Study library

Abusidu M, et al. · Frontiers in Nutrition · 2026

In a mouse model, polysaccharides alleviated cisplatin-induced intestinal damage, improving the intestinal barrier and microbiota composition.

American Diabetes Association · Diabetes Care · 2026

Annually updated clinical guidelines emphasizing the importance of repeated measurements and clinical context when interpreting metabolic results.

Zhou Z, Wei X, Zhang X, Ainsworth BE, Lü J, Liu Y · Journal of Sport and Health Science · 2026

A network meta-analysis of 74 studies (5,331 participants) compared different exercise forms for their effect on bone mineral density in postmenopausal women. Combining multidirectional exercise with resistance training proved most effective for the lumbar spine, femoral neck, Ward's triangle, and whole skeleton, and interventions lasting 52 weeks or longer produced more consistent effects than shorter programs.

Lu X, et al. · Nature Aging · 2026

A paper identifying Bifidobacterium pseudocatenulatum and its metabolite 5-AVAB as factors linked to milder age-related inflammation (inflammaging) and improved cognitive and motor function in aging mice; it also describes the MicroAge microbiome-based biological age clock. Data come mainly from mouse models — direct human interventional trials have not yet been conducted.

Zhao J, Hu M, Li S, et al. · Nature Communications · 2026

A study on two NHANES cohorts (over 5,900 people total) building a machine-learning model that predicts chronological age from 64 genera of oral bacteria; the difference between predicted and actual age (the OMAA Score) was linked to mortality risk, frailty, and impaired kidney function.

Zhao J, Hu M, Li S, et al. · Nature Communications · 2026

The paper introducing the OMAA Score — based on two NHANES cohorts (n = 4,675) and an independent validation cohort (n ≈ 1,293), a model was built predicting age from 64 oral bacterial genera; the OMAA Score independently predicted overall mortality (HR = 1.05) and frailty (OR = 1.05), and improved prediction of cancer and heart attack risk.

Karaca B, et al. · Food Science & Nutrition · 2025

The extract showed activity against MRSA, limiting biofilm formation and bacterial quorum-sensing signaling. An in vitro study on bacterial cultures.

Erbiai E.H., et al. · International Journal of Molecular Sciences · 2025

Analysis of fruiting bodies showed a high content of phenolic compounds and a broad spectrum of antimicrobial activity.

Saldanha A, et al. · Separations · 2025

A comparative analysis of nutritional composition and phenolic profile, confirming the species' rich phenolic profile described in earlier work.

Aditya, Neeraj, Bhatia JN, Yadav AN · Heliyon · 2025

A review gathering available in vitro and animal studies — confirms the presence of antioxidant beta-glucans and phenols, with no clinical studies in humans.

Świderski G, Kalinowska M, Zapora E, et al. · International Journal of Molecular Sciences · 2025

An analysis of 30 European samples of Phellinus fungi showed in vitro antimicrobial and antioxidant activity.

George A, Jose R, Valsan C, et al. · Medical Mycology Case Reports · 2025

A case report of invasive fungal sinusitis caused by S. radiatum, confirmed by sequencing.

Muir CA, Zhang T, Jayadev V, Conway AJ, Handelsman DJ. · Clinical Endocrinology · 2025

A meta-analysis of 41 studies and 1,673 patients with hypogonadotropic hypogonadism treated with gonadotropins: after a median of 18 months, mean sperm concentration was 11.6 million/mL, and combining hCG with FSH significantly improved sperm count relative to hCG alone, with no significant difference in the effect on testosterone or testicular volume between groups.

Liu J i wsp. · Blood Advances · 2025

A systematic review of drug-induced erythrocytosis, including from testosterone, analyzing the quality of evidence behind the adopted intervention thresholds (including 50% and 54% hematocrit) and the effectiveness of available management approaches — the authors note the limited number of studies directly testing these thresholds in TRT patients and emphasize that current recommendations rely heavily on extrapolation from other causes of erythrocytosis.

Khashaba S, Khashaba S, Krishan A, Bruce A, Almaghlouth A, Huang J, Mima M, Niederberger C · Asian Journal of Urology · 2025

The most current meta-analysis (10 RCTs) on fertility: pregnancy rate was 10.4% on clomiphene versus 7.1% on placebo, odds ratio 1.30 (95% CI 0.27-6.17), p=0.74 — not statistically significant. The most reliable, current word on clomiphene's real effect on fertility outcomes.

Milanović Ž, et al. · Chemico-Biological Interactions · 2025

A paper analyzing the chemical mechanisms by which urolithin D neutralizes free radicals and repairs oxidative DNA damage — a theoretical and in vitro analysis, without data from living organisms.

Xu T, Niu Y, Deng C, Cheung Y, Li Y, Hu Z, Sun S, Chen Y, He F, Yang G, Chen F, Duan C, Huang Y, Deng X · iMetaOmics · 2025

The publication introducing the MicroAge model — a machine-learning model trained on 4,532 saliva samples from six continents that predicts biological age from the oral microbiome; performance (R² ≈ 0.80 in the healthy population) dropped to R² ≈ 0.16 in populations with disease.

Li TY, Gao AW, Yang R, et al. · Nature Cell Biology · 2025

A study in C. elegans describing the LySR mechanism — mild weakening of a component of the lysosomal proton pump extended lifespan by about 60% through activation of a transcriptional program strengthening lysosomal function and clearance of protein aggregates in models of neurodegenerative disease.

Kivimäki M, Frank P, Pentti J, et al. · The Lancet Digital Health · 2025

Independent validation of the organ-clock concept in the UK Whitehall II cohort with 20 years of follow-up, confirming the link between accelerated aging of individual organs and elevated risk of organ-specific diseases.

Mavrommatis C, Belsky DW, Ying K, Moqri M, Campbell A, Richmond A, Gladyshev VN, Chandra T, McCartney DL, Marioni RE. · Nature Communications · 2025

A large, independent comparison of 14 popular epigenetic clocks in a sample of 18,859 people as predictors of 174 diseases and all-cause mortality over 10 years of follow-up; second- and third-generation clocks consistently outperformed first-generation clocks.

Ontawong A, Pengnet S, Thim-Uam A, et al. · Scientific Reports · 2024

An 8-week RCT: a fermented C. militaris beverage (2.85 mg cordycepin) increased NK cell activity and lowered pro-inflammatory markers (IL-1β, IL-6) in healthy adults.

Hao Y, Song W, Qu L · Food Science & Nutrition · 2024

A 4-week RCT on a multi-ingredient formula (Poria, Chinese hawthorn, GABA) showed improved sleep time, PSQI score, and skin hydration parameters — the effect cannot be attributed to Poria alone due to the preparation's complex composition.

Gitsomboon S, Ratanapornsompong G, Ongphiphadhanakul B, et al. · BMC Nutrition · 2024

A 12-week double-blind RCT in overweight people with prediabetes showed a small but statistically significant improvement in HbA1c and reduction in waist circumference after daily consumption of a Tremella beverage compared with placebo.

Rijia A., et al. · Pharmaceuticals (Basel) · 2024

Analysis of wild fruiting bodies showed a rich phytochemical composition, significant antioxidant activity, and antimicrobial action of the extract.

Bond P et al. · Endocrine Connections · 2024

A review critically examining the evidence behind testosterone-induced erythrocytosis and the rationale for phlebotomy as a standard intervention — the authors note that despite a real clotting risk tied to elevated hematocrit, evidence for the effectiveness and safety of routine blood removal is limited, and repeated phlebotomy can paradoxically worsen risk through tissue hypoxia and iron deficiency.

Loeb C, Miller JA, Schneider D et al. · International Journal of Impotence Research · 2024

A single-center survey of 140 men on TRT: 62.7% satisfied with their current treatment regimen, with significantly higher satisfaction among users of auto-injectors (91.7%) and subcutaneous implants (90.0%) than classic intramuscular injections (67.5%) — showing that even within injectable forms, the specific application method matters for perceived comfort.

Zitzmann M, Cremers JF, Krallmann C, Soave A, Kliesch S · Andrology · 2024

A nine-year real-world registry followed 650 patients across 4,362 treatment-years, all treated with intramuscular testosterone undecanoate 1000mg (the Nebido dose). Testosterone rose from 6.6±2.4 to 19.3±2.9 nmol/L (p<0.001). Hematocrit increases above 50% and PSA increases occurred at low but nonzero rates across the cohort over long-term follow-up.

Yang H, Wu B, Yang Q, Tan T, Shang D, Chen J, Cao C, Xu C · Journal of Natural Medicines · 2024

An in vitro and animal-model study showing that urolithin C inhibits proliferation and migration of colorectal cancer cells and arrests the cell cycle by blocking the AKT/mTOR pathway.

DeClercq V, Wright RJ, Nearing JT, Langille MGI · Scientific Reports · 2024

A cross-sectional study of 1,357 Canadian adults showing a link between oral microbiota diversity and composition (from saliva samples) and both chronological age and frailty index.

Wang H, Chen Y, Feng L, Lu S, Zhu J, Zhao J, Zhang H, Chen W, Lu W · Gut Microbes · 2024

A separate but conceptually related model (gAge) based on the gut microbiome, showing that a similar approach to 'microbiome clocks' recurs across different bacterial ecosystems in the body and correlates with health status and frailty risk.

Chen S.N., Nan F.H., Liu M.W., Yang M.F., Chang Y.C., Chen S. · Foods · 2023

An 84-day, double-blind RCT in healthy adults showed that beta-glucan from reishi increased T-cell counts, improved the CD4/CD8 ratio, raised NK-cell activity and IgA levels compared with placebo.

Ma KL, Kei N, Yang F, Lauw S, Chan PL, Chen L, Cheung PCK · Foods · 2023

An in vitro study using human fecal microbiota showed that Fu Ling polysaccharide increased acetic acid production and favored the growth of bacteria with anti-inflammatory activity — this is not an interventional study in living humans.

Kobayashi Y, et al. · DNA Research · 2023

Genome sequencing revealed features intermediate between mycorrhizal and saprotrophic fungi — a genomic study, not directly concerning health effects.

Wongkhieo S, et al. · Scientific Reports · 2023

A mycelial extract contained detectable lovastatin and inhibited HMG-CoA reductase activity in an in vitro liver spheroid model.

Tang SJ, Shao CX, Yang Y, Ren R, Jin L, Hu D, Wu SL, Lei P, He YL, Xu J · Journal of Ethnopharmacology · 2023

A peptide extract from the mycelium strongly inhibited HeLa cell proliferation in vitro and in a mouse xenograft model, inducing apoptosis.

Chaharmiri-Dokhaharani S, Ghobad-Nejhad M, Moghimi H, Norouzi H, Moghaddam M · Journal of Medicinal Plants and By-products · 2023

The only species-specific study found: chromatographic-spectrometric analysis identified phenolic compounds, with basic in vitro antibacterial tests.

Lincoff AM, Bhasin S, Flevaris P, et al. · New England Journal of Medicine · 2023

A large randomized trial (n>5000) assessing the cardiovascular safety of TRT in men with hypogonadism and risk factors — found no increased risk of major cardiovascular events.

Lincoff AM, Bhasin S, Flevaris P i wsp. (TRAVERSE Study Investigators) · New England Journal of Medicine · 2023

A randomized non-inferiority trial in over 5,200 men with hypogonadism and cardiovascular risk — TRT did not increase the risk of major cardiovascular events relative to placebo.

Agrawal P, Singh SM, Kohn T · European Urology Focus · 2023

A practical guide to assessing and monitoring hematocrit before and during testosterone therapy, with decision thresholds for dose reduction or discontinuation.

Lincoff AM et al. · New England Journal of Medicine · 2023

The large randomized TRAVERSE trial assessing the cardiovascular safety of TRT in men with hypogonadism and existing or elevated cardiovascular risk — testosterone proved non-inferior to placebo for major cardiovascular events (MACE), while the treated group showed more frequent pulmonary embolism, atrial fibrillation, and acute kidney injury.

Agrawal P, Singh SM, Kohn T · European Urology Focus · 2023

A practical guide covering the frequency of hematocrit checks during testosterone therapy and the decision thresholds for dose reduction, changing delivery form, or temporarily stopping treatment.

Lincoff AM, Bhasin S, Flevaris P et al. (TRAVERSE trial) · New England Journal of Medicine · 2023

A large randomized trial involving more than 5,200 men with hypogonadism and existing or high cardiovascular risk. Despite a slight HDL drop in the testosterone group, the rate of major cardiovascular events after an average of 22 months of follow-up didn't differ significantly from placebo — key context for interpreting TRT-related lipid changes.

Lincoff AM, Bhasin S, Flevaris P et al. (TRAVERSE Study Investigators) · New England Journal of Medicine · 2023

A large, placebo-controlled randomized trial (over 5,200 men, 45–80 years, with hypogonadism and existing or elevated cardiovascular risk), commissioned by the FDA specifically to settle the question of TRT's cardiovascular safety. Testosterone was non-inferior to placebo for major cardiovascular events (MACE: 7.0% vs. 7.3%), while showing higher rates of atrial fibrillation (3.5% vs. 2.4%), pulmonary embolism (0.9% vs. 0.5%), and acute kidney injury (2.3% vs. 1.5%) in the treated group.

Graziani A, Grande G, Ferlin A · Frontiers in Reproductive Health · 2023

A literature review on the complex, bidirectional relationship between OSA, hypogonadism, and TRT. The authors note that the evidence behind treating OSA as a TRT contraindication is qualitatively limited, and that short-term, high-dose testosterone therapy appears to worsen OSA more than chronic use of lower doses.

Adam JA, Pastuszak AW, Christensen MB, Spencer R, Sandberg A, Hotaling JM, Lipshultz LI · International Journal of Impotence Research · 2023

A review of 48 articles, including 29 studies covering 7,978 patients treated with testosterone undecanoate, identified a combined 88 POME or post-injection cough episodes across 8 of those studies. One postmarketing review recorded 223 cases out of 3,107,652 injections given. Almost all cases resolved spontaneously within 60 minutes without intervention — conclusion: POME is rare but real.

Tan JX, Finkel T · EMBO Reports · 2023

A review of the evidence for the role of lysosomal dysfunction in cellular aging and senescence, describing the accumulation of unprocessed metabolites and the decline in lysosomal digestive capacity with age.

Picca A, Faitg J, Auwerx J, et al. · Nature Metabolism · 2023

A comprehensive review of mitophagy mechanisms and their significance for health, aging, and age-related diseases, summarizing the current state of basic-science knowledge and clinical implications of impaired mitophagy.

Oh HSH, Rutledge J, Nachun D, et al. · Nature · 2023

A landmark study building 11 organ-aging clocks from plasma proteomics in more than 5,600 people across 5 cohorts; showed that accelerated aging of a specific organ increases the risk of diseases affecting that organ and overall mortality.

Oh HSH, Rutledge J, Nachun D, et al. · Nature · 2023

The study introducing 11 organ-aging clocks based on plasma proteomics as a separate, younger family of biological age clocks that complements epigenetic clocks.

Akhgarjand C, et al. · Phytotherapy Research · 2022

A meta-analysis of more than a dozen RCTs confirming a significant reduction in anxiety symptoms and cortisol levels compared with placebo.

Hu Q, Xie B · Acta Biochimica Polonica · 2022

A randomized trial in 141 patients with advanced laryngeal/pharyngeal cancer showed that maitake D-fraction given during chemoradiotherapy eased the severity of treatment side effects and improved quality of life.

Ku YH, Kang JH, Lee H · Medicine (Baltimore) · 2022

A randomized, double-blind trial with 98 participants showed a significant increase in NK cell activity after 8 weeks of supplementation with 1000 mg of extract daily versus placebo (p = 0.008).

Ku YH, Kang JH · Medicine (Baltimore) · 2022

A pilot trial (n = 30) observed a trend toward improved NK cell activity versus placebo at a dose of 1000 mg/day after 8 weeks.

Yen Y.-T. et al. · Frontiers in Pharmacology · 2022

A multicenter RCT (80 people) in adults with elevated GGT — 300 mg/day of extract for 12 weeks significantly lowered AST, ALT, and triglycerides versus placebo.

Bożek J, et al. · International Journal of Molecular Sciences · 2022

The extract dose-dependently limited melanoma cell proliferation and viability in vitro, with relatively low cytotoxicity toward normal fibroblasts.

Liao C, et al. · Molecules · 2022

The isolated polysaccharide showed strong antioxidant activity in chemical tests and protected human HepG2 liver cells from oxidative stress in vitro.

Kała K, et al. · Molecules · 2022

Analysis of the fruiting bodies found tryptophan, ergothioneine, lovastatin, and beta-glucans with potential antioxidant activity.

Zhou J, Gong J, Chai Y, Li D, Zhou C, Sun C, Regenstein JM · Glycoconjugate Journal · 2022

Isolated polysaccharide fractions showed the ability to disrupt the cell cycle and induce apoptosis in the HeLa cell line in in vitro tests.

Muñoz-Castiblanco T, et al. · International Journal of Molecular Sciences · 2022

The polysaccharide fraction showed high antioxidant activity and reduced the viability of osteosarcoma cells in vitro.

Kim M, et al. · Frontiers in Aging Neuroscience · 2022

A safety study showing good tolerance of doses up to 500 mg/day over 12 weeks in healthy adults.

Ory J et al. · Journal of Urology · 2022

An analysis of a large, multicenter database of TRT patients comparing the risk of major cardiovascular events and venous thromboembolism between men who developed secondary polycythemia (hematocrit ≥52%) and those with normal hematocrit — risk was higher in the polycythemia group during the first year of therapy.

Hudson J, Cruickshank M, Quinton R et al. · The Lancet Healthy Longevity · 2022

An individual patient data meta-analysis of more than 3,000 participants from randomized trials, showing a moderate drop in total cholesterol, HDL, and triglycerides in testosterone-treated groups, without demonstrating increased cardiovascular event risk in short- and medium-term follow-up.

Choi EJ, Xu P, Barham D, El-Khatib FM, Yafi FA, Kavoussi PK · The Journal of Urology · 2022

A retrospective comparison of 234 hypogonadal men treated with intramuscular cypionate or subcutaneous testosterone enanthate. The subcutaneous-injection group had a lower rise in estradiol and hematocrit — a difference attributed to route of administration and the peak-trough profile rather than the ester molecule itself, since the comparison varied both the ester and the route simultaneously.

Choi EJ, Xu P, Barham D, El-Khatib FM, Yafi FA, Kavoussi PK · The Journal of Urology · 2022

234 hypogonadal men, IM cypionate 100mg/week vs. SC enanthate 100mg/week, 12 weeks. Trough T rose from 313.6 to 536.4 ng/dL (IM cypionate) and 246.6 to 552.8 ng/dL (SC enanthate), both p<0.001, no significant difference between modalities (p=0.057). SC route was associated with lower estradiol and hematocrit (both p<0.001); neither modality significantly raised PSA. Important caveat: the comparison changed both ester and route of administration simultaneously.

Locquet M, Sanchez-Rodriguez D, Bruyère O, Geerinck A, Lengelé L, Reginster JY. · The Journal of Nutrition, Health & Aging · 2022

A post-hoc analysis of a Belgian prospective cohort (n=534) followed for 5 years, showing that a 1 standard deviation increase in intrinsic capacity was linked to roughly a 49% lower mortality risk, with the locomotion and psychological well-being domains independently associated with lower mortality.

Mijakovac A, Frkatović A, Hanić M, et al. · Frontiers in Cell and Developmental Biology · 2022

An analysis estimating the average heritability of the glycan clock at about 39%, suggesting a substantial role for environmental factors in shaping the result.

Mah J, Pitre T. · BMC Complementary Medicine and Therapies · 2021

A review pointing to improvements in subjective sleep parameters (time to fall asleep, quality) with magnesium supplementation, with a limited number of large RCTs.

Spim SRV, Pistila AMH, Pickler TB, Silva MT, Grotto D · International Journal of Medicinal Mushrooms · 2021

A randomized, double-blind trial in 68 people with borderline elevated cholesterol showed that shiitake bars used for 66 days lowered triglycerides and improved oxidative stress markers versus placebo.

Yang M, Zhang Z, He Y, Li C, Wang J, Ma X · Food Science and Human Wellness · 2021

A laboratory study on an isolated, purified fraction of Tremella polysaccharide showed stronger moisture-loss-limiting properties than glycerin — concerning the isolated compound tested on a skin model, not a finished supplement.

Jia W, Luo S, Lai G, Li S, Huo S, Li M, Zeng X · BMC Complementary Medicine and Therapies · 2021

An in vitro study on human cell lines showed that a homogeneous Polyporus polysaccharide reprogrammed macrophages toward an M1 phenotype, inhibiting the proliferation and migration of bladder cancer cells.

Kuo PC, et al. · Bioorganic Chemistry · 2021

34 lanostane triterpenes were isolated, and their anti-inflammatory activity assessed in a human neutrophil model — a purely laboratory study.

İrez E.İ., Hacıoğlu Doğru N., Demir N. · Biologica Nyssana · 2021

Extracts showed higher antioxidant activity than the standard BHT along with significant antimicrobial and antibiofilm activity.

Lin H, et al. · Antioxidants (Basel) · 2021

Polysaccharides inhibited the formation of advanced glycation end products in an albumin glycation model and protected cells from damage induced by methylglyoxal.

Govindan S, Jayabal A, Shanmugam J, Ramani P · Food Science and Human Wellness · 2021

In a rat model, the HUP polysaccharide reduced oxidative stress and alcohol-induced liver damage.

Pawlik A, Ciołek B, Sulej J, et al. · Biomolecules · 2021

An experimental paper on the regulation of laccase gene expression under the influence of metal ions and temperature — a purely biotechnological study.

Yoshino M, et al. · Science · 2021

A randomized trial (n=25) in women with prediabetes showing improved muscle insulin sensitivity after 10 weeks of supplementation — no significant effect on body weight or other markers.

Salminen S, Collado MC, Endo A, et al. · Nature Reviews Gastroenterology & Hepatology · 2021

The official ISAPP consensus statement formally defining the term 'postbiotic' and organizing terminology in this area.

Shah R, Patil V, Sarathi V, et al. · Pituitary · 2021

hCG therapy (up to 2000 IU 3x/week or 5000 IU 2x/week) combined with hMG, titrated to testosterone ≥3.5 ng/mL, achieved spermatogenesis in 70% of patients, but those with prior exposure to testosterone alone reached significantly lower peak sperm counts (median 0.05 vs 9 million/mL; p=0.004) than gonadotropin-treatment-naive patients.

Fiesel FC, et al. · Autophagy · 2021

Development of a sensitive ELISA assay detecting phospho-ubiquitin (p-S65-Ub) — a marker of PINK1/Parkin pathway activity — in human cells, brain tissue, and blood plasma, able to distinguish PINK1 mutation carriers from healthy individuals; an early-stage research tool, not a standard clinical test.

Greto VL, Cvetko A, Štambuk T, et al. · International Journal of Obesity · 2021

An intervention study (low-calorie diet and bariatric surgery) showing that substantial weight loss is linked to a reduction in the calculated glycan age over a year-long follow-up.

Covarrubias AJ, Perrone R, Grozio A, Imai SI. · Nature Reviews Molecular Cell Biology · 2021

A comprehensive review systematizing knowledge of NAD+ metabolism, including the salvage pathway, the roles of NAMPT and CD38, and links between declining NAD+ and age-related disease.

Bian C, Wang Z, Shi J · Molecules · 2020

Optimized extraction of the polysaccharides prolonged blood clotting time along both the intrinsic and extrinsic pathways.

Huang Y, et al. · Food Research International · 2020

A new triterpene, Resinacein S, reduced lipid droplet size and enhanced thermogenesis markers in adipocyte cultures.

Yang K, et al. · ACS Omega · 2020

The phenolic fraction inhibited alpha-glucosidase activity and improved glucose uptake by insulin-resistant liver cells in vitro.

Harada E, Morizono T, Kanno T, Saito M, Kawagishi H · International Journal of Medicinal Mushrooms · 2020

In mouse models of obesity and diabetes, the extract lowered blood glucose and triglycerides. In a very small clinical pilot (10 people, 4 weeks), a significant drop in triglycerides was recorded.

Lowe DA, et al. · JAMA Internal Medicine · 2020

An RCT comparing time-restricted eating (16:8) to three standard meals a day — similar weight loss in both groups after 12 weeks.

Frederiksen H i wsp. · Journal of Clinical Endocrinology & Metabolism · 2020

A large reference study establishing estrogen concentration ranges by LC-MS/MS across age and sex. In men aged 30–60, estradiol fell in a range of roughly 50–150 pmol/L (~14–41 pg/mL) and remained stable with age, unlike testosterone's clear age-related decline.

Pastuszak AW, Hu Y, Freid JD · Sexual Medicine · 2020

A postmarketing analysis explaining the rationale for the mandatory REMS program on the US product, introduced because of the POME and anaphylaxis risk. Over the March 2014–June 2018 surveillance period (4.3 years): 90,092 doses distributed, 633 safety reports reviewed, 28 confirmed POME cases — a yearly reporting rate under 0.1% per injection. 13 of 17 detailed cases resolved within 30 minutes or less, and over 60% needed no medical intervention. One death was reported 18 months after a POME event but judged unrelated on review; in 3 of 4 cases requiring emergency-room-level care, injection technique or dosing errors were implicated.

Choi FD, et al. · Journal of Drugs in Dermatology · 2019

A review of 11 studies suggesting improved skin elasticity and hydration, with the caveat of inconsistent methodology and partial manufacturer funding.

García-Coronado JM, et al. · International Orthopaedics · 2019

A meta-analysis pointing to a moderate improvement in joint pain symptoms in osteoarthritis after collagen supplementation.

Guo Z, Zang Y, Zhang L · Progress in Molecular Biology and Translational Science · 2019

A systematic review of more than 11,700 Chinese clinical cases suggested the efficacy of PPS in treating hepatitis B, mainly in combination with a vaccine or antiviral drugs.

Zhang M, Xie Y, Su X, Liu K, Zhang Y, Pang W, Wang J · Frontiers in Immunology · 2019

A cell study showed that a polyphenol-rich extract inhibited secretion of NO, TNF-α, IL-6, and MCP-1 by blocking the ERK, p38 MAPK, and STAT3 pathways.

Su X, Liu K, Xie Y, Zhang M, Wang Y, Zhao M, Guo Y, Zhang Y, Wang J · Life Sciences · 2019

In mice, supplementation with the extract inhibited inflammation and lung swelling induced by bleomycin, given for 3 weeks before the injury was induced.

Zhang Y, Jiang Y, Zhang M, Zhang L · Progress in Molecular Biology and Translational Science · 2019

A review chapter summarizing the anticancer, antioxidant and immunomodulatory action of GSP as an adjunctive therapy.

de Cabo R, Mattson MP. · New England Journal of Medicine · 2019

A review of the metabolic mechanisms of intermittent fasting — strong preclinical data, moderate and still developing clinical data in humans.

Fogacci F, et al. · Nutrients · 2019

A review pointing to a modest, inconsistent improvement in vascular endothelial function with resveratrol supplementation.

Arnett DK, Blumenthal RS, Albert MA, et al. · Journal of the American College of Cardiology · 2019

Clinical guidelines summarizing the evidence for LDL's causal role in the development of atherosclerotic cardiovascular disease and the principles of primary prevention.

Camaschella C · Blood · 2019

A review of the diagnosis and treatment of iron deficiency, including the role and limitations of ferritin as a marker of iron stores in the context of coexisting inflammation.

Duru KC, Kovaleva EG, Danilova IG, van der Bijl P · Chemico-Biological Interactions · 2019

A review of laboratory and animal studies on the pharmacological properties of Inonotus obliquus, including its exceptionally high antioxidant activity.

Ramachandran S, Hackett GI, Strange RC · Sexual Medicine Reviews · 2019

A review discussing how age and type 2 diabetes modify the relationship between SHBG and testosterone, and what prognostic significance SHBG level itself has independent of the total testosterone result.

Russell N, Grossmann M · European Journal of Endocrinology · 2019

A review of evidence that some effects traditionally attributed to testosterone in men actually depend on its aromatization to estradiol, and that estrogen circulates in men at genuinely physiological, not trace, concentrations.

Cignarelli A et al. · Frontiers in Endocrinology · 2019

A meta-analysis of 12 studies (10 cohort, 2 randomized) assessing CPAP therapy's effect on testosterone levels in men with OSA. Found no statistically significant change in total testosterone after CPAP treatment, indicating that treating apnea alone doesn't normalize hormone levels in every patient.

Cunningham GR, Ellenberg SS, Bhasin S i wsp. · Journal of Clinical Endocrinology & Metabolism · 2019

Analysis of data from a controlled trial (a Testosterone Trials substudy) showing a real, but for most men modest, scale of PSA rise on TRT: an average increase of 0.47 ng/mL after 12 months versus 0.06 ng/mL in the placebo group, with 5% of men reaching a rise of ≥1.7 ng/mL and 1.9% reaching a confirmed PSA >4.0 ng/mL (versus 0.3% on placebo). The authors note that despite the statistically significant difference, the proportion of men requiring biopsy remained small.

Hills RD Jr, Pontefract BA, Mishcon HR, Black CA, Sutton SC, Theberge CR · Nutrients · 2019

An extensive review discussing how diet and environmental factors shape the gut microbiome and its links to obesity, diabetes, irritable bowel syndrome, inflammatory bowel disease, depression, cardiovascular disease, and colorectal cancer.

Wheeler KM, Sharma D, Kavoussi PK, Smith RP, Costabile R · Sexual Medicine Reviews · 2019

A literature review noting headache, dizziness, gynecomastia and possible worsening of psychiatric illness as reported adverse effects; overall conclusion: 'generally safe and well tolerated.' Classic warnings about visual disturbance stem mainly from a different dosing context in women.

Kanakis GA, Nordkap L, Bang AK, et al. · Andrology · 2019

European Academy of Andrology clinical guidelines explicitly advise against using SERMs, aromatase inhibitors, and non-aromatizable androgens to treat gynecomastia in men (recommendation R14). Specific to the gynecomastia context, not general estradiol management on TRT, but reflects the same broader expert skepticism about routine use of this drug class in men.

Bayle M, Neasta J, Dall'Asta M, Gautheron G, Virsolvy A, Quignard JF, Youl E, Magous R, Guichou JF, Crozier A, Del Rio D, Cros G, Oiry C · British Journal of Pharmacology · 2019

A study on isolated pancreatic beta cells and islets showing that urolithin C enhances glucose-dependent insulin secretion by activating L-type calcium channels — a mechanism studied as a potentially safer alternative to classic insulin secretagogues.

Hipp MS, Kasturi P, Hartl FU · Nature Reviews Molecular Cell Biology · 2019

An extensive review describing the structure of the proteostasis network (chaperones, the proteasome, autophagy) and the mechanisms of its gradual weakening with age, linked to neurodegenerative diseases.

de Guia RM, Agerholm M, Nielsen TS, et al. · Physiological Reports · 2019

A human clinical study showing that aerobic and resistance training increases NAMPT content in skeletal muscle, reversing part of the age-related decline in NAD+ recovery capacity.

Avgerinos KI, et al. · Experimental Gerontology · 2018

A review pointing to a potential improvement in short-term memory and processing speed, stronger under sleep deprivation or in older adults.

Le Thi Nhu Ngoc, Oh YK, Lee YJ, Lee YC · International Journal of Molecular Sciences · 2018

A systematic review of 33 RCTs — all in animal models — showed, among other things, a significant reduction in serum insulin and faster wound healing. No studies in humans.

Chen XQ, et al. · Molecules · 2018

Fourteen triterpenes were isolated, two of which showed stronger α-glucosidase inhibition than acarbose in an in vitro enzymatic assay.

Loyd AL, Richter BS, Jusino MA, Truong C, Smith ME, Blanchette RA, Smith JA · Frontiers in Microbiology · 2018

A DNA analysis of 20 commercial products marketed as Ganoderma lucidum found that 93% contained material genetically corresponding to G. lingzhi, and none contained true European G. lucidum.

Sun Y, Zhong S, Yu J, Zhu J, Ji D, Hu G, Wu C, Li Y · PLoS ONE · 2018

A study in mice with induced intestinal inflammation showed that an aqueous extract lowered pro-inflammatory cytokine levels.

Estruch R, et al. (PREDIMED) · New England Journal of Medicine · 2018

A large randomized trial (n>7,000) showing a significant reduction in major cardiovascular events in groups following a Mediterranean diet supplemented with olive oil or nuts.

García-Hermoso A, et al. · Archives of Physical Medicine and Rehabilitation · 2018

A meta-analysis showing an inverse relationship between muscle strength and the risk of death from any cause.

Ford AC, et al. · American Journal of Gastroenterology · 2018

A systematic review pointing to moderate improvement in IBS symptoms with probiotics, with significant heterogeneity between the strains studied.

Bhasin S, Brito JP, Cunningham GR, et al. · Journal of Clinical Endocrinology & Metabolism · 2018

Official Endocrine Society clinical guidelines on the diagnosis, form selection, and monitoring of testosterone therapy.

Bhasin S, Brito JP, Cunningham GR, et al. · Journal of Clinical Endocrinology & Metabolism · 2018

Clinical guidelines defining the diagnostic criteria for hypogonadism and the principles for differentiating the primary and secondary forms.

Bhasin S, Brito JP, Cunningham GR, et al. · Journal of Clinical Endocrinology & Metabolism · 2018

Clinical guidelines defining the recommended monitoring schedule for testosterone therapy safety.

Mandsager K, Harb S, Cremer P, et al. · JAMA Network Open · 2018

An analysis of more than 122,000 patients undergoing exercise stress testing showing a continuous decline in mortality risk with increasing cardiorespiratory fitness, with no clear upper threshold of benefit.

Petersen MC, Shulman GI · Physiological Reviews · 2018

An extensive review of the molecular mechanisms of insulin action and the signaling defects underlying insulin resistance.

Teede HJ, Misso ML, Costello MF, et al. · Fertility and Sterility · 2018

International evidence-based guidelines on the diagnosis and treatment of PCOS, emphasizing the central role of insulin resistance in the syndrome's pathophysiology.

Whelton PK, Carey RM, Aronow WS, et al. · Hypertension · 2018

Comprehensive clinical guidelines for the diagnosis, assessment, and treatment of hypertension in adults, covering both lifestyle modification and pharmacotherapy.

Zondervan KT, Becker CM, Missmer SA · Nature Reviews Disease Primers · 2018

A comprehensive review of the epidemiology, mechanisms, diagnostics and treatment of endometriosis.

Bhasin S, Brito JP, Cunningham GR i wsp. · Journal of Clinical Endocrinology & Metabolism · 2018

The Endocrine Society clinical guideline defining diagnostic criteria for hypogonadism, indications for TRT, and rules for monitoring therapy.

Ponce OJ, Spencer-Bonilla G, Alvarez-Villalobos N i wsp. · Journal of Clinical Endocrinology & Metabolism · 2018

An RCT meta-analysis showing a moderate improvement in sexual function with TRT, with no confirmed benefit for mood, energy, or cognitive function, and an increased risk of erythrocytosis.

Bhasin S, Brito JP, Cunningham GR i wsp. · Journal of Clinical Endocrinology & Metabolism · 2018

Clinical guidelines describing the full diagnostic panel before TRT, including hematocrit and PSA criteria as contraindications to immediately starting therapy.

Mulhall JP, Trost LW, Brannigan RE i wsp. · The Journal of Urology · 2018

American Urological Association guidelines defining the <300 ng/dL threshold that supports a diagnosis of testosterone deficiency and the scope of testing preceding qualification for treatment.

Bhasin S, Brito JP, Cunningham GR i wsp. · Journal of Clinical Endocrinology & Metabolism · 2018

The Endocrine Society clinical guideline establishing the CDC-harmonized lower threshold for total testosterone (approx. 264 ng/dL) in healthy, non-obese young men and the principles for interpreting a result in the context of symptoms.

Bhasin S, Brito JP, Cunningham GR, et al. · Journal of Clinical Endocrinology & Metabolism · 2018

The Endocrine Society clinical guideline defining, among other things, the requirements for regular, long-term safety monitoring of testosterone therapy — the basis for the recurring monitoring cost described in this piece.

Fiers T, Wu F, Moghetti P, Vanderschueren D, Lapauw B, Kaufman JM · Journal of Clinical Endocrinology & Metabolism · 2018

A newer validation comparing free testosterone calculated with the Vermeulen formula against direct measurement by LC-MS/MS combined with equilibrium dialysis, confirming good agreement in the typical SHBG range and larger discrepancies at the extremes.

Bhasin S, Brito JP, Cunningham GR et al. · Journal of Clinical Endocrinology & Metabolism · 2018

Clinical guidelines defining a detailed TRT monitoring schedule — checks at months 3 and 6, prostate risk assessment in the 3–12 month window, and annual checks once therapy has stabilized.

Mulhall JP, Trost LW, Brannigan RE et al. · The Journal of Urology · 2018

American Urological Association guidelines describing the principles of monitoring men during testosterone therapy, including decision thresholds for PSA and hematocrit.

Bhasin S, Brito JP, Cunningham GR, et al. · Journal of Clinical Endocrinology & Metabolism · 2018

Clinical guidelines defining TRT qualification criteria, including severe, untreated obstructive sleep apnea as a condition requiring caution and additional assessment before starting testosterone therapy.

Bhasin S, Brito JP, Cunningham GR i wsp. · Journal of Clinical Endocrinology & Metabolism · 2018

Clinical practice guideline defining, among other things, the prostate monitoring protocol during TRT: PSA and digital rectal exam before starting therapy in men ≥40 with a baseline PSA above the median (0.6 ng/mL), follow-up at 3–6 months, and referral to a urologist for a confirmed PSA rise of >1.4 ng/mL within 12 months, a confirmed PSA >4.0 ng/mL, or an abnormal digital rectal exam.

Mulhall JP, Trost LW, Brannigan RE i wsp. · Journal of Urology · 2018

American Urological Association guideline on the diagnosis and treatment of testosterone deficiency, including a PSA/DRE monitoring protocol analogous to the Endocrine Society's — before therapy, at 3–6 months, and thresholds qualifying for urological referral. The guideline also notes that patients with a prostate cancer history should have PSA monitored at least at the standard rhythm, with clinicians free to increase frequency.

Bhasin S i wsp. · The Journal of Clinical Endocrinology & Metabolism · 2018

The Endocrine Society's key clinical guideline on diagnosing and treating hypogonadism in men, including concrete recommendations for hematocrit monitoring during TRT — including a recommendation to pause therapy at a hematocrit above 54% until the value normalizes, with the option to resume at a lower dose, and phlebotomy as one option for managing erythrocytosis.

Mulhall JP i wsp. · The Journal of Urology · 2018

American Urological Association guideline on evaluating and treating testosterone deficiency, specifying the numerical hematocrit thresholds relevant to clinical practice — above 50%, an explanation of the cause is recommended, and at ≥54%, dose reduction or temporarily pausing testosterone therapy.

Ohlander SJ, Varghese B, Pastuszak AW · Sexual Medicine Reviews · 2018

A literature review on erythrocytosis (excessive hematocrit rise) following testosterone therapy, pointing to delivery forms and dosing schedules that produce high peak testosterone concentrations as carrying higher risk of this side effect than profiles with a more stable, flattened concentration course.

Bi Y, Perry PJ, Ellerby M, Murry DJ · CPT: Pharmacometrics & Systems Pharmacology · 2018

31 healthy men received 14 weekly intramuscular injections at research doses of 100, 250, or 500mg/week (supraphysiologic doses, used for dose-response modeling, not standard TRT doses). One-compartment model: clearance 2.6 kL/day, volume of distribution 14.4 kL. Potency of total testosterone for LH suppression estimated at 9.33 ng/mL.

Wilson DM, Kiang TKL, Ensom MHH · American Journal of Health-System Pharmacy · 2018

Dose-normalized AUC comparable between routes (SC 1.7±0.6 vs. IM 1.9±0.6 nmol·days/L/mg); SC route was associated with lower pre-injection anxiety reported by patients — a finding about patient experience, not a hormonal parameter.

Klaips CL, Jayaraj GG, Hartl FU · Journal of Cell Biology · 2018

A review of cellular proteostasis pathways and evidence for their role in aging and diseases linked to protein aggregation, based largely on studies in model organisms and cell lines.

Horvath S, Raj K. · Nature Reviews Genetics · 2018

A foundational review of epigenetic clock theory, describing different generations of methylation clocks and their use as aging biomarkers.

Horvath S, Raj K. · Nature Reviews Genetics · 2018

A foundational review of epigenetic clock theory, describing the different generations of methylation clocks and the logic behind their increasing predictive accuracy for health and mortality.

Cesari M, de Carvalho IA, Thiyagarajan JA, Cooper C, Martin FC, Reginster JY, Vellas B, Beard JR. · The Journals of Gerontology: Series A · 2018

The paper formalizing the five domains of intrinsic capacity (locomotion, vitality, cognition, psychological well-being, sensory function) based on the International Classification of Functioning (ICF) framework and the available scientific evidence.

Pawelec G. · Experimental Gerontology · 2018

A review defining immunosenescence and summarizing its key clinical consequences: weaker vaccine response, reduced ability to fight cancer, heightened inflammation, and susceptibility to autoimmunity.

Nikolich-Žugich J. · Nature Immunology · 2018

A comprehensive review of immune-aging mechanisms, including the role of thymic involution, the shrinking T-cell repertoire, and the impact of chronic latent infections.

Fulop T, Larbi A, Dupuis G, et al. · Frontiers in Immunology · 2018

A review describing immunosenescence and inflammaging as two tightly linked, mutually reinforcing aspects of immune-system aging.

Fulop T, Larbi A, Dupuis G, et al. · Frontiers in Immunology · 2018

A review describing the tight, bidirectional link between inflammaging and immunosenescence as two aspects of the same immune-aging process.

Rajman L, Chwalek K, Sinclair DA. · Cell Metabolism · 2018

A review of in vivo evidence on NAD+-boosting compounds, distinguishing supplying precursors from the efficiency of NAD+ metabolism itself.

Kreider RB, et al. · Journal of the International Society of Sports Nutrition · 2017

A position-stand review summarizing decades of research — confirms the effectiveness and safety of creatine monohydrate in athletic populations.

Martineau AR, et al. · BMJ · 2017

An individual patient data meta-analysis (n>10,000) showing a protective effect of supplementation against acute respiratory tract infections, stronger in people with a baseline deficiency.

Boyle NB, et al. · Nutrients · 2017

A review pointing to a potential, though methodologically limited, link between magnesium supplementation and a reduction in subjectively perceived stress.

Hirsch KR, et al. · Journal of Dietary Supplements · 2017

Three weeks of supplementation showed no significant improvement in VO2max in trained cyclists compared with placebo.

Pleszczyńska M, Lemieszek MK, Siwulski M, Wiater A, Rzeski W, Szczodrak J · World Journal of Microbiology and Biotechnology · 2017

A literature review describing historical and modern laboratory research — documented in vitro antibacterial, antiparasitic, anti-inflammatory, and anti-cancer activity, with no clinical studies.

Jiang Y, et al. · Biomedicine & Pharmacotherapy · 2017

A review describing GSP as an adjunctive drug registered in China since 2010. The authors note that publicly available, published clinical trial data are practically nonexistent.

Laukkanen T, et al. · Age and Ageing · 2017

An analysis of the same KIHD cohort pointing to an inverse relationship between sauna-bathing frequency and dementia risk.

Shaffer F, Ginsberg JP · Frontiers in Public Health · 2017

A review of HRV measurement and interpretation methods, emphasizing the strong dependence on individual and methodological context.

Freedberg DE, Kim LS, Yang YX · Gastroenterology · 2017

An American Gastroenterological Association expert position statement summarizing the evidence on the benefits and potential risks of long-term proton pump inhibitor use.

Levine H, Jørgensen N, Martino-Andrade A, et al. · Human Reproduction Update · 2017

A systematic review and meta-analysis showing a significant decline in sperm concentration and total sperm count among men in Western countries over several decades.

Goldman AL, Bhasin S, Wu FCW, Krishna M, Matsumoto AM, Jasuja R · Endocrine Reviews · 2017

An extensive review of the physiology of testosterone binding by SHBG and albumin, including a discussion of the limitations of the classic free hormone hypothesis and the clinical consequences of misinterpreting total testosterone without accounting for SHBG.

Liu TZ, Xu C, Rota M, Cai H, Zhang C, Shi MJ, Yuan RX, Weng H, Meng XY, Kwong JS, Sun XT · Sleep Medicine Reviews · 2017

A meta-analysis of 40 prospective cohort studies (2,200,425 participants, 271,507 deaths) found a J-shaped relationship between sleep duration and all-cause mortality, with the lowest risk at 7 hours of sleep. Risk rose with both shorter and longer sleep, with the risk increase at very long sleep (10-11 hours) markedly larger than at short sleep (4-6 hours).

McFarland J, Craig W, Clarke NJ, Spratt DI · Journal of the Endocrine Society · 2017

11 patients on weekly subcutaneous cypionate, sampled at 8 time points across the week. Mean total T 627±206 ng/dL (range 205-1410), free T 146±51 pg/mL (range 38-348), stable throughout the week. Cohort was transgender men — authors assume results extend to hypogonadal men, but the study doesn't directly confirm this in that group.

Klupp N.L., Kiat H., Bensoussan A., Steiner G.Z., Chang D.H. · Scientific Reports · 2016

A 16-week RCT in 84 people with type 2 diabetes and metabolic syndrome found no significant effect of Ganoderma lucidum extract on HbA1c, fasting glucose, or other cardiometabolic parameters — an important counterpoint to reishi's marketing claims.

Arata S., Watanabe J., Maeda M., Yamamoto M., Matsuhashi H., Mochizuki M., Kagami N., Honda K., Inagaki M. · Heliyon · 2016

In a mouse model of lung cancer, daily administration of an aqueous chaga extract for 3 weeks inhibited tumor growth and metastasis. A promising preclinical result, but its extrapolation to people with cancer has not been confirmed by clinical trials.

Liu MM, Zeng P, Li XT, Shi LG · International Journal of Biological Macromolecules · 2016

The isolated polysaccharide significantly inhibited proliferation of HeLa and SGC-7901 cells in vitro and stimulated macrophage activity.

Im KH, Nguyen TK, Choi J, Lee TS · Molecules · 2016

Extracts showed antioxidant and digestive-enzyme-inhibiting activity in vitro, and in an animal model reduced carrageenan-induced paw swelling by up to 46%.

Siqueira JPZ, Sutton DA, Gené J, et al. · Journal of Clinical Microbiology · 2016

A phylogenetic analysis of 23 clinical isolates showed that 22 of them, previously classified as S. commune, belonged to S. radiatum.

Toledo CV, Barroetaveña C, Fernandes Â, Barros L, Ferreira ICFR · Molecules · 2016

Chemical profiling of wild mushrooms from Patagonian forests, including G. gargal — high trehalose content and moderate antioxidant activity.

Appleby PN, Key TJ · Proceedings of the Nutrition Society · 2016

A review of data from the EPIC-Oxford cohort study linking plant-based diets with lower risk of ischemic heart disease and lower BMI, while also flagging the risk of B12 and vitamin D deficiencies.

Snyder PJ, Bhasin S, Cunningham GR, et al. · New England Journal of Medicine · 2016

A set of large, randomized studies (the Testosterone Trials) evaluating the effects of testosterone therapy in older men with confirmed low hormone levels.

Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA · Cell Metabolism · 2016

A review paper presenting the scientific rationale for the TAME trial — the hypothesis that metformin might slow age-related diseases in people without diabetes.

Wexler A. · Frontiers in Human Neuroscience · 2016

A bioethical analysis of the social context of biohacking and neurohacking practices, describing their position at the boundary of self-knowledge, self-experimentation, and medicine.

Fothergill E, Guo J, Howard L, et al. · Obesity · 2016

A study showing persistently reduced resting energy expenditure in participants of a massive body-mass reduction program six years after its conclusion.

McLellan TM, Caldwell JA, Lieberman HR · Neuroscience & Biobehavioral Reviews · 2016

An extensive literature review confirming caffeine's consistent, positive effect on alertness, reaction time and physical performance across a wide range of doses.

Buijze GA, Sierevelt IN, van der Heijden BC, Dijkgraaf MG, Frings-Dresen MH · PLOS ONE · 2016

A large randomized trial showing that regular cold showers are associated with significantly lower sick-leave absence, though not with a lower frequency of infections themselves.

Snyder PJ, Bhasin S, Cunningham GR i wsp. · New England Journal of Medicine · 2016

A set of large randomized trials assessing the effects of TRT in older men with confirmed testosterone deficiency across sexual function, energy, cognitive function, and other domains.

Snyder PJ, Bhasin S, Cunningham GR, et al. · New England Journal of Medicine · 2016

A set of randomized trials (the Testosterone Trials) confirming that the benefits of testosterone therapy persist with continuous treatment — supporting the case for planning TRT as a long-term cost rather than a one-time expense.

Sender R, Fuchs S, Milo R · PLoS Biology · 2016

A paper revising popular estimates of bacterial cell counts in the human body, showing the ratio of bacterial to human cells is much closer to 1:1 (roughly 3.8×10^13 bacterial cells versus roughly 3.0×10^13 human cells) than the previously widely cited 10:1.

Global BMI Mortality Collaboration, Di Angelantonio E, Bhupathiraju ShN, Wormser D, Gao P, Kaptoge S, et al. · The Lancet · 2016

A meta-analysis of individual participant data from 239 prospective studies (10,625,411 participants), restricted to never-smokers without chronic disease at baseline, found the lowest death risk at a BMI of 22.5-25.0. Risk rose approximately log-linearly above a BMI of 25.0, reaching HR=2.76 at grade III obesity (BMI 40-60) relative to the reference range.

Finkelstein JS, Lee H, Leder BZ, et al. · Journal of Clinical Investigation · 2016

When aromatization was pharmacologically blocked, spine bone mineral density, measured by both DXA and QCT, fell significantly across all tested testosterone-dose groups — confirms that estrogen, not testosterone, is the primary hormonal driver of bone density maintenance in men, mechanistically explaining the Burnett-Bowie et al. 2009 finding.

Perna L, Zhang Y, Mons U, Holleczek B, Saum KU, Brenner H. · Clinical Epigenetics · 2016

A cohort study (n=1863) showing that each 5-year increase in epigenetic age acceleration according to the Horvath clock was linked to about a 23% higher all-cause mortality risk, independent of chronological age.

Beard JR, Officer A, de Carvalho IA, et al. · The Lancet · 2016

The landmark WHO report that introduced intrinsic capacity as the central element of a new definition of healthy ageing, based on a person's functional ability rather than solely on the presence or absence of disease.

Camacho-Pereira J, Tarragó MG, Chini CCS, et al. · Cell Metabolism · 2016

A mouse study identifying CD38 as the main enzyme responsible for the age-related degradation of NAD+ and externally administered NMN — CD38 knockout mice did not show the typical NAD+ decline.

Tarleton EK, Littenberg B. · Journal of the American Board of Family Medicine · 2015

An observational study describing an inverse relationship between magnesium intake and depressive symptoms in adults.

Dai X, Stanilka JM, Rowe CA, Esteves EA, Nieves C Jr, Spaiser SJ, Christman MC, Langkamp-Henken B, Percival SS · Journal of the American College of Nutrition · 2015

A randomized trial in 52 healthy adults showed that consuming 5 or 10 g of dried shiitake daily for 4 weeks increased proliferation of γδ-T and NK-T cells, raised sIgA levels, and lowered CRP.

Zhao S, et al. · Carbohydrate Polymers · 2015

In rats on a hypercholesterolemia-inducing diet, the polysaccharide lowered total cholesterol by as much as 33–35% after 29 days.

Chen ML, Hsieh CC, Chiang BL, Lin BF · Evidence-Based Complementary and Alternative Medicine · 2015

The triterpene fraction significantly inhibited the release of histamine and Th2 cytokines from activated mast cells in vitro.

Milovanovic I, Stanojkovic T, Stajic M, Brceskic I, Knezevic A, Cilerdzic J, Vukojevic J · Current Pharmaceutical Biotechnology · 2015

An in vitro study on selenium-enriched mycelium showed antioxidant activity and cytotoxicity against cancer cell lines.

Vasina DV, et al. · Biochimie · 2015

A molecular study identified five laccase genes and described their regulation by copper ions — an enzymology study, not related to health.

Melappa G, Chandrasekhar N, Pramod SN, Rangappa Nagaraj K · Pharmacognosy Journal · 2015

A methanol extract showed antioxidant, antimicrobial, and anti-inflammatory activity in vitro — the only published study of this species.

Milovanovic I, et al. · Current Pharmaceutical Biotechnology · 2015

Selenium-enriched mycelium showed stronger antioxidant and cytotoxic effects in vitro than unenriched mycelium.

Mizerska-Dudka M, Jaszek M, Błachowicz A, et al. · International Journal of Biological Macromolecules · 2015

An in vitro study of three fractions showed antiviral activity of laccase against HSV, macrophage stimulation by the polysaccharide fraction, and cytotoxicity toward cervical cancer cells.

Postemsky PD, Curvetto NR · International Journal of Medicinal Mushrooms · 2015

Methanol extracts from mycelium grown in submerged culture showed radical-scavenging ability in vitro — the only available data on this species' biological activity.

Postemsky PD, Curvetto NR · International Biodeterioration & Biodegradation · 2015

A biotechnological study on cultivation using cheap agricultural substrates for producing mycelial biomass and antioxidant compounds.

Morris MC, et al. · Alzheimer's & Dementia · 2015

A cohort study showing significantly lower Alzheimer's disease risk in people most closely following the MIND diet.

Laukkanen JA, et al. · JAMA Internal Medicine · 2015

A cohort study (KIHD, n≈2,300 Finnish men) showing an inverse relationship between sauna-bathing frequency and cardiovascular mortality.

Lan J, et al. · Journal of Ethnopharmacology · 2015

A meta-analysis showing a significant reduction in fasting glucose and HbA1c comparable to some oral drugs.

Manheimer EW, van Zuuren EJ, Fedorowicz Z, Pijl H · American Journal of Clinical Nutrition · 2015

A meta-analysis of several small studies showed short-term improvement in waist circumference, blood pressure, and triglycerides, while noting the low quality and small number of available studies.

Leidy HJ, Clifton PM, Astrup A, et al. · American Journal of Clinical Nutrition · 2015

A systematic review showing that diets with elevated protein content consistently improve satiety and support the preservation of muscle mass during weight loss.

U.S. Food and Drug Administration · FDA Drug Safety Communication · 2015

An official FDA safety communication from March 2015, narrowing approved testosterone indications to documented hypogonadism and adding a warning about possible increased heart attack and stroke risk — a decision based partly on the Vigen and Finkle studies, rescinded in 2025 following the TRAVERSE results.

Kaminetsky J, Jaffe JS, Swerdloff RS · Sexual Medicine · 2015

A phase II study comparing weekly subcutaneous doses of testosterone enanthate (50 or 100 mg) with a standard 200 mg intramuscular injection every two weeks. Weekly subcutaneous dosing kept testosterone within the reference range across the entire seven-day interval, with less variability than the two-week schedule.

Trauer JM, Qian MY, Doyle JS, Rajaratnam SM, Cunnington D · Annals of Internal Medicine · 2015

A systematic review and meta-analysis of 20 randomized trials (1,162 participants) comparing CBT-I to control groups found clinically meaningful improvement in sleep onset latency (by 19 minutes), wake time after sleep onset (by 26 minutes), and sleep efficiency (by 9.9 percentage points), with effects sustained in long-term follow-up and no reported adverse effects.

Giorgio C, Mena P, Del Rio D, Brighenti F, et al. · Molecular Nutrition & Food Research · 2015

An in vitro study on prostate cancer cell lines showing that urolithin D selectively inhibits EphA2 receptor phosphorylation more strongly than the other urolithins tested — a cell-level study only.

Theodoratou E, et al. · BMJ · 2014

An umbrella review of 107 meta-analyses — confirms strong evidence for vitamin D's role in bone health, while more cautiously assessing other associations as needing further research.

Reid IR, Bolland MJ, Grey A. · The Lancet · 2014

A meta-analysis finding that supplementation in people with normal baseline levels has limited additional effect on bone density.

Li JP, Lei YL, Zhan H · International Journal of Medicinal Mushrooms · 2014

In diabetic mice, the extract significantly lowered glucose and HbA1c levels and increased insulin secretion.

Liu K, Wang JL, Zhao L, Wang Q · International Journal of Medicinal Mushrooms · 2014

An ethanolic extract showed strong cytotoxic activity against the MDA-MB-231 breast cancer cell line and moderate activity against bacteria and fungi.

Kongkeaw C, et al. · Journal of Ethnopharmacology · 2014

A meta-analysis indicating a consistent improvement in information-processing speed and memory with supplementation lasting at least 12 weeks.

Hannibal KE, Bishop MD. · Physical Therapy · 2014

A review describing the consequences of chronic HPA axis dysregulation, including its effect on pain perception and inflammation.

Jonklaas J, Bianco AC, Bauer AJ, et al. · Thyroid · 2014

American Thyroid Association guidelines on the diagnosis and treatment of hypothyroidism, including principles of levothyroxine dosing and monitoring.

Halmos EP, Power VA, Shepherd SJ, Gibson PR, Muir JG · Gastroenterology · 2014

A randomized crossover trial showing a significant reduction in gastrointestinal symptoms in IBS patients following a diet low in FODMAPs.

Amanatkar HR, Chibnall JT, Seo BW i wsp. · Annals of Clinical Psychiatry · 2014

A meta-analysis of 16 RCTs showing a significant, though moderate, positive effect of testosterone on mood, more pronounced in men under 60 and in those with hypogonadism than in eugonadal men.

Kelsey TW, Li LQ, Mitchell RT, Whelan A, Anderson RA, Wallace WHB · PLOS ONE · 2014

A validated normative model based on thirteen population studies that found no further decline in total testosterone after age 40, instead noting growing variance in results between men — an important counterpoint to the simple picture of 'linear decline with age.'

Kovac JR, Rajanahally S, Smith RP, Coward RM, Lamb DJ, Lipshultz LI · Journal of Sexual Medicine · 2014

A survey of 382 men on TRT: 53% chose injections, 31% gel, 17% implants; overall satisfaction with therapy was around 70% and similar across forms — differences were mainly in cost (injections) and convenience (implants/gel), not effectiveness.

Finkle WD, Greenland S, Ridgeway GK et al. · PLOS ONE · 2014

An analysis of a large insurance database (over 55,000 men) showing an increased rate of non-fatal heart attacks within 90 days of starting TRT, with an especially pronounced increase in men 65 and older. Like the Vigen study, observational and susceptible to systematic bias, but a significant factor in the FDA's decision to add a warning.

Handelsman DJ i wsp. · Clinical Chemistry · 2014

A comparison of five popular direct estradiol immunoassays against the reference LC-MS/MS method on blood samples from more than a hundred healthy men. All five immunoassays showed a positive bias (result inflation) of roughly 6–74% depending on the assay, and only the LC-MS/MS result correlated sensibly with testosterone and SHBG — evidence of the limited reliability of standard immunoassays in the low, male estradiol concentration range.

Ramasamy R, Scovell JM, Kovac JR, Lipshultz LI · Journal of Urology · 2014

A head-to-head comparison found a median total testosterone of 504 ng/dL on clomiphene — lower than typically achieved with testosterone injections — with comparable patient satisfaction (qADAM questionnaire) across clomiphene, injection and gel groups.

Jovaisaite V, Mouchiroud L, Auwerx J · Journal of Experimental Biology · 2014

A review of UPRmt mechanisms and evidence for its evolutionarily conserved role in maintaining mitochondrial health and links to aging in model organisms.

Bennett CF, Vander Wende H, Simko M, Klum S, Barfield S, Choi H, Pineda VV, Kaeberlein M · Nature Communications · 2014

A study in nematodes showing that UPRmt activation is neither necessary nor sufficient for lifespan extension — an important caution against oversimplified claims about a direct link between UPRmt and longevity.

Krištić J, Vučković F, Menni C, et al. · The Journals of Gerontology: Series A · 2014

A foundational study in large human cohorts showing that the IgG glycan profile correlates with both chronological age and physiological parameters typical of biological aging.

Franceschi C, Campisi J. · The Journals of Gerontology: Series A · 2014

A review systematizing evidence linking chronic, low-grade inflammation to diseases of old age, including cardiovascular, metabolic, and neurodegenerative conditions.

Wang CR, Qiao WT, Zhang YN, Liu F · Molecules · 2013

In mice, injection of the adenosine fraction increased IL-10 expression and SOD activity while lowering IL-2, IL-6, and IFN-gamma.

Slavin J · Nutrients · 2013

A review of the mechanisms by which fiber and prebiotics affect gut health, immune function, and metabolic regulation.

Rasch B, Born J · Physiological Reviews · 2013

An extensive review of the neurobiological mechanisms through which sleep supports consolidation of various types of memory.

Hsieh TC, Pastuszak AW, Hwang K, Lipshultz LI. · The Journal of Urology · 2013

A clinical study found that men on TRT with concurrent low-dose hCG (500 IU every other day) did not develop azoospermia over an average 6-month follow-up, while TRT alone without hCG leads to azoospermia in a substantial proportion of patients.

Avci P, Gupta A, Sadasivam M, et al. · Seminars in Cutaneous Medicine and Surgery · 2013

A review of photobiomodulation applications in dermatology, including wound healing, reduction of inflammation, and support of collagen production.

Wallace IR, McKinley MC, Bell PM, Hunter SJ · Clinical Endocrinology · 2013

A review systematizing the relationship between SHBG and insulin resistance — discussing why low SHBG is one of the best-documented markers of insulin resistance and how this affects the interpretation of total testosterone in people with obesity.

Finkelstein JS i wsp. · New England Journal of Medicine · 2013

A classic study using a GnRH agonist and an aromatase inhibitor, showing that changes in fat mass in men are primarily linked to changes in estradiol rather than testosterone, and that deficiency of either androgens or estrogens worsens libido and sexual function.

Vigen R, O'Donnell CI, Barón AE et al. · JAMA · 2013

A retrospective analysis of a veterans registry (over 8,700 men after coronary angiography) suggesting a roughly 29% increase in risk of a composite endpoint (death, heart attack, stroke) in men on TRT. An observational study, later heavily criticized for methodological flaws and comparison-group problems — one of the two sources that launched the 2015 FDA warning.

Finkelstein JS, Lee H, Burnett-Bowie SA, et al. · New England Journal of Medicine · 2013

An RCT of 400 men in whom endogenous sex-hormone production was pharmacologically suppressed (goserelin), then given graded testosterone doses with or without anastrozole (not exemestane, but the same aromatase-inhibition class), designed to separate androgen from estrogen effects. Estrogen deficiency specifically drove increased body fat, while androgen deficiency specifically drove loss of lean mass and strength. A key mechanistic trial explaining why estradiol deficiency in men has distinct, documented health consequences — relevant to any potent aromatase inhibitor as a class, exemestane included, despite the lack of direct outcome data for exemestane itself.

Stabler SP · New England Journal of Medicine · 2013

A comprehensive clinical review in NEJM's respected Clinical Practice series, summarizing the causes, diagnosis and treatment of vitamin B12 deficiency — including the role of gastric mucosal atrophy, bowel disease, bariatric surgery, and chronic use of metformin and acid-reducing medications as acquired causes of deficiency, along with recommendations for confirming the diagnosis with additional markers (methylmalonic acid, homocysteine) when the total B12 result is ambiguous.

Chandrasekhar K, Kapoor J, Anishetty S. · Indian Journal of Psychological Medicine · 2012

A randomized, placebo-controlled trial (n=64) showing a significant reduction in perceived stress and cortisol levels in the group supplemented with ashwagandha root extract.

Ishaque S, et al. · BMC Complementary and Alternative Medicine · 2012

A systematic review pointing to promising but methodologically heterogeneous evidence for an anti-fatigue effect.

Torkelson CJ, Sweet E, Martzen MR, Sasagawa M, Wenner CA, Gay J, Putiri A, Standish LJ · ISRN Oncology · 2012

A phase 1 trial in 11 women with breast cancer after completing radiotherapy showed that oral doses of Trametes versicolor extract up to 9 g/day for 6 weeks were safe and well tolerated.

Lima CUJO, Souza VC, Morita MC, Chiarello MD, de Oliveira Karnikowski MG · Scandinavian Journal of Immunology · 2012

A randomized, double-blind, placebo-controlled study in 57 older women found no significant effect of 900 mg of Agaricus blazei extract daily on the inflammatory markers IL-6, IFN-gamma, and TNF-alpha.

Li H, Liu X, Li Y, Hua Y, Zhi D, Pang G · International Journal of Biological Macromolecules · 2012

A small study in healthy volunteers analyzing the effect of the PNPS-1 polysaccharide on 39 serum cytokines — significant anti-inflammatory activity was observed.

Yu YH, Kuo HP, Hsieh HH, Li JW, Hsu WH, et al. · Evidence-Based Complementary and Alternative Medicine · 2012

The extract inhibited the proliferation of doxorubicin-resistant lung cancer cells through cell-cycle arrest and apoptosis induction.

Cao Y, Wu SH, Dai YC · Fungal Diversity · 2012

The paper that formally split Ganoderma lingzhi off as a species distinct from Ganoderma lucidum based on phylogenetic analysis of ITS sequences.

Westcott WL. · Current Sports Medicine Reports · 2012

A review summarizing the evidence for the benefits of resistance training on metabolic, bone, and functional health at every age.

Hempel S, et al. · JAMA · 2012

A meta-analysis showing a significant reduction in the risk of antibiotic-associated diarrhea with selected probiotic strains.

Gibala MJ, Little JP, MacDonald MJ, Hawley JA · The Journal of Physiology · 2012

A review showing that low-volume, high-intensity interval training triggers metabolic and cardiovascular adaptations comparable to traditional endurance training.

Roenneberg T, Allebrandt KV, Merrow M, Vetter C · Current Biology · 2012

A study introducing the concept of social jet lag and demonstrating its link to increased obesity risk.

McGlade E, Locatelli A, Hardy J, et al. · Journal of Attention Disorders · 2012

A placebo-controlled trial showing improved psychomotor speed and attention measures after citicoline supplementation in healthy young men.

Yang L, Zhang SX, Dong Q, Xiong ZB, Li X. · International Urology and Nephrology · 2012

In 242 men with hypogonadotropic hypogonadism, hCG monotherapy increased testicular volume in 50% of patients (from 2.0 to 6.8 mL), and hCG plus hMG in 75.7% (to 8.8 mL); the group treated with testosterone alone showed no significant increase in testicular volume — direct evidence that testosterone alone does not replicate hCG's effect on the testes.

Miller MG, Rogol AD, ZumBrunnen TL · Current Medical Research and Opinion · 2012

A review of five phase 1 studies assessing testosterone transfer to female partners after skin contact with men using 1.62% gel — confirms a measurable rise in testosterone concentration in unmedicated women, along with the effectiveness of washing and covering the application site in reducing that risk.

Miller MG, Rogol AD, ZumBrunnen TL · Current Medical Research and Opinion · 2012

A review of five phase 1 studies assessing testosterone transfer to female partners after skin contact with men using gel — confirms a measurable rise in testosterone concentration in exposed people and the meaningful effectiveness of washing and covering the application site in reducing this transfer.

Martinez-Pajares JD, Diaz-Morales O, Ramos-Diaz JC, Gomez-Fernandez E · Journal of Pediatric Endocrinology and Metabolism · 2012

A case report of an 18-month-old boy who developed precocious puberty from unintended testosterone exposure through gel used by his father, along with a review of similar previously published cases — illustrating that transfer risk in household settings is real, not merely theoretical.

Kivimäki M, Nyberg ST, Batty GD, Fransson EI, et al. (IPD-Work Consortium) · The Lancet · 2012

An individual-participant-data meta-analysis of 13 European cohort studies (197,473 people) found that job strain (a combination of high demands and low control) was linked to a 23% higher risk of coronary heart disease (HR=1.23; 95% CI 1.10-1.37) after adjusting for age and sex, though the effect was markedly smaller than for classic risk factors.

Moskovic DJ, Katz DJ, Akhavan A, Park K, Mulhall JP · BJU International · 2012

In 46 patients followed long-term, testosterone rose from a baseline of 228 ng/dL to 612 ng/dL after one year and remained stable through 3 years. Femoral neck and lumbar spine bone density improved significantly, with no reported adverse events.

Katz DJ, Nabulsi O, Tal R, Mulhall JP · BJU International · 2012

In 86 men (mean age 29), most seeking treatment specifically to preserve fertility, testosterone and gonadotropins rose significantly after a mean 19 months of therapy with no major adverse events — clomiphene was concluded to be an effective, safe alternative to exogenous testosterone in this population.

Schneider I, Kressel G, Meyer A, Krings U, Berger RG, Hahn A · Journal of Functional Foods · 2011

A 21-day study in 20 healthy adults: daily consumption of a soup made with 30 g of dried oyster mushroom significantly lowered triglycerides and oxidized LDL.

Abrams DI, et al. · BMC Complementary and Alternative Medicine · 2011

An 8-week study with supplementation of 15 g of freeze-dried oyster mushroom daily showed a significant drop in triglycerides.

Alam N, Yoon KN, Lee JS, Cho HJ, Shim MJ, Lee TS · Saudi Journal of Biological Sciences · 2011

A 42-day rat study: fruiting body powder supplementation lowered total cholesterol, triglycerides, and LDL by 24–62%.

Zan LF, Qin JC, Zhang YM, Yao YH, Bao HY, Li X · Chemical & Pharmaceutical Bulletin · 2011

New hispidin derivatives with significant in vitro radical-scavenging activity were isolated from fruiting bodies.

Leproult R, Van Cauter E. · JAMA · 2011

Experimentally restricting sleep to 5 hours a night for 8 days lowered daytime testosterone levels by 10–15% in healthy young men.

Walle T. · Annals of the New York Academy of Sciences · 2011

A classic paper describing resveratrol's pharmacokinetics in humans and explaining the mechanism behind its very low systemic bioavailability.

Mozaffarian D, Wu JHY · Journal of the American College of Cardiology · 2011

An extensive review of the mechanisms and clinical evidence regarding the effect of omega-3 fatty acids on cardiovascular risk factors and events.

Bhasin S, Pencina M, Jasuja GK i wsp. · Journal of Clinical Endocrinology & Metabolism · 2011

A study establishing reference ranges for total and free testosterone by LC-MS/MS in a sample of healthy, non-obese young men from the Framingham Heart Study, validated across three independent cohorts.

de Ronde W, de Jong FH · Reproductive Biology and Endocrinology · 2011

A review concluding that the long-term efficacy and safety of aromatase inhibitors in men has not yet been established, and that their routine use is not yet recommended — a direct, citable statement of the ongoing controversy from a review focused specifically on this drug class in men.

Settembre C, Di Malta C, Polito VA, et al. · Science · 2011

A landmark paper showing that TFEB coordinates autophagosome formation, fusion with the lysosome, and substrate degradation through a single, coherent transcriptional program regulated by nutrient availability.

Nagano M, et al. · Biomedical Research · 2010

A small study in women showing reduced anxiety and depressive symptoms after 4 weeks of eating cookies containing Lion's Mane.

Chen S, et al. · Chinese Journal of Integrative Medicine · 2010

A study in mice (not humans) showing extended time to exhaustion and reduced muscle fatigue markers after administration of polysaccharides from C. sinensis mycelium.

Chen S, Li Z, Krochmal R, Abrazado M, Kim W, Cooper CB. · Journal of Alternative and Complementary Medicine · 2010

A 12-week RCT in 20 healthy older adults using fermented mycelium (Cs-4 strain, not the wild fruiting body) — improvement in metabolic and ventilatory threshold, but no significant change in VO2max versus placebo.

Wu FC, Tajar A, Beynon JM, et al. · New England Journal of Medicine · 2010

A large European cohort study (EMAS) establishing criteria for diagnosing late-onset hypogonadism based on the co-occurrence of low testosterone and specific sexual symptoms.

Geng J, Dong J, Ni H, et al. · Cochrane Database of Systematic Reviews · 2010

A Cochrane systematic review assessing ginseng's effect on cognitive function — results promising but methodologically heterogeneous.

Cholesterol Treatment Trialists' (CTT) Collaboration · The Lancet · 2010

A meta-analysis of 26 randomized trials showing that statin-driven LDL reduction translates into a proportional reduction in the risk of major cardiovascular events.

Panossian A, Wikman G · Pharmaceuticals · 2010

A comprehensive review of the mechanisms of action of classic adaptogens, including eleuthero, in the context of the response to physical and mental stress.

Seiler S · International Journal of Sports Physiology and Performance · 2010

A review of training-intensity distribution models in elite endurance athletes, pointing to the dominance of low-intensity training in their programs.

Stanczyk FZ, Jurow J, Hsing AW · Cancer Epidemiology, Biomarkers & Prevention · 2010

An analysis showing that direct estradiol immunoassays without a sample purification step are insufficiently sensitive and specific for reliable measurement in men and postmenopausal women, due to antibody cross-reactivity with numerous steroid metabolites present in the blood.

Wang C, Harnett M, Dobs AS, Swerdloff RS · Journal of Andrology · 2010

An 84-week phase III trial of testosterone undecanoate given every 10 weeks after loading doses. Steady state was reached after the third injection; at that point, 94% of men maintained an average testosterone concentration within normal range across the third dosing interval, with small peak-trough swings characteristic of this ester's very long half-life.

Cappuccio FP, D'Elia L, Strazzullo P, Miller MA · Sleep · 2010

A meta-analysis of 16 studies (27 cohorts, 1,382,999 participants, 112,566 deaths) found that both short (RR=1.12) and long (RR=1.30) sleep were linked to significantly higher death risk compared to moderate sleep duration — one of the first large papers confirming a U/J-shaped relationship for this topic.

Wang C, Harnett M, Dobs AS, Swerdloff RS · Journal of Andrology · 2010

In 130 hypogonadal men, 750mg of testosterone undecanoate given at weeks 0 and 4, then every 10 weeks for 84 weeks, kept trough testosterone within 300–1000 ng/dL (10.4–34.7 nmol/L) from the first injection onward, with stable DHT, estradiol and their ratios to testosterone at steady state. The trial used the 750mg/3mL dose (the formulation registered in the US as Aveed), not the European 1000mg/4mL dose.

Herzog AG, Farina EL, Drislane FW, et al. · Epilepsy & Behavior · 2010

Sexual function normalized in 72.2% of the anastrozole+testosterone group versus 47.4% on testosterone alone; sexual-function scores correlated inversely with estradiol levels. A positive finding for anastrozole, directly contradicting the null results of the two studies above — conducted in a specific population of men with epilepsy, an additional limitation on generalizability.

Olsson EM, von Schéele B, Panossian AG. · Planta Medica · 2009

An RCT (n=60) showing improvement in stress-related fatigue symptoms after 28 days of supplementation.

Mori K, et al. · Phytotherapy Research · 2009

A small study (n=30) in older adults with mild cognitive impairment showing improved test scores after 16 weeks — the effect faded after discontinuation.

Deng G, Lin H, Seidman A, Fornier M, D'Andrea G, Wesa K, Yeung S, Cunningham-Rundles S, Vickers AJ, Cassileth B · Journal of Cancer Research and Clinical Oncology · 2009

A dose-escalation phase I/II trial in 34 breast cancer survivors found a complex, nonlinear dose-response relationship in select immune parameters after oral maitake extract, with a good safety profile.

Chida Y, Steptoe A. · Biological Psychology · 2009

A systematic review describing the relationship between psychosocial stress levels and the cortisol response after waking.

Frassetto LA, Schloetter M, Mietus-Synder M, et al. · European Journal of Clinical Nutrition · 2009

A very small pilot study (n=9) showing short-term improvement in lipid profile and blood pressure after switching to a paleolithic diet.

Chan GC, Chan WK, Sze DM · Journal of Hematology & Oncology · 2009

A review of the mechanisms by which beta-glucans activate immune cells, including macrophages and NK cells, via the dectin-1 receptor.

Ophir E, Nass C, Wagner AD · Proceedings of the National Academy of Sciences · 2009

A study showing that people who regularly practice media multitasking perform worse on tests requiring filtering out irrelevant information and switching tasks.

Burnett-Bowie SM i wsp. · Journal of Clinical Endocrinology & Metabolism · 2009

A one-year study showing that inhibiting aromatase (lowering estradiol while raising testosterone) was linked to a decline in spinal bone mineral density compared with placebo — evidence of estradiol's physiological role in maintaining bone mass in men.

Burnett-Bowie SA, Roupenian KC, Dere ME, et al. · Clinical Endocrinology · 2009

A double-blind RCT: testosterone rose from 11.2±3.3 to 18.2±4.8 nmol/L by month three, estradiol fell from 55.8±15.4 to 42.2±13.6 pmol/L. Body composition and sexual outcomes showed no significant change versus placebo — a second independent RCT confirming the same 'hormones improve, symptoms don't' pattern.

Burnett-Bowie SA, McKay EA, Lee H, Leder BZ · Journal of Clinical Endocrinology & Metabolism · 2009

An RCT dedicated to evaluating anastrozole's effect on bone: spine bone mineral density fell from 1.121±0.141 to 1.102±0.138 g/cm² in the anastrozole group, while the placebo group's density rose from 1.180±0.145 to 1.189±0.146 g/cm² over the same period (P=0.0014) — direct, statistically significant evidence of real bone-density-loss risk.

Kasimsetty SG, Bialonska D, Reddy MK, Thornton C, Willett KL, Ferreira D · Journal of Agricultural and Food Chemistry · 2009

A cell-based study comparing the antioxidant activity of different urolithins (A, B, C, D) and ellagic acid — showed strong antioxidant activity for urolithin C in in vitro tests.

Kasimsetty SG, Bialonska D, Reddy MK, Thornton C, Willett KL, Ferreira D · Journal of Agricultural and Food Chemistry · 2009

A cell-based study comparing the antioxidant activity of urolithins A, B, C, and D and ellagic acid — urolithin D showed one of the strongest antioxidant activities in this comparison.

Sardiello M, Palmieri M, di Ronza A, et al. · Science · 2009

A paper identifying TFEB as the master regulator of a gene network responsible for lysosome biogenesis and function, foundational for the later link between TFEB and autophagy.

Jeong Y.T., et al. · Phytotherapy Research · 2008

In mice with transplanted sarcoma, an exo-biopolymer reduced tumor growth by 39.7% and increased NK-cell activity by 51.6% relative to control.

Owen GN, et al. · Nutritional Neuroscience · 2008

A study showing improved speed and accuracy of cognitive task performance with simultaneous administration of L-theanine and caffeine compared to placebo.

Nobre AC, Rao A, Owen GN. · Asia Pacific Journal of Clinical Nutrition · 2008

A review of L-theanine's neurophysiological mechanisms, including its effect on EEG alpha-wave activity associated with relaxation.

Yin J, Xing H, Ye J. · Metabolism · 2008

One of the first large clinical trials to directly compare berberine with metformin and rosiglitazone, showing comparable efficacy.

Neal EG, Chaffe H, Schwartz RH, et al. · Lancet Neurology · 2008

A randomized controlled trial showing a significant reduction in seizure frequency in children with drug-resistant epilepsy following the ketogenic diet.

Nathan DM, Kuenen J, Borg R, et al. · Diabetes Care · 2008

A study establishing the formula for converting the HbA1c result into estimated average glucose (eAG), making practical interpretation of the result easier.

Lanfranco F, Zirilli L, Baldi M, Pignatti E, Corneli G, Ghigo E, Aimaretti G, Carani C, Rochira V · Bone · 2008

A case report of an adult man with a rare genetic aromatase gene mutation preventing testosterone-to-estradiol conversion. Normal bone maturation and mineralization required raising serum estradiol above 73 pmol/L via external estrogen supplementation — direct evidence from human physiology that estradiol (not just testosterone) is genuinely necessary for men's bone health.

Hsu CH, Liao YL, Lin SC, Hwang KC, Chou P · Journal of Alternative and Complementary Medicine · 2007

In 72 patients with type 2 diabetes, adding 1500 mg of Agaricus blazei extract daily for 12 weeks was associated with improvement in the HOMA-IR insulin resistance index compared to placebo.

Ribeiro B, Valentão P, Baptista P, Seabra RM, Andrade PB · Food and Chemical Toxicology · 2007

HPLC analysis identified five phenolic compounds, including ellagic acid accounting for about 49.7% of the phenolics identified. Extracts showed strong antioxidant activity.

Mizushima N · Genes & Development · 2007

A review of the molecular mechanisms of autophagy and its physiological significance, based largely on studies in model organisms.

Klok MD, Jakobsdottir S, Drent ML · Obesity Reviews · 2007

A review of the role of leptin and ghrelin in appetite regulation, including their changes during and after weight loss.

Budoff MJ, Shaw LJ, Liu ST, et al. · Journal of the American College of Cardiology · 2007

A large observational study showing a strong, graded association between coronary artery calcium score and long-term cardiovascular mortality risk.

Rosner W, Auchus RJ, Azziz R, Sluss PM, Raff H · Journal of Clinical Endocrinology & Metabolism · 2007

The Endocrine Society's position statement documenting the systematic unreliability of direct analog free testosterone immunoassays and recommending calculation from SHBG (the Vermeulen formula) or equilibrium dialysis as the preferred methods.

Vandekerckhove P, Lilford R, Vail A, Hughes E · Cochrane Database of Systematic Reviews · 2007

An analysis of 10 RCTs (n=738) found that anti-estrogens (including clomiphene) raised testosterone, but pregnancy rate rose only from 12.5% (control) to 15.4% (treated) — not statistically significant. Note: this Cochrane review was subsequently WITHDRAWN from the database and no longer represents a standing Cochrane conclusion.

Fradet Y, Egerdie B, Andersen M, et al. · European Urology · 2007

In 282 prostate cancer patients on high-dose bicalutamide, at 6 months breast events occurred in 86.2% down to 8.8% of patients (depending on tamoxifen dose, 1-20 mg) versus 96.7% on placebo — a clear, dose-dependent protective effect, without weakening bicalutamide's PSA suppression.

Buscemi N, et al. · Journal of General Internal Medicine · 2006

A meta-analysis confirming a shorter time to fall asleep with a good short-term safety profile.

Barnard ND, Cohen J, Jenkins DJ, et al. · Diabetes Care · 2006

A randomized trial found that a low-fat vegan diet improved glycemic control and lipid profile in people with type 2 diabetes more effectively than standard ADA dietary recommendations.

Després JP, Lemieux I · Nature · 2006

A classic review showing that visceral fat is a key, metabolically active component of abdominal obesity and metabolic syndrome.

Blackburn EH · Nature Medicine · 2006

A review written by the Nobel laureate herself, describing the history of the discovery of the telomere mechanism and its significance for aging biology and cancer.

Nieschlag E · Clinical Endocrinology · 2006

A review of the testosterone forms available at the time, including injectable esters, summarizing their approximate half-lives and pharmacokinetic profiles — the source of the estimates for the close, though not identical, release rates of enanthate and cypionate.

Morales A, Nieschlag E, Schubert M, Yassin AA, Zitzmann M, Oettel M · Aging Male · 2006

An expert symposium report (not a primary clinical trial), stating that conventional testosterone enanthate regimens typically require about 16 injections per year (roughly every 3 weeks), compared with 4-5 injections per year for long-acting testosterone undecanoate.

Morales A, Nieschlag E, Schubert M, Yassin AA, Zitzmann M, Oettel M · Aging Male · 2006

A report describing the standard dosing schedule for the 1000mg testosterone undecanoate in 4mL castor oil product (the Nebido formulation): a second injection 6 weeks after the first (loading phase), followed by maintenance every 12 weeks, individually adjustable within a 10–14-week window based on trough levels.

Grundy SM, Cleeman JI, Daniels SR, et al. · Circulation · 2005

American Heart Association and National Heart, Lung, and Blood Institute guidelines defining the criteria for metabolic syndrome and its treatment principles.

Coviello AD, Matsumoto AM, Bremner WJ, et al. · The Journal of Clinical Endocrinology & Metabolism · 2005

A study showing that low doses of hCG added to testosterone therapy maintain intratesticular testosterone concentration despite suppression of natural LH secretion.

Isidori AM, Giannetta E, Greco EA et al. · Clinical Endocrinology · 2005

A meta-analysis of randomized trials showing a slight drop in total cholesterol under testosterone therapy, more pronounced in men with lower baseline hormone levels, with no significant change in LDL across the pooled studies.

Boccardo F, Rubagotti A, Battaglia M, et al. · Journal of Clinical Oncology · 2005

In 114 patients from the same population, at 48 weeks gynecomastia occurred in 73% (bicalutamide alone) versus 10% (+tamoxifen) and 51% (+anastrozole); breast pain: 39% versus 6% and 27%. Tamoxifen clearly outperformed anastrozole for this indication.

Saltzstein D, Sieber P, Morris T, Gallo J · Prostate Cancer and Prostatic Diseases · 2005

In 107 patients from the same population, tamoxifen (not anastrozole) significantly reduced the incidence of gynecomastia and breast pain both prophylactically and therapeutically; testosterone also rose with tamoxifen relative to placebo.

Park Y.K., Lee H.B., Jeon E.J., Jung H.S., Kang M.H. · BioFactors · 2004

An in vitro study on human lymphocytes showed that an aqueous chaga extract reduced hydrogen peroxide-induced oxidative DNA damage by more than 40% compared with the control group — this is a laboratory, not clinical, study.

Wang PH, Hsu CI, Tang SC, Huang YL, Lin JY, Ko JL · Journal of Agricultural and Food Chemistry · 2004

FIP-fve activates T lymphocytes and induces interferon-gamma secretion via the p38 MAPK pathway — a mechanistic study at the cellular level.

Thompson IM, Pauler DK, Goodman PJ, et al. · New England Journal of Medicine · 2004

A study showing a significant rate of prostate cancer detected on biopsy even in men with PSA below the commonly used cutoff.

Leder BZ, Rohrer JL, Rubin SD, et al. · Journal of Clinical Endocrinology & Metabolism · 2004

An RCT in elderly men: bioavailable testosterone rose from 99±31 to 207±65 ng/dL on anastrozole, estradiol fell from 26±8 to 17±6 pg/mL. Despite this clear, significant hormonal improvement, sexual function scores showed no significant change — a real, documented example of a gap between improved bloodwork and improved well-being.

Kreider RB, et al. · Molecular and Cellular Biochemistry · 2003

An observation of athletes using creatine for up to 5 years found no negative effect on markers of kidney and liver function.

Hsiao G, et al. · Journal of Agricultural and Food Chemistry · 2003

An in vitro and mouse study showed strong free-radical scavenging and dose-dependent liver protection against damage caused by CCl4.

Nameda S, et al. · Immunopharmacology and Immunotoxicology · 2003

In an ex vivo study on blood from human volunteers, the SCG preparation enhanced synthesis of the cytokine IL-8 in a dose-dependent manner.

Yoon SJ, Yu MA, Pyun YR, Hwang JK, Chu DC, Juneja LR, Mourão PAS · Thrombosis Research · 2003

An in vitro study showed that the isolated acidic polysaccharide inhibits blood clotting by enhancing antithrombin's action on thrombin.

Foster GD, Wyatt HR, Hill JO, et al. · New England Journal of Medicine · 2003

A one-year randomized trial comparing an Atkins-type low-carbohydrate diet with a low-fat diet — faster weight loss in the first 6 months, a difference that faded by 12 months.

Brand-Miller J, Hayne S, Petocz P, Colagiuri S · Diabetes Care · 2003

A meta-analysis of randomized trials showing a moderate but statistically significant improvement in glycemic control (HbA1c) in people with diabetes following low-glycemic-index diets.

George-Gay B, Parker K · Journal of PeriAnesthesia Nursing · 2003

A practical review of how to interpret the complete blood count with differential, explaining the clinical significance of individual parameters.

Guay AT, Jacobson J, Perez JB, Hodge MB, Velasquez E · International Journal of Impotence Research · 2003

In a 4-month trial of 178 patients, sexual function improved in 75% and remained unchanged in 25%. LH and free testosterone rose significantly in nearly all patients, but the clinical response correlated with age and comorbidity burden.

Adamopoulos DA, Pappa A, Billa E, Nicopoulou S, Koukkou E, Michopoulos J · Fertility and Sterility · 2003

Spontaneous pregnancy rate was 33.9% (treated) versus 10.3% (placebo), but the regimen combined tamoxifen with exogenous testosterone undecanoate rather than testing tamoxifen as monotherapy — a materially different regimen than SERM-monotherapy fertility preservation in the sense used for clomiphene studies.

Mauras N, Lima J, Patel D, Rini A, di Salle E, Kwok A, Lippe B · Journal of Clinical Endocrinology & Metabolism · 2003

A crossover study in 12 boys and young men aged 14-26 (a population including minors, not adult TRT patients), given 25 mg or 50 mg of exemestane daily for 10 days. Estradiol fell by 38% and 32% at the respective doses, testosterone rose by 60% and 56%. Lipids and IGF-1 were unchanged over this short observation period. Half-life was 8.9 hours, peak concentration about one hour post-dose. This is the only exemestane pharmacokinetic/endocrine study found in males — no dedicated study exists in the adult TRT population.

Herxheimer A, Petrie KJ. · Cochrane Database of Systematic Reviews · 2002

A Cochrane review confirming melatonin's effectiveness in reducing jet lag symptoms when crossing multiple time zones.

Rossouw JE, Anderson GL, Prentice RL, et al. · JAMA · 2002

A large randomized trial assessing the benefit-risk balance of hormone replacement therapy in healthy postmenopausal women, which significantly changed clinical practice worldwide.

Kanis JA · The Lancet · 2002

A review of osteoporosis diagnostic methods, including the role of dual-energy X-ray absorptiometry as the reference method.

Levine JA · Best Practice & Research Clinical Endocrinology & Metabolism · 2002

A review of the concept of non-exercise activity thermogenesis and its significance for total energy expenditure and individual differences in susceptibility to weight gain.

Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM (Diabetes Prevention Program Research Group) · New England Journal of Medicine · 2002

A randomized trial enrolled 3,234 people with prediabetes, assigned to placebo, metformin, or an intensive lifestyle change program. After an average of 2.8 years of follow-up, lifestyle change reduced the risk of developing diabetes by 58% (95% CI 48-66%), and metformin by 31% (95% CI 17-43%), compared with placebo.

Galhaup C, Haltrich D · Applied Microbiology and Biotechnology · 2001

Adding copper ions to the growth medium significantly increases laccase production — a biotechnological study.

Stough C, et al. · Psychopharmacology · 2001

One of the first modern RCTs showing improved memory-retention ability after 12 weeks of supplementation.

Sacks FM, Svetkey LP, Vollmer WM, et al. · New England Journal of Medicine · 2001

The DASH-Sodium trial showed an additive, dose-dependent blood-pressure-lowering effect when combining the DASH diet with reduced sodium intake.

Sonksen P · Journal of Endocrinology · 2001

A review of the physiology of growth hormone and insulin secretion in the context of physical exercise and doping abuse in sport.

Ridker PM · Circulation · 2001

A paper discussing the role of high-sensitivity CRP as an additional cardiovascular risk marker, independent of traditional risk factors.

Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR · Journal of Clinical Endocrinology & Metabolism · 2001

A classic longitudinal study showing a gradual, statistically significant decline in total and free testosterone with age, and a rising proportion of men meeting the laboratory criterion for hypogonadism in successive decades of life.

Maguire EG, Gadian DG, Johnsrude IS, et al. · Proceedings of the National Academy of Sciences (PNAS) · 2000

An imaging study showing a larger posterior hippocampal volume in London taxi drivers compared with a control group, correlating with years of professional experience.

Wang C, Berman N, Longstreth JA, Chuapoco B, Hull L, Steiner B, Faulkner S, Dudley RE, Swerdloff RS · Journal of Clinical Endocrinology & Metabolism · 2000

A pharmacokinetic study in hypogonadal men: steady-state testosterone concentration (4–5 times baseline) was reached after about 2 days of regular, daily gel application, regardless of whether the dose was spread across one or four application sites — this study is also the source of data on lower testosterone bioavailability with abdominal application compared to shoulders and arms.

Franceschi C, Bonafè M, Valensin S, et al. · Annals of the New York Academy of Sciences · 2000

The paper that coined the term 'inflamm-aging' based on years of research into centenarians — proposes an evolutionary theoretical framework linking chronic inflammation to immune-system aging.

Vermeulen A, Verdonck L, Kaufman JM · Journal of Clinical Endocrinology & Metabolism · 1999

The paper establishing the Vermeulen formula — a mathematical method for calculating free testosterone from total testosterone, SHBG, and albumin based on a binding equilibrium model, validated against equilibrium dialysis.

UK Prospective Diabetes Study Group · The Lancet · 1998

A long-term trial showing that metformin reduces the risk of diabetes-related complications in overweight patients with type 2 diabetes.

Appel LJ, Moore TJ, Obarzanek E, et al. · New England Journal of Medicine · 1997

The original DASH trial — an eating pattern rich in fruit, vegetables, and low-fat dairy significantly lowered blood pressure compared with a typical American diet.

Prasad AS, Mantzoros CS, Beck FW, et al. · Nutrition · 1996

A study showing that zinc supplementation in men with an experimentally induced zinc deficiency significantly raised testosterone concentration compared with a control group.

Ko JL, Hsu CI, Lin RH, Kao CL, Lin JY · European Journal of Biochemistry · 1995

The paper isolating and sequencing the FIP-fve protein, showing its mitogenic action on human lymphocytes and its ability to increase IL-2 and IFN-gamma secretion in vitro.

Partsch CJ, Weinbauer GF, Fang R, Nieschlag E · European Journal of Endocrinology · 1995

A study in castrated male cynomolgus monkeys (NOT a human study). After enanthate injection at 7.2mg/kg, concentrations reached 100-177 nmol/L from almost immediately post-injection through day 5, then declined rapidly to the lower limit of normal by around day 31. Useful only as an illustration of the qualitative peak-trough shape, not as a source of numbers for humans.

Nakazato H, Koike A, Saji S, Ogawa N, Sakamoto J · The Lancet · 1994

A randomized trial of 262 patients after gastric cancer resection showed that adding PSK to standard treatment improved 5-year recurrence-free survival and 5-year overall survival compared with standard treatment alone.

Diabetes Control and Complications Trial (DCCT) Research Group · New England Journal of Medicine · 1993

A landmark study showing that intensive glycemic control (measured in part via HbA1c) significantly reduces the risk of diabetes microvascular complications.

Noda K, et al. · Japanese Journal of Clinical Oncology · 1992

A multicenter RCT in 292 patients showed a significantly higher rate of complete treatment response and faster lymphocyte recovery in the SPG group.

Selby C · Annals of Clinical Biochemistry · 1990

A classic review discussing the origin, function, and clinical significance of SHBG in interpreting hormonal status.

Reaven GM · Diabetes · 1988

A classic lecture describing insulin resistance as the common underlying basis of obesity, hypertension, dyslipidemia and type 2 diabetes (the 'Syndrome X' concept).

Okamura K, et al. · Cancer · 1986

A randomized study in 220 patients with cervical cancer — survival time in the SPG group was significantly longer in stage II.

Matthews DR, Hosker JP, Rudenski AS, et al. · Diabetologia · 1985

The paper introducing the HOMA-IR index — a mathematical model for estimating insulin resistance from simultaneous fasting glucose and insulin measurement.

Schürmeyer T, Nieschlag E · International Journal of Andrology · 1984

A crossover study in healthy men at a dose equivalent to 140mg free testosterone. Enanthate produced supraphysiological levels within 2 hours, peaking at 4-5 times baseline between 8 and 24 hours, with return to baseline after 9 days; LH and FSH suppression was observed throughout. Primary real human data underlying knowledge of this ester's peak-trough curve shape.

Jenkins DJA, Wolever TMS, Taylor RH, et al. · American Journal of Clinical Nutrition · 1981

The foundational paper introducing the concept of the glycemic index as a way to classify carbohydrate foods by their actual effect on glycemia.

Hammerschmidt DE · New England Journal of Medicine · 1980

A classic clinical case report — after eating a dish with black fungus, the researcher's platelets stopped aggregating properly for several to several dozen days.

Schulte-Beerbühl M, Nieschlag E · Fertility and Sterility · 1980

A classic study directly comparing serum concentration profiles of testosterone, dihydrotestosterone, and LH/FSH suppression after injecting testosterone enanthate (194 mg) and cypionate (200 mg) at doses containing an equivalent amount of free hormone (140 mg). The concentration curves for both esters tracked nearly identically throughout the observation period.