task	score	input_score	alternative_score	cue_excerpt	rationale_ru	missing_ru	question	background	finding	key_points	N_core	N_hit	N_total	all_core	all_hit	all_total	gpt-6-astra_N_core	gpt-6-astra_N_hit	gpt-6-astra_A_core	gpt-6-astra_A_hit	gpt-6-astra_O_core	gpt-6-astra_O_hit	grok-4.5_N_core	grok-4.5_N_hit	grok-4.5_A_core	grok-4.5_A_hit	grok-4.5_O_core	grok-4.5_O_hit	claude-opus-5-5_N_core	claude-opus-5-5_N_hit	claude-opus-5-5_A_core	claude-opus-5-5_A_hit	claude-opus-5-5_O_core	claude-opus-5-5_O_hit	gemini-4-argon-high_N_core	gemini-4-argon-high_N_hit	gemini-4-argon-high_A_core	gemini-4-argon-high_A_hit	gemini-4-argon-high_O_core	gemini-4-argon-high_O_hit
R42581103	1	1	2	aged systemic environment causally impair intestinal stem-cell metabolism	Указаны системный источник воздействия и нарушение обмена в стволовых клетках; конкретный воспалительный сигнал скрыт.	TNF, TNFR1 и подавление окисления жирных кислот	How does the aged systemic environment causally impair intestinal stem-cell metabolism and regenerative function?	Intestinal stem-cell function and regenerative capacity decline with age, compromising maintenance and repair of the intestinal epithelium. Both cell-intrinsic changes and signals from the aged systemic environment may contribute to this decline. Chronic inflammation and altered cellular metabolism are common features of ageing, but how circulating conditions are translated into functional defects in intestinal regeneration was unresolved. It was also unclear whether manipulating systemic or metabolic processes could preserve or restore aged stem-cell activity.	Age-associated TNF acts as a systemic pro-ageing factor that signals through epithelial TNFR1 to suppress mitochondrial fatty acid oxidation, proliferation and regenerative capacity in intestinal stem cells. Blocking inflammation or TNF–TNFR1 signaling protects or restores ISC function, while enhancing mitochondrial fusion improves the function of aged ISCs.	"[""The old systemic environment transfers an ISC ageing phenotype to young mice."", ""TNF is a causal pro-ageing inflammatory factor."", ""Epithelial TNFR1 is required for the detrimental systemic effect."", ""TNF suppresses mitochondrial pathways and fatty acid oxidation."", ""Countering inflammation or improving mitochondrial function restores ISC activity.""]"	5	1	20	10	1	60	0.2	0.0	0.4	0.0	0.0	0.0	0.2	0.2	0.4	0.0	0.0	0.0	0.4	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.2	0.0	0.0	0.0
R42601407	2	2	2	physical activity delay ovarian ageing and extend reproductive lifespan	Прямо названы вмешательство и оба ожидаемых эффекта из эталона.	Адипонектин, его рецепторы и AdipoRon	Through what molecular mechanism does physical activity delay ovarian ageing and extend reproductive lifespan?	Ovarian ageing progressively reduces fertility, disrupts endocrine function and contributes to later-life disease risk. This decline involves losses in follicle quantity and quality as well as deterioration of the ovarian tissue environment. Although lifestyle and systemic metabolic factors have been associated with reproductive ageing, the causal mechanisms connecting them to ovarian function remain poorly understood. No approved treatment currently delays ovarian ageing or reliably extends reproductive lifespan.	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.	"[""Physical activity delays ovarian ageing in mice"", ""Physical activity increases ovarian adiponectin levels"", ""Adiponectin deficiency attenuates the protective effect"", ""AdipoRon delays ovarian ageing"", ""AdipoRon extends reproductive lifespan""]"	0	0	20	1	0	60	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0
R42605193	1	1	1	circulating regulator	Поиск ограничен циркулирующими регуляторами с действием через внутриклеточную передачу сигнала.	ANGPTL8, AKT2 и последовательность AKT-mTOR-S6K	Which circulating regulator causally promotes cellular senescence and organismal ageing, and through what intracellular signaling mechanism does it act?	Cellular senescence increases with age and can disrupt tissue function through persistent changes in cell state and signaling. Metabolic dysfunction and chronic inflammation are closely associated with this process and with broader age-related deterioration. Circulating factors can coordinate physiological changes across organs, but it remains unclear which factors actively cause senescence rather than merely correlate with ageing. Identifying the responsible signals and their intracellular mechanisms could reveal targets for extending healthspan.	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.	"[""ANGPTL8 is a causal pro-senescent regulator"", ""ANGPTL8 directly interacts with AKT2"", ""AKT–mTOR–S6K activation drives adipocyte senescence"", ""Angptl8 deletion improves function and extends mouse lifespan"", ""Pathway inhibition blocks the pro-senescent effect""]"	0	0	20	0	0	60	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0
R42608398	1	1	2	microbiota-derived factor directly cause	Задан микробный источник причинного фактора; вещество и клеточный механизм неизвестны.	Коризин и усиление убиквитин-протеасомной деградации	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?	Idiopathic pulmonary fibrosis is a progressive, age-associated disorder characterized by recurring tissue injury and excessive fibrotic remodeling. Abnormal cell-fate programs, including apoptosis, senescence, and phenotypic transitions, are thought to contribute to disease progression. Changes in the lung microbiota have also been associated with disease severity, but association alone has not established a direct pathogenic mechanism. It remained unclear whether a microbiota-derived product could independently initiate the cellular dysfunction and progressive fibrosis observed in this disease.	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.	"[""Corisin is present and functionally active in bronchoalveolar lavage fluid from patients with idiopathic pulmonary fibrosis."", ""Corisin enters epithelial cells, localizes to mitochondria, and induces apoptosis, senescence, and epithelial-mesenchymal transition."", ""Corisin enhances proteasome activity and disrupts epithelial proteostasis."", ""Removing corisin abolishes the proapoptotic activity of patient lavage fluid."", ""Native corisin expression is sufficient to cause progressive pulmonary fibrosis in mice.""]"	2	0	20	10	0	60	0.2	0.0	0.6	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.2	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.2	0.0	0.4	0.0
R42627902	0	1	1	shift away from erythroid differentiation and toward platelet-producing lineage programs	Описан сдвиг клеточной дифференцировки, который требуется объяснить; регулятор и способ его действия не заданы. Исходные сведения дополнительно направляют к регуляции транскрипции.	Pbx1 и подавление Gata1	Which regulatory mechanism drives the age-associated shift away from erythroid differentiation and toward platelet-producing lineage programs?	Ageing alters blood-cell production, commonly shifting lineage output and reducing regenerative balance. These changes can contribute to anemia, impaired immunity, and abnormal clotting in older organisms. Age-related transcriptional and epigenetic remodeling has been implicated, but the regulators that causally connect altered gene programs to lineage imbalance remain incompletely understood. Identifying such regulators could reveal ways to restore healthier blood production during ageing.	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.	"[""Pbx1 is a key regulator of HSC ageing"", ""Pbx1 represses Gata1 expression"", ""Pbx1 suppresses erythroid differentiation"", ""The mechanism contributes to age-related lineage imbalance""]"	2	0	20	4	0	60	0.0	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.2	0.0	0.0	0.0	0.2	0.0	0.0	0.0	0.2	0.0	0.0	0.0	0.0	0.0	0.0	0.0
R42630044	0	0	1	anabolic response of aged bone to mechanical loading	Названы физиологический ответ и его возрастное ослабление; просьба о целевой стимуляции не определяет молекулу или путь.	Piezo1, коннексин 43, PI3K-Akt и PGE2	What mechanism limits the anabolic response of aged bone to mechanical loading, and can targeted stimulation restore this response?	Mechanical loading normally stimulates bone formation and helps maintain skeletal strength. This anabolic response becomes weaker with age, contributing to cortical bone loss and osteoporosis risk. Bone cells detect physical forces and translate them into signals that regulate the balance between bone formation and resorption. The molecular defect responsible for diminished mechanosensitivity in aged bone, and whether it can be overcome, remained unclear.	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.	"[""Piezo1 activation must accompany mechanical loading to rescue aged bone"", ""Piezo1 interacts and co-localizes with connexin 43"", ""PI3K-Akt signaling activates connexin 43 hemichannels"", ""Hemichannel opening increases PGE2 and suppresses sclerostin"", ""The pathway increases cortical bone mass by favoring formation over resorption""]"	6	0	20	14	0	60	0.4	0.0	0.2	0.0	0.0	0.0	0.4	0.0	0.4	0.0	0.0	0.0	0.2	0.0	0.2	0.0	0.4	0.0	0.2	0.0	0.4	0.0	0.0	0.0
R42639736	0	1	0	disrupted intracellular homeostasis to DNA damage and senescence	Нарушение гомеостаза обозначает широкую проблему; вопрос не задаёт кальций или конкретную органеллу. Исходные сведения дополнительно упоминают взаимодействия органелл.	DHCR24, ENKUR и кальциевая перегрузка	What molecular mechanism links disrupted intracellular homeostasis to DNA damage and senescence?	Persistent DNA damage responses contribute to cellular senescence and age-related loss of tissue function. Disturbances in intracellular homeostasis can promote genomic stress through several mechanisms, including metabolic dysfunction and impaired cell-cycle control. Communication between organelles is increasingly recognized as an important regulator of stress responses during ageing. However, the causal mechanisms connecting disrupted cellular homeostasis to DNA damage in senescent cells remain incompletely understood.	Loss of DHCR24 increases ENKUR expression, causing calcium overload, endoplasmic-reticulum stress, and mitochondrial dysfunction that activate the ATM-mediated DNA damage response and promote endothelial-cell senescence. ENKUR knockdown suppresses these effects, while DHCR24 overexpression lowers ENKUR and mitigates calcium overload, establishing a causal DHCR24-ENKUR-Ca2+ signaling axis.	"[""DHCR24 deficiency activates ATM-mediated DNA damage responses"", ""DHCR24 loss upregulates ENKUR and causes calcium overload"", ""Calcium dysregulation drives ER stress and mitochondrial dysfunction"", ""ENKUR knockdown rescues organelle dysfunction and DNA damage signaling"", ""DHCR24 restoration reduces ENKUR and calcium overload""]"	2	0	20	2	0	60	0.2	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.0	0.0	0.0	0.0
R42642518	1	1	2	circulating factors that accumulate with age	Заданы накопление циркулирующих факторов, их причинное действие и возможность обратимости; состав факторов скрыт.	Метаболические показатели, опухолевые маркеры и изменение рациона	Which circulating factors that accumulate with age actively induce ageing-related cellular phenotypes, and is their resulting biological burden reversible?	Biological ageing progresses at different rates among individuals and is associated with broad changes in physiology and chronic-disease risk. Women and men can follow different ageing trajectories, particularly during midlife, but the biological basis and functional significance of these differences remain incompletely understood. Large clinical datasets can identify circulating features that change with age, although association alone cannot establish whether such features actively promote ageing. Experimental validation is therefore needed to distinguish causal contributors from passive biomarkers.	Age-associated accumulation of metabolic factors, including low-density lipoprotein, triglycerides, glucose and uric acid, and tumor markers, including carcinoembryonic antigen and human epididymis protein 4, induced senescence-related phenotypes in human endothelial cells. A high-fat-diet mouse model followed by dietary reversal further showed that ageing associated with metabolic burden is modifiable.	"[""Specific metabolic and tumor markers accumulate with age"", ""The identified circulating factors induce senescence-related phenotypes"", ""Causality was tested in human endothelial cells"", ""Dietary reversal in mice supports modifiability of metabolic burden-induced ageing"", ""Ageing trajectories differ by sex during midlife""]"	2	0	20	2	0	60	0.2	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.0	0.0	0.0	0.0
R42642521	2	2	1	age-depleted gut microbe and one of its metabolites causally suppress inflammaging and improve healthspan	Вопрос воспроизводит схему микроорганизм плюс его метаболит и ожидаемые эффекты; остаётся назвать участников.	Bifidobacterium pseudocatenulatum и 5-AVAB	Can a specific age-depleted gut microbe and one of its metabolites causally suppress inflammaging and improve healthspan in old animals?	The gut microbiome changes with age and is associated with immune dysregulation, chronic low-grade inflammation and functional decline. Microbiome composition also varies substantially among individuals and populations, making it difficult to distinguish consequential changes from incidental biomarkers of ageing. Animal studies suggest that manipulating gut microbial communities can influence age-related physiology, but the responsible organisms and molecular mediators have remained poorly defined. Establishing causality requires showing that a defined microbial intervention improves ageing phenotypes and identifying a functional mechanism that reproduces those effects.	Bifidobacterium pseudocatenulatum, which declines with age in human cohorts, causally improved intestinal homeostasis, reduced multiorgan inflammaging, enhanced cognitive and motor performance and extended healthspan in naturally aged mice. Its metabolite 5-aminovaleric acid betaine (5-AVAB), also reduced during human ageing, partially reproduced these systemic benefits when administered alone.	"[""B. pseudocatenulatum is depleted during ageing"", ""Oral bacterial treatment improves healthspan in aged mice"", ""Treatment suppresses intestinal and multiorgan inflammaging"", ""5-AVAB is a functional metabolite of the bacterium"", ""5-AVAB supplementation partially reproduces the benefits""]"	0	0	20	0	0	60	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0
R42647119	0	0	1	aging affect injury-induced neuronal reprogramming in the retina	Заданы ткань и исследуемое возрастное изменение; воспалительный механизм и вмешательство скрыты.	Воспалительное состояние глии Мюллера и дексаметазон	How does aging affect injury-induced neuronal reprogramming in the retina, and what mechanisms account for any age-related loss of regenerative capacity?	Cellular reprogramming offers a potential way to replace neurons lost through injury or neurodegenerative disease. Most regenerative strategies have been developed and validated in young experimental animals, although advanced age is the principal risk factor for many neurological disorders. Aging can alter both the plasticity of resident cells and the tissue response to injury. It was therefore unclear whether neuronal reprogramming would remain effective in aged neural tissue and which age-associated processes might limit it.	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.	"[""Aged Müller glia generate fewer neurons across three reprogramming strategies"", ""Aged glia fail to activate progenitor programs"", ""Reactive and inflammatory states increase with age"", ""The injured aged retina mounts an exaggerated neuroimmune response"", ""Dexamethasone partially rescues neurogenesis""]"	8	3	20	22	6	60	0.4	0.2	0.4	0.0	0.0	0.0	0.6	0.2	0.8	0.4	0.2	0.0	0.4	0.0	0.4	0.0	0.2	0.0	0.2	0.2	0.6	0.2	0.2	0.0
R42647635	2	2	2	increasing somatic mitochondrial DNA mutation burden cause premature ageing and shortened lifespan	Прямо дана причинная гипотеза об увеличении числа мутаций митохондриальной ДНК и двух исходах у крупного млекопитающего.	Дефект корректирующей функции POLG, свиньи и способ редактирования	Does experimentally increasing somatic mitochondrial DNA mutation burden cause premature ageing and shortened lifespan in a large mammal?	Ageing is accompanied by progressive molecular damage, impaired tissue maintenance, and declining physiological function. Genetic studies in laboratory organisms have identified processes that can influence lifespan and cellular senescence. However, findings from small-animal models do not always translate directly to humans because of major differences in physiology, metabolism, and lifespan. A large-mammal model is therefore valuable for testing whether a proposed source of molecular damage can directly produce systemic ageing phenotypes.	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.	"[""Proofreading-deficient POLG"", ""Increased somatic mitochondrial DNA mutations"", ""Systemic premature-ageing phenotypes"", ""Increased apoptosis and senescence markers"", ""Shortened lifespan""]"	10	3	20	24	7	60	0.6	0.0	0.4	0.2	0.0	0.0	0.6	0.2	1.0	0.2	0.0	0.0	0.2	0.2	0.2	0.2	0.2	0.0	0.6	0.2	0.8	0.2	0.2	0.0
R42663085	1	1	0	intrinsic molecular regulator be enhanced to reactivate quiescent hair follicles	Задано усиление внутреннего регулятора и выход фолликулов из покоя; тип регулятора остаётся широким.	TPP1, теломерная защита, теломераза и TELODIN	Can an intrinsic molecular regulator be enhanced to reactivate quiescent hair follicles and restore hair regeneration, and through what mechanism?	Ageing commonly impairs the cyclical regeneration of hair follicles, contributing to progressive hair thinning and alopecia. Hair growth depends on the orderly transition of follicles from a resting phase into a proliferative growth phase. With age, this transition becomes less efficient as regenerative cells lose functional capacity. Whether this decline can be reversed by directly restoring an intrinsic molecular control of follicle regeneration remained unresolved.	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.	"[""TPP1 causally promotes hair regeneration"", ""TPP1 activates bulge hair follicle stem cells"", ""Telomere capping and telomerase recruitment mediate the effect"", ""Follicles transition from telogen to anagen"", ""Topical TELODIN stabilizes TPP1 and promotes hair growth""]"	0	0	20	0	0	60	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0
R42664348	1	1	1	excess adiposity promote osteoarthritis progression	Указан источник воздействия в жировой ткани; механизм передачи материала хондроцитам скрыт.	Внеклеточные везикулы, митохондриальная ДНК и cGAS-STING	By what causal molecular mechanism does excess adiposity promote osteoarthritis progression, and can disrupting that mechanism reduce joint pathology?	Osteoarthritis is a common age-related disorder characterized by progressive joint deterioration, inflammation, pain, and loss of mobility. Obesity substantially increases osteoarthritis risk, including in joints that do not bear additional body weight, suggesting that mechanical loading alone cannot explain the association. Adipose tissue can influence distant organs through circulating signals, but the molecular basis of its contribution to joint degeneration remained unclear. Identifying the responsible signals and downstream processes could reveal targets for preventing or treating obesity-associated osteoarthritis.	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.	"[""Adipocyte-derived EV-Mito carry mitochondrial DNA"", ""Mitochondrial DNA is transferred to chondrocytes"", ""Transferred DNA activates cGAS-STING signaling"", ""The pathway drives senescence and cartilage degeneration"", ""cGAS-STING inhibition reduces osteoarthritis pathology""]"	4	0	20	5	0	60	0.2	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.0	0.0	0.2	0.0	0.2	0.0	0.0	0.0	0.0	0.0
R42665751	2	2	1	mitochondrial dysfunction initiate and propagate inflammatory signaling	Уже задана причинная последовательность от митохондриального нарушения через распространение воспалительного сигнала к дисфункции яичника.	Выход митохондриальной ДНК, cGAS-cGAMP-STING и щелевые контакты	How does age-associated mitochondrial dysfunction initiate and propagate inflammatory signaling that causes ovarian functional decline?	Ovarian function declines earlier than the function of many other organs, reducing fertility and altering endocrine health. Age-related deterioration of cellular quality, tissue communication and inflammatory homeostasis has been implicated in this process. Mitochondrial dysfunction is common in ageing reproductive tissues, but whether it directly initiates ovarian decline rather than merely accompanying it has remained uncertain. The molecular signals linking mitochondrial stress to dysfunction across the ovarian follicle were unknown.	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.	"[""Mitochondrial stress causes mtDNA leakage from oocytes"", ""Leaked mtDNA activates the cGAS–cGAMP–STING pathway"", ""Oocyte-derived cGAMP transmits signaling to granulosa cells through gap junctions"", ""Pathway activation promotes ovarian inflammation and functional decline"", ""Genetic or pharmacological pathway inhibition rescues ovarian dysfunction""]"	5	2	20	9	4	60	0.2	0.0	0.2	0.0	0.4	0.2	0.2	0.0	0.0	0.0	0.0	0.0	0.4	0.2	0.0	0.0	0.0	0.0	0.2	0.2	0.2	0.2	0.0	0.0
R42689491	2	2	2	in vivo correction of the HGPS-causing mutation rescue molecular, cellular, and structural defects in bone	Указаны исправление причинной мутации и ожидаемое восстановление кости; отдельно подсказано значение срока лечения.	Адениновое редактирование, LMNA и преимущество раннего введения	Can in vivo correction of the HGPS-causing mutation rescue molecular, cellular, and structural defects in bone, and how does treatment timing affect efficacy?	Hutchinson-Gilford progeria syndrome is a rare genetic disorder characterized by accelerated, multisystem features of ageing. Progressive skeletal abnormalities are a prominent component of the disease in both patients and experimental models. These abnormalities involve impaired bone formation, remodeling, and mechanical integrity. It remained unclear whether established skeletal pathology could be meaningfully reversed in vivo and how strongly therapeutic efficacy would depend on the age at treatment.	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.	"[""Correction of the pathogenic LMNA variant"", ""Reduced progerin transcripts and protein"", ""Improved osteoblast matrix deposition and mineralization"", ""Partial rescue of bone structure and physical properties"", ""Greater efficacy with early postnatal treatment""]"	10	3	20	23	5	60	0.4	0.0	0.6	0.0	0.0	0.0	0.6	0.0	1.0	0.4	0.0	0.0	0.6	0.2	0.4	0.0	0.0	0.0	0.4	0.4	0.2	0.0	0.4	0.0
R42696595	0	0	1	natural variation in seed longevity among rice varieties	Генетическая изменчивость задаёт объект объяснения; липиды, регуляция РНК и конкретный ген скрыты.	SL6, жирные кислоты, ABA-VP1 и элемент 5′-UTR	What genetic and molecular mechanism causes natural variation in seed longevity among rice varieties?	Seeds progressively lose viability during storage, limiting crop propagation and the preservation of genetic resources. Longevity varies substantially among rice varieties and is influenced by both environmental conditions and inherited traits. Although several genomic regions associated with seed longevity had been identified, the causal genes and regulatory mechanisms underlying this variation remained poorly understood. It was also unclear whether naturally occurring longevity alleles could improve seed survival without compromising agronomic performance.	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.	"[""qSL6 encodes the causal fatty acyl-ACP thioesterase SL6"", ""SL6 alters palmitic-acid synthesis and seed fatty-acid composition"", ""The ABA–VP1 module directly activates SL6 during seed desiccation"", ""A CT-rich 5′-UTR element stabilizes SL6HHZ mRNA"", ""Increasing SL6 expression improves seed longevity without major agronomic penalties""]"	0	0	20	0	0	60	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0
R42698274	1	1	0	dihydrotestosterone-induced mitochondrial dysfunction, oxidative stress and senescence	Указаны гормональное воздействие и клеточные нарушения, ограничивающие поиск; белковое взаимодействие скрыто.	SFRP2, FSTL1 и стабилизация белка	What molecular mechanism exacerbates dihydrotestosterone-induced mitochondrial dysfunction, oxidative stress and senescence during androgenetic alopecia?	Androgenetic alopecia is a common, progressive form of hair loss associated with genetic susceptibility and heightened follicular responses to dihydrotestosterone. Androgen exposure progressively impairs the cells that support follicle growth, contributing to follicular miniaturization and a shortened growth phase. Mitochondrial dysfunction, oxidative stress, inflammation and cellular senescence have been implicated in this deterioration. However, the molecular mechanism connecting androgen signaling to these pathogenic cellular changes remained incompletely understood.	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.	"[""SFRP2 directly binds FSTL1"", ""SFRP2 promotes FSTL1 protein stability"", ""The SFRP2–FSTL1 axis worsens DHT-induced mitochondrial dysfunction and senescence"", ""FSTL1 depletion suppresses the effects of SFRP2 overexpression"", ""SFRP2 depletion improves hair regeneration in an AGA mouse model""]"	0	0	20	0	0	60	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0
R42717261	1	2	0	immune-cell senescence in ulcerative colitis	Вопрос направляет к старению иммунных клеток как причине болезни. Исходные сведения дополнительно называют митохондриальное повреждение и выход компонентов в цитозоль.	NAD+, митохондриальная ДНК, cGAS-STING и CD8+ Т-клетки	What mechanism induces pathogenic immune-cell senescence in ulcerative colitis, and does this senescence causally exacerbate the disease?	Cellular senescence can develop in immune populations and alter tissue function through persistent inflammatory and dysfunctional states. Such immunosenescence has been associated with chronic inflammatory disorders, but whether senescent immune cells directly cause disease progression has remained uncertain. Metabolic disruption and mitochondrial damage are recognized triggers of senescence, including through the abnormal release of mitochondrial components into the cytosol. The causal sequence connecting these processes to intestinal inflammation and treatment resistance was unresolved.	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.	"[""NAD+ metabolic dysregulation initiates the process"", ""Mitochondrial dysfunction causes cytosolic mitochondrial DNA leakage"", ""cGAS-STING activation drives CD8+ T-cell senescence"", ""Senescent CD8+ T cells causally exacerbate colitis"", ""Senolytic clearance attenuates disease severity""]"	8	2	20	20	4	60	0.4	0.0	0.6	0.0	0.0	0.0	0.2	0.2	0.6	0.2	0.0	0.0	0.6	0.2	0.6	0.0	0.0	0.0	0.4	0.0	0.4	0.0	0.2	0.2
R42723546	1	1	2	cell-free regenerative treatment alleviate UV-induced skin photoaging	Назван класс бесклеточных вмешательств и положительный эффект; последовательность внутриклеточных событий скрыта.	Секретом, митофагия, митохондриальная ДНК и cGAS-STING	Can a cell-free regenerative treatment alleviate UV-induced skin photoaging, and which causal intracellular mechanism mediates its protective effects?	Chronic ultraviolet exposure causes skin photoaging characterized by impaired barrier function, collagen loss, cellular senescence, and persistent inflammation. Damaged cells can accumulate dysfunctional organelles and release intracellular danger signals that sustain sterile inflammatory responses. Regenerative cell-free therapies have shown potential for repairing aged or injured tissues, but their activity can involve many distinct biological processes. The causal mechanism by which such therapies might suppress photoaging-associated senescence and inflammation remained unresolved.	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.	"[""The secretome alleviates UV-induced photoaging and cellular senescence"", ""Enhanced mitophagy removes damaged mitochondria"", ""Reduced mitochondrial DNA leakage suppresses cGAS-STING signaling"", ""Mitophagy inhibition abolishes the protective effect"", ""STING inhibition rescues protection despite blocked mitophagy""]"	5	2	20	27	12	60	0.2	0.2	0.8	0.2	0.4	0.4	0.2	0.0	0.6	0.2	0.4	0.0	0.4	0.0	1.0	0.4	0.2	0.0	0.2	0.2	0.6	0.4	0.4	0.4
R42725837	1	1	1	transmembrane protein	Указан класс белка, но отсутствуют его название и направление действия.	PTCHD4 и усиление AKT	Does the transmembrane protein investigated in this study causally regulate cellular senescence and age-related tissue pathology, and through what signaling mechanism?	Cellular senescence is a stable stress response that contributes to tissue dysfunction, chronic inflammation, and multiple age-related diseases. Senescent cells accumulate with age, and experimentally reducing their abundance or activity can improve health-related outcomes in animal models. Transmembrane proteins can regulate intracellular signaling networks involved in stress responses and cell-fate decisions, but many remain poorly characterized in ageing. Identifying upstream regulators that causally control senescence could reveal therapeutic targets for age-associated disorders.	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.	"[""PTCHD4 causally promotes cellular senescence"", ""PTCHD4 deficiency improves ageing-related phenotypes and median lifespan in mice"", ""PTCHD4 deficiency reduces pulmonary fibrosis and preserves lung function"", ""AKT activation mediates the pro-senescent effect of PTCHD4""]"	4	2	20	6	2	60	0.2	0.2	0.2	0.0	0.0	0.0	0.2	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.0	0.0	0.0	0.0	0.2	0.2	0.2	0.0	0.0	0.0
R42736449	1	1	2	unannotated protein product	Поиск ограничен неаннотированным белковым продуктом; его локус, клетки и функция скрыты.	Микробелок MKKS и митохондриальное дыхание микроглии	Can an unannotated protein product that is altered in Alzheimer's disease causally regulate cellular function relevant to disease pathology?	Alzheimer's disease involves progressive neuronal dysfunction accompanied by broad molecular changes in the brain. Conventional genome annotation does not capture every translated product, leaving potentially functional proteins uncharacterized. Disease-associated changes in these overlooked products may occur independently of established proteins encoded at the same genomic loci. It remained unclear whether any such product contributes directly to cellular dysfunction in Alzheimer's disease.	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.	"[""63-amino-acid microprotein encoded at the MKKS locus"", ""Predominant translation product of the locus"", ""Downregulated in Alzheimer's disease"", ""Its loss impairs microglial mitochondrial respiration""]"	2	0	20	4	0	60	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.2	0.0	0.2	0.0
R42744804	0	1	0	actively eliminates motor neurons and accelerates mortality in SOD1G93A mice	Описаны исход и модель болезни; механизм поглощения нейронов отсутствует. Исходные сведения допускают взаимодействие с окружающими клетками.	Микроглия, Axl, Mer, фосфатидилсерин и поглощение живых нейронов	What disease-associated mechanism actively eliminates motor neurons and accelerates mortality in SOD1G93A mice?	Amyotrophic lateral sclerosis is a progressive neurodegenerative disease characterized by motor-neuron loss, neuromuscular denervation and premature death. Inherited SOD1 mutations cause some forms of ALS and are widely used to model disease progression in mice. Degeneration in these models involves interactions between vulnerable neurons and surrounding cells, but it remained unclear which responses actively cause neuronal death rather than merely accompany it. Identifying causal mechanisms could reveal ways to preserve neuromuscular function and extend survival.	Microglial Axl and Mer receptors recognize elevated phosphatidylserine on SOD1G93A motor neurons and drive their phagocytic elimination while the neurons are still alive. Germline or microglia-restricted inactivation of Axl and Mertk preserves cholinergic motor neurons and neuromuscular synapses and extends lifespan in SOD1G93A mice.	"[""Microglia phagocytically kill living motor neurons"", ""Axl and Mer are required for this elimination"", ""Motor-neuron phosphatidylserine provides the eat-me signal"", ""Axl/Mertk inactivation preserves neurons and neuromuscular synapses"", ""Blocking the mechanism extends lifespan""]"	4	1	20	10	3	60	0.2	0.0	0.0	0.0	0.2	0.0	0.2	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.4	0.0	0.0	0.0	0.2	0.2	0.2	0.0	0.4	0.4
R42749700	1	1	1	disrupted chromatin regulation	Поиск направлен к регуляции хроматина; молекулы и конкретный способ регуляции скрыты.	HMGA1, USP7, HP1β, ANGPTL2 и пептид UHP	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?	Hutchinson–Gilford progeria syndrome is a rare genetic disorder characterized by accelerated ageing and markedly shortened lifespan. Cells affected by the disease develop nuclear abnormalities, loss of chromatin organization, and premature senescence. Senescent cells can reinforce tissue dysfunction by releasing pro-inflammatory factors collectively known as the senescence-associated secretory phenotype. The molecular mechanisms connecting altered nuclear architecture to this secretory state remained incompletely understood, limiting the development of mechanism-based treatments.	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.	"[""HMGA1 stabilizes HP1β through USP7 recruitment"", ""HP1β closes chromatin at ANGPTL2"", ""ANGPTL2 and SASP expression are suppressed"", ""The effect on senescence depends on HP1β"", ""UHP reduces senescence and extends progeria-mouse lifespan""]"	1	0	20	1	0	60	0.0	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0
R42758848	1	1	2	developmentally established epigenetic mechanism preserves metabolic readiness	Заданы эпигенетическая природа и метаболическая функция; сигнальный фактор и гистоновый вариант скрыты.	IL-7, GABPα, H2A.Z и гены окислительного фосфорилирования	What developmentally established epigenetic mechanism preserves metabolic readiness for rapid immune activation, and how is it disrupted during ageing?	Ageing is accompanied by a progressive weakening of adaptive immune responses, which reduces protection against infections and cancer. Effective immunity requires resting immune cells to preserve metabolic competence while remaining ready for rapid activation. Age-related changes in chromatin regulation and cellular metabolism have both been implicated in immune dysfunction. However, the mechanism that establishes this latent metabolic readiness and how ageing disrupts it remained unclear.	Tonic IL-7 signaling establishes a GABPα-dependent program that deposits H2A.Z at oxidative-phosphorylation gene promoters in quiescent naïve CD8+ T cells, priming their rapid metabolic and functional activation. Age-related loss of IL-7 signaling reduces H2A.Z occupancy and impairs activation, while IL-7 supplementation or enforced H2A.Z expression rescues the defect.	"[""Ageing reduces tonic IL-7 signaling"", ""GABPα regulates H2A.Z deposition"", ""H2A.Z primes OXPHOS gene promoters"", ""Loss of this axis impairs naïve CD8+ T-cell activation"", ""IL-7 or H2A.Z restoration rescues the age-related defect""]"	2	0	20	5	0	60	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.0	0.0	0.2	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.2	0.0	0.2	0.0
R42759510	1	1	2	peripheral-to-brain signaling	Задано направление передачи сигнала с периферии в мозг и набор исходов; орган-источник и переносчик скрыты.	Селезёнка, RBMX, miR-10a-5p и γCaMKII	What molecular mechanism drives peripheral-to-brain signaling that promotes senescence, mitochondrial dysfunction, and cognitive vulnerability during female midlife?	Women show a disproportionate increase in cognitive and systemic vulnerability during midlife despite their longer average lifespan. Ageing is accompanied by mitochondrial dysfunction, cellular senescence, and altered communication between peripheral tissues and the brain. Circulating regulatory signals can influence brain physiology, but the mechanisms responsible for the female-biased transition from resilience to vulnerability remain poorly understood. It was also unclear whether this transition is reversible or contributes causally to age-related neurodegenerative phenotypes.	Epigenetic upregulation of splenic RBMX in middle-aged female mice increases peripheral miR-10a-5p, which contributes to cerebral miR-10a-5p abundance and represses γCaMKII. Manipulating this RBMX–miR-10a-5p–γCaMKII axis alters mitochondrial function, cellular senescence, and memory, while miR-10a-5p inhibition alleviates Alzheimer’s-associated phenotypes in patient-derived neurons and model mice.	"[""Female midlife induces epigenetic RBMX upregulation in the spleen"", ""RBMX promotes increased splenic miR-10a-5p"", ""Peripheral signaling contributes to brain miR-10a-5p abundance"", ""miR-10a-5p represses γCaMKII and drives mitochondrial, senescence, and memory phenotypes"", ""miR-10a-5p inhibition attenuates Alzheimer’s-associated phenotypes""]"	0	0	20	0	0	60	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0
R42775695	1	1	2	defective mitochondrial quality-control flux	Поиск ограничен контролем качества митохондрий; причина нарушения потока и конкретное вмешательство скрыты.	HIF-3α, BNIP3 и трансплантация митохондрий	What causes defective mitochondrial quality-control flux in the aging heart, and how can restoring mitochondrial homeostasis reverse cardiac aging?	Cardiac function progressively deteriorates with age, increasing susceptibility to heart failure and other cardiovascular disorders. Defective mitochondrial quality control is considered an important contributor to this decline. Selective removal of damaged mitochondria must remain properly balanced, because disruption at multiple stages of the process can impair cellular homeostasis. The upstream causes of this age-associated defect and whether it can be therapeutically reversed were not well established.	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.	"[""HIF-3α is aberrantly elevated with cardiac aging"", ""HIF-3α directly promotes excessive BNIP3 expression"", ""Overactive HIF-3α–BNIP3 signaling causes mitophagy flux congestion"", ""Mitochondrial transplantation restores ATP homeostasis and suppresses the axis"", ""Normalized mitophagy flux reverses age-related cardiac dysfunction""]"	2	0	20	4	0	60	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.2	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.2	0.0	0.0	0.0
R42775698	1	1	2	gut microbial community causally reprogram intestinal barrier function, systemic metabolism, and mucosal gene expression	Названы источник воздействия и три группы исходов; направление изменений и метаболиты остаются неизвестными.	Пересадка микробиоты, Tyr-Phe, простагландин E3 и подавление генов	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?	Intestinal structure and barrier integrity commonly deteriorate with age, contributing to altered nutrient handling, inflammation, and systemic metabolic dysfunction. Ageing is also accompanied by changes in circulating metabolites and intestinal gene expression. Observational studies have linked these features, but such associations cannot establish whether age-related changes in the intestinal ecosystem actively cause host dysfunction. The mechanisms connecting donor age-associated biological states to impaired intestinal physiology therefore remained unclear.	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.	"[""Elderly-donor microbiota causally impaired intestinal architecture and tight-junction integrity"", ""Elderly-donor transplantation reshaped the plasma metabolome"", ""Tyr-Phe strengthened and prostaglandin E3 weakened epithelial barrier function experimentally"", ""Seven mucosal hub genes were consistently downregulated after elderly-donor transplantation"", ""Blautia obeum enrichment was associated with the elderly-donor metabolic and barrier phenotype""]"	2	0	20	6	0	60	0.0	0.0	0.2	0.0	0.0	0.0	0.2	0.0	0.4	0.0	0.0	0.0	0.2	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.0	0.0
R42786310	2	2	1	commensal microorganism predicted from integrated human ageing profiles causally extend lifespan and healthspan	Задана схема выбора микроорганизма и перечень положительных эффектов, включая сдвиг молекулярных профилей к молодому состоянию.	Neisseria flavescens, живые и инактивированные бактерии и различие моделей	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?	Ageing involves coordinated deterioration across metabolic, immune and organ systems, accompanied by changes in host-associated microbial communities. Microbiome composition correlates with biological age and age-related physiological states, but such associations do not establish whether individual microorganisms can modify the ageing process. Some microbial interventions alter host metabolism and longevity in experimental models, although causal effects often depend on organism viability, microbial products and host context. It therefore remained unclear whether systematic integration of diverse human biological measurements could identify a microorganism with experimentally reproducible geroprotective activity.	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.	"[""Neisseria flavescens is the causal candidate"", ""Live bacteria extend C. elegans lifespan and healthspan"", ""Heat-killed bacteria rejuvenate multiple ageing-associated profiles in mice"", ""Isolated strains produce beneficial metabolites predicted by multi-modality analysis""]"	4	0	20	7	0	60	0.2	0.0	0.2	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.0	0.0	0.0	0.0	0.4	0.0	0.4	0.0	0.0	0.0
R42805954	0	1	0	age-related decline of thermogenic adipocytes	Названо явление для объяснения; нейронный путь присутствует только в исходных сведениях.	Микроглия, ALKBH5, Ntf5 и симпатическая иннервация	What causal mechanism contributes to the age-related decline of thermogenic adipocytes in subcutaneous white adipose tissue?	Ageing is associated with declining thermogenic capacity in adipose tissue, impaired energy expenditure, and increased susceptibility to metabolic dysfunction. Subcutaneous white adipose tissue can acquire heat-producing adipocytes in response to environmental stimuli, but this capacity diminishes with age. Communication between the nervous system and adipose tissue helps regulate this adaptive response. The mechanisms responsible for its age-related deterioration remained incompletely understood.	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.	"[""Microglial ALKBH5 restrains adipocyte browning"", ""ALKBH5 knockout increases Ntf5 mRNA m6A methylation and Ntf5 expression"", ""Ntf5 activates PVH TrkB-positive neurons and downstream sympathetic innervation"", ""Microglia-specific ALKBH5 loss prevents age-related brown adipocyte decline"", ""The causal findings were demonstrated in male mice""]"	2	0	20	3	0	60	0.0	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.2	0.0	0.0	0.0	0.2	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0
R42810392	2	2	2	direct pharmacological activation of a conserved metabolic target extend lifespan across evolutionarily diverse organisms	Заданы избирательная активация, межвидовое продление жизни и изменения у млекопитающих; центральная причинная схема уже сформулирована.	AMPK, соединение 991, конкретные виды и протеом мышей	Can direct pharmacological activation of a conserved metabolic target extend lifespan across evolutionarily diverse organisms and induce longevity-associated changes in mammals?	Ageing is strongly influenced by conserved systems that coordinate cellular metabolism with nutrient and energy availability. Genetic studies have shown that altering metabolic regulation can affect lifespan in several model organisms. Pharmacological studies, however, often use compounds with multiple targets, making it difficult to attribute longevity effects to a specific mechanism. It therefore remained unclear whether selective engagement of a single conserved metabolic target could directly produce longevity benefits across species.	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.	"[""Direct AMPK activation by compound 991"", ""Lifespan extension in yeast, worms, and flies"", ""Conserved causal longevity effect across species"", ""Pro-longevity proteomic response in mice""]"	10	3	20	18	7	60	0.8	0.2	0.4	0.0	0.0	0.0	0.4	0.2	0.6	0.4	0.0	0.0	0.6	0.0	0.2	0.0	0.0	0.0	0.2	0.2	0.4	0.4	0.0	0.0
R42811497	0	1	0	cellular senescence and fibrosis in localized scleroderma	Вопрос задаёт патологические исходы и общую возможность лечения; молекулярный процесс скрыт. Исходные сведения дополнительно упоминают гомеостаз органелл.	Партенолид, Ero1L и контакты эндоплазматической сети с митохондриями	What molecular mechanism drives cellular senescence and fibrosis in localized scleroderma, and can pharmacological disruption of that mechanism alleviate the disease phenotype?	Localized scleroderma is characterized by excessive extracellular-matrix deposition and progressive skin fibrosis. Cellular senescence can promote persistent tissue remodeling and fibrotic disease through altered cell function and inflammatory signaling. Disturbances in organelle homeostasis have also been associated with both senescence and fibrosis. The causal molecular mechanisms connecting these processes in localized scleroderma, and whether they can be therapeutically reversed, remained incompletely understood.	Parthenolide suppresses Ero1L, thereby normalizing Ero1L-mediated mitochondria-associated endoplasmic reticulum membrane function, regulating the IP3R1/Grp75/VDAC1 complex, and reducing mitochondrial damage, cellular senescence, and fibrosis. Ero1L overexpression reverses these protective effects, whereas Ero1L knockdown reproduces the anti-senescent and antifibrotic phenotype; ARG-449 is critical for parthenolide binding to Ero1L.	"[""Ero1L causally promotes senescence and fibrosis"", ""Parthenolide directly suppresses Ero1L through binding involving ARG-449"", ""The mechanism involves MAM stabilization and the IP3R1/Grp75/VDAC1 complex"", ""Ero1L gain- and loss-of-function experiments establish causality"", ""Targeting this axis reduces mitochondrial damage and fibrotic pathology""]"	4	0	20	8	0	60	0.2	0.0	0.4	0.0	0.0	0.0	0.2	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.0	0.0	0.2	0.0	0.2	0.0	0.2	0.0	0.0	0.0
R42821663	1	1	2	hypertension accelerate osteoarthritis	Заданы системное воздействие и чувствительность повреждённых суставов; циркулирующий посредник скрыт.	Вазопрессин, AVPR1A и NR4A3	Through what causal mechanism does hypertension accelerate osteoarthritis in joints predisposed by aging or mechanical injury?	Osteoarthritis is a common degenerative disease whose incidence and severity increase with age. Mechanical damage and age-associated changes in joint tissues create susceptibility to progressive cartilage loss. Systemic metabolic disorders, including hypertension, have been associated with greater osteoarthritis risk and severity. However, it was unclear whether elevated blood pressure actively promotes joint degeneration through a defined biological mechanism rather than merely sharing risk factors with osteoarthritis.	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.	"[""Hypertension elevates osteoarthritis progression"", ""OA-primed chondrocytes up-regulate AVPR1A"", ""Circulating AVP activates AVPR1A"", ""NR4A3 mediates the downstream catabolic program"", ""AVPR1A disruption protects cartilage""]"	0	0	20	0	0	58	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0
R42822442	1	1	2	nutrient scarcity	Поиск ограничен недостатком питательных веществ как причиной старения перенесённых иммунных клеток.	Глюкоза, Th9, AMPK, ZAK-NIK и IL-9	How does nutrient scarcity in the solid-tumor microenvironment cause senescence and loss of persistence in adoptively transferred antitumor immune cells?	Solid tumors create metabolically stressful microenvironments in which rapidly proliferating malignant and immune cells compete for limited nutrients. Adoptively transferred immune cells often lose function and fail to persist under these conditions, limiting therapeutic efficacy. Cellular senescence can produce durable functional decline in immune cells, but the metabolic signals that initiate this state within tumors have remained incompletely understood. Identifying the causal signaling events could reveal ways to preserve therapeutic immune-cell activity.	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.	"[""Glucose deprivation causes Th9-cell senescence"", ""AMPK is activated by glucose scarcity"", ""The ZAK–NIK cascade suppresses noncanonical NF-κB signaling and IL-9"", ""ZAK targeting rejuvenates Th9 cells and improves antitumor efficacy""]"	3	0	20	8	0	60	0.2	0.0	0.2	0.0	0.2	0.0	0.2	0.0	0.2	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.2	0.0	0.2	0.0
R42826184	1	1	2	three-dimensional genome organization	Указан класс изменений структуры генома и направление транскрипционного эффекта; архитектурный белок и способ перестройки скрыты.	SATB1, границы TAD и взаимодействия CTCF	What causal molecular mechanism remodels three-dimensional genome organization during ageing and thereby promotes age-associated inflammatory and activation-related transcription?	Three-dimensional genome organization helps regulate transcription by partitioning chromosomes into domains and controlling contacts between regulatory elements and gene promoters. Ageing is accompanied by widespread transcriptional dysregulation, including chronic inflammation and impaired immune function. Changes in chromatin structure have been observed during ageing, but whether they actively drive age-related gene-expression programs rather than merely accompany them has remained unclear. The molecular mechanisms connecting altered genome topology to physiological decline are also poorly understood.	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.	"[""SATB1 expression declines with age"", ""SATB1 normally constrains CTCF-mediated chromatin interactions"", ""SATB1 loss weakens TAD boundaries and rewires enhancer-promoter contacts"", ""Architectural remodeling activates inflammatory and T-cell activation genes"", ""Conditional SATB1 deletion phenocopies ageing""]"	1	0	20	5	1	60	0.0	0.0	0.2	0.2	0.0	0.0	0.0	0.0	0.2	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.0	0.0	0.2	0.0	0.2	0.0	0.0	0.0
R42839094	1	1	2	conserved form of lipid remodeling	Задана перестройка липидов как ограничитель жизни; тип изменения липидов и регулятор скрыты.	Удлинение ацильных цепей и Plb1	Does a conserved form of lipid remodeling actively constrain lifespan, and what molecular regulator controls it?	Ageing is accompanied by widespread changes in metabolism and cellular composition. Lipids support membrane organization, signaling and energy storage, and age-associated lipid disturbances have been observed across many tissues and organisms. Some lipid changes correlate with age-related disease and physiological decline, but their functional importance remains uncertain. A central unresolved question is whether conserved lipid remodeling actively drives ageing or merely reflects it.	Ageing produces a conserved shift toward longer lipid acyl chains, with depletion of shorter lipid species. Plb1 promotes this remodeling, and its knockdown in C. elegans reverses lipid elongation and extends lifespan in a lipid-length-dependent manner, supporting a causal role for lipid chain length in limiting longevity.	"[""Ageing shifts lipid composition toward longer acyl chains across species and tissues."", ""The remodeling is ratiometric, combining accumulation of longer lipids with depletion of shorter species."", ""Plb1 regulates age-associated lipid chain elongation."", ""Plb1 knockdown reverses lipid elongation and extends C. elegans lifespan."", ""Lifespan extension depends on lipid chain length.""]"	0	0	20	0	0	59	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0
R42841227	1	1	2	gut microbial metabolism causally impair antiviral defense	Задан микробный метаболический источник нарушения противовирусной защиты; метаболит и рецепторы скрыты.	Ацетат, FFAR2/FFAR3 и ацетилирование гистона H3	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?	Older individuals are more susceptible to severe influenza and often mount less effective antiviral immune responses. Ageing also alters the composition and metabolic activity of the gut microbiota, potentially affecting immune function at distant organs. Microbial metabolites are known to influence host immunity and gene regulation, but their contribution to age-related loss of antiviral protection remains poorly understood. It was therefore unclear whether altered microbial metabolism during ageing directly contributes to defective responses against respiratory viral infection.	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.	"[""Ageing-associated dysbiosis reduces acetate-producing microbial functions"", ""Acetate lowers influenza viral replication in senescent lung fibroblasts"", ""Acetate attenuates inflammatory responses"", ""Protection involves FFAR2/FFAR3 signaling"", ""Protection is associated with enhanced histone H3 acetylation""]"	4	0	20	10	0	60	0.2	0.0	0.4	0.0	0.0	0.0	0.2	0.0	0.2	0.0	0.0	0.0	0.2	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.4	0.0	0.2	0.0
R42842666	1	1	0	different cellular compartments of the vascular wall	Поиск направлен к разделению причинных функций клеток сосудистой стенки; соответствие клеток конкретным эффектам скрыто.	Роли фибробластов, гладкомышечных и эндотелиальных клеток	How do the different cellular compartments of the vascular wall causally contribute to distinct features of Hutchinson-Gilford progeria vascular pathology?	Hutchinson-Gilford progeria syndrome is a premature-ageing disorder caused by an LMNA mutation and is characterized by severe, early-onset vascular disease. Its vascular pathology includes extracellular-matrix abnormalities, fibrosis, collagen accumulation and inflammation. Blood-vessel models have often examined individual vascular compartments in isolation, limiting understanding of how interactions among the vessel wall layers produce disease. The cellular origins of the distinct pathological features and the extent to which they depend directly on the causal mutation remained unresolved.	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.	"[""Trilayer vessels separated cell-specific causal effects"", ""Fibroblasts drove matrix dysregulation and fibrotic signaling"", ""Smooth muscle cells promoted collagen accumulation"", ""Endothelial cells promoted inflammation"", ""Mutation correction reversed multiple disease features""]"	8	1	20	17	1	60	0.2	0.0	0.4	0.0	0.2	0.0	0.8	0.2	0.4	0.0	0.2	0.0	0.4	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.2	0.0	0.4	0.0
R42844664	2	2	2	time-restricted feeding protect against accelerated cardiovascular ageing	Прямо названы вмешательство и направление эффекта; требуется найти посредников.	Limosilactobacillus, ацетат, GPR43, HDAC3 и NLRP3	Through what causal mechanism does time-restricted feeding protect against accelerated cardiovascular ageing?	Cardiovascular ageing is characterized by hypertension, arterial stiffening, endothelial dysfunction, and maladaptive cardiac remodeling. Chronic inflammation, impaired tissue barriers, and regulated inflammatory cell death can accelerate these changes. Dietary patterns can influence age-related cardiovascular health, but causal chains connecting specific eating schedules to vascular protection remain incompletely understood. Identifying the necessary and sufficient mediators of such protection is important for developing non-pharmacological strategies against cardiovascular decline.	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.	"[""TRF remodels the gut microbiota and enriches Limosilactobacillus"", ""Microbiota depletion abolishes TRF-mediated cardiovascular protection"", ""Acetate supplementation restores the protective phenotype"", ""Acetate signals through GPR43 and inhibits HDAC3"", ""Increased H4K8ac suppresses NLRP3 pyroptosis and senescence""]"	3	0	20	4	0	60	0.0	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.0	0.0	0.0	0.0	0.4	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.0	0.0
R42853938	1	1	2	splicing-dependent mechanism enables resistance to CDK4/6 inhibition	Заданы сплайсинг и класс терапии; конкретный транскрипт и механизм устойчивости скрыты.	Экзон 2 SUV39H2, H3K9me3 и p21	What splicing-dependent mechanism enables resistance to CDK4/6 inhibition, and can disrupting it restore therapy-induced senescence?	Therapy-induced cellular senescence can durably arrest the proliferation of cancer cells and contribute to treatment efficacy. Cancer cells can acquire resistance to treatments that normally induce this state, allowing continued growth and disease progression. Alternative splicing and epigenetic regulation are both frequently altered during cancer evolution, but their causal roles in suppressing treatment-induced senescence remain incompletely understood. Identifying the molecular mechanism responsible could reveal a way to restore therapeutic sensitivity.	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.	"[""SUV39H2 exon 2 inclusion increases SUV39H2 expression"", ""SUV39H2 promotes resistance to CDK4/6 inhibitors"", ""SUV39H2 targeting reduces enhancer-associated H3K9me3 and opens promoters"", ""p21 and other senescence-associated genes are transcriptionally activated"", ""Therapy-induced senescence and drug sensitivity are restored""]"	1	0	20	1	0	60	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0
R42858183	2	2	1	preserve lysosomal function and protein homeostasis during aging, thereby extending lifespan	Вопрос задаёт последовательность от восстановления лизосом через протеостаз к продлению жизни; название вмешательства скрыто.	Rg3, фосфоинозитиды, TORC1-RSKS-1 и HLH-30	Can a defined intervention preserve lysosomal function and protein homeostasis during aging, thereby extending lifespan and maintaining organismal function, and through what mechanism?	Aging is accompanied by declining lysosomal activity, impaired autophagic clearance, and loss of protein homeostasis. These changes contribute to progressive functional deterioration and increase vulnerability to protein-aggregation disorders. Restoring cellular clearance systems can sometimes improve lifespan or healthspan in model organisms. However, interventions that preserve lysosomal competence during aging and the mechanisms through which they act remain incompletely understood.	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.	"[""Rg3 extends lifespan and preserves healthspan"", ""Lysosomal function and autophagic flux are restored during aging"", ""Neuronal phosphoinositides shift toward higher PI(4)P and lower PI(3)P"", ""TORC1–RSKS-1/S6K signaling is suppressed and HLH-30/TFEB enters the nucleus"", ""Protein aggregation and neurodegeneration are reduced""]"	3	0	20	6	0	60	0.2	0.0	0.2	0.0	0.0	0.0	0.2	0.0	0.2	0.0	0.0	0.0	0.2	0.0	0.0	0.0	0.2	0.0	0.0	0.0	0.0	0.0	0.0	0.0
R42806945	1	1	2	metabolic regulator causally mitigates ageing-related cognitive impairment	Названы метаболический класс регулятора и направление эффекта; идентичность регулятора и клеточный механизм скрыты.	Грелин, микроглия и SHBG-JNK1-Beclin1	Which metabolic regulator causally mitigates ageing-related cognitive impairment, and through what molecular mechanism does it suppress cellular senescence and inflammation?	Ageing is frequently accompanied by cognitive decline and chronic neuroinflammation. Cellular senescence and age-dependent changes in metabolic signaling can disrupt tissue homeostasis and contribute to functional deterioration in the brain. Although several circulating metabolic factors correlate with cognitive impairment, association alone does not establish which factors directly modify the ageing process. The molecular chain connecting a metabolic regulator to cellular dysfunction and cognitive outcomes therefore remained unresolved.	Ghrelin alleviates ageing-related cognitive impairment by promoting autophagy-related activity and reducing senescence and inflammation in microglia through the SHBG/JNK1/Beclin1 axis. SHBG overexpression and JNK1 inhibition attenuate these effects, while Beclin1 overexpression partially restores them, supporting the proposed causal pathway; excessive ghrelin can also cause GHSR desensitization.	"[""Ghrelin improves ageing-related cognitive impairment"", ""Microglial senescence and inflammation are reduced"", ""Autophagy-related signaling is enhanced"", ""The effect is mediated through the SHBG/JNK1/Beclin1 axis"", ""Beclin1 rescue supports the causal pathway""]"	0	0	20	0	0	60	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0
R42723144	2	2	1	equivalent heterogeneous nuclear backgrounds	Одинаковое распределение ядерных вариантов направляет поиск наследственной причины за пределы ядерного генома.	Митохондриальные гаплотипы, импорт TFAM и TOMM20	Can naturally occurring inherited genetic variation alter the rate of ovarian ageing on equivalent heterogeneous nuclear backgrounds, and what cellular mechanism mediates this effect?	Ovarian function declines with age, eventually causing reproductive senescence and broader endocrine changes that affect female healthspan. The pace of this decline varies substantially among individuals, even when chronological age is similar. Both nuclear and non-nuclear inherited factors could contribute to this variation, but their causal roles are difficult to separate because genetic backgrounds commonly differ at many loci. The mechanisms connecting inherited variation to follicle depletion, tissue pathology and loss of ovarian function therefore remain poorly understood.	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.	"[""Mitochondrial haplotype causally modifies the rate of ovarian ageing"", ""OKC-HETW accelerates follicle depletion and pathological ovarian remodelling"", ""The susceptible haplotype reduces respiratory activity, ATP production and mtDNA copy number"", ""Reduced TOMM20 and mitochondrial TFAM indicate defective TFAM import and mtDNA maintenance"", ""Molecular and tissue defects correspond to impaired ovarian function""]"	2	0	20	7	1	60	0.0	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.4	0.2	0.0	0.0	0.0	0.0	0.4	0.0	0.0	0.0	0.2	0.0	0.2	0.0	0.0	0.0
R42808804	1	1	0	blood-labyrinth barrier integrity	Поиск направлен к повреждению сосудистого барьера улитки; конкретные клетки и молекулярные причины скрыты.	Перициты, IGF-1, SLC25A33 и TGF-β/Smad2	What causal mechanism links cochlear ageing to loss of blood-labyrinth barrier integrity and auditory dysfunction?	Age-related hearing loss is a common progressive disorder associated with degeneration of cochlear structure and function. Maintenance of cochlear homeostasis depends on a specialized vascular barrier that controls exchange between the circulation and inner-ear tissues. Ageing can compromise this barrier, disturb the local microenvironment, and contribute to auditory dysfunction. However, the causal molecular events connecting cochlear ageing to barrier failure and hearing decline were not fully understood.	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.	"[""IGF-1 and SLC25A33 decline in aged strial pericytes"", ""SLC25A33 loss causes mitochondrial ROS accumulation"", ""Mitochondrial ROS activates TGF-β/Smad2 signaling and pericyte switching"", ""The pathway disrupts the blood-labyrinth barrier and aggravates hearing loss"", ""IGF-1 or SLC25A33 restoration partially rescues barrier and auditory function""]"	1	0	20	3	0	60	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.0	0.0	0.2	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.0	0.0
R42585340	1	1	2	mild cellular stress to preserve protein homeostasis	Заданы мягкий стресс, протеостаз и продление жизни; тип стресса и защитная программа скрыты.	Подавление дыхания, ELT-2 и протеазы CPR-5/CPR-8	Which molecular mechanism enables mild cellular stress to preserve protein homeostasis during ageing and extend organismal lifespan?	Ageing is accompanied by a progressive loss of protein homeostasis and an accumulation of damaged or aggregation-prone proteins. Mild perturbations of cellular physiology can trigger adaptive responses that increase stress resistance and extend lifespan in several species. Effective removal of damaged proteins is thought to contribute to these benefits, but the responsible transcriptional programs and degradation machinery are incompletely understood. It also remains unclear which components are causally required to connect such adaptive stress responses to improved proteostasis and longevity.	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.	"[""Mitochondrial respiration inhibition sustains lysosomal protease transcription"", ""Intestinal ELT-2 directly activates lysosomal protease genes"", ""ELT-2 residue R249 is required for transcriptional activity"", ""The pathway is largely independent of UPRmt"", ""CPR-5 and CPR-8 are required for aggregate clearance and lifespan extension""]"	1	0	20	1	0	60	0.2	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0
R42669067	2	2	2	SIRT1 regulate L1 retrotransposon activity	В вопросе прямо названы два молекулярных участника из центрального эталонного утверждения.	Направление регуляции, Lamin B1, KAP1, H3K9me3 и cGAS-STING	How does SIRT1 regulate L1 retrotransposon activity, and does this regulation affect cellular senescence?	Cellular senescence is an irreversible growth-arrest state that contributes to ageing and age-related pathology. Senescent cells undergo changes in genome organization and can activate normally repressed repetitive DNA elements. Such activation may compromise genome stability and provoke inflammatory signaling. The regulatory mechanisms that preserve repeat silencing and thereby limit senescence remained incompletely understood.	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.	"[""SIRT1 represses L1 transcription and retrotransposition"", ""SIRT1 stabilizes Lamin B1–KAP1 interactions at the L1 5′-UTR"", ""The mechanism increases repressive H3K9me3 chromatin"", ""SIRT1 loss activates L1-dependent cGAS–STING signaling and senescence"", ""3TC rescues senescence caused by SIRT1 deficiency""]"	10	0	20	21	1	60	0.6	0.0	0.4	0.0	0.0	0.0	0.6	0.0	0.4	0.0	0.0	0.0	0.6	0.0	1.0	0.0	0.0	0.0	0.2	0.0	0.2	0.2	0.2	0.0
R42811065	1	1	2	stress-induced sympathetic activity to cellular senescence and impaired osteogenesis	Задана нервная причина и промежуточное клеточное старение; локальные посредники и способ вмешательства скрыты.	Нейропептид Y, Y1R, семафорин 3A и импульсные электромагнитные поля	Which local mechanism connects stress-induced sympathetic activity to cellular senescence and impaired osteogenesis, and can it be modulated non-invasively?	Chronic stress can disrupt bone remodeling and promote osteoporosis through sustained sympathetic nervous system activity. Cellular senescence within the bone marrow microenvironment can impair regenerative functions and contribute to reduced bone formation. Neural and endocrine signals are therefore plausible links between psychological stress and deterioration of skeletal health. However, the local mediator responsible for stress-induced senescence and the mechanism by which peripheral stimulation could restore osteogenesis were unresolved.	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.	"[""Sympathetic neuropeptide Y is causally required for stress-induced bone loss"", ""Neuropeptide Y induces senescence in bone marrow adipocytes through Y1R"", ""Adipocyte senescence impairs osteogenesis"", ""Pulsed electromagnetic fields activate sensory nerve-dependent semaphorin 3A release"", ""Semaphorin 3A locally suppresses sympathetic neuropeptide Y secretion""]"	1	0	20	3	0	60	0.0	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.0	0.0	0.2	0.0	0.0	0.0
R42841610	1	1	2	causal metabolic mechanism	Поиск ограничен метаболическим объяснением нарушения митохондрий; метаболит и фермент скрыты.	p38 MAPK, GLS1, мочевина и CB-839	What causal metabolic mechanism links cellular senescence to mitochondrial dysfunction and functional decline in ageing skeletal muscle, and can this mechanism be therapeutically reversed?	Ageing commonly causes a progressive loss of skeletal muscle mass, strength and regenerative capacity known as sarcopenia. Mitochondrial respiratory dysfunction is a prominent feature of ageing muscle and is associated with cellular senescence. Senescent cells undergo extensive metabolic changes that may compromise tissue function. However, the causal metabolic processes connecting senescence to mitochondrial impairment and functional muscle decline remained incompletely understood.	Senescence-associated p38 MAPK signaling increases GLS1 expression and activity in skeletal muscle myoblasts, causing intracellular urea accumulation that impairs mitochondrial function. Inhibiting GLS1 with CB-839 lowers urea, restores electron transport chain complexes and mitochondrial respiration, and improves skeletal muscle integrity and strength in progeroid mice.	"[""Senescence activates a p38 MAPK–GLS1 axis"", ""Elevated GLS1 causes intracellular urea accumulation"", ""Urea accumulation impairs mitochondrial function"", ""GLS1 inhibition restores respiratory-chain function"", ""CB-839 improves muscle structure and strength in progeroid mice""]"	1	0	20	2	0	60	0.0	0.0	0.2	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0
R42806003	1	1	0	intercellular mechanism	Задан межклеточный характер причины; клеточные типы и переносимый метаболический дефицит скрыты.	Макрофаги, IRF5, CD38 и истощение NAD+ в стромальных клетках	What intercellular mechanism causes placental senescence during maternal ageing, and can disrupting this mechanism restore placental and offspring health?	Advanced maternal age is associated with placental dysfunction, impaired fetal growth, and increased risks to offspring health. Ageing tissues commonly exhibit metabolic disruption, chronic inflammation, and accumulation of senescent cells with a senescence-associated secretory phenotype. The placenta contains interacting maternal and fetal compartments whose metabolic state and inflammatory environment influence pregnancy outcomes. However, the causal processes through which maternal ageing induces placental senescence and developmental complications remained unclear.	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.	"[""Early inflammation and SASP activate macrophage IRF5"", ""IRF5 increases macrophage CD38 expression"", ""Macrophage CD38 depletes stromal-cell NAD+"", ""NAD+ loss drives placental senescence"", ""CD38 inhibition or NAD+ replenishment rescues age-related outcomes""]"	4	1	20	7	1	60	0.2	0.0	0.0	0.0	0.0	0.0	0.2	0.2	0.0	0.0	0.2	0.0	0.2	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.2	0.0	0.2	0.0
R42806572	2	2	2	dose-titratable immune engager safely eliminate senescent cells	Указаны терапевтическая конструкция, механизм иммунного удаления клеток, дозирование и перенос эффекта между мышами и приматами.	GFD-CD3, uPAR, эндотелиальная токсичность и аминотрансферазы	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?	Senescent cells accumulate with age and can promote tissue dysfunction through persistent inflammatory and remodeling signals. Experimental removal of these cells can improve several age-related phenotypes, supporting cellular senescence as a causal contributor to declining health. Immune-mediated senolysis offers a way to eliminate selected senescent cells, but differences between therapeutic and toxic exposure can complicate translation. A major open problem is whether an externally controllable treatment can achieve effective senolysis in both rodents and primates while providing a practical marker of emerging toxicity.	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.	"[""GFD-CD3 targets uPAR-positive senescent cells"", ""Low-dose treatment produces senolysis in mice and non-human primates"", ""Senolysis alleviates age-related pathologies"", ""High-dose toxicity results from T-cell attack on hepatic endothelial cells"", ""Serum aminotransferase activity provides a safety monitor for dose titration""]"	5	1	20	11	1	60	0.2	0.0	0.4	0.0	0.0	0.0	0.4	0.0	0.2	0.0	0.0	0.0	0.2	0.2	0.2	0.0	0.0	0.0	0.2	0.0	0.4	0.0	0.0	0.0
R42748238	1	1	2	vascular deterioration to promote systemic senescence	Задано направление от сосудистого нарушения к системному старению; ферментативная цепь и метаболит скрыты.	C/EBPβ, AEP, расщепление NAMPT и дефицит NAD+	What molecular mechanism causes age-related vascular deterioration to promote systemic senescence and shorten lifespan?	Microvascular function declines with age, impairing tissue perfusion, nutrient delivery, and waste clearance. Vascular deterioration is associated with dysfunction across multiple organs and with increased frailty and mortality. Cellular senescence and altered metabolic homeostasis are recognized contributors to age-related tissue decline. However, the molecular mechanism by which vascular aging can drive organism-wide aging and shorten lifespan remained unclear.	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.	"[""Endothelial C/EBPβ activates AEP during aging"", ""AEP cleaves the NAD+ biosynthetic enzyme NAMPT"", ""NAMPT cleavage causes systemic NAD+ depletion and senescence"", ""The pathway drives vascular dysfunction and lifespan reduction"", ""Blocking AEP or preventing NAMPT cleavage rescues the phenotype""]"	2	0	20	7	0	60	0.0	0.0	0.0	0.0	0.2	0.0	0.2	0.0	0.2	0.0	0.0	0.0	0.2	0.0	0.4	0.0	0.0	0.0	0.0	0.0	0.2	0.0	0.0	0.0