Rapamycin
Sirolimus; mTORC1 inhibitor that acts as a complex with FKBP12. With chronic dosing it can also disrupt mTORC2 assembly in some cell types and tissues (SAR2006; mouse liver in LAM2012), a time- and cell-type-dependent effect. Immunosuppressant; extends lifespan in mice.
The drug that made this pathway famous. Also called sirolimus. The original mTOR-blocking drug (mainly hits mTORC1; with long-term use it can also affect mTORC2 in some tissues). Used to prevent organ-transplant rejection, and the most reproducibly lifespan-extending drug in mice across the testing sites of the NIA programme.
Sirolimus. Not an active-site inhibitor: the FKBP12–rapamycin complex binds the FRB domain and partially occludes substrate access, which is why 4E-BP1 phosphorylation is only incompletely blocked.
TL;DR. Rapamycin appears in 113 curated studies in Oliver's mTOR Atlas: 18 in people (1 synthesis of human data, 17 human studies); 49 in animal models; 40 at the molecular level (cells, biochemistry, structure); 4 reviews; 1 preprint, not peer-reviewed; 1 registered trial without results yet. It has 5 interactions in the curated pathway model.
In the pathway model
| Interaction | Mechanism | Evidence | Studies |
|---|---|---|---|
| Rapamycin binds FKBP12 mechanism: binding · this link in full · on the map table | Rapamycin doesn't work alone – it first has to team up with a helper protein called FKBP12. Holds under: X-ray crystallography and in vitro work on bovine, rat and mouse material (CHO1996, BRO1994, SAB1995). Describes drug binding in purified systems; it says nothing about dose or effect in patients. plausible in people, not shown directly · settled in the literature | M | CHO1996, BRO1994, SAB1995 |
| Rapamycin inhibits Lymphangioleiomyomatosis mechanism: clinical-outcome · this link in full · on the map table | In a clinical trial, rapamycin stabilised lung function in a rare lung disease while patients kept taking it – the decline came back once they stopped. Holds under: Benefit is suppressive: lung function declined again after withdrawal. shown in people · settled in the literature | H | MCC2011 |
| Rapamycin activates Longevity mechanism: functional-consequence · this link in full · on the map table | Rapamycin makes mice live longer, even when given late in life – the single biggest result behind the whole "this pathway and ageing" idea. Holds under: Mouse only. No human lifespan or healthspan endpoint exists; EVERLAST has no results yet. BIT2016 shows a non-continuous schedule can still extend post-treatment life expectancy, but the result is dose- and route-specific: in the 8 mg/kg/day intraperitoneal arm males gained +60% post-treatment life expectancy (p=0.02) while females showed no survival benefit (p=0.261) and a shift toward aggressive haematopoietic cancers (16/16 vs 6/12, p=0.002); in the same paper's 126 ppm dietary encapsulated-rapamycin arm survival rose significantly in BOTH sexes, with a Cox model finding no evidence that sex modified the treatment effect (p=0.904). Cite the arm, not just the paper. ARR2016: an intermittent regimen (2 mg/kg every 5 days) started as late as 20 months of age extended lifespan in female C57BL/6J mice; the abstract reports the effect in females only. not tested in people · settled in the literature | A | HAR2009, BIT2016, KHA2014, CHE2009, ARR2016, ANI2011 |
| Rapamycin inhibits mTORC2 mechanism: complex-assembly · this link in full · on the map table | Rapamycin doesn't touch mTORC2 right away, but over days it stops new mTORC2 from being built. Holds under: Strictly time- and cell-type-dependent: absent acutely, present after prolonged exposure, and the sensitivity varies between cell lines. LAM2012 shows the same loss of mTORC2 signalling in mouse liver in vivo, so this is not a cell-culture-only phenomenon. Treating this edge as unconditional is a common error. plausible in people, not shown directly · settled in the literature | A | SAR2006, LAM2012 |
| Rapamycin inhibits mTORC1 mechanism: allosteric-inhibition · this link in full · on the map table | Rapamycin, carried by its helper protein FKBP12, jams part of mTORC1 – it blocks some of what mTORC1 does but not all of it. Holds under: Directness is graded indirect because the mechanism requires FKBP12, as for everolimus and the bi-sterics. Acute effect only; the chronic effect on mTORC2 is the separate RAPA-MTORC2 edge. plausible in people, not shown directly · settled in the literature | A | CHU1992, BRO1994, SAB1994, SAB1995, CHO1996, MEI2008, KAN2013, FIN2002, BRU1997, SAT2010, YIP2010, RAO2010, MAR2014, BAT2013 |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| S | Synthesis of human data | 1 |
| H | Human study | 17 |
| A | Animal model | 49 |
| M | Molecular — cells, biochemistry, structure | 40 |
| PP | Preprint, not peer-reviewed | 1 |
| RT | Registered trial, no results yet | 1 |
| R | Review — secondary literature, not a new result | 4 |
Human studies in the Atlas
Studies
| Year | Evidence | Study |
|---|---|---|
| 2024 | S | Targeting ageing with rapamycin and its derivatives in humans: a systematic review LEE2024 Described by its authors as the first systematic review of rapamycin/rapalogs in humans for aging. Screened 18,400 articles, included 19 studies. Found improvements in immune, cardiovascular, and skin (integumentary) parameters; NO significant effect on endocrine, muscular, or neurological systems. No serious adverse events in healthy people, but more infections and raised cholesterol/triglycerides in people with age-related disease. This is the highest-tier human-evidence summary in the whole Atlas - it aggregates many individual human studies rather than reporting one. |
| 2026 | H | Association of rapamycin treatment with the modulation of purine metabolism, reduced microglial inflammatory responses, improved mitochondrial energy metabolism, and alleviation of fatigue symptoms in ME/CFS subjects: pilot findings from phase-II observational study GIL2026 In an uncontrolled phase-II pilot (no placebo), low-dose rapamycin was associated with reduced fatigue in ME/CFS. In plasma from responders, purine intermediates shifted, consistent with lower IMP dehydrogenase activity in PBMCs. Lab assays suggest that altered purines can impair mitochondrial metabolism and promote microglial inflammation; these links were not measured in patients. |
| 2026 | H | Rapamycin increases cerebral blood flow and modulates metabolic, inflammatory, and microbiome profiles in healthy middle-aged APOE4 carriers: a pilot single-arm trial. AWARE2026 Single-arm pilot trial: 1 mg/day rapamycin for 4 weeks in 23 cognitively normal adults aged 45 to 65. Cerebral blood flow rose by more than 15% across several brain regions in the nine APOE4 carriers, while non-carriers showed no significant change; metabolic and inflammatory profiles improved and the gut microbiome was modulated. Uncontrolled, small and genotype-specific, so this is early evidence only. |
| 2026 | H | Rapamycin Exerts Its Geroprotective Effects in the Ageing Human Immune System by Enhancing Resilience Against DNA Damage KEL2026 Proposes a geroprotective mechanism for rapamycin that the authors call direct genoprotection. In human T cells exposed to acute genotoxic stress, rapamycin and other mTOR inhibitors suppressed senescence not by slowing protein synthesis, halting cell division, or stimulating autophagy, but by reducing DNA lesion burden and improving cell survival. Ex vivo aged human immune cells showed elevated DNA damage, senescence and mTORC-hyperactivation markers. In a placebo-controlled experimental medicine study, low-dose rapamycin significantly reduced p21 (a DNA-damage-induced senescence marker) in immune cells of older adults versus placebo. Boundary: what was measured is reduced DNA lesion burden under acute genotoxic stress ex vivo, plus one marker (p21) in vivo. 'Genoprotection' as a general property of rapamycin is the authors' interpretation, and no clinical endpoint was measured. |
| 2026 | H | Rapamycin in Frail Older Subjects with Heart Failure with Preserved Ejection Fraction LAN2026 Trial of low-dose rapamycin in frail older adults with heart failure with preserved ejection fraction (HFpEF), from a Mayo Clinic/UW-Madison team including senolytics/mTOR-aging researchers Kirkland and Lamming; abstract not yet available (ahead-of-print). |
| 2026 | H | Multivariate Survival Analysis of a Comprehensive Clinical Trial of Rapamycin in Amyotrophic Lateral Sclerosis Explores Prognostic Factors and Survival Patterns in C9orf72 Carriers DEN2026B Secondary, observational survival analysis of the RAP-ALS rapamycin trial (n=63) finds a protective association between rapamycin treatment and survival in C9orf72 mutation carriers (log-rank p=0.026), consistent with a comparison against an independent C9orf72+ cohort (n=40; RMST p=0.04); confounding by indication is not excluded, and the authors flag this as exploratory given the small treated-carrier subgroup (n=6). |
| 2026 | H | Leniolisib and rapamycin in Activated PI3-Kinase-δ-syndrome: a retrospective ESID registry-based analysis RIV2026 In a 95-patient ESID registry of Activated PI3Kδ Syndrome (APDS), rapamycin and the targeted PI3Kδ inhibitor leniolisib produced comparable overall response rates for lymphoproliferation (67% vs 64%), but treatment-limiting adverse events occurred only in the rapamycin-treated group; lymphoma cases were observed during follow-up in the cohort. |
| 2026 | H | Maternal Sirolimus Therapy for Fetal Extensive Lymphatic Cystic Malformation: Selection Criteria, Management, and Outcomes in a Series of Six Cases GUIB2026 Maternal rapamycin (sirolimus) therapy for extensive fetal lymphatic malformations. Prenatal mTOR inhibition feasible with partial/marked lesion regression in 5/6 newborns; transplacental transfer observed. Observational case series (n=6); confounding by indication not excluded. |
| 2026 | H | High Responsiveness of Head and Neck Kaposiform Hemangioendothelioma Without Kasabach-Merritt Phenomenon to Sirolimus Monotherapy. XU2026 In 71 children with kaposiform haemangioendothelioma without Kasabach-Merritt phenomenon, head and neck lesions achieved a 100% 12-month radiologic response to sirolimus monotherapy versus 76% elsewhere; anatomical location was the only independent predictor of response. Observational: a matched multicentre cohort, not a randomised comparison, so confounding by indication and by lesion characteristics cannot be excluded and the association between site and response is not established as causal. |
| 2026 | H | Sirolimus is effective for paediatric Evans syndrome and secondary autoimmune cytopenias: A retrospective cohort study. MCNEILL2026 Retrospective single-centre paediatric cohort reporting that sirolimus is effective in paediatric Evans syndrome and secondary autoimmune cytopenias. Abstract not yet indexed — effect sizes to be confirmed. |
| 2026 | H | Favorable response to second-line sirolimus regardless of STAT3/5b status in acquired pure red cell aplasia: A retrospective study from a single center. SUN2026 Second-line sirolimus achieved a 54.5% overall response rate in ciclosporin-refractory acquired pure red cell aplasia (64.3% in secondary disease) versus 25.0% for first-line ciclosporin, with responses independent of mutation status. Observational: a single-centre retrospective series with no randomisation and no concurrent control arm. The sirolimus and ciclosporin figures come from different lines of therapy in a selected population, so confounding by indication is not excluded and the two rates should not be read as a head-to-head comparison. |
| 2025 | H | Influence of rapamycin on safety and healthspan metrics after one year: PEARL trial results MOE2025 The authors describe PEARL as the longest trial of rapamycin for healthy ageing so far: 48 weeks, once a week, ages 50 to 85, 114 people finished (40 on 5 mg, 35 on 10 mg, 39 on placebo). The question the trial was built to answer was visceral fat on a DXA scan, and that did not change. Most of what gets quoted comes from secondary results. Lean mass rose in women on 10 mg, and these women also reported less pain, but pain came from a questionnaire the authors did not list as an endpoint, and only eight women were in the 10 mg group, hence the very wide interval (odds ratio 28, 95% CI 2.4 to 324). Side effects were similar to placebo, with more stomach complaints on rapamycin. Bone density was the one signal pointing the wrong way: in the 5 mg group the odds of an improvement in bone mineral density were lower than on placebo (odds ratio 0.24, 95% CI 0.06 to 0.93, p = 0.04), but 10 mg showed no change (odds ratio 1.00) and the comparisons between groups were not significant. Boundary: the capsules were compounded, and the authors found they reached about a third of the blood level of the commercial drug, so 10 mg here is closer to 3 mg of generic sirolimus. Dosing was self-reported, and the group was about two thirds men and health-conscious. |
| 2019 | H | Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial CHU2019 A small human trial testing whether rapamycin can slow aging in a tissue you can actually see and biopsy - skin. Topical rapamycin significantly lowered the senescence marker p16 and raised collagen VII, with visible improvement in skin appearance. Early, small-scale evidence (17 of 36 completed) that topical rapamycin can reduce a senescence marker in human skin. |
| 2018 | H | A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. KRA2018 A safety-first pilot RCT (n=25, ages 70-95) asking the basic question before any longevity trial: is daily rapamycin safe in healthy older people? Over 8+ weeks it was well tolerated with only minor red-blood-cell changes and - importantly - NO rise in blood glucose or insulin resistance in this short window. Groundwork for larger aging trials like PEARL. |
| 2011 | H | Efficacy and safety of sirolimus in lymphangioleiomyomatosis (MILES) MCC2011 MILES was a 12-month placebo-controlled trial of sirolimus in 89 women with lymphangioleiomyomatosis (LAM), a rare lung disease driven by overactive mTOR. On placebo, lung function (FEV1) fell by about 12 ml a month. On sirolimus it held steady (+1 ml a month), a 153 ml difference over the year. In the next year nobody took the drug, and the sirolimus group's decline resumed in parallel with placebo, so the benefit lasted only while the drug was taken. Walking distance and gas-transfer capacity did not improve. Boundary: patients had fairly advanced disease (average FEV1 about 48% of predicted), many dropped out of the observation year, and mouth ulcers and rashes may have revealed who was on the drug. Sirolimus was held at a blood level of 5 to 15 ng/ml, so this was continuous dosing, not intermittent. |
| 2009 | H | Rapamycin administration in humans blocks the contraction-induced increase in skeletal muscle protein synthesis DRU2009 Rapamycin given before resistance exercise blocked the early (1–2 h) post-exercise rise in human muscle protein synthesis, which was about 40% in the control group. Rapamycin also blocked the rise in ERK1/2 phosphorylation and blunted MNK1, so the authors conclude that mTORC1 drives the response only in part. The study measured acute protein synthesis, not muscle growth. |
| 2006 | H | Rapamycin causes regression of astrocytomas in tuberous sclerosis complex FRA2006 Five people with tuberous sclerosis complex whose brain astrocytomas were growing on serial scans (four subependymal giant cell astrocytomas, one pilocytic astrocytoma) were treated with oral rapamycin at standard immunosuppressive levels (blood 5-15 ng/ml) for 2.5 to 20 months. On MRI, every lesion shrank, and one showed necrosis. In one patient the tumour grew back when treatment was interrupted and shrank again when it was restarted. Treatment was well tolerated. This small uncontrolled series was one of the early reports that mTOR inhibition can shrink TSC brain tumours in patients, and it preceded the EXIST-1 everolimus trial. Boundary: 5 patients, open-label case series without a control group; TSC-associated astrocytomas only; regression depended on continued treatment. |
| 2000 | H | Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study KAH2000 The trial that established rapamycin (sirolimus) as an immunosuppressant in kidney transplant patients - its original, still-standard clinical use. |
| 2026 | A | LKB1/AMPK deficiency aggravates mitochondrial DNA leakage via mTOR-dependent mitophagy damage in liver injury sensitized by trichloroethylene. ZHU2026 LKB1/AMPK deficiency exacerbates trichloroethylene-induced liver injury by impairing mTOR-regulated mitophagy and causing mitochondrial DNA leakage; rapamycin and AMPK activation are protective, nominating the LKB1/AMPK/mTOR axis as a candidate therapeutic target in mice; no human data. |
| 2026 | A | Rapamycin-induced fatty liver in mice is attenuated by chloroquine co-treatment in an ERRα-dependent manner BCH2026 Chloroquine co-treatment attenuates rapamycin-induced hepatic steatosis (a known mTORC1-inhibitor side effect) in mice, and this rescue depends on the nuclear receptor ERRα; RNA-seq shows chloroquine reverses rapamycin-driven upregulation of lipid-metabolism genes, with ERRα identified as a top transcriptional regulator of the effect. |
| 2026 | A | Diet-dependent, beneficial and adverse effects of rapamycin on life span of Drosophila melanogaster JAC2026 Rapamycin's effect on Drosophila lifespan is highly diet-dependent: on a cornmeal/torula-yeast medium it was harmful in 19 of 26 experiments across 5 strains, but on a nutrient-rich brewer's-yeast medium it was beneficial in 8 and neutral in 14, with no significant harm. Effects on median lifespan ranged from -51.3% to +5.4%, varying by sex and strain; rapamycin was also toxic to development at 10-200 µM. |
| 2026 | A | High-concentration hydrogen mitigates cognitive impairment in a murine model of Sepsis-associated encephalopathy by enhancing oligodendrocyte maturation and myelination in the mPFC YU2026 In a mouse model of sepsis-associated encephalopathy (SAE), mTOR hyperactivation impairs oligodendrocyte maturation and causes cognitive deficits; hydrogen gas and rapamycin suppress mTOR, restore myelination, and improve cognition in these mice. |
| 2026 | A | Rapamycin attenuates age-related atrial remodeling and fibrillation by targeting HIF-1α-mediated metabolic dysregulation. JIN2026B Dietary rapamycin reduced aging-induced atrial fibrillation susceptibility and atrial remodelling in D-galactose-aged mice, acting through mTOR-independent inhibition of HIF-1α plus restored mitochondrial function and insulin sensitivity. |
| 2026 | A | Therapeutic Immune Reprogramming by Rapamycin Attenuates Plaque Inflammation and Lymphoid Immune Responses in Aged Atherosclerotic Mice JIN2026C In aged atherosclerotic mice, rapamycin (mTORC1 inhibition) reduced plaque macrophage content and total T cell numbers, shifted CD8 T cells from effector to central-memory phenotype, enriched aortic regulatory T cells (higher Foxp3/Tgfb1), reduced Tfh cells, germinal-center B cells, plasma cells and autoantibody levels, diminished age-associated B cells, and lowered senescence-enrichment scores in aortic leukocytes -- consistent with rapamycin acting as an immune-rejuvenation therapeutic that mitigates age-related atherogenic inflammation. |
| 2026 | A | Chronic Kidney Disease Risk Posed by 1-Ethoxy-2,3-difluoro-4-(trans-4-propylcyclohexyl) Benzene (EDPrB): An AOP of mTOR-Mediated Autophagy Dysregulation. MIAO2026 In mice, the environmental pollutant EDPrB accumulates in the kidney and causes CKD via mTOR hyperactivation, leading to autophagy dysregulation, inflammation and fibrosis; rapamycin rescue identified mTOR as the molecular initiating event, with corroborating data in HK-2 human kidney cells. |
| 2026 | A | mTORC1-TFEB/TFE3 signaling is associated with bile acid diversification during hepatic metabolic adaptation ZAU2026 Establishes a new mTORC1-TFEB/TFE3 signaling axis controlling hepatic bile acid metabolism. Depending on mTORC1 signaling state, mice show coordinated shifts in bile-acid species (non-12-OH vs 12-OH) via altered enzyme expression and cholesterol trafficking; these shifts are reversed by mTORC1 pathway deletion or rapamycin treatment. Dietary protein restriction (which inhibits mTORC1) produces a similar bile-acid shift in mice and correlates with improved metabolic outcomes in human MASLD patients, linking mTORC1 nutrient sensing directly to bile-acid homeostasis and fatty liver disease. |
| 2026 | A | Role of Autophagy in Scleral Remodeling During Form-Deprivation Myopia WEN2026 Excess scleral autophagy links hypoxic stress to extracellular matrix remodelling in experimental myopia. In form-deprived guinea pigs, subconjunctival rapamycin made myopia worse and 3-MA alleviated it, while atropine slowed myopia and suppressed autophagy-related changes. AMPK/mTOR/P70S6K signalling was measured, but the paper does not establish it as the mediating route. |
| 2026 | A | Impaired mTOR/SREBP1-Mediated Lipogenesis as a Mechanism of Hepatic Glycogen Accumulation in a Carnivorous Fish Model, Largemouth Bass (Micropterus salmoides) TAO2026 mTOR/SREBP1 signaling governs hepatic glucose partitioning; the insulin-responsive mTOR/SREBP1 axis promotes lipogenesis versus glycogen accumulation. In this model -- a carnivorous fish -- impairment of the axis is associated with hepatic glycogen overload mimicking glucose intolerance. |
| 2026 | A | Early-life exposure to polypropylene microplastics and DEHP induces ASD-relevant neurodevelopmental alterations involving mTOR-regulated autophagy impairment YANG2026 PP-MPs and DEHP activate mTOR and impair autophagy, inducing ASD-like neurodevelopmental deficits in mice; rapamycin rescues autophagic flux and social/behavioral phenotypes. |
| 2026 | A | Sex-stratified immune patterns across the canine lifespan and short-term responses to geroprotective interventions LAI2026 In 24 young Beagles given a 90-day course of rapamycin, the SGLT2 inhibitor canagliflozin, or dietary restriction, rapamycin produced the broadest shift in blood cytokines of the three, while a separate cross-sectional cohort of 80 Beagles aged 1-11 showed that immune aging in dogs is non-linear and sex-stratified rather than a steady decline. Dogs are an increasingly used translational model for geroscience because of their size and lifespan diversity, so this adds a rare canine data point to the rapamycin-immune-aging picture; the authors flag the intervention findings as exploratory given small group sizes and endpoint-only measurements. |
| 2026 | A | Rapamycin Attenuates Age-Related Changes in Marmoset Submandibular Gland: A Non-Human Primate Model of Human Oral Aging. ABD2026 In the aging marmoset submandibular gland the authors found fewer mucous and serous acinar units, expansion of ductal and collagen-rich stromal compartments, more extracellular matrix remodeling, dysregulated lipid metabolism, and more apoptotic and senescent cells. Chronic oral rapamycin was associated with partial preservation of acinar structure and with less fibrosis, lipid accumulation and fewer apoptotic and senescent cells, giving a tissue picture closer to that of younger animals. Boundary: histological and immunofluorescence associations in one tissue of a short-lived primate; the abstract gives no dose or group sizes, does not show that gland function improved, and reports no lifespan outcome. |
| 2023 | A | A masked, placebo-controlled, randomized clinical trial evaluating safety and the effect on cardiac function of low-dose rapamycin in 17 healthy client-owned dogs BAR2023 In 17 healthy pet dogs, 6 months of low-dose rapamycin (0.025 mg/kg, three times a week) caused no clinically significant adverse events. Echocardiography, however, showed NO statistically significant difference from placebo at 6 or 12 months, so the heart benefit hinted at in the earlier 10-week trial (URF2017) was not reproduced. Owners did report perceived positive changes in behavior or health more often in the rapamycin group (26.8% vs 8.1% of bi-weekly surveys), but that is a subjective, owner-reported outcome. A small safety-focused trial, not designed to test lifespan. |
| 2022 | A | Lifespan benefits for the combination of rapamycin plus acarbose and for captopril in genetically heterogeneous mice STR2022 NIA Interventions Testing Program C2017 cohort. In MALE mice, rapamycin plus acarbose started at 9 months produced a longer lifespan than either of the two prior ITP cohorts treated with rapamycin alone, suggesting the combination is more potent than its components used separately. In FEMALES the combination was neither better nor worse than rapamycin alone, which the authors relate to the limited survival benefit acarbose alone had shown in earlier female cohorts. Captopril gave a small but significant lifespan increase in females (4-5%). CAVEAT (important for how this is cited): the rapamycin-only comparison is HISTORICAL, against prior cohorts, not a concurrent rapamycin-only arm in the same experiment, so 'more potent than either component' is the authors' suggestion rather than a within-experiment randomised comparison. |
| 2021 | A | DNA methylation age analysis of rapamycin in common marmosets. HOR2021 The authors built two epigenetic clocks for common marmoset blood from DNA methylation data; the human-marmoset clock for relative age correlated moderately well with age in vervet monkeys and rhesus macaques. In a separate marmoset cohort they tested whether rapamycin would change epigenetic age. The clocks did not detect a significant effect of rapamycin on the epigenetic age of marmoset blood. Boundary: a null result on one biomarker (DNA methylation age in blood). It does not show that rapamycin has no effect on aging in marmosets, only that these clocks did not register one; the abstract gives no dose, duration or group size. |
| 2018 | A | mTOR signaling regulates central and peripheral circadian clock function RAM2018 mTOR sets how fast and how strongly the circadian clock ticks. Inhibiting mTOR lengthened the clock period and flattened its amplitude; activating it shortened the period and raised the amplitude, in cells, in ex vivo brain (SCN) and liver clocks, and in mTOR heterozygous mice, whose locomotor rhythm ran longer. The study starts from the observation that mTOR activity itself oscillates over 24 hours in many tissues. |
| 2018 | A | Long-term treatment with the mTOR inhibitor rapamycin has minor effect on clinical laboratory markers in middle-aged marmosets. SIL2018 In middle-aged marmosets given daily rapamycin, 9 months of treatment produced only minor changes in cellular blood counts, so hematological side effects are not likely outcomes of long-term rapamycin in relatively healthy middle-aged animals. Trough blood concentrations of rapamycin were significantly lower in females than in males, yet both sexes changed little. At baseline, males and females differed little in morphology or in markers of blood cell counts, metabolism and inflammation. Boundary: healthy middle-aged marmosets, 9 months, hematology and clinical laboratory markers only; it says nothing about efficacy or lifespan, and the abstract does not give the dose or group sizes. |
| 2017 | A | A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs URF2017 A short 10-week course of low-dose rapamycin in healthy pet dogs caused no clinical side effects, and echocardiography suggested improved measures of heart function. |
| 2016 | A | Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice BIT2016 Mice got rapamycin for only 3 months, starting at 20 to 21 months of age, and were then taken off it. A high injected dose (8 mg/kg a day) raised the males' remaining life expectancy after treatment by 60% (p = 0.02), which is a 16% longer median lifespan counted from birth. In females the same dose did not extend life (p = 0.26), and all 16 treated females examined had aggressive blood-cell tumours of the lymphoma type, against 6 of 12 controls, while other tumour types became rarer. A lower dose in the diet (126 ppm; the injected dose was estimated to equal about 378 ppm) raised post-treatment life expectancy by 42% in both sexes together and median lifespan by 13%, improved grip strength and rotarod performance, and changed the gut bacteria (more segmented filamentous bacteria). Boundary: mice only. The tumour counts come from small groups (12 to 16 per arm), side effects such as cataracts or testis changes were not tested at the dietary dose, and 'life expectancy' is counted from the end of treatment, so it makes the gain look larger than the change in total lifespan. |
| 2016 | A | Intermittent Administration of Rapamycin Extends the Life Span of Female C57BL/6J Mice ARR2016 Female C57BL/6J mice that started rapamycin at 20 months of age, 2 mg/kg once every 5 days, lived longer than control females. This is the schedule that the same group had earlier shown to have a smaller effect on glucose tolerance and T cells than daily dosing (ARR2015), so the authors argue that rapamycin's effect on lifespan can be separated from many of its side effects. Boundary: this record rests on the abstract only. The size of the lifespan gain, any male data and any side-effect measurements in these old mice are not extracted yet. The separation claim comes from combining two mouse studies (ARR2015 used young males), not from a single experiment. |
| 2016 | A | Pharmaceutical inhibition of mTOR in the common marmoset: effect of rapamycin on regulators of proteostasis in a non-human primate. LEL2016 In liver and skeletal muscle from rapamycin-treated marmosets (the earlier pilot cohort), rapamycin was associated with higher expression of PSMB5, a core 20S proteasome subunit, in both tissues but not of PSMB8; proteasome activity itself did not change. Mitochondria-targeted chaperones rose in skeletal muscle but not liver, and autophagy rose in skeletal muscle and adipose tissue but not liver. The authors conclude that only some components of the proteostasis network were upregulated, and in a tissue-specific way. Boundary: tissue samples from a small pilot cohort; the changes are expression-level associations and are not shown to cause any health or lifespan effect. |
| 2015 | A | Health Effects of Long-Term Rapamycin Treatment: The Impact on Mouse Health of Enteric Rapamycin Treatment from Four Months of Age throughout Life FIS2015 Mice of both sexes were fed rapamycin in their food (14 ppm, encapsulated) from 4 months of age until death, 40 per sex per group, and the same animals were tested repeatedly for health measures from 16 months of age. Some measures improved: females had stronger grip at all ages, females kept body mass and fat longer during late-life weight loss, and sleep fragmentation fell in males (with a trend in females). Others did not change, such as stride length and age-related cochlear damage, and male rotarod performance was worse. In body mass, percent fat and resting metabolic rate, rapamycin moved males and females in opposite directions. The study showed that lifelong rapamycin in mice affects healthspan measures in a mixed and strongly sex-specific way rather than improving health across the board. Boundary: C57BL/6J mice only, one dietary dose; survival was reported in a companion paper, not in this one, and mTOR activity was not measured here. |
| 2015 | A | Metabolic consequences of long-term rapamycin exposure on common marmoset monkeys (Callithrix jacchus). ROS2015 Long-term oral encapsulated rapamycin in marmosets had only minor metabolic consequences. Body weight was unchanged overall and fat mass fell only slightly over the first few months. Daily activity counts, blood lipids and glucose metabolism, including oral glucose tolerance, did not change significantly, and adipose tissue showed no difference in metabolic-marker gene expression. In liver, G6Pase activity was suppressed while PCK and GPI activity increased. Boundary: marmoset, oral rapamycin, metabolic endpoints only; the abstract gives neither the dose nor group sizes, and no lifespan result is reported. |
| 2014 | A | BMAL1-dependent regulation of the mTOR signaling pathway delays aging KHA2014 Loss of the clock protein BMAL1 raised mTORC1 activity in mice and in cultured cells, and rapamycin extended the lifespan of Bmal1-/- mice by 50%. Places the circadian clock upstream of mTORC1 as a brake, and links that brake to ageing. |
| 2014 | A | The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells MAR2014 This study separated two arms of IL-15 signalling in NK cells by dose: low IL-15 mainly phosphorylated STAT5 (EC50 about 1.5 ng/ml), while higher IL-15 was needed to switch on mTOR (EC50 about 5.3 ng/ml for S6 phosphorylation), and IL-15 was the only one of many tested stimuli that strongly raised pS6. Deleting mTOR in NK cells left bone-marrow numbers normal but blocked the CD11b-low to double-positive transition, cut proliferation about three-fold and left almost no mature NK cells in the periphery, with lower CD71, glucose uptake and about half the surface CD122 and CD132, so the receptor feedback is itself mTOR-dependent. In activation, mTOR-deficient NK cells failed to grow or raise nutrient uptake after poly(I:C) and made about half as much granzyme B, while IFN-gamma production in response to IL-12 plus IL-18 stayed normal. Oral rapamycin lowered pS6 and granzyme B in vivo and made rejection of MHC-class-I-negative target cells significantly less efficient, and mTOR inhibitors also blocked IL-2-driven granzyme B induction in human NK cells. Boundary: mouse genetics and mouse in vivo pharmacology, with the human arm limited to healthy-donor NK cells stimulated in culture; the clinical implication for patients on rapalogs is inference, not a measured patient outcome. |
| 2014 | A | Testing efficacy of administration of the antiaging drug rapamycin in a nonhuman primate, the common marmoset. TAR2014 First description of dosing, pharmacokinetics, biochemical action and tolerability of rapamycin in the common marmoset. Eudragit-encapsulated rapamycin given orally at roughly 1.0 mg/kg/day gave mean trough blood levels of 5.2 ng/mL (range 1.93-10.73), comparable to rodent studies and within the human therapeutic range. In long-term animals (6 of 8) the phospho-rpS6 to total rpS6 ratio fell after 2 weeks, and rapamycin was detectable in liver and adipose tissue with reduced mTOR signalling there. There was no evidence of clinical anemia, fibrotic lung changes or mouth ulcers, and the death rate in the 14-month study was as expected for the animals' ages. Boundary: small cohort (6 of 8 long-term animals showed the pS6 drop), a 3-week and a 14-month study, pharmacology and tolerability only; no lifespan or healthspan outcome was measured, and nothing here is tested in people. |
| 2013 | A | Late-life rapamycin treatment reverses age-related heart dysfunction FLY2013 Striking evidence that in mice mTOR inhibition doesn't just SLOW aging - it can partly reverse an established age-related phenotype. Giving rapamycin to already-old (24-month) female mice for 3 months improved aged heart function, reversing or attenuating age-related cardiac changes, with RNA-seq changes suggesting anti-hypertrophic and anti-inflammatory effects. Started late, still worked. |
| 2012 | A | Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity LAM2012 Chronic rapamycin (about 2 mg/kg a day, close to the lifespan-extending dose) made mice glucose intolerant and insulin resistant. A clamp test placed the problem in the liver, which kept making glucose, while muscle and fat took up glucose normally. Removing mTORC1 from the liver did not cause this. Rapamycin did break up mTORC2 (it separated mTOR from Rictor) in liver, fat and muscle, and deleting Rictor in the liver alone reproduced the glucose problem. In the genetic part, female mice with one working copy each of mTOR and mLST8 had about 50% less mTORC1 signalling in the liver, normal mTORC2 signalling and normal glucose tolerance, and lived 14.4% longer on average (p = 0.046). Males did not. Boundary: mouse drug and genetics work, not people, and the lifespan gain is female-only. It supports separating the two effects, but the paper does not test a drug that blocks mTORC1 without touching mTORC2. |
| 2012 | A | Rapamycin slows aging in mice WIL2012 Answered a crucial objection: does rapamycin really slow AGING, or just prevent the cancers that kill mice? By showing slower age-related change across many tissues (heart, liver, tendon, activity), it argued for genuine slowing of aging. Honestly reported harms too - more cataracts and testicular degeneration - making it a balanced landmark, not hype. |
| 2012 | A | Chronic inhibition of mammalian target of rapamycin by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice. HAL2012 Asked whether the lifespan-extending dose of rapamycin harms or helps the aging BRAIN. Reassuringly, it enhanced learning and memory in young mice, prevented age-related cognitive decline in old ones, and even reduced anxiety and depression-like behavior - linked to boosted brain monoamines. Cognitive benefit, not cost. |
| 2012 | A | Lifelong rapamycin administration ameliorates age-dependent cognitive deficits by reducing IL-1β and enhancing NMDA signaling MAJ2012 Mice were fed rapamycin in their food either from 2 months of age or only from 15 months, when age-related memory deficits were already present, and all were tested at 18 months in a water maze (20 mice per group). Mice treated from 2 months learned the hidden-platform location faster and spent more time in the target quadrant in the memory test (28.7 vs 21.3 seconds for controls), while mice started at 15 months did no better than controls. Both rapamycin groups had lower phosphorylation of S6K in the brain, a marker of mTOR activity. The improvement in the early-treated mice went together with lower IL-1beta in brain and hippocampus and higher phosphorylation of the NMDA receptor subunit NR2B and of CREB, which the authors propose as the route. Boundary: Mice of one mixed strain, normal ageing (not an Alzheimer model); the late-start arm showed no reversal of existing deficits, and the IL-1beta and NMDA links are correlations, not tested by blocking them. |
| 2012 | A | Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice TSA2012 Deleting one or both copies of Tsc1 only in cerebellar Purkinje cells raised phospho-S6 (a readout of mTORC1) in those cells. Both heterozygous and homozygous mutants showed autism-like behaviour: no preference for a mouse over an object or for a new mouse, more self-grooming, more pup ultrasonic calls and poorer reversal learning in a water T-maze. Purkinje cells fired fewer action potentials, both spontaneously and when driven, in a gene-dose-dependent way, while their synaptic inputs looked largely normal; homozygous mutants also lost Purkinje cells from about 2 months of age and became ataxic. Rapamycin (6 mg/kg intraperitoneally, three times a week from postnatal day 7) prevented the Purkinje cell loss and enlargement and the social, learning and motor deficits. Boundary: mouse, cell-type-specific genetic deletion; rapamycin given from early postnatal life, so this is prevention, not reversal; relevance to human autism is by analogy with TSC patients. |
| 2011 | A | Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice MIL2011 In the same experimental design that showed rapamycin extended median lifespan by 10-18%, neither resveratrol nor simvastatin had any significant effect on survival - a direct head-to-head negative control run at the same time, in the same mice. |
| 2011 | A | Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice ANI2011 Female 129/Sv inbred mice received rapamycin intermittently, 2 weeks in every month, from 2 months of age for the rest of their lives. Treated mice gained less weight with age, showed a slower estimated rate of ageing, lived longer, with the gain most visible among the last survivors, and developed spontaneous tumours later. 22.9% of rapamycin-treated mice were still alive when the last control mouse died. The paper provided evidence that an intermittent rapamycin schedule can extend lifespan in a normal inbred mouse strain, adding to earlier results in genetically heterogeneous mice. Boundary: Female mice of a single inbred strain (129/Sv) only; drafted from the abstract only, so dose, group sizes and median-lifespan statistics are not given here. |
| 2010 | A | Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster BJE2010 Feeding rapamycin extended fly lifespan through autophagy and reduced translation, and worked even in flies already on a lifespan-maximizing diet. |
| 2010 | A | Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer's disease SPI2010 Connected the longevity drug to a specific age-related disease. Long-term rapamycin prevented memory deficits and lowered toxic amyloid-beta in an Alzheimer's mouse model - and the benefit tracked with INCREASED autophagy in neurons. Suggested that the same autophagy boost that may slow aging could also help clear disease-causing proteins. |
| 2010 | A | Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments. CAC2010 Revealed a vicious cycle: amyloid-beta RAISES mTOR activity, and high mTOR in turn blocks the autophagy needed to clear amyloid and tau - so the disease feeds itself. Rapamycin broke the loop in 3xTg-AD mice, rescuing memory and lowering BOTH amyloid and tau, with autophagy induction shown to be necessary for the reduction in amyloid levels. |
| 2009 | A | Rapamycin fed late in life extends lifespan in genetically heterogeneous mice HAR2009 Rapamycin fed from 600 days of age extended median and maximal lifespan in both sexes; age at 90% mortality rose 14% in females and 9% in males. |
| 2009 | A | mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells CHE2009 mTOR hyperactivation drives HSC aging; rapamycin restores hematopoietic stem-cell function. |
| 2009 | A | Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice ZHO2009 In neural Pten-knockout mice, rapamycin prevented and reversed neuronal hypertrophy and improved a subset of the PTEN-associated abnormal behaviours. |
| 2009 | A | Enhancing CD8 T-cell memory by modulating fatty acid metabolism PEA2009 Mice whose T cells lacked the adaptor protein TRAF6 mounted a normal effector CD8 T-cell response to Listeria infection, but the antigen-specific cells vanished during contraction and almost no memory cells formed. The TRAF6-deficient cells failed to activate AMPK and mitochondrial fatty acid oxidation when the growth factor IL-2 was withdrawn. Daily metformin restored fatty acid oxidation and memory formation, and also raised memory CD8 T-cell numbers in normal mice: in a tumour vaccine model 6 of 9 metformin-treated mice survived beyond day 33 against 1 of 8 controls. Daily rapamycin (1.5 mg/kg), used as a second drug that promotes fatty acid oxidation, likewise increased memory CD8 T-cell development and recall responses. Boundary: mouse only, one bacterial infection model and one transplantable tumour; the rapamycin arm is a secondary experiment and mTOR activity itself was not measured in these cells. |
| 2008 | A | Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function MEI2008 mTOR inhibition rescues a neuronal tuberous-sclerosis model, supporting rapamycin for TSC neurology. |
| 2008 | A | Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis EHN2008 Rapamycin reverses learning and memory deficits in a Tsc2+/- tuberous sclerosis model. |
| 2008 | A | Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex ZEN2008 Mice lacking Tsc1 mainly in glial cells (Tsc1 GFAP conditional knockout) develop glial overgrowth, progressive epilepsy and early death. Rapamycin started at postnatal day 14, before symptoms, prevented epilepsy and premature death; started at 6 weeks, after seizures had begun, it suppressed seizures and prolonged survival. In the brain, rapamycin reversed the abnormal mTOR pathway activation (measured as phospho-S6), the astrogliosis and the neuronal disorganisation, and increased brain size, compared with vehicle-treated knockouts. The study provided evidence in mice that mTOR inhibition can act on epilepsy itself in TSC, not only on tumours, and it is part of the rationale for the later EXIST-3 seizure trial in patients. Boundary: mouse model with Tsc1 deleted mainly in glia, not the human germline mutation; seizure and survival outcomes in mice only; abstract does not state dose or schedule. |
| 2006 | A | Hypothalamic mTOR signaling regulates food intake COT2006 In rats, hypothalamic mTOR signalling (phosphorylated S6K1 and S6) changed with energy status in specific hypothalamic regions and was found in NPY and POMC neurons of the arcuate nucleus. Injecting leucine into the brain ventricles raised hypothalamic mTOR signalling and lowered food intake and body weight. Leptin also raised hypothalamic mTOR activity, and blocking mTOR with rapamycin in the brain blunted leptin's effect on reducing food intake. The authors proposed that hypothalamic mTOR acts as a fuel sensor linked to how much an animal eats. Boundary: rats, direct brain (intracerebroventricular) dosing, short-term food intake; drawn from the abstract only, so doses and effect sizes are not given here. |
| 2005 | A | Ribosomal protein S6 phosphorylation is a determinant of cell size and glucose homeostasis RUV2005 The authors made knock-in mice in which all five phosphorylatable serines of ribosomal protein S6 were replaced by alanine, so rpS6 could not be phosphorylated. Contrary to the then widely accepted model, translational control of 5'TOP mRNAs was unaffected. Fibroblasts from these mice made protein faster and divided faster, yet were smaller than wild-type cells, and rapamycin did not shrink them further, which points to rpS6 phosphorylation as a downstream effector of mTOR in cell-size control. Adult mutant mice also had smaller pancreatic beta-cells, less pancreatic insulin, low blood insulin and impaired glucose tolerance. Boundary: Mouse knock-in and mouse cells. Separates rpS6 phosphorylation from 5'TOP control in these systems; not tested in people. Drafted from the abstract only. |
| 2002 | A | A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells KWI2002 The authors built a Tsc1 knockout mouse to model tuberous sclerosis. Embryos lacking both copies of Tsc1 died at mid-gestation because the liver failed to develop. Mice with one copy often developed kidney cystadenomas and liver hemangiomas; the hemangiomas were more common, more severe and more often fatal in females. Fibroblasts lacking Tsc1 showed persistent phosphorylation of S6K and its substrate S6 that rapamycin could reverse, and S6 phosphorylation was also high in kidney tumours from the mice. The authors suggested that blocking this pathway might help control TSC tumours. Boundary: mouse model and mouse cells; the rapamycin result is in cultured cells, and treatment of the mouse tumours was not tested here. |
| 1998 | A | Disruption of the p70(s6k)/p85(s6k) gene reveals a small mouse phenotype and a new functional S6 kinase SHI1998 Mice with the S6K1 gene disrupted were viable and fertile but smaller, with the growth effect strongest during embryonic development. Unexpectedly, ribosomal protein S6 was still phosphorylated normally after mitogen stimulation in knockout liver and fibroblasts, and in knockout fibroblasts S6 phosphorylation and the rise in 5'TOP mRNA translation were as sensitive to rapamycin as in wild-type cells. A database search identified a second S6 kinase, S6K2, which had mitogen-dependent and rapamycin-sensitive S6 kinase activity and was up-regulated in all tissues of the knockout mice examined, most of all in thymus. S6K2 can therefore partly compensate for loss of S6K1. Boundary: Mouse knockout and mouse cells. Body size and S6 signalling only; the 5'TOP result means S6K1 alone is not required in these cells, not that S6 kinases are irrelevant. Drafted from the abstract only. |
| 2026 | R | Biological limits of lifespan extension: evidence for a shift from pathway leverage to system-level buffering across species PIR2026 mTOR/TOR pathway interventions achieve large lifespan extensions in simple organisms but face declining efficacy in mammals due to distributed multi-tissue buffering, redundancy, and pharmacokinetic complexity - proposing a unifying framework for the translational challenge of aging pathway targeting. |
| 2026 | M | Rapamycin co-exposure fails to reduce cisplatin-induced damage in GC6-spg spermatogonial cell line. JIB2026 Rapamycin did not protect a mouse spermatogonial cell line from cisplatin damage in vitro, unlike reports in female fertility models. |
| 2026 | M | A Systems Pharmacology Model of Aging Identifies Optimal Combination Therapies With Secondary Benefits on Weight Loss and Metabolic Health GOR2026 A calibrated systems-pharmacology model of aging finds that optimal drug combinations diverge by objective: GLP-1 receptor agonist + SGLT2 inhibitor + metformin is best for metabolic (weight/HbA1c) improvement, while GLP-1 receptor agonist + SGLT2 inhibitor + rapamycin is predicted best for aging-related (frailty/biological-age-gap) benefit — the two goals do not converge on the same regimen. Authors flag the aging predictions as hypothesis-generating, pending external validation. |
| 2026 | M | Recurrent reversible mutations at gaf1 driving metastable TORC1 inhibitor resistance in fission yeast. DAN2026 Metastable resistance to TORC1 inhibitors (rapamycin plus caffeine) in fission yeast is driven by recurrent, spontaneously reversible loss-of-function mutations in gaf1, a GATA transcription factor and negative growth regulator downstream of TORC1 - a genetic (not epigenetic) toggle that can silently contaminate lab yeast stocks. |
| 2026 | M | Medulloblastoma-associated mutations in the RNA helicase DDX3X/DED1 cause defects in the translational response to TORC1 inhibition SWA2026 Medulloblastoma-associated DDX3X mutations, modeled in the yeast ortholog Ded1 (ded1-mam), cause rapamycin-resistant growth and selectively upregulate translation of unstructured-5'UTR pro-growth transcripts after TORC1 inhibition, a mechanism by which mutant DDX3X may let tumor cells bypass TORC1-dependent stress/growth control. |
| 2026 | R | Rapamycin across biology and medicine: From molecular mechanisms to clinical and translational frontiers NOL2026 Comprehensive review tracing rapamycin from its discovery as an antifungal macrolide to its identification as the founding mTOR inhibitor. Covers mTOR's role integrating nutrient/growth-factor/stress signals, established and emerging clinical applications of rapamycin/rapalogs, limitations and adverse effects of mTOR inhibition, and translational prospects for using mTOR inhibition to prevent or delay chronic disease and extend healthspan. |
| 2026 | M | 5-Fluorouracil-based chemotherapy disrupts autophagy flux and protein synthesis in cultured myotubes: a role for mTORC1 signaling HAL2026 FOLFOX and oxaliplatin disrupted mTORC1/AMPK regulation of autophagy flux and protein synthesis in cultured myotubes; the effect was not easily reversible on drug withdrawal. Rapamycin (but not metformin) restored autophagy flux and AMPK phosphorylation, though without restoring protein synthesis. |
| 2025 | R | What is the clinical evidence to support off-label rapamycin therapy in healthy adults? HAN2025 A deliberately cautious review of low-dose rapamycin in healthy adults, and re-models one cohort using the PhenoAge biological-aging clock. Verdict: despite strong animal lifespan data, human evidence does NOT yet prove rapamycin delays aging in healthy people. A valuable counterweight to longevity-community hype - it holds the human evidence to a strict standard rather than over-reading promising signals. |
| 2024 | M | Suppressed basal mitophagy drives cellular aging phenotypes that can be reversed by a p62-targeting small molecule KEL2024 Healthy primary human cells run a high level of basal mitophagy, started by mitochondrial superoxide and carried out through the PINK1/Parkin pathway with p62 as the selective receptor. That housekeeping shuts down on entry into senescence and in naturally aged cells. Blocking mitophagy in young proliferating cells was by itself enough to trigger the senescence program, and reactivation of mitophagy was necessary for the anti-senescence effect of rapamycin and of NAD precursors, which places part of rapamycin's action on cellular ageing downstream of mitochondrial quality control rather than beside it. A p62-targeting small molecule restored mitophagy and rescued markers of cellular ageing. |
| 2017 | M | Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism WAN2017 The authors asked whether the transcription factor Nrf2 is needed for rapamycin to hold back cellular senescence. In wild-type mouse fibroblasts exposed to hydrogen peroxide, rapamycin raised Nrf2, switched on autophagy and lowered the senescence markers p16 and p21, beta-galactosidase staining and the inflammatory secretory profile (SASP). In Nrf2-knockout cells rapamycin still lowered beta-galactosidase staining and the SASP, but no longer lowered p16 and p21 or activated autophagy; re-expressing Nrf2 restored those effects, and human WI38 cells with Nrf2 knocked out by CRISPR behaved the same way. In Nrf2-knockout mice given rapamycin (4 mg/kg every other day for 6 weeks, 8 mice per group), fat-tissue beta-galactosidase staining and pro-inflammatory cytokines fell while p16 did not, and rapamycin lowered STAT3 phosphorylation in lung tissue and WI38 cells. The study provided evidence that rapamycin's effect on the SASP can be separated from its Nrf2-dependent effect on cell-cycle arrest. Boundary: Mouse and human fibroblasts in culture plus a short 6-week dosing study in young Nrf2-knockout mice; mTOR inhibition was by rapamycin, which was given before and during the senescence trigger, so this is prevention of senescence onset rather than treatment of established senescent cells. |
| 2016 | M | L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity GEI2016 Tracking metabolites and proteins in activated human T cells, the authors found intracellular L-arginine falls sharply after activation even in 1 mM medium, because uptake and conversion to ornithine, proline and spermidine rise. Raising L-arginine shifted metabolism from glycolysis towards oxidative phosphorylation, increased oxygen consumption and spare respiratory capacity, and produced central-memory-like cells (CCR7 and CD62L high, less IFN-gamma) with greater survival capacity; blocking arginase gave the same survival gain at physiological 150 uM L-arginine. Limited-proteolysis mass spectrometry plus knockout clones identified three nuclear proteins, BAZ1B, PSIP1 and TSN, that sense L-arginine and contribute to the survival programme. In mice, oral L-arginine raised serum levels from about 160 uM to 700 uM and roughly doubled intracellular L-arginine in activated T cells, and L-arginine-treated OT-I cells slowed B16-OVA growth and extended survival. The authors report explicitly that the survival effect was independent of mTOR: L-arginine did not change S6K1 or 4E-BP phosphorylation, and rapamycin, while also improving survival, changed metabolism in an entirely different way. Boundary: mostly human T cells in culture plus mouse transfer and transplantable-tumour models; the dietary arm is a mouse supplementation experiment, not a human trial, and mTOR enters only as a negative control. |
| 2015 | M | mTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation LAB2015 Explained HOW rapamycin calms 'inflammaging'. Senescent cells spew inflammatory signals (the SASP) that damage surrounding tissue and even feed tumors. mTOR powers this by translating IL1A, the cytokine at the top of the cascade. Rapamycin selectively shuts it down - and blocked senescent cells from fueling prostate tumor growth in mice. |
| 2015 | M | Architecture of human mTOR complex 1 AYL2015 Cryo-EM architecture of human mTORC1 reveals its dimeric organization and active site access. |
| 2013 | M | mTOR kinase structure, mechanism and regulation YAN2013 Solved the crystal structure of the mTOR kinase itself. Revealed why the active site is so hard to reach - it sits in a deep recess guarded by the FRB domain, which acts as a 'gatekeeper' letting substrates in. This structure explains at the atomic level exactly how FKBP12-rapamycin blocks access, and why activating cancer mutations cluster where they do. |
| 2013 | R | mTOR is a key modulator of ageing and age-related disease JOH2013 The landmark Nature review that put mTOR at the center of aging biology. Lays out the case that inhibiting mTOR extends lifespan across species and guards against a growing list of age-related diseases - while being candid that side effects currently block its use in healthy people. Excellent orientation map for the whole field. |
| 2013 | M | mTORC1 phosphorylation sites encode their sensitivity to starvation and rapamycin KAN2013 Each mTORC1 phosphorylation site has its own intrinsic 'substrate quality'. Good substrates stay phosphorylated when mTORC1 is partly inhibited by rapamycin or starvation, poor ones drop out first, and changing a few residues around a site shifts its sensitivity in cells. One level of mTORC1 activity can therefore produce different output profiles. |
| 2013 | M | Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity KID2013 Activating T cells switch on cholesterol and fatty acid synthesis genes within hours, and this paper showed the switch runs through PI3K and mTOR to SREBP: 100 nM rapamycin given 30 minutes before stimulation blocked the induction of the lipogenic programme, prevented processing of full-length SREBP and its accumulation in the nucleus, and reduced SREBP1 and SREBP2 occupancy at lipogenic promoters to background. Deleting Scap in T cells, which removes both SREBP1 and SREBP2 activity, left thymic and peripheral T-cell numbers normal but the cells could not blast: they entered G1 and stalled, failed to raise cholesterol and fatty acids after activation, and increased ECAR and OCR only modestly where controls rose about ten-fold and four-fold. Adding cholesterol conjugated to methyl-beta-cyclodextrin roughly doubled survival at 48 hours (21 to 45 percent) and restored growth, cell-cycle entry and ER expansion, which points to cholesterol as the limiting step. After LCMV-Armstrong infection the Scap-deficient mice had fewer virus-specific CD8 T cells with lower IFN-gamma and TNF, while homeostatic proliferation was unaffected. Boundary: mouse genetics and mouse cells; the mTOR step is shown with rapamycin pretreatment in cultured T cells, and the in vivo arm measures the consequence of losing SREBP activity rather than of inhibiting mTOR. |
| 2013 | M | Excitatory/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis BAT2013 Deleting Tsc1 from cultured mouse hippocampal neurons raised phospho-S6 and made the network fire more than twice as much as controls by day 14, in an epilepsy-like bursting pattern; four days of rapamycin brought activity back to control levels. Many gene-expression and synaptic changes in the knockout cultures, such as high Arc and fewer surface AMPA receptors, turned out to be secondary responses to the high activity, not direct effects of mTOR. In hippocampal CA1, Tsc1 loss in single pyramidal neurons weakened the inhibitory synaptic input they received and raised their excitation/inhibition ratio, while their intrinsic excitability was lower, not higher. Forebrain Tsc1 knockout mice had more severe kainate-induced seizures (80% died, while all controls survived), and seven days of rapamycin in vivo restored inhibition and normalised the E/I ratio. Boundary: mouse neurons, cultures and brain slices; Tsc1 deleted in excitatory neurons only; seizure test used a chemical convulsant. |
| 2012 | M | Distinct perturbation of the translatome by the antidiabetic drug metformin LAR2012 The authors compared genome-wide changes in mRNA translation caused by metformin with those caused by the mTOR inhibitors rapamycin and PP242 in cancer cells. Metformin changed gene expression at the level of translation to an extent comparable to the classic mTOR inhibitors. Its antiproliferative effect could be explained by selective suppression of translation of mRNAs encoding cell-cycle regulators, acting through the mTORC1 / 4E-BP pathway. The paper provided evidence that metformin's effect on cell growth in vitro goes through selective translational control rather than a general drop in protein synthesis. Boundary: Cultured cancer cells at drug concentrations used in vitro; does not show that metformin at clinical doses acts this way in patients. Drafted from the abstract only. |
| 2012 | M | mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake YIL2012 Mice kept on calorie restriction (60% of normal intake) had more intestinal stem cells and Paneth cells, the cells that form the stem-cell niche (Lgr5+ stem cells 5.6% vs 4.3% of crypt cells, Paneth cells 9.8% vs 6.7%), and their crypts were nearly twice as likely to form organoids. In co-culture, Paneth cells from restricted mice, not stem cells, carried the boost. Restriction lowered S6 and S6K1 phosphorylation in crypts, and feeding or insulin switched on mTORC1 in Paneth cells but not in stem cells; forcing mTORC1 back on during restriction (Rheb induction or Tsc1 deletion) cancelled the effect, while one week of rapamycin copied it and did not add to restriction. The niche signal ran through higher Bst1 in Paneth cells, an enzyme that makes the paracrine messenger cyclic ADP ribose, and knocking down Bst1 removed the restriction effect in culture. Boundary: Mouse intestine and ex vivo organoid assays; restriction started in young adult mice, and no lifespan or human tissue was studied. |
| 2011 | M | Regulation of TFEB and V-ATPases by mTORC1 PEN2011 Using Tsc2-null and wild-type mouse fibroblasts with and without rapamycin, the authors looked for genes whose expression follows mTORC1 activity and found 75 genes, enriched for subunits of the lysosomal proton pump (V-ATPase). mTORC1 also raised V-ATPase expression in mouse liver after Tsc1 deletion and in a prostate tumour model, through a transcriptional mechanism that needed the transcription factor TFEB: knocking down Tfeb cut the number of mTORC1-induced genes from 1146 to 424 probes, and about a quarter of mTORC1-induced genes depended on Tfeb. mTORC1 promoted albumin uptake (endocytosis) in a Tfeb- and V-ATPase-dependent way. In these serum-deprived cells, active mTORC1 (TSC loss) increased nuclear TFEB and rapamycin or Raptor knockdown reduced it, which is the opposite direction to the TFEB inhibition reported by later studies in fed or starved cells. Boundary: Mostly mouse and human cell lines under low serum; liver and prostate data are expression measurements. The direction of mTORC1 control over TFEB localisation here differs from later work and is condition-dependent. |
| 2011 | M | Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets MIC2011 Comparing CD4 T cells grown under effector and regulatory conditions, the authors showed that Th1, Th2 and Th17 cells carry high surface Glut1 and are strongly glycolytic, while inducible Treg carry little Glut1, oxidise lipid at a higher rate and have more phosphorylated AMPK. Blocking lipid oxidation with etomoxir selectively suppressed Treg generation and left effector differentiation intact, whereas removing glucose blocked Th17 but not Treg. Both rapamycin and metformin raised fatty acid oxidation in stimulated CD4 T cells, and etomoxir prevented the Treg increase produced by rapamycin or TGF-beta, which ties the pro-Treg effect of mTOR inhibition to lipid oxidation. In a mouse asthma model, metformin lowered Glut1 on activated CD4 T cells and increased the proportion and number of Treg in draining lymph nodes, although airway responsiveness itself did not change significantly. Boundary: mouse cells and one mouse allergic-airway model; mTOR inhibition is pharmacological (rapamycin) and mTOR activity was not measured directly, so the mTOR arm is inferred from drug effects. |
| 2010 | M | Single amino-acid changes that confer constitutive activation of mTOR are discovered in human cancer SAT2010 Screened point mutations from cancer genome databases and found two, S2215Y (large intestine adenocarcinoma) and R2505P (renal cell carcinoma), that kept mTOR signalling on even under nutrient starvation. mTORC1 purified from starved cells carrying the mutants still phosphorylated 4E-BP1 in vitro. Mutant cells had more S-phase cells (42.0% vs 28.2% for S2215Y) and resisted the shrinkage caused by amino-acid withdrawal. The mutants stayed sensitive to rapamycin. Boundary: overexpressed mutants in cultured cells; the mutations were found in tumour databases, their driver role in patients was not tested. |
| 2010 | M | Structure of the human mTOR complex I and its implications for rapamycin inhibition YIP2010 The authors purified intact, active human mTORC1 and solved its shape by cryo-electron microscopy at about 26 angstrom resolution. The complex is an obligate dimer with a rhomboid outline and a central cavity, held together by interlocking contacts between mTOR and Raptor; antibody labelling placed mLST8 at the outer 'feet' and PRAS40 next to Raptor. Exposing purified mTORC1 to FKBP12-rapamycin first added a bound density in about 10% of particles, then broke the complex apart, with virtually no intact particles left after one hour, while the ATP-competitive inhibitor Torin1 left it intact. In matching kinase assays, FKBP12-rapamycin blocked S6K1 phosphorylation quickly but 4E-BP1 phosphorylation only after at least 60 minutes, and Raptor-free mTOR still phosphorylated S6K1 (rapamycin-sensitively) but not 4E-BP1. The authors proposed that rapamycin inhibits the two substrates by different mechanisms. Boundary: Purified protein and low-resolution EM; the authors note that in cells rapamycin neither fully blocks 4E-BP1 phosphorylation nor dismantles mTORC1, so the disassembly model is an in vitro result. |
| 2010 | M | The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and Eomesodermin RAO2010 Working with naive OT-I CD8 T cells stimulated by antigen plus B7.1, the authors showed that IL-12 both raised and prolonged mTOR phosphorylation and S6K1 Thr389 phosphorylation out to 48 hours, and that this required PI3K throughout and STAT4 for the late phase. Rapamycin, added at the start or only at 12 hours, blocked the sustained expression of T-bet and with it the heritable type I effector programme, while raising Eomesodermin and producing cells with a memory-precursor phenotype (CD62L high, KLRG1 low, Bcl-2 high). Restoring T-bet by a tamoxifen-inducible construct brought back IFN-gamma production and lowered Eomesodermin, which places T-bet downstream of mTOR in this system. After transfer, the rapamycin-treated cells persisted better, gave stronger antigen-recall responses, and more than 78 percent of recipients stayed tumour-free to day 120 against 50 percent fatality with IL-12-conditioned effector cells. Boundary: mouse CD8 T cells, one TCR-transgenic system with pharmacological mTOR inhibition in vitro before transfer; the transplantable E.G7 tumour is a model, not a treatment result in people, and the memory-precursor phenotype faded by day 40 after transfer. |
| 2009 | M | An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1 THO2009 Dropped a bombshell: rapamycin does NOT fully block mTORC1. Using Torin1 (which jams the active site directly), the authors showed rapamycin leaves important mTORC1 jobs running - notably 4E-BP1 phosphorylation and autophagy suppression. This reframed a decade of rapamycin experiments and launched the search for complete inhibitors. |
| 2009 | M | Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2 FEL2009 The parallel discovery to Thoreen 2009 (same year), from the Shokat lab. Their TORKinibs (PP242, PP30) block mTOR's active site, hitting both complexes and shutting down cap-dependent translation that rapamycin misses. Together these two papers established a whole new drug class beyond rapamycin. |
| 2009 | M | Rapamycin decelerates cellular senescence DEM2009 Blagosklonny's key experiment behind his 'hyperfunction' theory of aging. When a cell's division is blocked but mTOR keeps driving growth, the cell tips into permanent senescence. Rapamycin uncouples the two - keeping arrested cells reversible instead of senescent. Direct evidence that mTOR actively drives the senescent state, not just passively accompanies it. |
| 2008 | M | The TSC-mTOR signaling pathway regulates the innate inflammatory response WEI2008 The TSC-mTOR pathway controls the innate inflammatory response of monocytes/macrophages. |
| 2007 | M | mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex CUN2007 Showed mTOR isn't just about building proteins - it also runs the cell's POWER plants. mTORC1 drives mitochondrial gene expression and oxygen consumption through a YY1-PGC-1alpha transcriptional program; block mTOR with rapamycin and mitochondrial output falls. Explains part of why mTOR inhibition reshapes metabolism. |
| 2007 | M | siRNA screening of the kinome identifies ULK1 as a multidomain modulator of autophagy CHA2007 The authors screened a kinase-targeted siRNA library in human HEK293 cells, using lipidation of the autophagy marker GFP-LC3 after amino-acid starvation as the readout. ULK1 came out of the screen: knocking it down blocked starvation-induced autophagy, while knocking down the related kinase ULK2 did not. ULK1 knockdown also blocked autophagy induced by rapamycin, which fits ULK1 acting downstream of mTOR. Overexpressed ULK1 inhibited autophagy independently of its kinase activity, and the dominant-negative effect mapped to residues 1-351, while the conserved C-terminal domain was needed for ULK1 to reach cytoplasmic structures, some of them LC3-positive. One of the early papers to place ULK1 as a required kinase for starvation-induced autophagy in mammalian cells. Boundary: Cultured human cell lines with siRNA and overexpression; no whole-animal data. The link to mTOR rests on rapamycin-induced autophagy, not on a measurement of mTORC1 acting on ULK1. Drafted from the abstract only (no PMC full text). |
| 2006 | M | Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB SAR2006 The molecular explanation for rapamycin's dark side. Short-term rapamycin only hits mTORC1, but prolonged treatment can also inhibit the assembly of NEW mTORC2 in susceptible cell types, reducing mTORC2 abundance and cutting Akt signaling over time. The wording matters: this is prevention of new assembly, not the dismantling of complexes already built, and the response depends on cell context and length of exposure. This is the mechanistic root of the insulin-resistance side effect later shown in mice (see Lamming 2012) - crucial for anyone dosing rapamycin for longevity. |
| 2006 | M | TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth INO2006 TSC2 integrates Wnt and energy signals through coordinated AMPK and GSK3 phosphorylation. |
| 2006 | M | Extension of chronological life span in yeast by decreased TOR pathway signaling POW2006 Decreased TOR pathway signalling extends chronological lifespan in yeast. |
| 2006 | M | The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity SCH2006 In human cultured cells, the amount of mTOR-raptor complex correlated with overall mitochondrial activity. Disrupting the complex with rapamycin lowered mitochondrial membrane potential, oxygen consumption and ATP-synthetic capacity. mTOR and mTOR-raptor complexes were found in purified mitochondrial fractions, and rapamycin markedly changed the mitochondrial phosphoproteome. RNA interference against TSC2, S6K1, raptor or rictor led the authors to conclude that mTOR regulates mitochondrial activity independently of its previously known targets, and they proposed that mTOR activity shifts the balance between mitochondrial and non-mitochondrial ATP production. Boundary: Cultured human cell line with acute pharmacological and RNAi manipulation; the link to lifespan is a hypothesis drawn from lower organisms, not tested here. Drafted from the abstract only. |
| 2006 | M | Rapamycin alleviates toxicity of different aggregate-prone proteins BER2006 Building on their earlier work with mutant huntingtin, the authors showed in cell models that rapamycin, used as an autophagy inducer, increased the clearance of several proteins with long polyglutamine tracts and of a polyalanine-expanded protein, and reduced their toxicity. In fruit flies expressing wild-type or mutant human tau, rapamycin reduced tau toxicity, and this went with less insoluble tau. The authors argued that inducing autophagy with rapamycin could be useful across several aggregate-prone protein diseases, not only Huntington's disease. Boundary: cultured cells and Drosophila overexpressing disease proteins; drawn from the abstract only; no mammalian in vivo or human data. |
| 2002 | M | A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus TAN2002 The authors showed that mTOR, 4E-BP1, 4E-BP2 and eIF4E are present in rat hippocampus and sit in dendrites, close to synapses, where their staining overlapped with the postsynaptic protein PSD-95. Blocking mTOR with rapamycin in hippocampal slices reduced late-phase long-term potentiation (LTP) after high-frequency stimulation, while early-phase LTP was unaffected. Rapamycin also blocked the synaptic potentiation induced by the growth factor BDNF. This was one of the early papers to tie a rapamycin-sensitive pathway to the protein-synthesis-dependent phase of synaptic plasticity and to suggest it controls local translation at synapses. Boundary: rodent brain slices and cultured neurons; mTOR targets were localised but their phosphorylation during LTP was not reported in the abstract; no behaviour or memory test. |
| 2000 | M | Tor-mediated induction of autophagy via an Apg1 protein kinase complex KAM2000 The founding experiment of the whole TOR-to-autophagy axis. Starvation or rapamycin raises the kinase activity of Apg1 (the yeast counterpart of ULK1), and TOR keeps autophagy off by holding Apg13 hyperphosphorylated so that it cannot bind and activate Apg1. Boundary: yeast only, and the mammalian version of the same step (ULK1-ATG13-FIP200) was shown separately nine years later. |
| 1997 | M | Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin BRU1997 mTOR directly phosphorylates 4E-BP1 (PHAS-I), releasing eIF4E and establishing mTOR's role in translational control. |
| 1997 | M | Rapamycin suppresses 5'TOP mRNA translation through inhibition of p70s6k JEF1997 In mammalian cells, rapamycin selectively blocked the mitogen-induced increase in translation of 5'TOP mRNAs, which encode ribosomal proteins and elongation factors, and in parallel blocked activation of p70 S6 kinase. Using reporter mRNAs, the authors showed that an intact 5'TOP tract was required for the rapamycin effect. A dominant-interfering p70s6k reduced translation of the reporter with the intact 5'TOP but not the disrupted one, and a rapamycin-resistant p70s6k (Thr389 changed to an acidic residue) removed the inhibitory effect of rapamycin on 5'TOP translation. The authors concluded that rapamycin suppresses 5'TOP translation through p70s6k. Boundary: Cell lines with overexpressed kinase mutants and reporter mRNAs. Later genetic work (S6K knockouts, rpS6 knock-in) found 5'TOP control persisting without S6K1 or rpS6 phosphorylation, so the S6K step proposed here is not the current consensus. Drafted from the abstract only. |
| 1996 | M | Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP CHO1996 The crystal structure that showed HOW rapamycin works at the atomic level: one rapamycin molecule glues two proteins together - FKBP12 and mTOR's FRB domain - by plugging into two hydrophobic pockets at once. A textbook example of a small molecule acting as 'molecular glue' to force protein dimerization. |
| 1994 | M | RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs SAB1994 Discovery of the protein RAFT1 (today's mTOR) as the direct target of the FKBP12-rapamycin complex; one of three 1994 reports (with Brown et al. and Chiu et al.) that identified mammalian TOR, three years after TOR was found in yeast. |
| 1991 | M | Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast HEI1991 Discovery of the TOR1 and TOR2 genes in yeast as the targets whose disruption causes rapamycin's cell-cycle-arresting toxicity - the original genetic identification of the TOR pathway. |
| 1975 | M | Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle VEZ1975 The original isolation of rapamycin from a soil bacterium found on Easter Island, discovered first as an antifungal compound decades before its mTOR-inhibiting mechanism was known. |
| 2025 | RT | Test of Rapamycin in Aging Dogs (TRIAD): study design and rationale for a prospective, parallel-group, double-masked, randomized, placebo-controlled, multicenter trial of rapamycin in healthy middle-aged dogs from the Dog Aging Project COL2025 Design and rationale paper (protocol), NOT results. TRIAD is a double-masked, randomized, placebo-controlled, multicenter trial testing whether rapamycin prolongs lifespan and improves healthspan measures in healthy middle-aged dogs from the Dog Aging Project. Its authors describe it as the first rigorous test of a drug against biological aging with lifespan and healthspan endpoints performed outside the laboratory in any species. Planned size is 580 dogs with 3 years of treatment (NIH-funded, per Texas A&M announcement; 170 dogs enrolled at that time). No efficacy or safety results exist yet, so this must not be cited as evidence of benefit. |
| 2024 | PP | Targeting mTOR restores tau-induced metabolic, mitochondrial, and cognitive deficits in a tauopathy mouse model TAN2024 In mice engineered to overexpress a phosphomimetic tau variant, one week of rapamycin partially mitigated tau-driven mitochondrial dysfunction and cognitive impairment in the Morris water maze - extends the mTOR-autophagy-neurodegeneration link (already seen with Huntington's) to a direct tau-phosphorylation mechanism relevant to Alzheimer's. |
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