Cellular senescence
State in which a cell permanently stops dividing but stays alive, secreting inflammatory signals (the SASP). Senescent cells accumulate with age and drive age-related disease. mTOR powers the inflammatory secretions of cells that are already senescent (LAB2015, the stronger evidence); that it also promotes entry into the senescent state rests on weaker cell-culture evidence (DEM2009).
Cells that stop dividing but do not die. A state where a cell permanently stops dividing but stays alive and starts pumping out inflammatory signals. These 'zombie cells' build up with age and drive age-related disease. mTOR powers the inflammatory signals these cells release; whether it also pushes cells into this state is less firmly shown.
mTORC1 drives the SASP translationally; rapamycin suppresses SASP without reversing arrest, so 'senescence' and 'SASP' must not be conflated.
TL;DR. Cellular senescence appears in 19 curated studies in Oliver's mTOR Atlas: 3 in people (1 synthesis of human data, 2 human studies); 8 in animal models; 8 at the molecular level (cells, biochemistry, structure). It has 1 interaction in the curated pathway model.
In the pathway model
| Interaction | Mechanism | Evidence | Studies |
|---|---|---|---|
| cGAS-STING pathway activates Cellular senescence mechanism: functional-consequence · this link in full · on the map table | In aged immune cells called macrophages, cGAS-STING switches on an inflammatory programme that spreads to neighbouring cells, so the ageing effect does not stay in the cell where it started. This comes from a single mouse study, and whether the same spread happens in human tissue has not been tested. Holds under: Single mouse study; the human magnitude of this effect, and whether the same paracrine spread occurs in human tissue, are untested. not tested in people · emerging, few independent studies | A | LV2026 |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| S | Synthesis of human data | 1 |
| H | Human study | 2 |
| A | Animal model | 8 |
| M | Molecular — cells, biochemistry, structure | 8 |
Human studies in the Atlas
| Year | Evidence | Study | Design / population |
|---|---|---|---|
| 2026 | S | Therapeutic reversal of cellular senescence: A systematic review of senolytics, senomorphics and anti-ageing therapies in human clinical trials TRI2026 | Human clinical trials (PRISMA 2020 systematic review, 6 completed studies + 1 ongoing) |
| 2026 | H | Rapamycin Exerts Its Geroprotective Effects in the Ageing Human Immune System by Enhancing Resilience Against DNA Damage KEL2026 | Human T cells (ex vivo, genotoxic stress); ex vivo aged human immune cells; placebo-controlled experimental medicine study in older adults (low-dose oral rapamycin, in vivo) |
| 2019 | H | Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial CHU2019 | Humans, RCT (skin, age >40; n=17 completed) |
Studies
| Year | Evidence | Study |
|---|---|---|
| 2026 | S | Therapeutic reversal of cellular senescence: A systematic review of senolytics, senomorphics and anti-ageing therapies in human clinical trials TRI2026 A PRISMA-guided systematic review of six completed human clinical studies that met its eligibility criteria, testing drugs that clear or calm senescent ("zombie") cells -- senolytics such as dasatinib+quercetin, plus senomorphic and mTOR-targeting approaches. It reported limited and heterogeneous results, a mixture of biomarker and functional outcomes, with mostly mild side effects, and judged the evidence too thin (small samples, short follow-up) to call any of it an established therapy yet. Six INCLUDED studies is not a census of every completed human senotherapeutic trial: inclusion depends on the review's search date and eligibility criteria, and those have to be stated before any field-wide coverage conclusion is drawn. Useful mainly as a rare systematic look at where human senescence-targeting trials, mTOR inhibitors included, stand -- not as proof that any one drug works. |
| 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. |
| 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. |
| 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 | Impaired Chaperone-Mediated Autophagy Accelerates Intervertebral Disc Degeneration by Inducing MIDN Accumulation to Target TSC2 for Proteasomal Degradation CHEN2026C Loss of chaperone-mediated autophagy lets its substrate midnolin (MIDN) accumulate; MIDN binds TSC2 and drives its proteasomal degradation independently of ubiquitination, de-repressing mTORC1 and causing senescence, SASP and matrix loss in disc cells. MIDN knockdown, LAMP2A overexpression or rapamycin each blocked the degeneration - a new upstream route to mTORC1 hyperactivation. |
| 2026 | A | Hepassocin prevents age-related liver senescence and facilitates liver regeneration by activating AMPK YAN2026B Hepassocin (HPS/FGL1), a hepatokine, activates AMPK via an ANXA2-ERK-p90RSK-LKB1 cascade, restraining mTOR activity. Aged HPS-knockout mice show reduced LKB1/AMPK activation and elevated mTOR activity, impaired autophagy, exacerbated cellular senescence, and severely compromised liver regeneration after partial hepatectomy. AMPK agonist AICAR or exogenous HPS rescued the aging/regeneration phenotype. |
| 2026 | A | An ANGPTL8-AKT2-mTOR Axis Drives Adipose Senescence and Aging-Related Functional Decline HE2026 Identifies ANGPTL8 as an endocrine driver of adipose-tissue aging: circulating ANGPTL8 tracked with biological age and mortality risk in a large human cohort, and genetic deletion of Angptl8 in mice extended lifespan and reduced senescence markers. Mechanistically, ANGPTL8 binds AKT2 and drives the AKT-mTOR-S6K axis to promote adipocyte senescence; blocking that axis abolished the pro-senescent effect. |
| 2026 | A | Dioscorea polystachya Turcz. attenuates male reproductive aging through modulation of mTOR-Beclin-1-mediated autophagy in Leydig and Sertoli cells ZHANG2026B Chinese yam protein extract (CYCSE) attenuates male reproductive aging by activating testicular autophagy through the mTOR-Beclin-1 axis in Leydig and Sertoli cells; mTOR activation blocks protective effects. |
| 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. |
| 2018 | A | Rapamycin improves healthspan but not inflammaging in nfκb1(-/-) mice. COR2018 Separates two effects of rapamycin that are usually assumed to travel together. In mice with genetically enhanced NF-kB activity, rapamycin showed no benefit in lifespan and no reduction of inflammaging, yet still reduced frailty and improved long-term memory, neuromuscular coordination and tissue architecture, with lower markers of cellular senescence. Healthspan benefit is therefore uncoupled here from suppression of inflammation, which is a boundary condition on the common claim that rapamycin acts on ageing mainly by damping inflammation. Note the mixed result: the healthspan outcomes are positive, the lifespan and inflammaging outcomes are null. |
| 2009 | A | mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells CHE2009 mTOR hyperactivation drives HSC aging; rapamycin restores hematopoietic stem-cell function. |
| 2026 | M | LINP1 suppresses radiation-induced cellular senescence in keratinocytes by modulating the mTOR-p53 axis LIANG2026 LncRNA LINP1 binds the FAT domain of mTOR, reduces mTOR-p53 interaction and p53 Ser15 phosphorylation, thereby suppressing radiation-induced cellular senescence in keratinocytes and human skin. |
| 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 | Persistent mTORC1 signaling in cell senescence results from defects in amino acid and growth factor sensing CAR2017 Explains why mTORC1 stays switched on in senescent cells. In human fibroblasts rendered senescent three different ways, mTORC1 is constitutively active and no longer responds to serum or amino acid withdrawal. The defect is upstream, not in mTORC1 itself: it is driven in part by depolarisation of the senescent plasma membrane, which leads to primary cilia defects and a failure to shut off growth-factor signalling, while increased autophagy and high intracellular amino acid levels may act to support the nutrient arm. Correcting these inputs restored sensitivity of the pathway and killed the cells, which frames persistent mTORC1 signalling as a survival dependency of senescent cells rather than a by-product of senescence. |
| 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. |
| 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. |
| 2011 | M | Spatial coupling of mTOR and autophagy augments secretory phenotypes NAR2011 Protein synthesis and autophagic degradation are usually described as opposites that mTOR switches between, and this paper shows a compartment where the cell deliberately runs both at once. In senescent cells, autolysosomes and mTOR gather at one side of the Golgi (the TASCC), mTOR gets there in an amino-acid- and Rag-dependent way, and destroying that arrangement cuts interleukin-6/8 secretion. Boundary: cells, not organisms; it explains how the senescent secretory programme is fuelled, not whether blocking it helps an animal. |
| 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. |
| 2005 | M | AMP-activated protein kinase induces a p53-dependent metabolic checkpoint JON2005 Described a glucose checkpoint at the G1/S boundary run by AMPK. Cells arrested when glucose ran short even though amino acids were present and mTOR stayed active, so this arrest works in parallel to mTOR rather than through it. AMPK phosphorylated p53 on serine 15, which was needed for the arrest; arrested cells re-entered the cycle when glucose returned, while persistent AMPK activation pushed them into p53-dependent senescence. Boundary: worked from the abstract only (no PMC full text); cultured cells. |
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