# Таблица S. Отобранные гипотезы, эталонные утверждения и баллы судей

Дополнительные материалы к препринту [«Генерация и отбор четырьмя большими языковыми моделями научных гипотез, совпадающих с опубликованным экспериментальным результатом, в бенчмарке на 50 статьях по биологии старения»](2026-10-25-benchmark-preprint-ru.md).

В таблице приведены все 60 гипотез, которые двухэтапный отбор сохранил для трёх генераторов: ответ «да» GPT-6 Astra на первом этапе и единогласный положительный прогноз группы из четырёх предикторов на втором. Для каждой гипотезы указаны полный текст, исследовательский вопрос задания, эталонное утверждение статьи и баллы трёх судей других компаний. Основной критерий требует балла не ниже 3 от большинства судей, строгий критерий балла 4 или 5. Баллы приведены в порядке перечисления судей для данного генератора. Решение большинства по основному критерию названо пограничным, если судьи разделились два к одному: при другом голосе одного судьи оно изменилось бы. Пограничных решений 6 из 60.

Тексты гипотез, вопросов и эталонных утверждений приведены на языке опыта без сокращений: модели получали именно эти формулировки. Таблица сформирована программно из опубликованных отчётов отбора; контрольные суммы источников приведены в разделе «Контрольные суммы источников».

| № | Модель-генератор | Задача | Гипотеза | Исследовательский вопрос | Полный текст гипотезы | Эталонное утверждение статьи | Баллы трёх судей других компаний | Соответствие по основному критерию | Пограничное решение большинства | Соответствие по строгому критерию | DOI статьи |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Grok 4.5 | R42605193 | H4 | Which circulating regulator causally promotes cellular senescence and organismal ageing, and through what intracellular signaling mechanism does it act? | Age-elevated circulating TGF-β1 is a causal driver of multi-tissue cellular senescence and organismal ageing. Chronic exposure of young tissues to aged plasma levels of TGF-β1 is sufficient to induce p16INK4a/p21-positive senescence and accelerate functional decline. Mechanism: Circulating TGF-β1 binds TGFBR1/2, activates Smad2/3–Smad4 complexes that transcriptionally induce CDKN2A/CDKN1A and remodel chromatin toward a stable senescence program, while also reinforcing SASP output that further elevates systemic TGF-β1. Prediction: Neutralizing circulating TGF-β1 (or tissue-specific TGFBR1 deletion) in aged animals will reduce senescence markers across distant organs and improve healthspan metrics more than neutralizing IL-6 or insulin signaling alone; conversely, sustained infusion of TGF-β1 into young animals will recapitulate the aged senescence signature even when inflammatory cytokines remain low. | ANGPTL8 directly interacts with AKT2 and activates the AKT–mTOR–S6K pathway, thereby driving cell-autonomous adipocyte senescence. Deleting Angptl8 in mice reduces adipose senescence, delays age-related functional decline, and extends lifespan, while genetic or pharmacological pathway inhibition abolishes ANGPTL8-induced senescence. | GPT-5.6 Sol 2; Claude Opus 5.5 1; Gemini 4 Argon 1 | нет | нет | нет | 10.1111/acel.70671 |
| 2 | Grok 4.5 | R42630044 | H3 | What mechanism limits the anabolic response of aged bone to mechanical loading, and can targeted stimulation restore this response? | Age-related decline in osteocyte Piezo1 (or associated ion-channel/Ca2+ entry) blunts early mechanotransduction, so downstream anabolic gene programs are not activated by physiological strain. Agonism or overexpression of Piezo1 will restore loading responsiveness in aged bone. Mechanism: Reduced Piezo1-dependent calcium influx and YAP/TAZ or NFAT activation in osteocytes cuts the initiation of load-adaptive transcriptional responses. Prediction: Aged osteocytes will show weaker load-evoked Ca2+ transients and Piezo1-dependent gene induction; Piezo1 activation will rescue formation indices after loading, while Piezo1 loss in young bone will phenocopy the aged loading defect. | In aged mouse bone, activation of Piezo1 during mechanical loading promotes its membrane co-localization with connexin 43 and increases connexin 43 hemichannel activity through PI3K-Akt signaling. Hemichannel opening increases PGE2 release, suppresses sclerostin, promotes endosteal bone formation, inhibits resorption, and thereby restores the cortical anabolic response to loading. | GPT-5.6 Sol 3; Claude Opus 5.5 4; Gemini 4 Argon 3 | да | нет | нет | 10.1111/acel.70687 |
| 3 | Grok 4.5 | R42647119 | H1 | How does aging affect injury-induced neuronal reprogramming in the retina, and what mechanisms account for any age-related loss of regenerative capacity? | Aging reduces injury-induced neuronal reprogramming in the retina because chronic low-grade inflammation progressively impairs Müller glial competence to activate neurogenic programs after injury. Suppressing age-associated inflammatory signaling in old retina should restore reprogramming efficiency toward youthful levels. Mechanism: Persistent innate immune activation (inflammaging) elevates NF-κB/STAT-driven glial reactivity that antagonizes Ascl1 and related neurogenic gene networks required for Müller glia-to-neuron conversion after injury. Prediction: Aged retinas will show higher baseline and post-injury inflammatory cytokine signatures coincident with fewer reprogrammed neurons; neutralizing key inflammatory mediators (e.g., IL-6/TNF or microglial depletion) will increase reprogrammed neuron yield in old but not young animals, whereas adding the same cytokines to young tissue will reduce yield. | Aging suppresses Müller glia-to-neuron reprogramming by preventing activation of progenitor programs while promoting reactive and inflammatory glial states and an exaggerated retinal neuroimmune response. Dexamethasone partially restores neurogenesis, confirming that age-associated inflammation is a causal, therapeutically tractable component of the regenerative defect, alongside glial-intrinsic barriers. | GPT-5.6 Sol 4; Claude Opus 5.5 4; Gemini 4 Argon 4 | да | нет | да | 10.1073/pnas.2612369123 |
| 4 | Grok 4.5 | R42647635 | H1 | Does experimentally increasing somatic mitochondrial DNA mutation burden cause premature ageing and shortened lifespan in a large mammal? | Experimentally elevating the somatic mtDNA mutation rate in a large mammal will accelerate multi-tissue functional decline and shorten median and maximum lifespan relative to isogenic controls with a wild-type mtDNA polymerase proofreading capacity. Mechanism: Proofreading-deficient mtDNA polymerase increases the load of random somatic mtDNA mutations, impairing oxidative phosphorylation, elevating ROS and bioenergetic failure in post-mitotic and stem-cell niches, and thereby driving systemic ageing phenotypes. Prediction: Mutator animals will show dose-dependent earlier onset of sarcopenia, anemia, fertility loss, and cardiac dysfunction together with reduced lifespan, with these traits correlating quantitatively with measured tissue mtDNA mutation burden and respiratory-chain deficiency. | Prime-edited pigs expressing proofreading-deficient POLG accumulated elevated somatic mitochondrial DNA mutations and developed systemic premature-ageing phenotypes. These included weight loss, rough hair, anaemia, tissue abnormalities, increased apoptosis, elevated senescence-associated markers, and shortened lifespan. | GPT-5.6 Sol 4; Claude Opus 5.5 5; Gemini 4 Argon 4 | да | нет | да | 10.1126/sciadv.adu0632 |
| 5 | Grok 4.5 | R42665751 | H3 | How does age-associated mitochondrial dysfunction initiate and propagate inflammatory signaling that causes ovarian functional decline? | Age-associated mitochondrial DNA damage in oocytes and granulosa cells releases oxidized mtDNA into the cytosol, which activates cGAS–STING and thereby initiates type-I interferon and NF-κB inflammatory programs that impair follicle survival and steroidogenesis. Mechanism: Cytosolic mtDNA sensing by cGAS–STING drives interferon and NF-κB transcription in follicular cells, creating a local inflammatory milieu that reduces oocyte competence and granulosa endocrine function. Prediction: Ovary-specific cGAS or STING deletion (or mtDNA packaging rescue) will reduce follicular inflammatory transcripts and preserve ovulation and estradiol output with age, whereas parallel inflammasome blockade alone will not fully rescue the same endpoints. | Ageing-associated mitochondrial DNA leakage from oocytes activates oocyte cGAS, generating cGAMP that triggers STING signaling and passes through gap junctions to activate STING in surrounding granulosa cells. Genetic deletion of oocyte Cgas or pharmacological STING inhibition ameliorates inflammation and ovarian dysfunction, establishing this signaling axis as a causal driver of ovarian ageing. | GPT-5.6 Sol 3; Claude Opus 5.5 4; Gemini 4 Argon 3 | да | нет | нет | 10.1038/s43587-026-01195-y |
| 6 | Grok 4.5 | R42689491 | H4 | Can in vivo correction of the HGPS-causing mutation rescue molecular, cellular, and structural defects in bone, and how does treatment timing affect efficacy? | In vivo correction of the HGPS-causing LMNA mutation before a critical developmental window fully restores osteoblast differentiation, bone matrix deposition, and adult bone mechanical integrity because early progerin toxicity primarily impairs formation rather than locking in irreversible structural damage. Mechanism: Progerin-driven nuclear lamina dysfunction and DNA-damage signaling in osteoprogenitors disrupt Runx2/Osterix programs during peak bone accrual; removing progerin early reopens normal lineage progression and mineralization before cortical architecture is permanently compromised. Prediction: Correction in juvenile animals normalizes osteoblast transcriptomes, mineral apposition rate, cortical thickness, and fracture toughness to wild-type levels, whereas identical correction after skeletal maturity leaves residual deficits in geometry and strength despite molecular normalization. | Adenine base editing of the pathogenic LMNA variant reduced progerin expression, restored extracellular-matrix deposition and mineralization in progeroid osteoblasts, and partially rescued bone structure and physical properties in mice. In vivo correction was strongly age-dependent, with early postnatal delivery producing substantially greater editing and skeletal benefit than later treatment. | GPT-5.6 Sol 3; Claude Opus 5.5 3; Gemini 4 Argon 4 | да | нет | нет | 10.1111/acel.70700 |
| 7 | Grok 4.5 | R42696595 | H3 | What genetic and molecular mechanism causes natural variation in seed longevity among rice varieties? | Natural allelic variation in a rice IAA-amido synthetase (OsGH3-family) gene alters free auxin homeostasis in developing seeds, changing seed-coat structure and thereby storage longevity. Accessions carrying a high-activity longevity allele conjugate more IAA, produce a less permeable coat, and retain higher germination after aging. Mechanism: Auxin conjugation reduces free IAA during late seed maturation, remodeling testa cell-wall and cuticle deposition and slowing oxidative aging. Prediction: Near-isogenic lines that differ only at the OsGH3 longevity QTL will show correlated differences in free IAA, seed-coat permeability (tetrazolium uptake), and post-aging germination; CRISPR knockout of the high-longevity allele will shorten longevity without changing primary yield components when auxin is restored chemically. | Natural variation at qSL6 causally determines rice seed longevity through SL6, a fatty acyl-ACP thioesterase that changes seed fatty-acid composition and increases resistance to oxidation. Desiccation-induced ABA signaling activates SL6 through VP1, while a virus-derived CT-rich element in the 5′ UTR of the ancestral SL6HHZ allele stabilizes its mRNA bidirectionally and contributes to longevity differences between indica and japonica rice. | GPT-5.6 Sol 1; Claude Opus 5.5 1; Gemini 4 Argon 1 | нет | нет | нет | 10.1126/sciadv.aeg8609 |
| 8 | Grok 4.5 | R42698274 | H4 | What molecular mechanism exacerbates dihydrotestosterone-induced mitochondrial dysfunction, oxidative stress and senescence during androgenetic alopecia? | Dihydrotestosterone-bound androgen receptor transcriptionally represses PGC-1α in dermal papilla cells, collapsing mitochondrial biogenesis and antioxidant capacity. The resulting electron-transport inefficiency elevates ROS, which accelerates cellular senescence and shortens anagen. Mechanism: AR-dependent transcriptional downregulation of the PGC-1α–NRF1/TFAM biogenesis axis, with secondary loss of SOD2/GPX activity. Prediction: Forced PGC-1α expression or AR DNA-binding blockade will restore mtDNA copy number and oxygen consumption and reduce SA-β-gal/p16 under DHT, whereas NOX or inflammasome inhibitors will not fully rescue biogenesis markers. | SFRP2 binds FSTL1 and increases its protein stability, establishing an SFRP2–FSTL1 axis that exacerbates DHT-induced mitochondrial dysfunction, oxidative stress, inflammation and senescence in dermal papilla cells. SFRP2 knockdown alleviated these defects and improved hair regeneration and follicle morphology, while FSTL1 knockdown counteracted the harmful effects of SFRP2 overexpression. | GPT-5.6 Sol 2; Claude Opus 5.5 0; Gemini 4 Argon 1 | нет | нет | нет | 10.1111/acel.70666 |
| 9 | Grok 4.5 | R42717261 | H5 | What mechanism induces pathogenic immune-cell senescence in ulcerative colitis, and does this senescence causally exacerbate the disease? | In ulcerative colitis, chronic metabolic stress damages mitochondria in lamina propria T cells, releasing mtDNA into the cytosol; cytosolic mtDNA activates cGAS–STING, which drives a senescence program that produces a SASP that amplifies mucosal inflammation and impairs epithelial repair. Mechanism: Mitochondrial damage → cytosolic mtDNA → cGAS–STING → immune-cell senescence → SASP-driven colitis exacerbation Prediction: Selective blockade or genetic deletion of cGAS or STING in T cells will reduce senescence markers (p16, SA-β-gal), lower SASP cytokines in the mucosa, and improve histological colitis scores even when upstream mitochondrial stress persists; exogenous cytosolic mtDNA will recapitulate senescence and worsen disease in a STING-dependent manner. | NAD+ metabolic dysregulation causes mitochondrial dysfunction and cytosolic mitochondrial DNA leakage, activating cGAS-STING signaling to drive CD8+ T-cell senescence. These senescent cells exacerbate colitis, while systemic senolytic treatment reduces disease severity; their associated signature also predicts severe disease and non-response to biologic therapy. | GPT-5.6 Sol 3; Claude Opus 5.5 4; Gemini 4 Argon 4 | да | нет | да | 10.1111/acel.70706 |
| 10 | Grok 4.5 | R42723546 | H2 | Can a cell-free regenerative treatment alleviate UV-induced skin photoaging, and which causal intracellular mechanism mediates its protective effects? | A cell-free regenerative preparation alleviates UV-induced photoaging by restoring mitophagy in keratinocytes and fibroblasts, which clears dysfunctional mitochondria and thereby reduces mitochondrial danger-signal release that drives senescence and sterile inflammation. Mechanism: Enhanced PINK1/Parkin-dependent mitophagy lowers mtDNA and ROS leakage, interrupting NLRP3 inflammasome activation and SASP maintenance. Prediction: Pharmacologic or genetic blockade of mitophagy will abolish the therapy’s anti-senescence and anti-inflammatory benefits even when barrier and collagen markers partially recover; mitophagy flux reporters and circulating mtDNA will normalize only in treated, mitophagy-competent skin. | Human umbilical cord mesenchymal stem cell secretome protects against UV-induced photoaging by enhancing mitophagy, which clears damaged mitochondria and reduces cytosolic mitochondrial DNA leakage. This suppresses cGAS-STING signaling and downstream inflammatory cytokines; mitophagy inhibition abolishes protection, while STING inhibition restores it. | GPT-5.6 Sol 3; Claude Opus 5.5 4; Gemini 4 Argon 3 | да | нет | нет | 10.1111/acel.70701 |
| 11 | Grok 4.5 | R42805954 | H2 | What causal mechanism contributes to the age-related decline of thermogenic adipocytes in subcutaneous white adipose tissue? | Age-related loss of sympathetic innervation density and norepinephrine release in subcutaneous white adipose tissue causally impairs β3-adrenergic recruitment of thermogenic (beige) adipocytes. Restoring local catecholaminergic tone would therefore rescue cold- or agonist-induced browning in aged animals. Mechanism: Progressive sympathetic axon rarefaction and reduced vesicular norepinephrine availability lower β3-AR–cAMP–PKA signaling in adipocyte progenitors and mature adipocytes, preventing UCP1 induction and beige differentiation. Prediction: Aged scWAT will show reduced tyrosine hydroxylase+ fiber density and lower tissue norepinephrine; local β3-agonist delivery or chemogenetic reactivation of adipose-projecting sympathetic neurons will restore UCP1+ beige adipocytes and cold-induced energy expenditure without requiring systemic endocrine rescue. | Microglial ALKBH5 suppresses Ntf5 expression by demethylating Ntf5 mRNA, thereby limiting activation of PVH TrkB-positive neurons, sympathetic innervation of subcutaneous white adipose tissue, and adipocyte browning. Microglia-specific ALKBH5 knockout preserved brown adipocytes and improved metabolic activity during ageing in male mice. | GPT-5.6 Sol 3; Claude Opus 5.5 3; Gemini 4 Argon 2 | да | да | нет | 10.1038/s41467-026-77050-w |
| 12 | Grok 4.5 | R42810392 | H3 | Can direct pharmacological activation of a conserved metabolic target extend lifespan across evolutionarily diverse organisms and induce longevity-associated changes in mammals? | Selective pharmacological activation of AMPK is sufficient to extend lifespan in evolutionarily distant invertebrates and to induce longevity-associated physiological and molecular signatures in mammals. The longevity benefit is caused by AMPK itself rather than off-target pharmacology of multi-target drugs. Mechanism: Direct AMPK activation increases catabolic programs (fatty-acid oxidation, autophagy, mitochondrial biogenesis) and dampens anabolic growth signaling, shifting cells into a conserved energy-sparing, stress-resistant state that slows aging. Prediction: A highly selective AMPK agonist will extend lifespan in C. elegans and Drosophila and, in mice, raise AMPK activity, improve metabolic healthspan markers, and induce transcriptomic/proteomic aging-delay signatures, whereas chemically related inactive analogs will not. | Direct pharmacological activation of AMPK with compound 991 extends lifespan in Drosophila melanogaster, Caenorhabditis elegans, and Schizosaccharomyces pombe. In mice, 991 induces a proteomic profile associated with pro-longevity biology, supporting the translational potential of AMPK activation. | GPT-5.6 Sol 4; Claude Opus 5.5 5; Gemini 4 Argon 4 | да | нет | да | 10.1111/acel.70721 |
| 13 | Grok 4.5 | R42842666 | H1 | How do the different cellular compartments of the vascular wall causally contribute to distinct features of Hutchinson-Gilford progeria vascular pathology? | Progerin expression specifically in vascular smooth muscle cells is sufficient to cause medial VSMC depletion and collagen-rich extracellular-matrix accumulation, independently of endothelial or adventitial progerin. Mechanism: Cell-autonomous nuclear lamina disruption in VSMCs triggers DNA damage responses, senescence and apoptosis, while dysregulating matrix gene programs that favor collagen deposition and medial remodeling. Prediction: Mice or vessel organoids with VSMC-restricted LMNA G609G (or equivalent) will reproduce medial VSMC loss and collagen accumulation, whereas endothelium- or adventitia-restricted progerin will not. | In trilayer engineered blood vessels, HGPS fibroblasts causally promoted extracellular-matrix dysregulation and fibrotic signaling, while HGPS smooth muscle cells drove collagen accumulation and endothelial cells drove inflammation. Correcting the HGPS-associated mutation by base editing restored many pathological characteristics toward healthy levels. | GPT-5.6 Sol 3; Claude Opus 5.5 3; Gemini 4 Argon 3 | да | нет | нет | 10.1126/sciadv.aeh3785 |
| 14 | Grok 4.5 | R42844664 | H3 | Through what causal mechanism does time-restricted feeding protect against accelerated cardiovascular ageing? | Time-restricted feeding protects against accelerated cardiovascular ageing by restoring intestinal epithelial barrier integrity, thereby limiting chronic low-grade endotoxemia that drives endothelial dysfunction and arterial stiffening. The barrier restoration is necessary and sufficient for the vascular benefit under otherwise matched caloric intake. Mechanism: Extended daily fasting upregulates tight-junction proteins (e.g., occludin, claudin-1) and mucus production via circadian and AMPK-dependent pathways in enterocytes; reduced translocation of LPS and other microbial products lowers TLR4/NF-κB signaling in endothelium and vascular smooth muscle, slowing hypertension, stiffening, and maladaptive remodeling. Prediction: In aged or progeroid models, TRF that improves gut barrier markers and lowers plasma LPS will prevent arterial stiffening and endothelial dysfunction, whereas TRF combined with experimental barrier disruption (or chronic low-dose LPS infusion matched to ad libitum levels) will abolish protection despite preserved feeding-window compliance and body weight. | Time-restricted feeding enriches acetate-producing Limosilactobacillus, and microbiota-derived acetate is necessary and sufficient for its protection against angiotensin II-induced cardiovascular ageing. Acetate activates GPR43, inhibits HDAC3, increases H4K8 acetylation, and suppresses NLRP3-mediated pyroptosis and cellular senescence. | GPT-5.6 Sol 2; Claude Opus 5.5 1; Gemini 4 Argon 2 | нет | нет | нет | 10.1111/acel.70728 |
| 15 | Grok 4.5 | R42858183 | H1 | Can a defined intervention preserve lysosomal function and protein homeostasis during aging, thereby extending lifespan and maintaining organismal function, and through what mechanism? | Chronic low-dose Tor inhibition preserves lysosomal acidification and autophagic flux during aging, which sustains protein homeostasis and extends lifespan. The benefit depends on maintained lysosomal protease activity rather than reduced protein synthesis alone. Mechanism: Reduced mTORC1 signaling derepresses TFEB/HLH-30 nuclear translocation, upregulating lysosomal biogenesis and v-ATPase subunits, thereby keeping lumenal pH low and clearance competent with age. Prediction: Genetic or pharmacological blockade of TFEB/HLH-30 or v-ATPase will abolish lifespan extension and lysosomal pH preservation under Tor inhibition, while matching the translation-rate reduction without Tor inhibition will not restore lysosomal competence. | 20(S)-ginsenoside Rg3 extended lifespan and preserved physiological and neuronal function in Caenorhabditis elegans by restoring lysosomal activity and autophagic flux. Rg3 remodeled neuronal lysosomal phosphoinositide signatures toward increased PI(4)P and reduced PI(3)P, suppressed RSKS-1/S6K–TORC1 signaling, and promoted nuclear HLH-30/TFEB activity, thereby improving proteostasis and resistance to polyglutamine- and α-synuclein-associated toxicity. | GPT-5.6 Sol 3; Claude Opus 5.5 4; Gemini 4 Argon 3 | да | нет | нет | 10.1111/acel.70755 |
| 16 | Grok 4.5 | R42669067 | H1 | How does SIRT1 regulate L1 retrotransposon activity, and does this regulation affect cellular senescence? | SIRT1 maintains L1 silencing by deacetylating histone H3K9/H4K16 at L1 promoter and 5' UTR chromatin; decline of SIRT1 activity during senescence causes L1 transcriptional derepression that accelerates the senescence program. Mechanism: NAD+-dependent local chromatin deacetylation by SIRT1 preserves repressive chromatin at L1 loci; loss of this mark permits RNA polymerase II access and L1 mRNA production. Prediction: ChIP-seq will show increased H3K9ac/H4K16ac and reduced H3K9me3 specifically at L1 5' UTRs after SIRT1 knockdown or catalytic inhibition, preceding elevated L1 RNA and earlier SA-β-gal/p16 induction; a L1-promoter-targeted deacetylase tether will rescue silencing without restoring global SIRT1 activity. | SIRT1 suppresses L1 transcription and retrotransposition by promoting the association and recruitment of Lamin B1 and KAP1 at the L1 5′-UTR, increasing repressive H3K9me3 chromatin. SIRT1 deficiency derepresses L1, activates cGAS–STING signaling, and induces cellular senescence; reverse-transcriptase inhibition with 3TC rescues this phenotype. | GPT-5.6 Sol 3; Claude Opus 5.5 3; Gemini 4 Argon 3 | да | нет | нет | 10.1111/acel.70689 |
| 17 | Grok 4.5 | R42811065 | H1 | Which local mechanism connects stress-induced sympathetic activity to cellular senescence and impaired osteogenesis, and can it be modulated non-invasively? | Chronic psychological stress elevates bone-marrow norepinephrine from sympathetic terminals, which acts through β2-adrenergic receptors on mesenchymal stem/progenitor cells to drive p53/p21-dependent cellular senescence and thereby suppress osteogenic differentiation. Non-invasive peripheral neuromodulation that reduces local norepinephrine tone or blocks β2 signaling will reverse marrow senescence and restore bone formation. Mechanism: Sympathetic norepinephrine → β2-AR → cAMP/PKA → ROS/p53/p21 senescence program in osteoprogenitors Prediction: Marrow β2-AR knockout or selective β2 blockade will abolish stress-induced senescence markers (p16, SA-β-gal) and rescue osteogenesis even when circulating catecholamines remain high, whereas β1-selective blockade will not; peripheral nerve stimulation that lowers marrow NE will phenocopy β2 blockade. | Sympathetic neuropeptide Y drives stress-induced osteoporosis by activating adipocyte Y1R and inducing senescence in bone marrow adipocytes, which impairs osteogenesis. Pulsed electromagnetic fields activate sensory nerves, causing local semaphorin 3A release that suppresses sympathetic neuropeptide Y secretion through a peripheral circuit independent of central pathways. | GPT-5.6 Sol 2; Claude Opus 5.5 2; Gemini 4 Argon 2 | нет | нет | нет | 10.1038/s41467-026-77654-2 |
| 18 | Grok 4.5 | R42806003 | H1 | What intercellular mechanism causes placental senescence during maternal ageing, and can disrupting this mechanism restore placental and offspring health? | Maternal ageing elevates CD38 on decidual and circulating immune cells, depleting NAD+ in the shared placental microenvironment and thereby suppressing SIRT1/PARP activity in trophoblasts, which accelerates placental cellular senescence and metabolic failure. Restoring NAD+ or inhibiting maternal CD38 should reverse placental senescence and improve fetal growth. Mechanism: Maternal CD38-driven NAD+ depletion creates a metabolic niche that forces trophoblast senescence. Prediction: Placental NAD+ and SIRT1 activity fall with maternal age in parallel with CD38+ immune infiltration; CD38 inhibition or NAD+ precursors restore trophoblast NAD+/SIRT1, reduce senescence markers, and improve fetal outcomes even when maternal chronological age is unchanged. | Early inflammation and senescence-associated secretory phenotype activity induce IRF5-dependent CD38 expression in macrophages, which depletes NAD+ in decidual stromal cells and thereby promotes age-related placental senescence. Genetic or pharmacological disruption of this axis, including CD38 inhibition or NAD+ precursor treatment, reduces placental senescence, rescues intrauterine growth restriction, and improves offspring metabolic outcomes. | GPT-5.6 Sol 3; Claude Opus 5.5 4; Gemini 4 Argon 4 | да | нет | да | 10.1038/s41467-026-77217-5 |
| 19 | Grok 4.5 | R42806572 | H2 | Can a dose-titratable immune engager safely eliminate senescent cells and alleviate age-related pathology across mice and non-human primates, and what measurement can guide its safe dosing? | A dose-titratable bispecific immune engager that redirects T cells to a senescence-associated surface antigen will clear a therapeutically relevant fraction of senescent cells in aged mice and non-human primates at exposures below those that trigger systemic cytokine release. Circulating IL-6 and IFN-γ rise steeply only after the efficacious dose window, so their early kinetics can guide safe titration. Mechanism: Target engagement on senescent cells forms an immunological synapse that drives selective cytotoxicity; off-target or excess engagement expands systemic cytokine production once a threshold of T-cell activation is crossed. Prediction: In both species, intermediate engager doses will reduce senescence markers (p16INK4a, SA-β-gal, SASP factors) and improve tissue function without grade ≥2 cytokine release, while cytokine AUC will increase nonlinearly only at higher doses that do not further improve efficacy. | A GFD-CD3 bispecific T-cell engager targeting uPAR-positive senescent cells caused dose-dependent senolysis and alleviated age-related pathologies in aged mice and non-human primates at low doses. High doses caused hepatotoxicity through T-cell attack on hepatic endothelial cells, while serum aminotransferase monitoring enabled dosing that retained senolytic efficacy without observed adverse effects. | GPT-5.6 Sol 3; Claude Opus 5.5 3; Gemini 4 Argon 3 | да | нет | нет | 10.1111/acel.70742 |
| 20 | Gemini 4 Argon | R42605193 | H3 | Which circulating regulator causally promotes cellular senescence and organismal ageing, and through what intracellular signaling mechanism does it act? | Age-related elevation of circulating interleukin-11 (IL-11) causally promotes multi-organ cellular senescence, metabolic dysfunction, and organismal ageing. Secreted progressively by aged hepatocytes, adipocytes, and stromal cells, circulating IL-11 coordinates systemic tissue decline by simultaneously driving pro-senescent anabolic signaling and suppressing cellular energy-sensing pathways. Mechanism: Circulating IL-11 binds the cell-surface IL-11Rα/gp130 receptor complex in target parenchymal and stromal cells to activate MEK/ERK1/2, which phosphorylates and inactivates LKB1 (at Ser428) to suppress AMPK while concurrently activating mTORC1–S6K1 and canonical JAK2/STAT3 signaling. This dual ERK–mTORC1 activation and AMPK inhibition halts autophagic and mitophagic flux, increases mitochondrial reactive oxygen species (ROS), and transcriptionally upregulates p16INK4a, p21CIP1, and NF-κB-dependent senescence-associated secretory phenotype (SASP) factors. Prediction: Systemic administration of neutralizing anti-IL-11 or anti-IL-11Rα antibodies, or adult-onset Il11ra1 deletion, in middle-aged mice will restore tissue AMPK activity, suppress mTORC1 and STAT3 hyperactivation, reduce multi-organ p16INK4a/p21CIP1 senescence burden, reverse age-related insulin resistance and hepatic steatosis, and extend median and maximum lifespan; conversely, chronic IL-11 infusion in young mice will induce widespread senescence that is blocked by pharmacological ERK1/2 or mTORC1 inhibition. | ANGPTL8 directly interacts with AKT2 and activates the AKT–mTOR–S6K pathway, thereby driving cell-autonomous adipocyte senescence. Deleting Angptl8 in mice reduces adipose senescence, delays age-related functional decline, and extends lifespan, while genetic or pharmacological pathway inhibition abolishes ANGPTL8-induced senescence. | GPT-5.6 Sol 2; Claude Opus 5.5 2; Grok 4.7 2 | нет | нет | нет | 10.1111/acel.70671 |
| 21 | Gemini 4 Argon | R42608398 | H3 | Can a microbiota-derived factor directly cause the cellular dysfunction and progressive tissue remodeling characteristic of idiopathic pulmonary fibrosis, and if so, through what mechanism? | A conserved pro-apoptotic peptide proteolytically cleaved from bacterial cell-wall transglycosylases (such as corisin derived from lung-resident Staphylococcus and related commensal bacteria) directly initiates progressive pulmonary fibrosis without requiring live infection. This microbiota-derived peptide acts on alveolar epithelial cells to simultaneously trigger apoptosis, cellular senescence, and epithelial-to-mesenchymal phenotypic transitions. Mechanism: Extracellular bacterial serine proteases cleave conserved regions of bacterial transglycosylases to release a bioactive peptide into the alveolar space. Upon internalization or receptor engagement on alveolar type II (AT2) epithelial cells, the peptide disrupts mitochondrial membrane potential and increases mitochondrial reactive oxygen species, triggering intrinsic caspase-3-mediated apoptosis in a subset of cells while activating ATM/p53/p21 DNA damage signaling, senescence-associated secretory phenotype (SASP) release, and TGF-beta1/SMAD- and Snail-mediated epithelial-to-mesenchymal transition (EMT) in surviving cells to drive myofibroblast accumulation and extracellular matrix deposition. Prediction: Intratracheal instillation of the purified synthetic bacterial peptide alone into uninjured mice will be sufficient to induce AT2 apoptosis, p21/SA-beta-gal-positive senescence, EMT marker expression, and progressive collagen deposition, whereas protease-resistant removal of peptidic factors or treatment with a peptide-neutralizing monoclonal antibody will completely abolish these cell-fate abnormalities and fibrotic remodeling. | The microbiota-derived peptide corisin directly disrupts epithelial proteostasis by targeting and enhancing the ubiquitin-proteasome system, thereby inducing apoptosis, cellular senescence, epithelial-mesenchymal transition, and fibrotic remodeling. Depleting native corisin from patient bronchoalveolar lavage fluid removes its proapoptotic activity, while constitutive corisin expression in mice causes spontaneous progressive pulmonary fibrosis and worsens bleomycin-induced injury and mortality. | GPT-5.6 Sol 3; Claude Opus 5.5 4; Grok 4.7 3 | да | нет | нет | 10.1038/s41467-026-76162-7 |
| 22 | Gemini 4 Argon | R42627902 | H5 | Which regulatory mechanism drives the age-associated shift away from erythroid differentiation and toward platelet-producing lineage programs? | Age-associated upregulation and chromatin pioneering of the transcription factor FLI1 in hematopoietic stem and megakaryocyte-erythroid progenitor cells (MEPs) directly activates platelet-lineage gene programs while competitively repressing KLF1-driven erythroid differentiation. This shift in the FLI1-to-KLF1 transcriptional balance causally redirects bipotent progenitors and stem cells toward megakaryocytopoiesis during ageing. Mechanism: During ageing, increased accessibility at ETS-family binding motifs allows FLI1 (in cooperation with RUNX1 and GATA2) to occupy and activate megakaryocytic enhancers (such as MPL, ITGA2B, and GP1BA) while physically sequestering GATA1 away from KLF1 and recruiting corepressors to erythroid-specific loci (such as EPOR and HBB), thereby blocking erythroid commitment and promoting direct megakaryocyte generation. Prediction: Single-cell ATAC/RNA-seq of aged HSCs and MEPs will show selective enrichment of open FLI1/ETS motifs prior to lineage commitment, and partial genetic knockdown or degron-mediated reduction of FLI1 in aged progenitors will restore KLF1 target gene expression and normalize the erythroid-to-platelet output ratio even in the presence of an aged inflammatory bone marrow niche. | Pbx1 is a regulatory hub that drives age-related transcriptional and differentiation changes in hematopoietic stem cells. It suppresses erythroid differentiation by repressing Gata1 expression, thereby contributing to the lineage imbalance characteristic of HSC ageing. | GPT-5.6 Sol 2; Claude Opus 5.5 2; Grok 4.7 2 | нет | нет | нет | 10.1126/sciadv.aeb1346 |
| 23 | Gemini 4 Argon | R42647119 | H4 | How does aging affect injury-induced neuronal reprogramming in the retina, and what mechanisms account for any age-related loss of regenerative capacity? | Aging impairs injury-induced retinal neuronal reprogramming by priming resident microglia toward a persistent pro-inflammatory state that locks Müller glia into reactive gliosis rather than neurogenesis. Chronic inflammatory signaling after injury in aged retinas actively antagonizes proneural transcription factor activity in Müller glia. Mechanism: In aged retinas, senescent and dystrophic microglia respond to injury with sustained secretion of TNF-alpha, IL-6, and IL-1beta, driving prolonged hyperactivation of JAK/STAT3 and NF-kappaB signaling within Müller glia. Phosphorylated STAT3 and RelA/p65 directly compete with proneural pioneer factors such as Ascl1 for transcriptional co-activators and promote expression of gliogenic and inhibitory factors (such as Id1/3, Socs3, and Gfap), blocking the transition from reactive glia to neurogenic progenitors. Prediction: Microglial depletion (e.g., via CSF1R inhibition) or Müller glia-specific inhibition of STAT3/NF-kappaB signaling in aged injured retinas will restore Ascl1-driven neurogenic reprogramming efficiency to youthful levels, even without directly altering the intrinsic epigenetic landscape of Müller glia prior to injury. | Aging suppresses Müller glia-to-neuron reprogramming by preventing activation of progenitor programs while promoting reactive and inflammatory glial states and an exaggerated retinal neuroimmune response. Dexamethasone partially restores neurogenesis, confirming that age-associated inflammation is a causal, therapeutically tractable component of the regenerative defect, alongside glial-intrinsic barriers. | GPT-5.6 Sol 4; Claude Opus 5.5 4; Grok 4.7 4 | да | нет | да | 10.1073/pnas.2612369123 |
| 24 | Gemini 4 Argon | R42647635 | H4 | Does experimentally increasing somatic mitochondrial DNA mutation burden cause premature ageing and shortened lifespan in a large mammal? | Experimentally increasing the somatic mtDNA mutation rate via proofreading-deficient DNA polymerase gamma (POLG) in a large mammal directly drives systemic premature ageing and shortens lifespan by exhausting adult stem and progenitor cell pools. This progeroid phenotype arises even without elevated mitochondrial reactive oxygen species (ROS). Mechanism: Accumulation of random point mutations and linear deletions in mtDNA destabilizes respiratory chain complexes I and IV, triggering bioenergetic failure and intrinsic caspase-dependent apoptosis specifically within rapidly dividing somatic stem cell compartments (such as hematopoietic, intestinal, and neural progenitors), thereby impairing tissue regeneration. Prediction: Large mammals engineered with exonuclease-deficient POLG will exhibit early-onset alopecia, kyphosis, anemia, sarcopenia, and reduced lifespan accompanied by severe depletion of tissue-resident stem cells and respiratory chain complex instability, but without a corresponding increase in oxidative macromolecular damage (e.g., 8-oxodG or lipid peroxidation) or rescue by mitochondrial antioxidants. | Prime-edited pigs expressing proofreading-deficient POLG accumulated elevated somatic mitochondrial DNA mutations and developed systemic premature-ageing phenotypes. These included weight loss, rough hair, anaemia, tissue abnormalities, increased apoptosis, elevated senescence-associated markers, and shortened lifespan. | GPT-5.6 Sol 4; Claude Opus 5.5 5; Grok 4.7 4 | да | нет | да | 10.1126/sciadv.adu0632 |
| 25 | Gemini 4 Argon | R42663085 | H1 | Can an intrinsic molecular regulator be enhanced to reactivate quiescent hair follicles and restore hair regeneration, and through what mechanism? | Genetic or pharmacological induction of intrinsic microRNA-205 (miR-205) expression in aged hair follicle stem cells (HFSCs) reactivates quiescent telogen follicles and restores anagen hair regeneration. This reactivation occurs by reversing age-associated cellular stiffening in the bulge and hair germ compartments. Mechanism: miR-205 directly binds and post-transcriptionally represses transcripts encoding RhoA-ROCK pathway activators and actomyosin regulators (including Arhgef11 and Plekhg5), reducing myosin light chain II phosphorylation (p-MLC2) and cortical F-actin polymerization, which lowers intracellular mechanical tension and permits cell-cycle re-entry. Prediction: Atomic force microscopy will show reduced cortical stiffness in aged HFSCs upon miR-205 induction prior to proliferation, and hair regeneration will be phenocopied by ROCK/myosin II inhibition (e.g., blebbistatin) or abolished by expressing miR-205-resistant Arhgef11 without altering upstream BMP or Wnt ligand levels. | Increasing TPP1, either through stem-cell Acd overexpression or topical stabilization with the peptide TELODIN, accelerates hair regeneration in mice. TPP1 coordinates telomere capping and telomerase recruitment, activating bulge hair follicle stem cells and promoting their proliferation, differentiation, and migration as follicles transition synchronously from telogen to anagen. | GPT-5.6 Sol 2; Claude Opus 5.5 0; Grok 4.7 2 | нет | нет | нет | 10.1111/acel.70692 |
| 26 | Gemini 4 Argon | R42664348 | H5 | By what causal molecular mechanism does excess adiposity promote osteoarthritis progression, and can disrupting that mechanism reduce joint pathology? | Excess adipose tissue promotes osteoarthritis progression by secreting complement factor D (adipsin) into the circulation, which acts as the rate-limiting protease to activate the alternative complement cascade within synovial fluid and drive complement-mediated joint injury. Genetic deletion or pharmacological inhibition of circulating adipsin will protect against obesity-induced cartilage degeneration and synovitis. Mechanism: Adipocytes serve as the primary endocrine source of circulating adipsin (CFD), which diffuses into the joint space and cleaves factor B complexed with C3b to form the alternative pathway C3 convertase (C3bBb); subsequent cascade amplification generates C3a/C5a anaphylatoxins and deposits sublytic membrane attack complexes (C5b-9) on chondrocytes and synovial macrophages, activating C5aR1 and MAPK/ERK signaling to induce catabolic metalloproteinases and synovial inflammation. Prediction: Cfd-deficient mice or lipodystrophic mice fed an obesogenic diet will be protected from synovial C3b/C5b-9 deposition and osteoarthritis, and surgical transplantation of wild-type—but not Cfd-knockout—adipose tissue into fat-free mice will restore synovial alternative complement activation and susceptibility to joint degeneration. | Adipocyte-derived extracellular vesicles enriched in mitochondrial components transfer mitochondrial DNA to chondrocytes, where it activates cGAS-STING signaling and causes inflammation, metabolic dysfunction, senescence, and cartilage degeneration. Genetic or pharmacological inhibition of this pathway attenuates cartilage damage, pain behaviors, and gait abnormalities. | GPT-5.6 Sol 2; Claude Opus 5.5 0; Grok 4.7 2 | нет | нет | нет | 10.1126/sciadv.aee6780 |
| 27 | Gemini 4 Argon | R42665751 | H4 | How does age-associated mitochondrial dysfunction initiate and propagate inflammatory signaling that causes ovarian functional decline? | Age-associated loss of mitochondrial membrane integrity in granulosa cells and oocytes causes cytosolic leakage of mitochondrial DNA (mtDNA), activating the cGAS-STING pathway to initiate sterile follicular inflammation. Intercellular transfer of 2'3'-cGAMP through connexin gap junctions and paracrine type I interferon/NF-kB cytokine secretion propagate this inflammatory state across the cumulus-oocyte complex and ovarian stroma, driving follicular atresia and endocrine decline. Mechanism: Age-related decline in TFAM stoichiometry and cristae remodeling promote VDAC1 oligomerization and BAX/BAK macropore formation on the outer mitochondrial membrane, releasing mtDNA fragments into the cytosol. Cytosolic mtDNA binds cGAS to synthesize 2'3'-cGAMP, which activates STING-TBK1-IRF3/NF-kB signaling within the stressed cell and diffuses through Connexin-43 and Connexin-37 gap junctions at transzonal projections into adjacent follicular cells, amplifying IL-6, TNF-alpha, CXCL10, and IFN-beta production throughout the follicle. Prediction: Oocyte- or granulosa-specific genetic deletion or pharmacological inhibition of STING (e.g., H-151) or gap-junctional cGAMP transfer in aged mice will abolish pan-follicular interferon-stimulated gene expression and preserve follicular reserve and estradiol production, even when mitochondrial bioenergetic dysfunction or NLRP3 inflammasome competence remains intact. | Ageing-associated mitochondrial DNA leakage from oocytes activates oocyte cGAS, generating cGAMP that triggers STING signaling and passes through gap junctions to activate STING in surrounding granulosa cells. Genetic deletion of oocyte Cgas or pharmacological STING inhibition ameliorates inflammation and ovarian dysfunction, establishing this signaling axis as a causal driver of ovarian ageing. | GPT-5.6 Sol 4; Claude Opus 5.5 5; Grok 4.7 5 | да | нет | да | 10.1038/s43587-026-01195-y |
| 28 | Gemini 4 Argon | R42689491 | H5 | Can in vivo correction of the HGPS-causing mutation rescue molecular, cellular, and structural defects in bone, and how does treatment timing affect efficacy? | In vivo correction of the HGPS-causing LMNA mutation rescues molecular and cellular osteoblast defects regardless of age, but complete restoration of bone microarchitecture and biomechanical strength requires early intervention before osteoprogenitor exhaustion and growth plate senescence occur. Late treatment achieves only partial structural rescue because recovery is rate-limited by slow adult bone remodeling turnover and a depleted mesenchymal progenitor pool. Mechanism: Eliminating progerin production and restoring wild-type lamin A/C repairs nuclear lamina architecture and relieves p53/p21-mediated cell-cycle arrest in surviving osteoprogenitors and osteoblasts. When correction occurs during early postnatal growth, abundant mesenchymal stem and progenitor cells rapidly populate modeling bone surfaces to normalize cortical thickness and trabecular volume; when initiated after skeletal maturity, irreversible senescence of chondro-osseous progenitors and low baseline remodeling rates restrict the replacement of pre-existing dysplastic bone matrix. Prediction: Both early and late genetic correction will normalize nuclear morphology and osteogenic gene expression in active osteoblasts within weeks, whereas micro-CT cortical bone volume and three-point bending fracture resistance will fully normalize only in the early-treated cohort, with late-treated animals showing a rescue trajectory proportional to bone formation rate and residual Sca-1+/PDGFRa+ progenitor frequency. | Adenine base editing of the pathogenic LMNA variant reduced progerin expression, restored extracellular-matrix deposition and mineralization in progeroid osteoblasts, and partially rescued bone structure and physical properties in mice. In vivo correction was strongly age-dependent, with early postnatal delivery producing substantially greater editing and skeletal benefit than later treatment. | GPT-5.6 Sol 4; Claude Opus 5.5 4; Grok 4.7 3 | да | нет | да | 10.1111/acel.70700 |
| 29 | Gemini 4 Argon | R42723546 | H4 | Can a cell-free regenerative treatment alleviate UV-induced skin photoaging, and which causal intracellular mechanism mediates its protective effects? | Cell-free regenerative therapy (such as stem cell-derived extracellular vesicles) alleviates UV-induced skin photoaging by activating PINK1/Parkin-mediated mitophagy to clear damaged mitochondria. This targeted organelle clearance prevents the leakage of mitochondrial DNA (mtDNA) into the cytosol, thereby suppressing activation of the cGAS–STING innate immune pathway and downstream senescence-associated secretory phenotype (SASP) inflammation. Mechanism: Bioactive cargo within the cell-free treatment stimulates PINK1 stabilization and Parkin recruitment to depolarized mitochondria in UV-irradiated keratinocytes and dermal fibroblasts, promoting their autophagic degradation. By eliminating dysfunctional mitochondria before outer membrane permeabilization or mPTP opening can occur, the treatment prevents cytosolic accumulation of oxidized mtDNA, blocking cGAS recognition, 2'3'-cGAMP synthesis, STING/TBK1/IRF3/NF-κB phosphorylation, and the resulting sterile inflammatory and senescent state. Prediction: Genetic depletion of PINK1/Parkin or pharmacological inhibition of mitophagy in UV-exposed skin models will abolish the therapy's ability to reduce cytosolic mtDNA levels, STING phosphorylation, SASP cytokine secretion, and p16/p21 expression, whereas exogenous STING agonists (e.g., DMXAA or cGAMP) will override the protective effects despite intact mitochondrial clearance. | Human umbilical cord mesenchymal stem cell secretome protects against UV-induced photoaging by enhancing mitophagy, which clears damaged mitochondria and reduces cytosolic mitochondrial DNA leakage. This suppresses cGAS-STING signaling and downstream inflammatory cytokines; mitophagy inhibition abolishes protection, while STING inhibition restores it. | GPT-5.6 Sol 4; Claude Opus 5.5 5; Grok 4.7 4 | да | нет | да | 10.1111/acel.70701 |
| 30 | Gemini 4 Argon | R42736449 | H4 | Can an unannotated protein product that is altered in Alzheimer's disease causally regulate cellular function relevant to disease pathology? | Disease-associated dysregulation of an unannotated small open reading frame (sORF)-encoded microprotein localized to the inner mitochondrial membrane causally impairs oxidative phosphorylation and drives bioenergetic failure in Alzheimer's disease neurons independently of the canonical protein encoded at the same locus. Mechanism: Uncoupled translational regulation or transcript isoform switching in Alzheimer's disease alters the abundance of a mitochondrial-targeted microprotein encoded by an upstream or overlapping reading frame. This microprotein normally acts as an assembly or stabilizing factor for electron transport chain supercomplexes, and its perturbation in disease disrupts Complex I/IV activity, reduces ATP synthesis, and elevates mitochondrial reactive oxygen species (mtROS). Prediction: Selective genetic restoration or ablation of the unannotated microprotein in neuronal models—while holding canonical host protein expression constant—directly modifies basal and maximal oxygen consumption rates, mitochondrial membrane potential, and mtROS levels, and affinity purification-mass spectrometry confirms its physical interaction with respiratory chain subunits. | A small open reading frame at the MKKS locus encodes a 63-amino-acid microprotein that is the locus's predominant translation product and is downregulated in Alzheimer's disease. Experimental loss of this microprotein impairs mitochondrial respiration in microglia, supporting a causal role in microglial bioenergetics. | GPT-5.6 Sol 3; Claude Opus 5.5 3; Grok 4.7 3 | да | нет | нет | 10.1038/s43587-026-01207-x |
| 31 | Gemini 4 Argon | R42775695 | H4 | What causes defective mitochondrial quality-control flux in the aging heart, and how can restoring mitochondrial homeostasis reverse cardiac aging? | Age-associated hyperactivation of cardiac mTORC1 and upregulation of the Beclin-1 inhibitor Rubicon, combined with impaired TFEB nuclear translocation, block late-stage mitophagosome-lysosome fusion and lysosomal acidification in cardiomyocytes, stalling mitophagy flux mid-stream. Therapeutically restoring lysosomal biogenesis and autolysosomal fusion clears accumulated mitophagosomal intermediates, suppresses cytosolic mtDNA sensing, and reverses age-related diastolic and systolic dysfunction. Mechanism: In aged cardiomyocytes, chronic nutrient and stress signaling elevates mTORC1 activity and Rubicon expression, which inhibits the UVRAG-Vps34 complex and retains TFEB in the cytosol while diminishing v-ATPase-dependent lysosomal acidification. Because early mitochondrial damage continues to trigger priming and autophagosomal engulfment against a downstream bottleneck in Rab7/SNARE-mediated lysosomal fusion and proteolysis, un-degraded mitophagosomes accumulate, leak oxidized mtDNA into the cytosol, and activate cGAS-STING and NLRP3 inflammatory signaling. Prediction: Dual-fluorescent mitophagy reporter mice (such as mt-Keima or mito-QC) will show an increased ratio of neutral-pH mitophagosomes to acidic mitolysosomes in aged hearts rather than a lack of autophagosomal sequestration; furthermore, stimulating early mitophagy initiation alone will exacerbate cardiomyocyte toxicity, whereas Rubicon depletion or TFEB activation will restore acidic mitolysosome formation and rescue ventricular function. | Age-associated upregulation of HIF-3α drives excessive BNIP3 expression in senescent cardiomyocytes, causing mitophagy flux congestion and cardiac aging. Mitochondrial transplantation restores intracellular ATP homeostasis, restrains pathological HIF-3α–BNIP3 signaling, normalizes mitophagy flux, and rejuvenates the aging heart. | GPT-5.6 Sol 2; Claude Opus 5.5 2; Grok 4.7 2 | нет | нет | нет | 10.1111/acel.70720 |
| 32 | Gemini 4 Argon | R42805954 | H5 | What causal mechanism contributes to the age-related decline of thermogenic adipocytes in subcutaneous white adipose tissue? | Age-related decline in subcutaneous white adipose tissue (scWAT) thermogenesis is driven by the loss of adipocyte- and stromal-derived neurotrophic factors (such as NGF, BDNF, and S100B) alongside increased repulsive axon guidance cues (such as SEMA3A), causing structural retraction of sympathetic nerve arborizations. Without dense peri-adipocyte sympathetic innervation, environmental cold stimuli fail to deliver sufficient local norepinephrine to recruit beige adipocytes. Mechanism: Transcriptional and epigenetic remodelling of ageing adipocytes and PDGFRalpha+ stromal progenitors downregulates retrograde neurotrophic signals (NGF/TrkA and CLSTN3B-S100B axes) while upregulating semaphorin-neuropilin repulsive signalling, leading to axonal die-back of tyrosine hydroxylase-positive (TH+) sympathetic fibres and physical uncoupling of the neuro-adipose junction. Prediction: 3D whole-mount immunolabelling of aged scWAT will reveal a marked reduction in TH+ sympathetic nerve fibre density and branching prior to losing intrinsic adipocyte responsiveness to exogenous beta-3-adrenergic agonists (CL316,243), and viral restoration of NGF or S100B in aged scWAT will regenerate axonal arbors and restore cold-induced UCP1+ beige adipocyte formation. | Microglial ALKBH5 suppresses Ntf5 expression by demethylating Ntf5 mRNA, thereby limiting activation of PVH TrkB-positive neurons, sympathetic innervation of subcutaneous white adipose tissue, and adipocyte browning. Microglia-specific ALKBH5 knockout preserved brown adipocytes and improved metabolic activity during ageing in male mice. | GPT-5.6 Sol 2; Claude Opus 5.5 2; Grok 4.7 2 | нет | нет | нет | 10.1038/s41467-026-77050-w |
| 33 | Gemini 4 Argon | R42810392 | H4 | Can direct pharmacological activation of a conserved metabolic target extend lifespan across evolutionarily diverse organisms and induce longevity-associated changes in mammals? | Direct allosteric activation of the conserved energy sensor AMP-activated protein kinase (AMPK) is sufficient to extend lifespan across evolutionarily diverse invertebrates and induce caloric-restriction-like metabolic rejuvenation in mammals without requiring mitochondrial electron transport chain inhibition. Engaging AMPK directly via its allosteric binding pocket bypasses the pleiotropic off-target effects of indirect metabolic poisons to drive conserved pro-longevity programs. Mechanism: Selective small-molecule binding to the AMPK heterotrimeric complex (such as at the allosteric drug and metabolite [ADaM] site between the alpha-kinase domain and beta-carbohydrate-binding module) stabilizes the active enzyme conformation and prevents dephosphorylation of Thr172. Activated AMPK directly phosphorylates conserved downstream substrates—including ULK1 to initiate autophagy, ACC1/2 to promote fatty acid beta-oxidation, Raptor/TSC2 to restrain mTORC1 signaling, and FOXO/PGC-1alpha to enhance mitochondrial quality control and oxidative stress resistance. Prediction: Administration of a selective direct AMPK activator extends median and maximum lifespan in wild-type C. elegans and Drosophila and improves insulin sensitivity, autophagic flux, and transcriptomic age biomarkers in aged mice without altering cellular ATP/AMP ratios or complex I respiration, whereas genetic ablation of the catalytic AMPK alpha-subunit (aak-2 in worms, AMPKalpha in flies and mice) or point mutation of the allosteric drug-binding pocket completely abolishes both lifespan extension and mammalian metabolic benefits. | Direct pharmacological activation of AMPK with compound 991 extends lifespan in Drosophila melanogaster, Caenorhabditis elegans, and Schizosaccharomyces pombe. In mice, 991 induces a proteomic profile associated with pro-longevity biology, supporting the translational potential of AMPK activation. | GPT-5.6 Sol 3; Claude Opus 5.5 5; Grok 4.7 4 | да | нет | да | 10.1111/acel.70721 |
| 34 | Gemini 4 Argon | R42826184 | H1 | What causal molecular mechanism remodels three-dimensional genome organization during ageing and thereby promotes age-associated inflammatory and activation-related transcription? | Chronic age-associated stress and metabolic signaling induce persistent chromatin engagement of pioneer and inducible transcription factors—principally AP-1 (FOS/JUN) and NF-κB—which actively redistribute SWI/SNF (BAF) chromatin remodelers and cohesin complexes to form de novo enhancer-promoter loops at inflammatory and activation-related loci. This factor-driven recruitment sequesters architectural loop-extrusion machinery away from homeostatic lineage-identity super-enhancers, simultaneously promoting basal activation programs and impairing specialized immune function. Mechanism: Persistent low-grade signaling stabilizes AP-1 complexes at latent distal enhancers, where they recruit BAF remodelers to open chromatin and anchor cohesin-Mediator complexes, establishing de novo long-range chromatin loops with cytokine and activation promoters at the expense of homeostatic cell-identity loops. Prediction: Acute genetic or pharmacological inhibition of AP-1 DNA binding or BAF ATPase activity in aged cells will selectively collapse age-acquired enhancer-promoter loops at inflammatory loci in H3K27ac/cohesin HiChIP assays, redistribute cohesin back to homeostatic identity loci, and reverse the basal activation transcriptional signature. | Age-associated reduction of SATB1 in naive CD4+ T cells weakens TAD boundaries and expands the range of CTCF-mediated interactions without changing CTCF occupancy, producing enhancer-promoter rewiring and increased expression of proinflammatory and proactivation genes. Conditional SATB1 deletion recapitulates these ageing-associated architectural and transcriptional changes, establishing SATB1 deficiency as a causal contributor. | GPT-5.6 Sol 2; Claude Opus 5.5 1; Grok 4.7 2 | нет | нет | нет | 10.1126/sciadv.aeg1622 |
| 35 | Gemini 4 Argon | R42842666 | H3 | How do the different cellular compartments of the vascular wall causally contribute to distinct features of Hutchinson-Gilford progeria vascular pathology? | Progerin expression in medial vascular smooth muscle cells (VSMCs) and intimal endothelial cells (ECs) drives distinct pathological features in a strictly cell-autonomous, compartment-specific manner: mutant VSMCs directly generate extracellular-matrix (ECM) abnormalities and collagen accumulation, whereas mutant ECs independently drive vascular inflammation. Neither compartment requires the LMNA mutation in the neighbouring layer to manifest its signature pathology. Mechanism: In the tunica media, progerin-induced nuclear lamina stiffening disrupts LINC-complex mechanotransduction under cyclic stretch, shifting VSMCs from a contractile to a synthetic, profibrotic phenotype with elevated collagen and matrix metalloproteinase production. Concurrently, in the tunica intima, progerin impairs endothelial adaptation to laminar shear stress, directly activating NF-kappaB transcriptional programs and surface adhesion molecules (ICAM-1, VCAM-1) without altering mural matrix synthesis. Prediction: In heterotypic three-dimensional blood-vessel models or lineage-specific mosaic mice, vessels composed of HGPS VSMCs and wild-type ECs will exhibit medial ECM disorganization and collagen accumulation without endothelial inflammatory activation, whereas vessels with HGPS ECs and wild-type VSMCs will display robust intimal inflammation and leukocyte adhesion without medial fibrosis. | In trilayer engineered blood vessels, HGPS fibroblasts causally promoted extracellular-matrix dysregulation and fibrotic signaling, while HGPS smooth muscle cells drove collagen accumulation and endothelial cells drove inflammation. Correcting the HGPS-associated mutation by base editing restored many pathological characteristics toward healthy levels. | GPT-5.6 Sol 3; Claude Opus 5.5 4; Grok 4.7 3 | да | нет | нет | 10.1126/sciadv.aeh3785 |
| 36 | Gemini 4 Argon | R42853938 | H4 | What splicing-dependent mechanism enables resistance to CDK4/6 inhibition, and can disrupting it restore therapy-induced senescence? | Sustained activity of the protein arginine methyltransferase PRMT5 enables resistance to CDK4/6 inhibition by maintaining spliceosomal fidelity required for productive splicing of MDM4 and the histone methyltransferase EZH2. Pharmacological inhibition of PRMT5 or antisense oligonucleotide-mediated skipping of MDM4 exon 6 disrupts this axis, restoring p53 activation, H3K27me3 loss at senescence loci, and durable therapy-induced senescence. Mechanism: In drug-sensitive cells, CDK4/6 inhibition suppresses E2F-dependent expression of PRMT5 cofactors (such as WDR77/MEP50), reducing symmetric dimethylation of spliceosomal Sm proteins (SmD1/SmD3). This hypomethylation impairs recognition of weak 5' splice sites, causing exon 6 skipping in MDM4 (generating unstable MDM4-S subject to nonsense-mediated decay) and intron retention in EZH2, which together unleash p53-p21 signaling and derepress H3K27me3-silenced senescence genes. Resistant cells maintain high PRMT5-WDR77 activity independently of CDK4/6, preserving full-length MDM4 to degrade p53 and full-length EZH2 to epigenetically silence CDKN2A and SASP enhancers; blocking PRMT5 or directly forcing MDM4 exon 6 skipping re-establishes both p53 transcriptional activity and chromatin derepression required for irreversible arrest. Prediction: In CDK4/6 inhibitor-resistant cells with wild-type TP53, RNA-seq and anti-sDMA immunoprecipitation will reveal preserved Sm protein symmetric dimethylation alongside full-length MDM4 (exon 6 inclusion) and EZH2 transcripts, and combining palbociclib with a PRMT5 inhibitor or an MDM4 exon 6 splice-switching oligonucleotide—unlike inhibiting downstream CDK2 alone—will selectively restore SA-beta-gal activity and p21/SASP induction without requiring exogenous DNA damage. | Increased inclusion of exon 2 drives SUV39H2 overexpression and CDK4/6 inhibitor resistance. Suppressing SUV39H2 expression or methyltransferase activity removes H3K9me3 from enhancer regions, opens associated promoters, activates p21 and other senescence-associated genes, and restores therapy-induced senescence. | GPT-5.6 Sol 2; Claude Opus 5.5 2; Grok 4.7 2 | нет | нет | нет | 10.1126/sciadv.aea2001 |
| 37 | Gemini 4 Argon | R42858183 | H3 | Can a defined intervention preserve lysosomal function and protein homeostasis during aging, thereby extending lifespan and maintaining organismal function, and through what mechanism? | Dietary supplementation with the polyamine spermidine preserves lysosomal proteolytic activity and maintains protein homeostasis during aging, thereby extending lifespan and organismal function, by sustaining the eIF5A-dependent translation of the master lysosomal transcription factor TFEB (HLH-30). Mechanism: Spermidine serves as the sole aminobutyl donor for the enzymatic hypusination of eukaryotic translation initiation factor 5A (eIF5A) via deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). Hypusinated eIF5A resolves ribosome stalling at polyproline motifs within TFEB/HLH-30 mRNA, preventing age-related translational decline of TFEB and maintaining transcription of the Coordinated Lysosomal Expression and Regulation (CLEAR) network, including V-ATPase subunits and cathepsin hydrolases. Prediction: Spermidine treatment in aged organisms will restore nuclear TFEB/HLH-30 levels, lysosomal cathepsin activity, and clearance of insoluble ubiquitinated protein aggregates to extend lifespan, whereas pharmacological inhibition of DHPS (via GC7) or mutation of the eIF5A hypusination site (K50A) will completely abolish these benefits even when mTORC1 is pharmacologically inhibited to force nuclear translocation of existing TFEB. | 20(S)-ginsenoside Rg3 extended lifespan and preserved physiological and neuronal function in Caenorhabditis elegans by restoring lysosomal activity and autophagic flux. Rg3 remodeled neuronal lysosomal phosphoinositide signatures toward increased PI(4)P and reduced PI(3)P, suppressed RSKS-1/S6K–TORC1 signaling, and promoted nuclear HLH-30/TFEB activity, thereby improving proteostasis and resistance to polyglutamine- and α-synuclein-associated toxicity. | GPT-5.6 Sol 3; Claude Opus 5.5 2; Grok 4.7 2 | нет | да | нет | 10.1111/acel.70755 |
| 38 | Gemini 4 Argon | R42585340 | H5 | Which molecular mechanism enables mild cellular stress to preserve protein homeostasis during ageing and extend organismal lifespan? | Mild thermal or proteotoxic stress extends lifespan and prevents age-related protein aggregation by co-activating heat shock factor 1 (HSF-1) and the transcription factor TFEB/HLH-30 to transcriptionally upregulate the macroautophagy-lysosome machinery. Rather than relying solely on molecular chaperones to refold proteins, this hormetic response causally requires autophagic clearance of misfolded and aggregation-prone proteins to maintain organismal proteostasis. Mechanism: Transient sub-lethal stress triggers HSF-1 trimerization and nuclear translocation alongside calcineurin- and mTORC1-regulated nuclear entry of TFEB (HLH-30 in C. elegans). Together, HSF-1 and TFEB/HLH-30 drive coordinated transcription of core autophagy-related genes (such as ATG8/LC3/lgg-1, ULK1/unc-51, and SQSTM1/p62/sqst-1) and lysosomal hydrolases, increasing autophagic flux to encapsulate and degrade ubiquitinated protein oligomers before they form insoluble toxic aggregates. Prediction: Genetic ablation or RNAi knockdown of TFEB/HLH-30 or core autophagy execution genes (such as ATG5, ATG7, or BECN1/bec-1) specifically after mild stress exposure will abolish both the clearance of polyglutamine or amyloid aggregates and the lifespan extension, even when HSF-1-dependent chaperone induction (HSP70/HSP90) and 26S proteasome activity remain intact. | In Caenorhabditis elegans, inhibition of mitochondrial respiration activates an intestinal ELT-2-dependent transcriptional program that increases lysosomal proteolysis during ageing, largely independently of the mitochondrial unfolded protein response. Direct promoter binding by ELT-2, requiring residue R249, and the lysosomal proteases CPR-5 and CPR-8 are necessary for toxic polyglutamine aggregate clearance and mitochondrial stress-induced lifespan extension. | GPT-5.6 Sol 2; Claude Opus 5.5 2; Grok 4.7 3 | нет | да | нет | 10.1126/sciadv.aeh0657 |
| 39 | Claude Opus 5.5 | R42630044 | H2 | What mechanism limits the anabolic response of aged bone to mechanical loading, and can targeted stimulation restore this response? | Aged osteocytes lose mechanosensitivity because the stretch-activated cation channel PIEZO1 is downregulated in cortical bone, so load-induced calcium influx and downstream Wnt1/Wnt10b output collapse; pharmacological agonism of PIEZO1 (e.g. Yoda1) restores the anabolic response without mechanical loading. Mechanism: Reduced PIEZO1 expression/membrane availability in aged osteocytes lowers load-evoked Ca2+ transients, blunting NFAT/YAP-dependent induction of Wnt ligands and suppression of sclerostin, which shifts the formation/resorption balance toward resorption. Direct chemical gating of the residual channel pool bypasses the sensing deficit. Prediction: In aged mice, Yoda1 (or equivalent PIEZO1 agonist) increases cortical thickness and periosteal mineral apposition to a degree comparable with loading in young animals, and this effect is abolished in osteocyte-specific Piezo1 knockouts, whereas overcoming the deficit by increasing strain magnitude alone does not normalize Wnt1/Wnt10b induction. | In aged mouse bone, activation of Piezo1 during mechanical loading promotes its membrane co-localization with connexin 43 and increases connexin 43 hemichannel activity through PI3K-Akt signaling. Hemichannel opening increases PGE2 release, suppresses sclerostin, promotes endosteal bone formation, inhibits resorption, and thereby restores the cortical anabolic response to loading. | GPT-5.6 Sol 3; Gemini 4 Argon 3; Grok 4.7 3 | да | нет | нет | 10.1111/acel.70687 |
| 40 | Claude Opus 5.5 | R42664348 | H5 | By what causal molecular mechanism does excess adiposity promote osteoarthritis progression, and can disrupting that mechanism reduce joint pathology? | Adipose tissue is a major source of a circulating complement-pathway protease that reaches synovial fluid and locally activates the alternative complement cascade on chondrocyte surfaces and damaged matrix, driving cartilage catabolism. Genetic or pharmacological interruption of this adipose-to-joint complement axis should reduce cartilage loss and synovitis in diet-induced obesity without requiring weight loss. Mechanism: Hypertrophic adipocytes secrete a rate-limiting complement activator; it enters the joint, amplifies C3/C5 convertase assembly on cartilage debris, generates C5a and the membrane attack complex sublytically on chondrocytes, which induces MMP-13/ADAMTS-5 and recruits C5aR1+ synovial macrophages. Prediction: Adipocyte-specific deletion of the secreted activator (or C5aR1 blockade) in obese mice reduces OARSI cartilage score and synovitis while body mass, fat mass and joint loading stay unchanged; parabiosis or serum transfer from obese wild-type mice restores pathology in the knockout, and the protection is lost in complement-deficient recipients. | Adipocyte-derived extracellular vesicles enriched in mitochondrial components transfer mitochondrial DNA to chondrocytes, where it activates cGAS-STING signaling and causes inflammation, metabolic dysfunction, senescence, and cartilage degeneration. Genetic or pharmacological inhibition of this pathway attenuates cartilage damage, pain behaviors, and gait abnormalities. | GPT-5.6 Sol 2; Gemini 4 Argon 1; Grok 4.7 2 | нет | нет | нет | 10.1126/sciadv.aee6780 |
| 41 | Claude Opus 5.5 | R42665751 | H2 | How does age-associated mitochondrial dysfunction initiate and propagate inflammatory signaling that causes ovarian functional decline? | Age-associated loss of mitochondrial DNA integrity in oocytes and granulosa cells causes release of mtDNA into the cytosol, which activates the cGAS–STING pathway and initiates type I interferon and NF-κB–driven inflammatory signaling within the follicle. This cell-intrinsic innate-immune activation, rather than infiltrating immune cells, is the initiating event of ovarian functional decline. Mechanism: Oxidative damage and reduced mitophagy in aged follicles permit mtDNA escape through BAX/BAK macropores and VDAC oligomers into the cytosol. Cytosolic mtDNA binds cGAS, generating cGAMP that activates STING, driving TBK1/IRF3 interferon output and NF-κB induction of IL-6, IL-1β and CXCL10. The resulting local inflammatory milieu impairs granulosa steroidogenesis and accelerates follicular atresia. Prediction: Oocyte- or granulosa-specific deletion of Cgas or Sting1, or pharmacological STING inhibition (H-151), in aged or mitochondrially stressed mice preserves follicle reserve, estradiol/AMH levels and fertility while leaving mtDNA copy number and oxidative damage unchanged — i.e. the mitochondrial lesion persists but the functional decline is prevented. Conversely, ovarian expression of a mitochondrial nuclease-resistant mtDNA-releasing mutant (e.g. TFAM haploinsufficiency) reproduces the decline, and it is rescued by STING loss. | Ageing-associated mitochondrial DNA leakage from oocytes activates oocyte cGAS, generating cGAMP that triggers STING signaling and passes through gap junctions to activate STING in surrounding granulosa cells. Genetic deletion of oocyte Cgas or pharmacological STING inhibition ameliorates inflammation and ovarian dysfunction, establishing this signaling axis as a causal driver of ovarian ageing. | GPT-5.6 Sol 4; Gemini 4 Argon 4; Grok 4.7 4 | да | нет | да | 10.1038/s43587-026-01195-y |
| 42 | Claude Opus 5.5 | R42689491 | H3 | Can in vivo correction of the HGPS-causing mutation rescue molecular, cellular, and structural defects in bone, and how does treatment timing affect efficacy? | Mutation correction before the onset of radiographically detectable skeletal disease will prevent bone pathology almost completely, whereas the identical intervention delivered after structural deficits are established will halt progression and partially rebuild bone but will not fully normalize geometry or strength. Efficacy will therefore show a threshold dependence on treatment age rather than a smooth linear decline. Mechanism: Early correction acts on a still-intact progenitor pool and an unremodeled matrix, so normal modeling can proceed. Once progerin has driven progenitor exhaustion/senescence and produced irreversibly altered cortical geometry and hypermineralized or collagen-cross-link-abnormal matrix, correction restores cell function but remodeling cannot re-sculpt macroscopic shape (e.g., clavicular and rib thinning, acro-osteolysis-like resorption) within the animal's lifespan. Prediction: Matched cohorts treated at a pre-symptomatic versus an established-disease age will show equal normalization of molecular markers (progerin levels, osteogenic gene expression) but divergent structural outcomes: near-complete rescue early, and in the late group restoration of dynamic bone formation rate with only partial recovery of cortical area and failure load. | Adenine base editing of the pathogenic LMNA variant reduced progerin expression, restored extracellular-matrix deposition and mineralization in progeroid osteoblasts, and partially rescued bone structure and physical properties in mice. In vivo correction was strongly age-dependent, with early postnatal delivery producing substantially greater editing and skeletal benefit than later treatment. | GPT-5.6 Sol 4; Gemini 4 Argon 3; Grok 4.7 3 | да | нет | нет | 10.1111/acel.70700 |
| 43 | Claude Opus 5.5 | R42717261 | H1 | What mechanism induces pathogenic immune-cell senescence in ulcerative colitis, and does this senescence causally exacerbate the disease? | In ulcerative colitis, metabolic stress in mucosal T cells causes mitochondrial DNA to leak into the cytosol, activating the cGAS–STING pathway and driving these cells into a senescent, SASP-secreting state that worsens colitis. Blocking mtDNA release or STING signaling should prevent senescence and attenuate disease. Mechanism: Inflamed mucosal metabolic conditions damage mitochondria in lamina propria T cells; mitochondrial permeability transition/VDAC- or BAX/BAK-dependent pore formation releases mtDNA into the cytosol; cGAS detects it, STING–TBK1–IRF3/NF-κB signaling plus p53/p21 engagement enforces a stable cell-cycle arrest with a pro-inflammatory secretome (IL-6, IL-1β, TNF, chemokines) that recruits and activates neutrophils and macrophages, sustaining epithelial injury. Prediction: In colitis models, T-cell-specific deletion of Cgas or Sting1 (or mtDNA depletion/TFAM-dependent packaging rescue, or inhibition of the mPTP/VDAC oligomerization) reduces p16/p21-positive senescent mucosal T cells and SASP cytokines and lessens histological colitis, whereas deleting the same genes in epithelium or myeloid cells does not reproduce the senescence rescue; cytosolic mtDNA is measurable in sorted UC patient mucosal T cells and correlates with their senescence score. | NAD+ metabolic dysregulation causes mitochondrial dysfunction and cytosolic mitochondrial DNA leakage, activating cGAS-STING signaling to drive CD8+ T-cell senescence. These senescent cells exacerbate colitis, while systemic senolytic treatment reduces disease severity; their associated signature also predicts severe disease and non-response to biologic therapy. | GPT-5.6 Sol 4; Gemini 4 Argon 4; Grok 4.7 4 | да | нет | да | 10.1111/acel.70706 |
| 44 | Claude Opus 5.5 | R42717261 | H2 | What mechanism induces pathogenic immune-cell senescence in ulcerative colitis, and does this senescence causally exacerbate the disease? | Senescent immune cells cause resistance to anti-inflammatory therapy in UC: their SASP maintains an inflammatory circuit that is not dependent on the single cytokine being blocked. Adding senescence-targeting treatment restores responsiveness. Mechanism: The SASP is multi-cytokine and self-reinforcing (IL-6/STAT3, IL-1β, TNF, chemokine-driven neutrophil recruitment, and local paracrine spread of senescence to neighboring immune and stromal cells). Blocking one node (TNF, IL-12/23, JAK partially) leaves the rest of the circuit intact, so inflammation persists; removing the senescent source collapses the whole circuit. Prediction: Pre-treatment mucosal senescence burden (p16/p21-high immune cells, SASP transcriptional signature) is higher in future non-responders to anti-TNF and stratifies response better than baseline CRP/histology; in a colitis model refractory to anti-TNF, combining anti-TNF with senolytics or a STING inhibitor restores remission whereas either alone does not. | NAD+ metabolic dysregulation causes mitochondrial dysfunction and cytosolic mitochondrial DNA leakage, activating cGAS-STING signaling to drive CD8+ T-cell senescence. These senescent cells exacerbate colitis, while systemic senolytic treatment reduces disease severity; their associated signature also predicts severe disease and non-response to biologic therapy. | GPT-5.6 Sol 2; Gemini 4 Argon 2; Grok 4.7 2 | нет | нет | нет | 10.1111/acel.70706 |
| 45 | Claude Opus 5.5 | R42717261 | H3 | What mechanism induces pathogenic immune-cell senescence in ulcerative colitis, and does this senescence causally exacerbate the disease? | Senescent immune cells are not bystanders but causal drivers of UC severity: their selective removal is sufficient to improve colitis. Senolytic clearance or genetic ablation of p16-high immune cells will reduce inflammation independently of any effect on epithelial cells. Mechanism: A small population of senescent mucosal lymphocytes/myeloid cells acts as a persistent inflammatory hub; because senescent cells are apoptosis-resistant (BCL-2/BCL-xL, PI3K–AKT survival dependence), they accumulate and continuously emit SASP factors that amplify local immune activation and block epithelial regeneration. Eliminating them removes the amplifier. Prediction: In INK-ATTAC/p16-3MR mice (or with dasatinib+quercetin/navitoclax), induced clearance of p16-positive cells after colitis onset lowers colonic SASP cytokines, restores crypt regeneration and reduces disease activity; adoptive transfer of in vitro-senesced T cells into recipients worsens colitis in a dose-dependent manner, while transfer of equal numbers of non-senescent cells does not. | NAD+ metabolic dysregulation causes mitochondrial dysfunction and cytosolic mitochondrial DNA leakage, activating cGAS-STING signaling to drive CD8+ T-cell senescence. These senescent cells exacerbate colitis, while systemic senolytic treatment reduces disease severity; their associated signature also predicts severe disease and non-response to biologic therapy. | GPT-5.6 Sol 3; Gemini 4 Argon 3; Grok 4.7 3 | да | нет | нет | 10.1111/acel.70706 |
| 46 | Claude Opus 5.5 | R42723546 | H5 | Can a cell-free regenerative treatment alleviate UV-induced skin photoaging, and which causal intracellular mechanism mediates its protective effects? | Topical or intradermal application of a cell-free regenerative preparation (mesenchymal stromal cell-derived small extracellular vesicles / conditioned-medium secretome) alleviates UV-induced photoaging primarily by restoring mitophagy in keratinocytes and dermal fibroblasts. Restored PINK1/Parkin-dependent clearance of UV-damaged mitochondria prevents accumulation of depolarized organelles, thereby blocking senescence and sterile inflammation. Mechanism: UV irradiation depolarizes mitochondria and simultaneously blunts autophagic flux, so damaged mitochondria persist. The cell-free preparation delivers/induces PINK1 stabilization and Parkin recruitment, increasing LC3-II-tagged mitophagosome formation and lysosomal delivery; removal of dysfunctional mitochondria lowers mitochondrial ROS, preserves ATP, prevents p16/p21-driven senescence and reduces NF-kB-driven cytokine output, with secondary recovery of collagen I via reduced MMP-1/MMP-3. Prediction: Protection is abolished when mitophagy is blocked — in PINK1- or Parkin-silenced cells, or with Mdivi-1/bafilomycin or mito-QC/mt-Keima reporters showing no flux increase — while generic antioxidant capacity of the preparation is unchanged; conversely mitophagy inducers (urolithin A) reproduce the benefit. Alternatives predicting barrier-first or purely paracrine-growth-factor action would retain protection in PINK1-null skin. | Human umbilical cord mesenchymal stem cell secretome protects against UV-induced photoaging by enhancing mitophagy, which clears damaged mitochondria and reduces cytosolic mitochondrial DNA leakage. This suppresses cGAS-STING signaling and downstream inflammatory cytokines; mitophagy inhibition abolishes protection, while STING inhibition restores it. | GPT-5.6 Sol 3; Gemini 4 Argon 3; Grok 4.7 3 | да | нет | нет | 10.1111/acel.70701 |
| 47 | Claude Opus 5.5 | R42725837 | H2 | Does the transmembrane protein investigated in this study causally regulate cellular senescence and age-related tissue pathology, and through what signaling mechanism? | The transmembrane protein acts as a cell-autonomous driver of senescence: its expression rises in aged and stressed tissue, and raising it is sufficient to push proliferating cells into a stable senescent arrest, while deleting it blocks senescence entry and reduces age-related tissue pathology. Mechanism: Stress-induced upregulation of the protein at the plasma membrane raises its local surface density, enabling ligand-independent clustering and constitutive assembly of an intracellular adaptor complex. The signal converges on NF-kB/p38 to sustain the SASP while p53-p21 and p16-Rb enforce the arrest, creating a feed-forward loop in which SASP cytokines further induce the protein. Prediction: Overexpression in young primary cells with intact p53 produces SA-beta-gal positivity, p21/p16 induction and SASP secretion without added stress, and conditional knockout in an aged or progeroid mouse lowers p16 burden and improves tissue histology and function; a signaling-dead point mutant that still reaches the membrane fails to do either, excluding mere protein-burden or ER-stress effects. | PTCHD4 promotes cellular senescence and age-associated tissue dysfunction by enhancing AKT signaling. PTCHD4 deficiency suppressed senescence, alleviated ageing-related phenotypes and bleomycin-induced pulmonary fibrosis in mice, and its anti-senescent effect was reversed by restoring AKT signaling. | GPT-5.6 Sol 3; Gemini 4 Argon 2; Grok 4.7 3 | да | да | нет | 10.1111/acel.70711 |
| 48 | Claude Opus 5.5 | R42736449 | H2 | Can an unannotated protein product that is altered in Alzheimer's disease causally regulate cellular function relevant to disease pathology? | A microprotein translated from a small ORF within a lncRNA or 5' uORF is depleted in Alzheimer's disease neurons, and this loss causally impairs mitochondrial respiration independently of any annotated protein at the same locus. Mechanism: The microprotein localizes to the inner mitochondrial membrane and stabilizes assembly of respiratory complex I/IV or ATP synthase dimers. Depletion lowers ATP output and raises mitochondrial ROS, which degrades synaptic maintenance in high-demand neurons. Prediction: CRISPR knockout of only the sORF start codon (leaving the host transcript and any overlapping annotated ORF intact) reduces oxygen consumption rate and complex activity in neurons, and re-expression of the microprotein cDNA from a separate locus rescues it; knockdown of the host lncRNA by itself does not reproduce the defect. | A small open reading frame at the MKKS locus encodes a 63-amino-acid microprotein that is the locus's predominant translation product and is downregulated in Alzheimer's disease. Experimental loss of this microprotein impairs mitochondrial respiration in microglia, supporting a causal role in microglial bioenergetics. | GPT-5.6 Sol 3; Gemini 4 Argon 3; Grok 4.7 3 | да | нет | нет | 10.1038/s43587-026-01207-x |
| 49 | Claude Opus 5.5 | R42749700 | H2 | What molecular mechanism links disrupted chromatin regulation to cellular senescence in Hutchinson–Gilford progeria syndrome, and can targeting that mechanism ameliorate disease phenotypes and extend lifespan? | Progerin-induced heterochromatin decompaction and nuclear-envelope rupture release genomic and mitochondrial DNA fragments into the cytosol, where cGAS–STING sensing produces the type-I-interferon arm of the SASP; STING loss or inhibition should uncouple nuclear damage from inflammation and improve HGPS phenotypes. Mechanism: Loss of lamin B1/heterochromatin tethering → micronuclei, cytoplasmic chromatin fragments and de-repressed LINE-1 retroelement cDNA → cGAS activation → STING–TBK1–IRF3 → IFN-β and NF-κB SASP → paracrine senescence in vasculature and adipose tissue. Prediction: Cytosolic dsDNA and ISG signatures (Ifit1, Isg15) are elevated in HGPS fibroblasts and G609G aorta and precede p16 induction; Sting1-null G609G mice or STING/TBK1 inhibitor treatment reduce SASP and vascular smooth-muscle loss and extend lifespan, while cGAS-independent DNA-damage signalling (ATM) remains unchanged — separating sensing from damage itself. | HMGA1 recruits the deubiquitinase USP7 to stabilize HP1β, which reduces chromatin accessibility at ANGPTL2 and suppresses senescence-associated secretory factors, thereby alleviating HGPS cellular senescence. An HMGA1-derived peptide, UHP, prevents HP1β degradation, reduces senescence, and significantly extends the lifespan of LmnaG609G/G609G mice. | GPT-5.6 Sol 2; Gemini 4 Argon 2; Grok 4.7 2 | нет | нет | нет | 10.1038/s41467-026-76789-6 |
| 50 | Claude Opus 5.5 | R42775698 | H4 | Can age-associated differences in the human gut microbial community causally reprogram intestinal barrier function, systemic metabolism, and mucosal gene expression, and what mediators contribute to these effects? | Transplantation of faecal microbiota from aged human donors into germ-free or antibiotic-depleted young mice is sufficient to cause reduced small-intestinal villus height and surface area, increased paracellular permeability, and a pro-inflammatory mucosal transcriptional programme, whereas microbiota from young donors does not. The effect is donor-age-driven rather than recipient-age-driven, establishing the aged community as an active cause rather than a consequence of host ageing. Mechanism: Age-associated communities are depleted of saccharolytic, butyrate-producing Firmicutes (Faecalibacterium, Roseburia, Eubacterium rectale) and enriched in Proteobacteria/Enterobacteriaceae and pathobionts. Loss of luminal butyrate removes the dominant colonocyte energy substrate and HDAC-inhibitory/HIF-1α-stabilising signal that maintains tight-junction (claudin-1, occludin, ZO-1) expression and epithelial oxygen consumption; the resulting epithelial oxygenation further expands facultative anaerobes, creating a feed-forward loop that degrades barrier integrity and drives NF-κB-dependent mucosal gene expression. Prediction: Recipients of aged-donor microbiota show lower caecal/portal butyrate, reduced claudin/occludin protein, elevated serum FITC-dextran or LPS-binding protein, and villus atrophy; oral tributyrin or butyrate supplementation (or co-colonisation with a butyrogenic consortium) in aged-donor recipients restores villus morphology, tight-junction expression and permeability to young-donor levels without changing overall community membership, while butyrate-receptor-deficient (Ffar2/Ffar3 or Hdac3^ΔIEC) recipients are refractory to that rescue. | Transplanting elderly-human gut microbiota into pigs caused reduced ileal villus height, loss of tight-junction proteins, altered plasma metabolites, and coordinated suppression of seven ileal mucosal antiviral-response hub genes compared with young-donor microbiota. The elderly-donor-associated metabolic shift was functionally linked to barrier impairment: Tyr-Phe increased epithelial electrical resistance, whereas prostaglandin E3 decreased it in IPEC-1 cells. | GPT-5.6 Sol 3; Gemini 4 Argon 3; Grok 4.7 3 | да | нет | нет | 10.1111/acel.70725 |
| 51 | Claude Opus 5.5 | R42786310 | H5 | Can a commensal microorganism predicted from integrated human ageing profiles causally extend lifespan and healthspan and shift age-associated molecular and microbial states toward younger configurations? | A commensal bacterium nominated by multi-omic human ageing profiles (e.g. a Lactobacillus/Lactiplantibacillus- or Akkermansia-class strain whose relative abundance is high in biologically young individuals after adjusting for chronological age) causally extends median and maximum lifespan when colonised in gnotobiotic or conventional mice, and the effect requires live, metabolically active cells. Heat-killed or irradiated preparations of the same strain at matched dose produce no lifespan gain. Mechanism: Viable colonisation sustains continuous production of a secreted small-molecule or peptide effector in the gut lumen that signals to host enterocytes and the enteric immune compartment; killed cells deliver cell-wall ligands but no renewable effector flux, so downstream host signalling is not maintained. Prediction: Live-strain cohorts show a significant (>8%) median lifespan increase versus vehicle, while heat-killed cohorts overlap vehicle survival curves; the lifespan effect scales with faecal colonisation density/CFU and disappears in animals that fail to engraft. | Neisseria flavescens was identified as a candidate geroprotective commensal and experimentally shown to extend lifespan and healthspan in Caenorhabditis elegans when administered live. In aged mice, heat-killed N. flavescens shifted the serum metabolome, liver transcriptome and gut microbiome toward younger states, while isolated strains were confirmed to produce predicted beneficial metabolites. | GPT-5.6 Sol 2; Gemini 4 Argon 0; Grok 4.7 2 | нет | нет | нет | 10.1038/s43587-026-01220-0 |
| 52 | Claude Opus 5.5 | R42841227 | H5 | Do age-related changes in gut microbial metabolism causally impair antiviral defense during influenza infection, and through what host mechanism can this deficit be counteracted? | Ageing reduces gut microbial production of short-chain fatty acids (notably butyrate), and this loss causally impairs antiviral defense in the lung during influenza infection. Restoring butyrate signalling in the host — pharmacologically or by transferring a young/SCFA-producing microbiota — rescues antiviral protection in aged animals. Mechanism: Diminished abundance of fibre-fermenting commensals lowers luminal and systemic butyrate. Butyrate acts on haematopoietic precursors and lung-resident myeloid cells via GPR41/43 and HDAC inhibition, tuning the differentiation of monocytes into patrolling/antiviral phenotypes and limiting damaging neutrophil influx. Without it, aged mice generate excessive tissue-damaging inflammation with weaker type I/III interferon-dependent viral control, raising viral load and mortality. Prediction: Faecal transfer from young to aged mice, or oral butyrate/tributyrin supplementation starting before challenge, lowers lung viral titre and mortality in aged mice; the rescue is abolished in Ffar2/Ffar3-deficient hosts or by myeloid-specific blockade, and germ-free mice colonised with aged microbiota are protected by butyrate but not by fibre alone. | Age-associated gut microbiota dysbiosis reduces microbial acetate-production capacity during influenza infection, while acetate supplementation suppresses viral replication and inflammation in senescent human lung fibroblasts. This protection is associated with FFAR2/FFAR3 signaling and increased histone H3 acetylation, supporting acetate as a mechanistic mediator of the ageing gut–lung axis. | GPT-5.6 Sol 3; Gemini 4 Argon 3; Grok 4.7 3 | да | нет | нет | 10.1111/acel.70750 |
| 53 | Claude Opus 5.5 | R42842666 | H3 | How do the different cellular compartments of the vascular wall causally contribute to distinct features of Hutchinson-Gilford progeria vascular pathology? | Smooth muscle cells are the primary driver of progeroid vascular degeneration, and progerin expression restricted to the smooth muscle layer is sufficient to reproduce medial cell loss, wall thinning and adverse remodelling even when endothelium, fibroblasts and immune cells carry no mutation. Conversely, sparing smooth muscle cells from progerin largely protects the vessel from this degenerative component. Mechanism: Progerin accumulates in the stiff, mechanically loaded medial smooth muscle compartment, where repeated contractile cycling and nuclear strain amplify lamina damage, DNA-damage signalling and mechanosensitive apoptosis; the resulting cell-autonomous attrition cannot be compensated because medial smooth muscle cells have very low replicative reserve. Prediction: In cell-type-restricted progerin models (or three-layer engineered vessels assembled from mutant versus isogenic corrected cells), smooth-muscle-only progerin yields the full medial depletion/wall-thinning phenotype, whereas endothelium-only or fibroblast-only progerin yields near-normal medial cellularity; mechanical unloading or reduced contractile cycling attenuates loss in the smooth-muscle-mutant condition. | In trilayer engineered blood vessels, HGPS fibroblasts causally promoted extracellular-matrix dysregulation and fibrotic signaling, while HGPS smooth muscle cells drove collagen accumulation and endothelial cells drove inflammation. Correcting the HGPS-associated mutation by base editing restored many pathological characteristics toward healthy levels. | GPT-5.6 Sol 2; Gemini 4 Argon 2; Grok 4.7 2 | нет | нет | нет | 10.1126/sciadv.aeh3785 |
| 54 | Claude Opus 5.5 | R42844664 | H4 | Through what causal mechanism does time-restricted feeding protect against accelerated cardiovascular ageing? | Time-restricted feeding protects arteries by suppressing NLRP3-inflammasome-driven gasdermin-D pore formation and pyroptosis in endothelial and perivascular myeloid cells; inflammasome activation is the necessary mediator of the accelerated vascular ageing that TRF prevents. Mechanism: The prolonged daily fast lowers postprandial glycemic excursions, lipotoxic DAMPs and mtROS, raises β-hydroxybutyrate (a direct NLRP3 inhibitor) and induces mitophagy, so ASC-speck assembly, caspase-1 activation and IL-1β/IL-18 release fall; less gasdermin-D pore formation preserves endothelial junction integrity, NO bioavailability and prevents the IL-1β→smooth-muscle osteogenic/fibrotic program that stiffens the wall. Prediction: TRF's protection of endothelium-dependent relaxation, pulse-wave velocity and cardiac remodeling is abolished (no further benefit) in Nlrp3−/−, Casp1−/− or Gsdmd−/− animals — i.e. TRF and inflammasome deletion are epistatic, not additive — and conversely constitutively active NLRP3 (Nlrp3^D301N) blocks TRF benefit despite unchanged feeding rhythm; vascular ASC specks and plasma IL-18 fall before any change in blood pressure. | Time-restricted feeding enriches acetate-producing Limosilactobacillus, and microbiota-derived acetate is necessary and sufficient for its protection against angiotensin II-induced cardiovascular ageing. Acetate activates GPR43, inhibits HDAC3, increases H4K8 acetylation, and suppresses NLRP3-mediated pyroptosis and cellular senescence. | GPT-5.6 Sol 3; Gemini 4 Argon 3; Grok 4.7 3 | да | нет | нет | 10.1111/acel.70728 |
| 55 | Claude Opus 5.5 | R42853938 | H3 | What splicing-dependent mechanism enables resistance to CDK4/6 inhibition, and can disrupting it restore therapy-induced senescence? | Resistance to CDK4/6 inhibition is enabled by an aberrant splice isoform of a chromatin-modifying enzyme that loses its regulatory domain while retaining catalytic activity, and this isoform silences the senescence transcriptional program. Forcing expression of the full-length isoform, or blocking production of the truncated one, restores palbociclib-induced senescence. Mechanism: A splicing factor whose expression rises under prolonged CDK4/6 inhibition promotes use of an alternative exon/termination site in a histone methyltransferase or demethylase transcript. The resulting protein is mistargeted to CDKN1A/CDKN2A and SASP loci, where it deposits repressive marks that prevent the stable heterochromatin-plus-p21 state needed for arrest. Cells therefore resume cycling despite sustained RB-pathway inhibition. Prediction: Isoform-specific knockdown of the truncated transcript (antisense oligonucleotide or splice-switching ASO) with no change in total gene mRNA restores SA-β-gal positivity, p21 induction and durable arrest in resistant cells, while catalytically dead rescue of the truncated isoform does not; ChIP-seq shows loss of the repressive mark specifically at senescence loci. | Increased inclusion of exon 2 drives SUV39H2 overexpression and CDK4/6 inhibitor resistance. Suppressing SUV39H2 expression or methyltransferase activity removes H3K9me3 from enhancer regions, opens associated promoters, activates p21 and other senescence-associated genes, and restores therapy-induced senescence. | GPT-5.6 Sol 2; Gemini 4 Argon 3; Grok 4.7 3 | да | да | нет | 10.1126/sciadv.aea2001 |
| 56 | Claude Opus 5.5 | R42723144 | H4 | Can naturally occurring inherited genetic variation alter the rate of ovarian ageing on equivalent heterogeneous nuclear backgrounds, and what cellular mechanism mediates this effect? | Naturally occurring mitochondrial DNA (mtDNA) haplotype variation is sufficient to shift the rate of ovarian ageing when nuclear background is held equivalent (e.g. conplastic strains or reciprocal F1/outbred crosses sharing a heterogeneous nuclear genome but differing in maternally inherited mtDNA). The effect is mediated by haplotype-specific OXPHOS coupling efficiency in the oocyte–granulosa unit, which sets the rate at which the non-renewable primordial follicle pool is activated and lost. Mechanism: Non-synonymous and tRNA/rRNA variants distinguishing wild-derived mtDNA haplotypes alter complex I/III assembly and proton-leak-adjusted coupling efficiency. Lower coupling raises the ATP/ADP-sensing load on primordial oocytes, de-repressing the PI3K–AKT–FOXO3a/mTORC1 switch that holds follicles dormant, so a larger fraction of the reserve is recruited per cycle and atresia-driven depletion accelerates. The nuclear genome is permissive but not causal because it is identical in distribution across the compared groups. Prediction: At matched chronological age (e.g. 9–12 months), mtDNA-divergent animals on the same heterogeneous nuclear background differ ≥2-fold in primordial follicle counts and in age at cycle irregularity, with the direction predicted by oocyte respirometry (coupling efficiency measured in isolated cumulus–oocyte complexes) and by nuclear-pFOXO3a exit in primordial oocytes — while nuclear SNP association in the same cohort explains no additional variance. Cytoplasmic transfer or mitochondrial replacement reverses the phenotype; a nuclear-background-matched but mtDNA-identical control shows no difference. | The OKC-HETW mitochondrial haplotype accelerated ovarian ageing, causing faster primordial-follicle loss, inflammatory and fibrotic remodelling, mitochondrial dysfunction and impaired ovulation relative to the OKC-HETB haplotype on equivalently distributed nuclear backgrounds. Despite normal TFAM expression and elevated total TFAM protein, OKC-HETW ovaries had reduced mitochondrial TFAM, TFAM–mtDNA binding and TOMM20, supporting defective mitochondrial protein import and compromised mtDNA maintenance as the mechanism linking haplotype to accelerated decline. | GPT-5.6 Sol 3; Gemini 4 Argon 2; Grok 4.7 2 | нет | да | нет | 10.1111/acel.70710 |
| 57 | Claude Opus 5.5 | R42808804 | H3 | What causal mechanism links cochlear ageing to loss of blood-labyrinth barrier integrity and auditory dysfunction? | Age-dependent loss of pericyte coverage in the cochlear stria vascularis is the primary causal event driving blood-labyrinth barrier (BLB) leakage and endocochlear potential decline. Pericyte dropout removes the paracrine signals that maintain endothelial tight junctions, so capillaries become permeable before hair cells die. Mechanism: Senescent/stressed cochlear pericytes detach and are lost, reducing pericyte-derived signalling (e.g. PDGFB–PDGFRB axis, angiopoietin-1/TIE2, TGF-beta) to strial endothelium. Endothelial tight-junction and adherens proteins (claudin-5, occludin, ZO-1, VE-cadherin) are downregulated and redistributed, transcytosis rises, plasma proteins and ions enter the intrastrial fluid space, K+ recycling by marginal cells fails and the endocochlear potential falls, raising auditory thresholds. Prediction: In aged animals, quantitative pericyte coverage of strial capillaries falls before measurable tracer leakage and before outer-hair-cell loss; conditional pericyte ablation in young animals reproduces leakage, endocochlear-potential drop and threshold shifts, while pericyte-targeted rescue (PDGF-BB or TIE2 agonism) restores claudin-5, barrier tightness and hearing in aged animals without changing hair-cell counts. | Age-dependent loss of IGF-1 lowers SLC25A33 expression in strial pericytes, causing mitochondrial reactive oxygen species accumulation and activation of TGF-β/Smad2 signaling. This drives pericyte phenotypic switching, disrupts blood-labyrinth barrier integrity, and worsens hearing loss, whereas IGF-1 supplementation or SLC25A33 overexpression suppresses the pathway and partially restores auditory function. | GPT-5.6 Sol 2; Gemini 4 Argon 2; Grok 4.7 2 | нет | нет | нет | 10.1111/acel.70712 |
| 58 | Claude Opus 5.5 | R42669067 | H5 | How does SIRT1 regulate L1 retrotransposon activity, and does this regulation affect cellular senescence? | SIRT1 is a direct repressor of L1 retrotransposons: it is recruited to L1 5'UTR promoter regions and deacetylates histone H4K16 (and H3K9/H3K56) there, maintaining a closed chromatin state. Loss or decline of SIRT1 during ageing de-represses L1 transcription, and this de-repression is itself sufficient to accelerate the onset of cellular senescence. Mechanism: SIRT1 occupies the L1 5'UTR, removes H4K16ac, and enables SUV39H1/HP1-dependent H3K9 methylation and heterochromatin compaction over young, full-length L1 loci. Reduced SIRT1 activity (lower NAD+, SIRT1 protein loss, or its known relocalization away from repeats after DNA damage) leaves H4K16ac high, opens the promoter, and allows RNA Pol II to transcribe L1, generating ORF1p/ORF2p and cytoplasmic L1 cDNA. Prediction: SIRT1 ChIP shows enrichment at L1 5'UTRs in proliferating cells that is lost in senescent cells; SIRT1 knockdown raises L1 5'UTR H4K16ac and L1 RNA/ORF1p and triggers premature senescence markers (SA-β-gal, p16, p21), while SIRT1 overexpression or a deacetylase-dependent rescue (not the H363Y catalytic mutant) restores silencing and delays senescence. Critically, blocking L1 downstream of SIRT1 loss — L1 ASOs, ORF2p-targeting shRNA, or reverse-transcriptase inhibitors such as lamivudine — prevents the senescence acceleration without restoring SIRT1 activity, placing L1 causally downstream. | SIRT1 suppresses L1 transcription and retrotransposition by promoting the association and recruitment of Lamin B1 and KAP1 at the L1 5′-UTR, increasing repressive H3K9me3 chromatin. SIRT1 deficiency derepresses L1, activates cGAS–STING signaling, and induces cellular senescence; reverse-transcriptase inhibition with 3TC rescues this phenotype. | GPT-5.6 Sol 3; Gemini 4 Argon 3; Grok 4.7 3 | да | нет | нет | 10.1111/acel.70689 |
| 59 | Claude Opus 5.5 | R42806003 | H5 | What intercellular mechanism causes placental senescence during maternal ageing, and can disrupting this mechanism restore placental and offspring health? | Maternal ageing drives placental senescence through transfer of senescence-promoting signals from aged maternal decidual cells to fetal trophoblast across the maternal–fetal interface. Blocking this directional paracrine transfer in aged mothers prevents trophoblast senescence and restores fetal growth. Mechanism: Aged decidual stromal and immune cells acquire a SASP enriched in IL-6, IL-1β, CXCL ligands and TGF-β-family factors. These diffuse into the adjacent trophoblast layer, where receptor-driven NF-κB and p38 signalling induces p16/p21 and a secondary senescence programme — paracrine 'bystander' senescence spreading from the maternal to the fetal compartment. The senescent trophoblast loses nutrient-transport and endocrine capacity, causing growth restriction. Prediction: In aged-mother/young-decidua chimeric or decidua-specific interventions (e.g. decidual-restricted p16-INK-ATTAC clearance, or decidua-restricted IL-1R/IL-6R knockout), fetal trophoblast senescence markers and placental efficiency normalise, whereas the same intervention applied to trophoblast alone gives partial rescue. Spatial transcriptomics should show a senescence gradient decaying with distance from the decidual border, with maternal-compartment onset preceding fetal-compartment onset in time-course sampling. | Early inflammation and senescence-associated secretory phenotype activity induce IRF5-dependent CD38 expression in macrophages, which depletes NAD+ in decidual stromal cells and thereby promotes age-related placental senescence. Genetic or pharmacological disruption of this axis, including CD38 inhibition or NAD+ precursor treatment, reduces placental senescence, rescues intrauterine growth restriction, and improves offspring metabolic outcomes. | GPT-5.6 Sol 2; Gemini 4 Argon 2; Grok 4.7 2 | нет | нет | нет | 10.1038/s41467-026-77217-5 |
| 60 | Claude Opus 5.5 | R42748238 | H3 | What molecular mechanism causes age-related vascular deterioration to promote systemic senescence and shorten lifespan? | Aged endothelial cells lose a key metabolic enzyme that supplies a circulating NAD+ precursor to downstream tissues, so systemic NAD+ availability falls and senescence spreads organism-wide. Restoring the endothelial enzyme, or supplying the precursor, reverses systemic senescence and extends lifespan. Mechanism: Microvascular endothelium normally secretes an extracellular NAD+-biosynthetic enzyme (e.g., eNAMPT in extracellular vesicles) into plasma. Age-related endothelial dysfunction and capillary rarefaction reduce this secretion; parenchymal cells in muscle, brain, heart and kidney consequently cannot maintain NAD+ pools, sirtuin activity drops, mitochondrial and DNA-repair capacity fail, and cells enter a p16/p21 senescent state with SASP output that further damages the vasculature — a feed-forward loop. Prediction: Endothelial-specific knockout of the secreted enzyme in young mice lowers plasma precursor levels, drops NAD+ and raises senescence markers in distal non-vascular organs, and shortens lifespan; endothelial-specific overexpression (or precursor repletion) in aged mice restores distal-tissue NAD+, clears senescence and extends lifespan. Parenchymal-cell-specific knockout of the same enzyme does not reproduce the systemic phenotype, distinguishing a vascular-origin secreted factor from cell-autonomous metabolic decline. | Progressive activation of endothelial C/EBPβ induces AEP, which cleaves NAMPT and thereby causes systemic NAD+ depletion, vascular dysfunction, senescence, and reduced lifespan. Genetic disruption of AEP or expression of cleavage-resistant NAMPT N136A ameliorates these effects, while AEP inhibition or NMN supplementation alleviates age-related vascular decline. | GPT-5.6 Sol 3; Gemini 4 Argon 3; Grok 4.7 3 | да | нет | нет | 10.1126/sciadv.aed1961 |

## Гипотезы повторной генерации Claude Opus 5.5

Повторная генерация с подтверждённым отключением инструментов относится к анализу чувствительности (раздел 3.9 рукописи). Отбор по тому же правилу сохранил 17 гипотез, из них с пограничным решением 1.

| № | Модель-генератор | Задача | Гипотеза | Исследовательский вопрос | Полный текст гипотезы | Эталонное утверждение статьи | Баллы трёх судей других компаний | Соответствие по основному критерию | Пограничное решение большинства | Соответствие по строгому критерию | DOI статьи |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Claude Opus 5.5, повторная генерация | R42601407 | H4 | Through what molecular mechanism does physical activity delay ovarian ageing and extend reproductive lifespan? | Physical activity delays ovarian ageing primarily by restoring NAD+ availability in oocytes and granulosa cells, which reactivates SIRT1/SIRT3-dependent mitochondrial quality control. Mechanism: Contraction-driven energy turnover raises NAMPT expression and flux through the NAD+ salvage pathway in systemic circulation and ovarian tissue, countering age-related NAD+ decline. Higher NAD+ raises SIRT1 and SIRT3 deacetylase activity, increasing PGC-1α-driven biogenesis, SOD2 activation and mitophagy. Oocyte mitochondrial membrane potential and ATP for meiotic spindle assembly are preserved, lowering aneuploidy and atresia rates. Prediction: Ovary-specific Nampt deletion, or granulosa/oocyte-specific Sirt3 deletion, abolishes exercise-associated gains in oocyte ATP, spindle normality and litter size in aged mice, while sedentary aged mice given NMN partially reproduce the exercise phenotype without further additive benefit from exercise. | Physical activity delays ovarian ageing in mice partly by increasing ovarian adiponectin signaling. Its protective effects were attenuated in adiponectin-deficient mice, while pharmacological activation of adiponectin receptors with AdipoRon delayed ovarian ageing and extended reproductive lifespan. | GPT-5.6 Sol 2; Gemini 4 Argon 1; Grok 4.7 2 | нет | нет | нет | 10.1038/s43587-026-01177-0 |
| 2 | Claude Opus 5.5, повторная генерация | R42605193 | H1 | Which circulating regulator causally promotes cellular senescence and organismal ageing, and through what intracellular signaling mechanism does it act? | Rising circulating interleukin-11 (IL-11) from aged adipose and stromal cells is a causal driver of cellular senescence and shortened healthspan, not a downstream marker of inflammation. IL-11 acts on IL11RA1/gp130 on fibroblasts, hepatocytes and muscle progenitors to establish a self-sustaining senescent, fibrotic state. Mechanism: IL-11 binding to IL11RA1/gp130 activates JAK1/STAT3 and, non-canonically, ERK-dependent stabilization of translation regulators; STAT3 drives CDKN1A and IL11 itself, forming an autocrine loop, while ERK/mTORC1 output blocks autophagic clearance of damaged mitochondria. The resulting ROS and cGAS-independent chronic STAT3 tone lock cells out of cycle and amplify SASP secretion, which spreads senescence to neighbouring cells. Prediction: Neutralizing IL-11 or deleting Il11ra1 only in non-immune parenchymal cells of 18-month-old mice should reduce p16/p21-positive cell burden in liver, muscle and kidney within 8 weeks and extend remaining lifespan, whereas IL-6 blockade in matched animals reduces circulating SASP cytokines without lowering p16 burden. Conversely, chronic low-dose recombinant IL-11 in young mice should induce tissue senescence that is abolished by concurrent JAK1 inhibition but not by NF-kB inhibition. | ANGPTL8 directly interacts with AKT2 and activates the AKT–mTOR–S6K pathway, thereby driving cell-autonomous adipocyte senescence. Deleting Angptl8 in mice reduces adipose senescence, delays age-related functional decline, and extends lifespan, while genetic or pharmacological pathway inhibition abolishes ANGPTL8-induced senescence. | GPT-5.6 Sol 2; Gemini 4 Argon 2; Grok 4.7 2 | нет | нет | нет | 10.1111/acel.70671 |
| 3 | Claude Opus 5.5, повторная генерация | R42608398 | H4 | Can a microbiota-derived factor directly cause the cellular dysfunction and progressive tissue remodeling characteristic of idiopathic pulmonary fibrosis, and if so, through what mechanism? | A specific bacterial peptide released by lung-resident staphylococci (a fragment of a bacterial cell-wall transglycosylase, 'corisin-like') is sufficient on its own to cause alveolar type II epithelial cell apoptosis and to convert a self-limited lung injury into progressive fibrosis. Mechanism: The peptide inserts into the epithelial plasma membrane and triggers intrinsic mitochondrial apoptosis (BAX/BAK activation, cytochrome c release, caspase-9/3 cleavage) in AT2 cells. Loss of AT2 cells removes the alveolar progenitor pool needed for re-epithelialization, and the dying cells release TGF-β and DAMPs that activate neighboring fibroblasts, so each microbial bloom produces a new wave of injury and matrix deposition. Prediction: Intratracheal administration of the synthetic peptide alone to mice with mild, otherwise resolving bleomycin injury produces sustained increases in collagen and AT2 apoptosis, while a single-residue-mutant inactive analogue does not; neutralizing monoclonal antibody against the peptide, or colonization with an isogenic mutant unable to generate it, blocks fibrosis progression despite equal bacterial burden. | The microbiota-derived peptide corisin directly disrupts epithelial proteostasis by targeting and enhancing the ubiquitin-proteasome system, thereby inducing apoptosis, cellular senescence, epithelial-mesenchymal transition, and fibrotic remodeling. Depleting native corisin from patient bronchoalveolar lavage fluid removes its proapoptotic activity, while constitutive corisin expression in mice causes spontaneous progressive pulmonary fibrosis and worsens bleomycin-induced injury and mortality. | GPT-5.6 Sol 3; Gemini 4 Argon 3; Grok 4.7 3 | да | нет | нет | 10.1038/s41467-026-76162-7 |
| 4 | Claude Opus 5.5, повторная генерация | R42630044 | H2 | What mechanism limits the anabolic response of aged bone to mechanical loading, and can targeted stimulation restore this response? | Diminished anabolic response in aged bone results from reduced osteocytic expression and membrane availability of the mechanosensitive cation channel PIEZO1, so the same strain magnitude produces a smaller Ca2+ influx and weaker downstream YAP/TAZ-dependent transcription of Wnt1 and Wnt10b. Pharmacological agonism of the remaining channels with Yoda1 (or equivalent chemical activation) restores load-induced cortical bone formation in aged animals. Mechanism: Age-related decline in PIEZO1 transcript/protein and altered membrane lipid order reduce strain-gated Ca2+ entry in osteocytes; loss of Ca2+-dependent YAP/TAZ nuclear translocation lowers Wnt ligand output, shifting the osteocyte secretome toward sclerostin-high, RANKL-high signalling. Chemical agonists lower the strain threshold for channel opening, re-coupling loading to Wnt-driven periosteal formation. Prediction: In aged mice, in vivo tibial loading plus Yoda1 restores periosteal mineral apposition rate and cortical thickness to young-adult levels, with recovery of osteocytic Wnt1/Wnt10b induction; the rescue is abolished in osteocyte-specific Piezo1 conditional knockouts, whereas young mice gain little additional benefit from the agonist. | In aged mouse bone, activation of Piezo1 during mechanical loading promotes its membrane co-localization with connexin 43 and increases connexin 43 hemichannel activity through PI3K-Akt signaling. Hemichannel opening increases PGE2 release, suppresses sclerostin, promotes endosteal bone formation, inhibits resorption, and thereby restores the cortical anabolic response to loading. | GPT-5.6 Sol 3; Gemini 4 Argon 3; Grok 4.7 3 | да | нет | нет | 10.1111/acel.70687 |
| 5 | Claude Opus 5.5, повторная генерация | R42647635 | H4 | Does experimentally increasing somatic mitochondrial DNA mutation burden cause premature ageing and shortened lifespan in a large mammal? | Elevating the somatic mtDNA point-mutation rate in a large mammal is sufficient to cause systemic premature ageing and shortened lifespan. Specifically, pigs carrying a homozygous proofreading-deficient knock-in allele of the mitochondrial DNA polymerase gamma catalytic subunit (POLG D257A-equivalent) will accumulate mtDNA point mutations at several-fold the wild-type rate and develop multi-organ ageing phenotypes — kyphosis, sarcopenia, alopecia and skin thinning, osteoporosis, anaemia, cardiomyopathy, hearing and visual loss — with a proportionate reduction in median and maximum lifespan relative to littermate controls. Mechanism: Loss of 3'-5' exonuclease proofreading during mtDNA replication raises the fixation rate of base-substitution errors. Mutations accumulate across the 13 OXPHOS-subunit genes and 22 tRNAs, producing mistranslated and misassembled respiratory complexes. Falling complex I/III/IV assembly lowers membrane potential and ATP output, raises NADH/NAD+ ratio, and impairs biosynthesis and repair in tissues with high oxidative demand, so damage outruns maintenance in many organs simultaneously. Prediction: Mutant pigs show a dose-dependent relationship: heterozygotes have an intermediate mtDNA mutation load and intermediate phenotype onset, homozygotes the highest load and earliest onset, with mutation burden measured by duplex or single-molecule sequencing correlating quantitatively (per-animal r on the order of 0.6-0.9) with a composite ageing score and inversely with survival. Crucially, the phenotype must track mutation load rather than any off-target effect of the engineered allele: a catalytically matched control knock-in that alters POLG protein sequence without impairing proofreading fidelity produces neither the mutation accumulation nor the phenotype. | Prime-edited pigs expressing proofreading-deficient POLG accumulated elevated somatic mitochondrial DNA mutations and developed systemic premature-ageing phenotypes. These included weight loss, rough hair, anaemia, tissue abnormalities, increased apoptosis, elevated senescence-associated markers, and shortened lifespan. | GPT-5.6 Sol 4; Gemini 4 Argon 4; Grok 4.7 4 | да | нет | да | 10.1126/sciadv.adu0632 |
| 6 | Claude Opus 5.5, повторная генерация | R42717261 | H3 | What mechanism induces pathogenic immune-cell senescence in ulcerative colitis, and does this senescence causally exacerbate the disease? | Senescent immune cells are causally required for disease progression in ulcerative colitis: their selective removal is sufficient to attenuate established colitis even without blocking upstream cytokines. Mechanism: Senescent lamina propria immune cells are apoptosis-resistant through BCL-2/BCL-xL and PI3K–AKT dependence, so they persist and continuously secrete SASP factors that degrade epithelial barrier function (claudin loss, goblet-cell depletion) and recruit inflammatory myeloid cells. Removing these cells collapses the SASP source and permits barrier restitution. Prediction: Senolytic treatment (navitoclax or dasatinib+quercetin) or genetic clearance of p16-positive cells begun after colitis is established lowers histological score, restores barrier integrity, and reduces SASP transcripts; transfer of sorted senescent (p21-high) colonic immune cells into recipients worsens colitis, while the same number of non-senescent counterparts does not. Dose-matched broad immunosuppression would reduce inflammation without specifically lowering p16/p21 burden, discriminating the two explanations. | NAD+ metabolic dysregulation causes mitochondrial dysfunction and cytosolic mitochondrial DNA leakage, activating cGAS-STING signaling to drive CD8+ T-cell senescence. These senescent cells exacerbate colitis, while systemic senolytic treatment reduces disease severity; their associated signature also predicts severe disease and non-response to biologic therapy. | GPT-5.6 Sol 3; Gemini 4 Argon 3; Grok 4.7 3 | да | нет | нет | 10.1111/acel.70706 |
| 7 | Claude Opus 5.5, повторная генерация | R42723546 | H5 | Can a cell-free regenerative treatment alleviate UV-induced skin photoaging, and which causal intracellular mechanism mediates its protective effects? | A cell-free secretome/extracellular-vesicle preparation from stem cells alleviates UV photoaging primarily by re-activating PINK1–Parkin-dependent mitophagy in keratinocytes and dermal fibroblasts. Clearance of depolarized mitochondria prevents cytosolic leakage of mitochondrial DNA, which is the proximate danger signal driving cGAS–STING activation, SASP secretion and senescence after chronic UV. Mechanism: Vesicle cargo (PINK1 transcript/protein, Parkin-stabilizing factors, or deubiquitinase-modulating miRNAs) restores recruitment of Parkin to damaged mitochondria, lowers the burden of depolarized organelles, reduces cytosolic mtDNA, and thereby suppresses cGAS–STING–TBK1–IRF3/NF-κB signalling, type I interferon and IL-6/IL-8 release. Prediction: In UV-irradiated skin or fibroblasts, treatment raises LC3/LAMP1–mitochondria colocalization and lowers cytosolic mtDNA, p16/p21 and SA-β-gal; siRNA knockdown of PINK1 (or Parkin) abolishes the anti-senescence and anti-inflammatory benefit, whereas it persists when autophagy of non-mitochondrial cargo is left intact. A STING agonist given downstream of restored mitophagy reinstates the SASP, showing mtDNA–STING is the mediated arm. | Human umbilical cord mesenchymal stem cell secretome protects against UV-induced photoaging by enhancing mitophagy, which clears damaged mitochondria and reduces cytosolic mitochondrial DNA leakage. This suppresses cGAS-STING signaling and downstream inflammatory cytokines; mitophagy inhibition abolishes protection, while STING inhibition restores it. | GPT-5.6 Sol 4; Gemini 4 Argon 5; Grok 4.7 4 | да | нет | да | 10.1111/acel.70701 |
| 8 | Claude Opus 5.5, повторная генерация | R42749700 | H5 | What molecular mechanism links disrupted chromatin regulation to cellular senescence in Hutchinson–Gilford progeria syndrome, and can targeting that mechanism ameliorate disease phenotypes and extend lifespan? | In HGPS, progerin accumulation causes a gain of the histone acetyltransferase KAT7 (HBO1) activity at the promoters of senescence effector genes; the resulting excess H3K14 acetylation licenses transcription of CDKN2A/p16INK4a and SASP genes, and KAT7 loss-of-function is therefore sufficient to reverse senescence and extend lifespan in progeroid animals. Mechanism: Progerin-driven heterochromatin disorganization redistributes KAT7/HBO1 to euchromatic senescence loci. Elevated H3K14ac opens these promoters to the general machinery and drives p16INK4a and NF-kB-dependent SASP transcription, locking the cell into a stable senescent, pro-inflammatory state independent of further DNA damage. Prediction: ChIP-seq of HGPS fibroblasts shows KAT7 and H3K14ac enrichment specifically at CDKN2A and core SASP promoters versus isogenic controls; CRISPR knockout or small-molecule inhibition of KAT7 (but not of unrelated HATs such as p300) lowers p16INK4a and IL-6/IL-1B secretion, restores proliferation, and lentiviral/AAV-delivered Kat7 knockdown extends median lifespan of Zmpste24-/- or LmnaG609G mice; H3K14ac rescue by catalytically active KAT7 re-establishes senescence. | HMGA1 recruits the deubiquitinase USP7 to stabilize HP1β, which reduces chromatin accessibility at ANGPTL2 and suppresses senescence-associated secretory factors, thereby alleviating HGPS cellular senescence. An HMGA1-derived peptide, UHP, prevents HP1β degradation, reduces senescence, and significantly extends the lifespan of LmnaG609G/G609G mice. | GPT-5.6 Sol 2; Gemini 4 Argon 2; Grok 4.7 2 | нет | нет | нет | 10.1038/s41467-026-76789-6 |
| 9 | Claude Opus 5.5, повторная генерация | R42775698 | H4 | Can age-associated differences in the human gut microbial community causally reprogram intestinal barrier function, systemic metabolism, and mucosal gene expression, and what mediators contribute to these effects? | Germ-free or antibiotic-depleted young mice colonized with faecal microbiota from elderly human donors develop impaired intestinal barrier function (reduced villus height, shallower crypts, increased paracellular permeability) relative to recipients of young-donor microbiota, demonstrating that the aged human community is sufficient to cause host intestinal dysfunction independent of host age. Mechanism: Aged donor communities are depleted of saccharolytic short-chain fatty acid producers and enriched in proteolytic and mucin-degrading taxa; the resulting fall in luminal butyrate starves colonocyte mitochondrial beta-oxidation, raises epithelial oxygenation, and lowers expression of tight-junction and mucin genes, thinning the mucus layer and loosening the junctional seal. Prediction: Aged-donor recipients show lower caecal butyrate, reduced Occludin/Claudin-1/Muc2 transcript and protein levels, higher serum FITC-dextran or LPS-binding protein, and these deficits are rescued by oral butyrate or tributyrin supplementation without altering the transplanted community's composition. | Transplanting elderly-human gut microbiota into pigs caused reduced ileal villus height, loss of tight-junction proteins, altered plasma metabolites, and coordinated suppression of seven ileal mucosal antiviral-response hub genes compared with young-donor microbiota. The elderly-donor-associated metabolic shift was functionally linked to barrier impairment: Tyr-Phe increased epithelial electrical resistance, whereas prostaglandin E3 decreased it in IPEC-1 cells. | GPT-5.6 Sol 3; Gemini 4 Argon 3; Grok 4.7 3 | да | нет | нет | 10.1111/acel.70725 |
| 10 | Claude Opus 5.5, повторная генерация | R42786310 | H4 | Can a commensal microorganism predicted from integrated human ageing profiles causally extend lifespan and healthspan and shift age-associated molecular and microbial states toward younger configurations? | The commensal shifts the host transcriptome, DNA-methylation clock and gut metagenome of aged animals toward younger configurations, i.e. the intervention produces a coordinated rejuvenation signature rather than isolated phenotypic improvement. Mechanism: Reduced inflammatory tone plus metabolite-driven epigenetic substrate changes (acetyl-CoA, SAM, alpha-ketoglutarate availability) remodel chromatin and transcription in liver, intestine and immune cells, while niche competition and cross-feeding displace age-expanded pathobionts (Enterobacteriaceae, Desulfovibrio) and restore butyrate producers. Prediction: Treated old animals show significantly reduced epigenetic-clock age acceleration and transcriptomic age versus age-matched controls, with the direction of change in old-vs-young differential genes reversed (negative enrichment correlation), and metagenomic composition moving along the young-old principal axis toward young centroid; effect sizes correlate across host and microbial readouts within individuals. | Neisseria flavescens was identified as a candidate geroprotective commensal and experimentally shown to extend lifespan and healthspan in Caenorhabditis elegans when administered live. In aged mice, heat-killed N. flavescens shifted the serum metabolome, liver transcriptome and gut microbiome toward younger states, while isolated strains were confirmed to produce predicted beneficial metabolites. | GPT-5.6 Sol 3; Gemini 4 Argon 3; Grok 4.7 3 | да | нет | нет | 10.1038/s43587-026-01220-0 |
| 11 | Claude Opus 5.5, повторная генерация | R42821663 | H3 | Through what causal mechanism does hypertension accelerate osteoarthritis in joints predisposed by aging or mechanical injury? | Hypertension accelerates osteoarthritis because circulating and locally generated angiotensin II acts on chondrocyte and synovial AT1 receptors (AGTR1). This drives catabolic signalling and chondrocyte senescence that add to the damage already present after injury or in the aged joint. Mechanism: Angiotensin II binds AT1R on chondrocytes, synovial fibroblasts and subchondral osteoclast precursors. This activates NADPH oxidase and ROS production, which induces NF-κB/MAPK-dependent expression of MMP13, ADAMTS5 and IL-6/IL-1β, together with p16/p21-mediated senescence. The joint renin-angiotensin system is itself upregulated by mechanical injury and aging, so systemic hypertension raises a ligand whose receptor the injured joint has already sensitized. Prediction: In destabilization of the medial meniscus (DMM) or aged mice, angiotensin II infusion worsens OARSI scores compared with normotensive controls. Chondrocyte-specific Agtr1a deletion or losartan abolishes this effect. Lowering blood pressure to the same degree with hydralazine, which does not block AT1R, rescues joint damage much less. | Hypertension-associated circulating arginine vasopressin activates up-regulated AVPR1A in osteoarthritis-primed chondrocytes, driving NR4A3-dependent catabolic signaling and suppressing anabolic regulation. Genetic deletion or pharmacological inhibition of AVPR1A prevents the hypertension-induced acceleration of osteoarthritis. | GPT-5.6 Sol 2; Gemini 4 Argon 2; Grok 4.7 2 | нет | нет | нет | 10.1126/science.aed8207 |
| 12 | Claude Opus 5.5, повторная генерация | R42822442 | H4 | How does nutrient scarcity in the solid-tumor microenvironment cause senescence and loss of persistence in adoptively transferred antitumor immune cells? | Glucose scarcity in the tumor microenvironment drives senescence in adoptively transferred T cells through a cell-intrinsic energy-stress kinase relay: falling ATP/AMP ratio activates AMPK, which engages the scaffold TAB1 to autoactivate p38 MAPK, installing a stable p21/p16-dependent senescence program rather than reversible exhaustion. Disabling this relay (AMPK or TAB1 or p38 loss) preserves persistence without restoring glucose. Mechanism: Low glucose → reduced glycolytic ATP → AMP-bound AMPK → AMPK-dependent TAB1 association with p38α → MAPK-independent (non-MKK) p38 autophosphorylation → p53/p21 and p16 induction, SASP, permanent cell-cycle withdrawal and effector-function loss. Prediction: In CAR-T or TCR-T cells transferred into glucose-poor tumors, TAB1 knockout or a TAB1-p38 interaction-blocking mutant abolishes SA-β-gal/p16/p21 induction and restores intratumoral expansion and tumor control, whereas it has no effect in glucose-replete subcutaneous or in vitro conditions; pharmacologic AMPK activation in high glucose reproduces senescence. | Glucose deprivation activates AMPK in transferred Th9 cells, initiating a ZAK–NIK cascade that suppresses noncanonical NF-κB signaling and IL-9 production, thereby driving cellular senescence. Restoring glucose or targeting ZAK reduces senescence, improves Th9-cell persistence, and enhances CAR-Th9 efficacy against solid tumors. | GPT-5.6 Sol 3; Gemini 4 Argon 3; Grok 4.7 3 | да | нет | нет | 10.1016/j.immuni.2026.09.004 |
| 13 | Claude Opus 5.5, повторная генерация | R42858183 | H3 | Can a defined intervention preserve lysosomal function and protein homeostasis during aging, thereby extending lifespan and maintaining organismal function, and through what mechanism? | Preventing lysosomal lipofuscin and oxidized-lipid accumulation by enhancing lysosomal lipid catabolism (lysosomal acid lipase or LIPL-4 induction) preserves hydrolase function during aging and extends lifespan through a lipid-messenger signal rather than bulk clearance alone. Mechanism: Undegraded lipid and lipofuscin bind hydrolases and quench their activity, progressively poisoning the lysosome. Enhanced lysosomal lipolysis clears this load and releases specific fatty-acid ligands that engage nuclear receptors, which in turn reinforce lysosomal and mitochondrial gene programs. Prediction: Lysosomal lipase induction reduces autofluorescent lipofuscin and restores cathepsin activity in aged tissue, while a catalytically dead enzyme does not. Supplying the specific released fatty acid to animals lacking the lipase partially restores lifespan extension, showing a signaling rather than purely clearance mechanism. | 20(S)-ginsenoside Rg3 extended lifespan and preserved physiological and neuronal function in Caenorhabditis elegans by restoring lysosomal activity and autophagic flux. Rg3 remodeled neuronal lysosomal phosphoinositide signatures toward increased PI(4)P and reduced PI(3)P, suppressed RSKS-1/S6K–TORC1 signaling, and promoted nuclear HLH-30/TFEB activity, thereby improving proteostasis and resistance to polyglutamine- and α-synuclein-associated toxicity. | GPT-5.6 Sol 2; Gemini 4 Argon 2; Grok 4.7 2 | нет | нет | нет | 10.1111/acel.70755 |
| 14 | Claude Opus 5.5, повторная генерация | R42723144 | H4 | Can naturally occurring inherited genetic variation alter the rate of ovarian ageing on equivalent heterogeneous nuclear backgrounds, and what cellular mechanism mediates this effect? | Naturally occurring mitochondrial DNA (mtDNA) haplotype variation is sufficient to change the rate of ovarian ageing when nuclear genomes are equivalently heterogeneous: conplastic/mitochondrial-nuclear-exchange females carrying a divergent wild-derived mtDNA haplotype on a randomized heterogeneous nuclear background will deplete the primordial follicle reserve faster (or slower) than haplotype-matched siblings. The mediating cellular defect is reduced OXPHOS coupling efficiency in the oocyte-granulosa unit, which raises per-follicle oxidative burden and atresia probability. Mechanism: Haplotype-specific coding and regulatory substitutions in mtDNA-encoded complex I/III/IV subunits alter electron-transfer kinetics and proton leak. In the metabolically quiescent but long-lived primordial and primary oocyte, even a small decrease in P/O ratio chronically elevates superoxide production at complexes I and III, oxidizing mtDNA, cardiolipin and the meiotic spindle machinery. Damaged follicles cross an atresia threshold earlier, so the exponential decay constant of the resting pool increases while the starting pool size (set at birth) is unchanged. Prediction: At 2-3 months of age follicle counts and litter size are indistinguishable between haplotypes, but the log-linear decay slope of primordial follicle number from 3 to 12 months differs significantly between mtDNA haplotypes on the same heterogeneous nuclear background; isolated oocytes/cumulus complexes from the fast-ageing haplotype show lower ATP-linked respiration, higher leak-fraction respiration and higher mitochondrial superoxide (MitoSOX) before follicle loss is detectable. A nuclear-genetics-only explanation predicts no haplotype effect after nuclear randomization; a purely maternal-environment explanation predicts the effect disappears after embryo transfer or cross-fostering, which it should not. | The OKC-HETW mitochondrial haplotype accelerated ovarian ageing, causing faster primordial-follicle loss, inflammatory and fibrotic remodelling, mitochondrial dysfunction and impaired ovulation relative to the OKC-HETB haplotype on equivalently distributed nuclear backgrounds. Despite normal TFAM expression and elevated total TFAM protein, OKC-HETW ovaries had reduced mitochondrial TFAM, TFAM–mtDNA binding and TOMM20, supporting defective mitochondrial protein import and compromised mtDNA maintenance as the mechanism linking haplotype to accelerated decline. | GPT-5.6 Sol 3; Gemini 4 Argon 3; Grok 4.7 3 | да | нет | нет | 10.1111/acel.70710 |
| 15 | Claude Opus 5.5, повторная генерация | R42585340 | H3 | Which molecular mechanism enables mild cellular stress to preserve protein homeostasis during ageing and extend organismal lifespan? | Mild cellular stress activates TFEB/HLH-30, which induces genes for autophagy and lysosome formation. The resulting increase in autophagic flux removes protein aggregates and is required for the lifespan extension. Mechanism: Stress inhibits mTORC1, which leads to TFEB dephosphorylation and nuclear entry. TFEB then activates CLEAR-motif genes covering autophagosome formation, lysosomal acidification and hydrolases. Greater delivery of aggregates to lysosomes lowers the proteotoxic load in ageing cells. Prediction: Mutants lacking HLH-30, or with autophagy genes such as bec-1 or atg-18 knocked down, should show neither better aggregate clearance nor longer life after mild stress. Autophagic flux reporters should rise only when HLH-30 is present. | In Caenorhabditis elegans, inhibition of mitochondrial respiration activates an intestinal ELT-2-dependent transcriptional program that increases lysosomal proteolysis during ageing, largely independently of the mitochondrial unfolded protein response. Direct promoter binding by ELT-2, requiring residue R249, and the lysosomal proteases CPR-5 and CPR-8 are necessary for toxic polyglutamine aggregate clearance and mitochondrial stress-induced lifespan extension. | GPT-5.6 Sol 2; Gemini 4 Argon 2; Grok 4.7 2 | нет | нет | нет | 10.1126/sciadv.aeh0657 |
| 16 | Claude Opus 5.5, повторная генерация | R42669067 | H5 | How does SIRT1 regulate L1 retrotransposon activity, and does this regulation affect cellular senescence? | SIRT1 is a direct, locus-resident silencer of young L1 elements: it is recruited to the L1 5'UTR promoter and keeps it in a deacetylated, heterochromatic state. Age- or stress-associated loss of SIRT1 from these loci de-represses L1 transcription, and this de-repression is a causal driver of senescence entry rather than a passive consequence of it. Mechanism: SIRT1 occupies the CpG-island promoter in the 5'UTR of evolutionarily young (L1HS/L1PA) elements and removes activating acetyl marks (H4K16ac, H3K9ac) from local nucleosomes. Deacetylated H3K9 becomes a substrate for SUV39H1/SETDB1-mediated H3K9 trimethylation and HP1 binding, locking the promoter in heterochromatin. When SIRT1 protein or NAD+ falls, H4K16ac/H3K9ac accumulate, H3K9me3 and HP1 are lost, and RNA Pol II engages the L1 promoter. Prediction: ChIP of SIRT1 in proliferating fibroblasts shows enrichment at L1 5'UTRs that is lost during replicative or oxidative senescence; acute SIRT1 knockdown raises H4K16ac and lowers H3K9me3 specifically at L1 5'UTRs within 48 h, before SASP gene induction, and catalytically dead SIRT1 (H363Y) fails to restore silencing while wild-type SIRT1 does. Crucially, the chromatin change at L1 must precede, not follow, p16/IL-6 induction in a time-course. | SIRT1 suppresses L1 transcription and retrotransposition by promoting the association and recruitment of Lamin B1 and KAP1 at the L1 5′-UTR, increasing repressive H3K9me3 chromatin. SIRT1 deficiency derepresses L1, activates cGAS–STING signaling, and induces cellular senescence; reverse-transcriptase inhibition with 3TC rescues this phenotype. | GPT-5.6 Sol 3; Gemini 4 Argon 3; Grok 4.7 2 | да | да | нет | 10.1111/acel.70689 |
| 17 | Claude Opus 5.5, повторная генерация | R42806003 | H5 | What intercellular mechanism causes placental senescence during maternal ageing, and can disrupting this mechanism restore placental and offspring health? | Maternal ageing drives accumulation of senescent maternal decidual cells whose SASP acts across the maternal-fetal interface to induce paracrine senescence in fetal-derived trophoblast, and blocking this specific SASP signal restores placental function and offspring growth. The decidual compartment is the initiating site; trophoblast senescence is secondary and propagated, not autonomous. Mechanism: Age-associated metabolic stress and DNA damage in decidual stromal cells activate cGAS-STING and NF-kB, producing a SASP enriched in IL-6, IL-1b, CXCL1 and TGF-b. These factors diffuse into the adjacent trophoblast layer, imposing a bystander senescence program (p16/p21, SA-b-gal, loss of proliferation) that reduces labyrinth vascular branching and nutrient transporter density, impairing fetal growth. Prediction: Senolytic or SASP-neutralising intervention restricted to the maternal compartment (or maternal-genotype-specific deletion of a SASP driver such as Il6 or Cgas) rescues trophoblast senescence markers, labyrinth vascularisation and fetal weight, whereas the same intervention targeted to fetal trophoblast genotype does not; in young hosts, transfer of aged decidual conditioned medium reproduces trophoblast senescence. | Early inflammation and senescence-associated secretory phenotype activity induce IRF5-dependent CD38 expression in macrophages, which depletes NAD+ in decidual stromal cells and thereby promotes age-related placental senescence. Genetic or pharmacological disruption of this axis, including CD38 inhibition or NAD+ precursor treatment, reduces placental senescence, rescues intrauterine growth restriction, and improves offspring metabolic outcomes. | GPT-5.6 Sol 2; Gemini 4 Argon 2; Grok 4.7 2 | нет | нет | нет | 10.1038/s41467-026-77217-5 |

## Контрольные суммы источников

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```