekly dosing protocol that allows for immune recovery?”
A: Unknown. The continuous suppression of immune surveillance in the prostate might be the culprit. Pulsed dosing might avoid this, but no human data exists to confirm.
8. Generalizability
Q: “These patients are immunosuppressed and have high comorbidity burdens. Can we genuinely extrapolate anyof this cancer risk data to a healthy, immune-competent biohacker?”
A:[Confidence: Low]. Transplant biology is distinct. However, the directionality of the signal (Lung/Kidney protection vs. Prostate risk) is a strong mechanistic clue that should not be ignored.
Sirolimus Paradox—Longevity Drug Linked to Lower General Cancer Risk but Spikes Prostate Diagnoses in Transplant Patients
Institution: National Cancer Institute (NCI) & Scientific Registry of Transplant Recipients (SRTR), USA **Journal:**American Journal of Transplantation Impact Evaluation: The impact score of this journal is an Impact Factor of ~8.9 and a CiteScore of ~13.1, therefore this is a High impact journal.
In a massive retrospective analysis of 32,604 US kidney transplant recipients, researchers have uncovered a striking paradox regarding Sirolimus (rapamycin), the gold-standard drug in longevity biohacking. While the drug is famed for its ability to inhibit mTOR—a pathway often hyperactivated in tumors—this study reveals a complex reality in humans.
Recipients treated with Sirolimus showed a suggestive reduction in overall cancer incidence (excluding non-melanoma skin cancer) and a statistically significant 26% reduction in non-prostate cancers compared to those on other immunosuppressants. This supports the “rapamycin as anti-cancer” hypothesis for lung, kidney, and breast tissues.
However, the data delivered a sharp warning: Sirolimus exposure was associated with a 70–86% increase in diagnosed prostate cancer. The authors argue this may not be a true increase in tumorigenesis, but rather a “detection bias” caused by Sirolimus interacting with prostate-specific antigen (PSA) screening or indolent tumor biology. For the longevity community, this underscores that systemic mTOR inhibition is not a universal shield and may have tissue-specific effects that complicate clinical translation.
Mechanistic Deep Dive
mTOR Inhibition & Tumor Suppression: The study grounds its findings in the inhibition of the PI3K/Akt/mTOR pathway, which controls cellular growth and proliferation. Hyperactivation of this pathway is a hallmark of malignancy. Sirolimus blocks mTOR kinase binding, theoretically hindering tumor growth. The observed reduction in kidney, lung, and breast cancers aligns with phase 1 trials where mTOR inhibitors showed partial responses in these tissue types.
The Prostate Anomaly (Detection vs. Biology): The specific mechanism for increased prostate cancer diagnoses is unknown and unexpected. The authors propose a Screening Effect/Detection Bias:
Most excess cases were localized (early stage), not advanced.
Localized prostate cancer is driven by PSA screening. If Sirolimus alters PSA levels (even indirectly via inflammatory modulation) or affects the presentation of indolent tumors, it could lead to higher biopsy and detection rates without increasing actual tumorigenesis.
Critical Limitations
Observational Confounding: As an observational study, it cannot prove causation. There is a high risk of Indication Bias: Clinicians may have preferentially prescribed Sirolimus to patients they already suspected were at high cancer risk (due to its known anti-cancer reputation), which would theoretically mask the drug’s protective benefit.
No Dose/Level Data: The study relied on pharmacy “fills” and did not have data on blood concentrations, dosage intensity, or biological availability. This is a critical gap for biohackers attempting to extrapolate to low-dose or pulsed protocols.
Detection Bias (Prostate): The prostate finding is highly susceptible to screening bias. The study lacks data on PSA screening frequency; if Sirolimus patients were screened more often, the “risk” is artificial.
Missing Lifestyle Data: The registry lacks granular data on smoking, obesity, and family history—major confounders for cancer risk.
Skin Cancer Exclusion: Non-melanoma skin cancers (squamous/basal cell) were excluded because registries don’t track them. This excludes a major category where Sirolimus is known to be highly effective.
I have been on rap for a year and a half. I was doing 6mg weekly but have switched to 5mg with 12oz GFJ every 15 days about 6 months ago. It has not help me and my peeing issue is slowly getting worse. I don’t like the effects of the common drugs you can take because if i didn’t have bad luck i wouldn’t have any at all… (possible permanent side effects even if you stop) so I’m not taking any of them. I’m going to be talking to my urologist about doing a PAE procedure. A relatively new procedure that has preservation of sexual function. (The PAE procedure has a much lower risk of urinary incontinence and sexual side effects (retrograde ejaculation or erectile dysfunction), when compared with more invasive surgical procedures). From the Michigan institute of urology: Very low complication rate and no reports of erectile dysfunction or urinary leakage after PAE. They have done like 1500 procedures. (other sites say the same thing). There is one interventional radiologist Dr. at my Hosp that does them. In the meantime I have recently (about a month ago or so) started using graminex flower pollen extract, stinging nettle/saw palmetto capsule, pumpkin seed oil, and beta sitosterol. I have noticed an improved flow and I used to get up 5 times a night to pee but now down to 2 or 3. Hoping it gets better as it’s only been about a month on them.
I want to say I’ve experienced this benefit. It’s hard to say but I noticed taking a break from rapamycin then reintroducing it I had reduced nighttime urination, but I also drastically reduced coffee intake at the same time.
While it is odd that prostate cancer increased among transplant patients on sirolimus, it wouldn’t surprise me that cancers in general increased because of the immunosuppression effects of daily dosing.
(possible permanent side effects even if you stop) so I’m not taking any of them. I’m going to be talking to my urologist about doing a PAE procedure. A relatively new procedure that has preservation of sexual function. (The PAE procedure has a much lower risk of urinary incontinence and sexual side effects (retrograde ejaculation or erectile dysfunction), when compared with more invasive surgical procedures). From the Michigan institute of urology: Very low complication rate and no reports of erectile dysfunction or urinary leakage after PAE. They have done like 1500 procedures. (other sites say the same thing). There is one interventional radiologist Dr. at my Hosp that does them. In the meantime I have recently (about a month ago or so) started using graminex flower pollen extract, stinging nettle/saw palmetto capsule, pumpkin seed oil, and beta sitosterol. I have noticed an improved flow and I used to get up 5 times a night to pee but now down to 2 or 3. Hoping it gets better as it’s only been about a month on them.