# PathMap Report Trace Context: #00000145
Hypothesis: The use of cGAS-STING inhibitors (e.g., H151) and senotherapeutics, currently being explored for cancer and neurodegeneration, may provide a novel pharmacological path for rescuing sarcopenic muscle function.
Author: Joshua Dungan (PathMap.org)
License: 'Apache License 2.0
Full provenance JSON trace: https://pathmap.org/download.php/?id=145
==================================================

SYSTEM NOTE: The eight-digit ID numbers (e.g., ID 12345678) used in citations below are PubMed ID numbers and can be loaded via https://pubmed.ncbi.nlm.nih.gov/{ID}/ for verification.

==================================================

## Primary Synthesis & Clinical Bottom-Line
This synthesis evaluates the potential for repurposing cGAS-STING inhibitors and senolytic agents, historically targeted for neoplastic and neurodegenerative conditions, as clinical interventions to mitigate age-related muscle decline (sarcopenia) by modulating sterile inflammation and cellular senescence.

## Novel & Overlooked Insights
- Pharmacological inhibition of STING in mouse models preserves muscle mass during cisplatin-induced atrophy, suggesting that cGAS-STING-mediated signaling is a driver of chemotherapy-induced sarcopenia.
- The cGAS-STING axis is not only a contributor to muscle loss but is also implicated in the "mechano-metabolic-immune" cross-talk that governs skeletal muscle quality.
- Senescent cells within the muscle microenvironment are not uniformly detrimental; in young mice, their removal can paradoxically delay repair kinetics, implying that therapeutic senolysis requires precise temporal windows.
- Microgravity-induced muscle atrophy and stem cell senescence are directly linked to the activation of the mtDNA-cGAS-STING signaling axis.
- Natural compounds such as Jintiange (JTG) and 6-shogaol demonstrate anti-sarcopenic potential by modulating the cGAS-STING-NF-κB signaling axis.
- The gut-muscle axis appears to involve MMA-driven systemic inflammation, which activates the cGAS-STING pathway in peripheral tissues, bridging metabolic dysregulation with muscle aging.
- Cell cycle regulators like CCND1/CDK6 act as upstream regulators of cGAS-STING signaling in senescent cells, suggesting that clinical CDK4/6 inhibitors (e.g., palbociclib) could serve as senomorphics to suppress inflammation-driven aging.

## Extracted Custom Discoveries
### Suggested Experiments
- Test the efficacy of H151 in aged mouse models of sarcopenia to assess the impact on muscle cross-sectional area and fiber force production.
- Perform single-nucleus RNA sequencing on sarcopenic muscle before and after senolytic (D+Q) clearance to map the transcriptional rejuvenation of specific myonuclear compartments.
- Evaluate the long-term metabolic health of aged mice subjected to systemic vs. muscle-specific STING inhibition using adeno-associated viral (AAV) delivery.

### Suggested Studies
- A prospective longitudinal study measuring urinary mtDNA/cGAMP as predictive biomarkers of sarcopenia risk in older adults.
- A meta-analysis mapping the overlap of senolytic resistance across sarcopenic and cancer-associated cachexia models to identify shared molecular vulnerabilities.
- An exploration of the interaction between gut-derived metabolites (SCFA) and the cGAS-STING axis in the context of age-related sarcopenia.

### Swansons Literature Based Discovery Candidates
- {"Discovered Hypothesis (A to C)":"Inhibition of cGAS-STING can attenuate muscle insulin resistance in Type 4 Diabetes (T4DM) by interrupting the inflammatory metaflammatory loop driven by mtDNA leakage.","Literature A (Origin)":"T4DM-driven insulin resistance and neuroendocrine metaflammation (ID: 42324036).","Literature C (Target)":"cGAS-STING signaling in age-related metabolic dysregulation and inflammation (ID: 42621049, ID: 42625172).","The Intersecting Bridge B":"Mitochondrial DNA (mtDNA) leakage as an activator of the cGAS-STING axis in inflammatory\/metabolic cells (ID: 42621049, ID: 42642438).","Biological Rationale":"Since mitochondrial DNA leakage is an identified trigger for cGAS-STING activation, and Type 4 Diabetes is characterized by bioenergetic collapse and metaflammation, the activation of this axis is likely the bridging factor causing chronic muscle insulin resistance."}

### Contradictions Between Evidences
- There is a discordance regarding the net utility of senolytics. While ID: 42348390 and ID: 42202008 suggest clearing senescent cells restores muscle function, ID: 42314772 indicates that senescent cells act as a regulatory mechanism during repair, suggesting that total senolysis in specific regenerative contexts may temporarily delay repair kinetics.

### Repurposed Solutions
- Repurposing cGAS-STING inhibitors (e.g., H151) and senolytics from oncology/neurodegeneration to geriatric sarcopenia targets, and applying CDK4/6 inhibitors (e.g., palbociclib) as senomorphics to suppress the SASP and improve physical performance in the frail elderly.

## Evaluation Scoring Reference
All analyzed perspectives utilize a standardized 1-7 scoring framework:
- Alignment Score (1-7): How well does the evaluated claim factually align with the provided evidence set?
  [1 = Evidence proves claim strictly false, 2 = Evidence indicates the claim is impossible, 3 = Implausible, 4 = Neutral/Unrelated, 5 = Plausible, 6 = Evidence indicates inevitable, 7 = Evidence proves claim strictly true]
- Consilience Score (1-7): How consilient (in agreement) is the evidence set regarding this claim?
  [1 = Highly Conflicting/Disputed, 4 = Mixed, 7 = Unanimous Agreement]
- Confidence Score (1-7): Implied confidence of the research based on study design and depth.
  [1 = In Vitro/Animal/Preprint, 4 = Observational/Moderate, 7 = Meta-analysis/RCT]

## Evaluated Perspectives & Findings
### Perspective R1: Claim [Run1 Eval1 Synthesis] evaluated against Evidence [N/A]
- Alignment Score: 6/7
- Consilience Score: 6/7
- Directional Logic: High Score = SUPPORTS Original Claim
###[CLAIM EVALUATED AND ANSWER TO USER]
"The use of cGAS-STING inhibitors (e.g., H151) and senotherapeutics, currently being explored for cancer and neurodegeneration, may provide a novel pharmacological path for rescuing sarcopenic muscle function."

### [ABSTRACT & REWRITTEN CLAIM]
This synthesis evaluates the potential for repurposing cGAS-STING inhibitors and senolytic agents, historically targeted for neoplastic and neurodegenerative conditions, as clinical interventions to mitigate age-related muscle decline (sarcopenia) by modulating sterile inflammation and cellular senescence.

### [INTRODUCTION & JUSTIFICATION]
Sarcopenia is increasingly recognized as a systemic degenerative state involving chronic inflammation, mitochondrial dysfunction, and cellular senescence. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway has emerged as a central mediator that couples cellular stress—such as mitochondrial DNA leakage—to inflammatory programs, including the senescence-associated secretory phenotype (SASP). Current preclinical evidence suggests that mitochondrial dysfunction, a hallmark of sarcopenia, activates this pathway in multiple tissues, directly promoting muscle atrophy. Pharmacological interventions targeting this axis, such as STING inhibitors (e.g., H151, C176, or DMXAA blockade), have demonstrated the ability to preserve muscle mass and myofiber integrity. Simultaneously, senolytic agents are being evaluated for their capacity to clear the accumulated burden of senescent cells that drive sarcopenic progression. The synergy between these strategies represents a significant opportunity for therapeutic development in geriatric endocrinology.

### [DISCUSSION: NOVEL & OVERLOOKED]
*   Pharmacological inhibition of STING in mouse models preserves muscle mass during cisplatin-induced atrophy, suggesting that cGAS-STING-mediated signaling is a driver of chemotherapy-induced sarcopenia.
*   The cGAS-STING axis is not only a contributor to muscle loss but is also implicated in the "mechano-metabolic-immune" cross-talk that governs skeletal muscle quality.
*   Senescent cells within the muscle microenvironment are not uniformly detrimental; in young mice, their removal can paradoxically delay repair kinetics, implying that therapeutic senolysis requires precise temporal windows.
*   Microgravity-induced muscle atrophy and stem cell senescence are directly linked to the activation of the mtDNA-cGAS-STING signaling axis.
*   Natural compounds such as Jintiange (JTG) and 6-shogaol demonstrate anti-sarcopenic potential by modulating the cGAS-STING-NF-κB signaling axis.
*   The gut-muscle axis appears to involve MMA-driven systemic inflammation, which activates the cGAS-STING pathway in peripheral tissues, bridging metabolic dysregulation with muscle aging.
*   Cell cycle regulators like CCND1/CDK6 act as upstream regulators of cGAS-STING signaling in senescent cells, suggesting that clinical CDK4/6 inhibitors (e.g., palbociclib) could serve as senomorphics to suppress inflammation-driven aging.

### [EVIDENCE, METHODOLOGY & CITATIONS]
1. ID: 42142553 - Application: Jintiange (JTG) mitigates age-related sarcopenia by blocking the cGAS-STING pathway. - "JTG benefits for alleviating aging conditions of skeletal muscle by maintaining mitochondrial homeostasis, thus, effectively ameliorates age-related sarcopenia by blocking the cGAS-STING signaling pathway."
2. ID: 42286673 - Application: STING activation promotes atrophy, while cGAS or STING knockout preserves it. - "Pretreatment with the STING agonist DMXAA exacerbated cisplatin-induced body weight loss and skeletal muscle atrophy. In contrast, genetic deletion of cGAS or STING attenuated the loss of gastrocnemius and tibialis anterior muscle mass."
3. ID: 42607424 - Application: RLX-2 inhibits STING to manage joint fibrosis and senescence. - "Notably, pharmacological blockade of STING by H-151 partially phenocopied the protective effects of RLX-2, suggesting a coordinated regulation of fibrosis and senescence."
4. ID: 42621049 - Application: Central role of cGAS-STING in sterile inflammation. - "The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway, a central sensor of cytosolic DNA, plays a critical role in mediating innate immune responses."
5. ID: 42572354 - Application: Microgravity links mtDNA to cGAS-STING in stem cells. - "In this study, it was found that microgravity simulated by Rotating Flat Chamber induced MSC senescence and promoted the expression of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING), and C176, a STING inhibitor, alleviated the rotating culture-induced MSC senescence."
6. ID: 42619765 - Application: Neuronal LINE-1 links to cGAS-STING. - "Mechanistically, LINE-1-derived cytoplasmic DNA activates the cGAS-STING innate immune pathway in post-mitotic neurons, and inhibition of cGAS phenocopies the effects of LINE-1 suppression."
7. ID: 42653188 - Application: Novelty of cGAS-STING in natural senotherapy. - "Ginkgetin-mediated cyclic GMP-AMP-synthase-stimulator of interferon genes (cGAS-STING) inhibition was identified as a mechanistically novel target within natural senotherapy."
8. ID: 42642519 - Application: cGAS knockout and aging. - "Unexpectedly, we found that cGAS KO mice exhibit an accelerated-aging phenotype, with induction of inflammation in multiple organs."
9. ID: 42585804 - Application: EDB mitigates neuronal senescence. - "EDB treatment notably decreased the expression of senescence markers (p16/p21/p53). Mechanistic studies revealed that EDB not only alleviated oxidative stress but also inhibited the cGAS-STING-mediated innate immune signaling pathway."
10. ID: 42624917 - Application: CCND1/CDK6 regulates cGAS-STING. - "CCND1 and its kinase partner CDK6 drive SASP and ISG expression in senescent cells by promoting DNA damage accumulation. This leads to the formation of cytoplasmic chromatin fragments that activate pro-inflammatory cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling."
11. ID: 42028013 - Application: Senolysis as a mechanism for aging amelioration. - "The accumulation of senescent cells drives age-related diseases, and their removal (senolysis) has been reported to ameliorate pathological aging phenotypes."
12. ID: 42594754 - Application: 6-shogaol drives senescence via cGAS-STING. - "Pharmacological blockade of individual nodes within this signaling cascade significantly reversed 6-shogaol-induced senescence and blunted its anti-activation effect in LX-2 cells."
13. ID: 42473083 - Application: HDAC2-PRELP axis in COPD-related muscle dysfunction. - "Targeting the PRELP-HDAC2 axis may represent a potential therapeutic strategy for COPD-related SMD."
14. ID: 42542973 - Application: GPR81 regulation of myoblast senescence. - "Knockdown of GPR81 in young healthy myoblasts led to an increase in senescence hallmarks such as DNA damage, accumulation of reactive oxygen species (ROS), impaired mitochondrial activity, and autophagy."
15. ID: 42166975 - Application: GRo effects on muscle degeneration. - "This study demonstrates that GRo targets the pathological mechanisms underlying age-related muscle degeneration by regulating oxidative stress, inflammatory responses, metabolic processes, and gut microbiota homeostasis."
16. ID: 42640588 - Application: LMNA mutations hyperactivate cGAS-STING. - "R527C pathogenic variant disrupted the interaction between Lamin A and DNA-binding proteins, causing abnormal protein aggregation and hyperactivation of the cGAS-STING."
17. ID: 42625172 - Application: IL-35 mediated STING senescence. - "Mechanistically, IL-35 signaled through the glycoprotein 130 (GP130) receptor to activate the cGAS-STING-TBK1-IRF3 pathway, leading to upregulated senescence markers (p16, p21, p53)."
18. ID: 42624351 - Application: Mathematical aging model. - "The principal accounting identity states that coupled repair reserve equals material-repair closure plus regulatory-interface closure minus cross-hallmark obstruction rank."
19. ID: 42628192 - Application: PFDA induced ovarian aging. - "The release of mitochondrial DNA into the cytoplasm activated the cGAS-STING signaling pathway. The subsequent oxidative stress-inflammatory cascade drove ovarian cellular senescence."
20. ID: 42606684 - Application: LCCP and ovarian senescence. - "LCCPs induce excessive mitochondrial fission by blocking the interaction between Drp1 and Parkin, leading to the leakage of mitochondrial DNA into the cytoplasm, which in turn activates the cGAS-STING pathway and ultimately drives granulosa cell senescence."
21. ID: 42257028 - Application: Cathepsin B and NLRP3/cGAS crosstalk. - "The functional significance of this pathway was confirmed, as the STING agonist DMXAA abolished the polarizing effects of CTSB silencing."
22. ID: 42324036 - Application: Metabolic care shifts toward senescence. - "Senolytics, NAD⁺ replenishment, SIRT1 activators, mitophagy inducers, anti-myostatin medicines, and exosome-based therapies shift metabolic care towards senescence."
23. ID: 42605704 - Application: TRF2 and mitochondrial protection. - "TRF2 also inhibited activation of the cGAS/STING pathway by increasing mitophagy during H/Post in aged myocardiocytes."
24. ID: 42626086 - Application: TPT1 in muscle. - "Single-nucleus analysis of 97,154 nuclei from 17 donors showed broad TPT1 expression across myonuclear, satellite-cell, stromal, endothelial, and immune compartments, with lower expression in older muscle."
25. ID: 42586256 - Application: Formononetin and ferroptosis. - "FMN alleviates age-related sarcopenia by targeting mitochondrial function and ferroptosis, providing potential targets for sarcopenia treatment."
26. ID: 42523681 - Application: Hysterectomy and sarcopenia pathways. - "Molecular analyses suggested activation of the FOXO1-MuRF-1/Atrogin-1 pathway and changes consistent with ferroptosis-related signaling."
27. ID: 42229217 - Application: Vitamin D and sarcopenia in diabetics. - "In aged diabetic rats, vitamin D deficiency aggravated hyperglycemia, insulin resistance, intramuscular lipid accumulation, and muscle senescence, whereas vitamin D3 supplementation improved muscle strength, myofiber cross-sectional area, and lipid infiltration."
28. ID: 42202008 - Application: Senolysis effectiveness in disuse atrophy. - "Senolytic treatment reduced overall senescent cell burden, attenuated macrophage accumulation, and restored muscle mass and function in aged mice following disuse."
29. ID: 42653402 - Application: Glycyrrhizin anti-inflammatory role. - "These effects were associated with inhibition of the cGAS-STING pathway, as indicated by reduced 2',3'-cGAMP and HMGB1 levels."
30. ID: 42652048 - Application: Kongsheng Zhenzhong Pill mechanism. - "Western blotting further confirmed that KSZZP dose-dependently suppressed the expression of key cGAS-STING pathway proteins (cGAS, STING) and downstream proteins associated with M1 polarization (iNOS, TNF-α, COX-2)."
31. ID: 42642438 - Application: STING inhibition in autoimmunity. - "Together, these findings define an mtDNA-driven pathogenic mechanism in autoimmune thyroiditis and identify STING as a potential therapeutic target."
32. ID: 42625172 - Application: IL-35 essentiality of STING. - "This STING activation was essential, as its inhibition abolished the pro-senescent effect."
33. ID: 42624917 - Application: CDK4/6 inhibitors as senomorphics. - "Hepatocyte-specific Ccnd1 knockout or treatment with the clinical grade CDK4/6 inhibitor palbociclib reduces DNA damage and ISGs in aged mouse liver."
34. ID: 42619765 - Application: Senescent neurons in AD. - "Spatial transcriptomic analysis of human AD brain tissue further supports that senescent neurons with high LINE-1 expression are localized to inflammatory niches in the brain."
35. ID: 42607021 - Application: Aging as a hub of mitochondrial dysfunction. - "Mitochondrial dysfunction serves as a fundamental driver of the aging process, precipitating progressive functional decline through complex molecular cascades."
36. ID: 42605704 - Application: TRF2 in myocardial protection. - "TRF2 improved myocardial I/Post protection in vivo."
37. ID: 42588050 - Application: Tuber borchii extract protective effect. - "Morphological analysis confirmed this protective effect, showing that treated myotubes maintained greater thickness and exhibited a larger cross-sectional area despite exposure to the sarcopenic stimulus."
38. ID: 42587787 - Application: RNA exosome as epigenetic effector. - "We conclude that the exosome couples RNA decay to epigenetic state across the lifespan, positioning RNA surveillance as an emerging therapeutic target."
39. ID: 42579361 - Application: KDM4C in AML. - "The study supports KDM4C inhibition as a potential therapeutic strategy for TP53-mutated AML, particularly in patients receiving NK cell-based immunotherapy or undergoing allo-HSCT."
40. ID: 42568976 - Application: Piroxicam DFU healing. - "Piroxicam's protection of mitochondrial function and suppression of oxidative stress was also abolished upon blocking ERα by tamoxifen."
41. ID: 42516952 - Application: Exerkine-mediated myocardial rejuvenation. - "We propose that targeting the bimodal SkM-EV axis will accelerate the development of EV-based liquid biopsies for sarcopenic cardiomyopathy and pioneer cell-free "exercise mimetics" for frail, exercise-intolerant aging populations."
42. ID: 42511674 - Application: Candidate markers for sarcopenia. - "Among the candidate biomarkers, GDF-15, FGF-21, IL-6, TNF-α, CAF22, p16INK4a, p21/CDKN1A, IGF-1, and myostatin appear particularly promising for characterizing the biological heterogeneity of sarcopenia."
43. ID: 42462036 - Application: TRM efferocytosis and aging. - "Reducing TRM EP2 signaling in aged mice preserved youthful mitochondrial fitness and prevented cognitive decline, frailty, sarcopenia, adiposity, cardiac impairment, and systemic inflammation."
44. ID: 42402137 - Application: MC1 lifespan extension. - "MC1 significantly extends the lifespan of Caenorhabditis elegans, accompanied by an improvement in muscle strength and physiological functions."
45. ID: 42370191 - Application: Dual role of senescent cells. - "These senescent features may exert both detrimental and beneficial effects on tissue homeostasis and systemic physiological integrity."
46. ID: 42344418 - Application: Molecular intersections of DKD and sarcopenia. - "These genes were mainly primarily found to be associated with oxygen and hypoxia response, energy metabolism, peptide hormone signaling, protein phosphorylation regulation, growth factor activity, insulin receptor binding, PI3K-Akt signaling, MAPK signaling, AGE-RAGE signaling in diabetic complications, FoxO signaling, HIF-1 signaling, diabetic cardiomyopathy, and cellular senescence."
47. ID: 42025545 - Application: Sesamin in high-fat diet models. - "Sesamin bound STING with high affinity, inhibited cGAS-STING activation, restored insulin signaling, improved glucose uptake, and enhanced mitochondrial respiratory function."
48. ID: 42348390 - Application: Senolytics in ACL-induced injury. - "Clearance of senescent cells using the senolytic dasatinib and quercetin (D + Q) mitigated injury-induced muscle atrophy and cartilage degradation, with greater senescent cell clearance within muscle compared with cartilage."
49. ID: 42646271 - Application: BIA-derived phase angle correlation. - "BIA-derived phase angle constitutes a macroscopic electrobiological correlate of inflammaging: low phase angle values in visceral obese subjects overlap with those of frail elderly individuals, reflecting impaired membrane integrity, loss of active cell mass, and altered ICW/ECW balance."
50. ID: 42613625 - Application: SLC25A12 mitochondrial protection. - "SLC25A12 expression ameliorates myoblast senescence and mitochondrial dysfunction, while also attenuating cuproptosis-related changes under copper stress."



## Logical Systems Map (Logical Gates)
- "Mitochondrial dysfunction" -> "DNA, Mitochondrial"
- "DNA, Mitochondrial" -> "cGAS-STING signaling"
- "cGAS-STING signaling" -> "Cellular Senescence"
- "STING Agonist" -> "Muscle, Skeletal"

## Verified Verbatim Quotes
- "Senolytic treatment reduced overall senescent cell burden, attenuated macrophage accumulation, and restored muscle mass and function in aged mice following disuse."
- "In this study, it was found that microgravity simulated by Rotating Flat Chamber induced MSC senescence and promoted the expression of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING), and C176, a STING inhibitor, alleviated the rotating culture-induced MSC senescence."
- "JTG benefits for alleviating aging conditions of skeletal muscle by maintaining mitochondrial homeostasis, thus, effectively ameliorates age-related sarcopenia by blocking the cGAS-STING signaling pathway."
- "Pretreatment with the STING agonist DMXAA exacerbated cisplatin-induced body weight loss and skeletal muscle atrophy. In contrast, genetic deletion of cGAS or STING attenuated the loss of gastrocnemius and tibialis anterior muscle mass."
- "Mechanistically, LINE-1-derived cytoplasmic DNA activates the cGAS-STING innate immune pathway in post-mitotic neurons, and inhibition of cGAS phenocopies the effects of LINE-1 suppression."
- "Ginkgetin-mediated cyclic GMP-AMP-synthase-stimulator of interferon genes (cGAS-STING) inhibition was identified as a mechanistically novel target within natural senotherapy."
- "The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway, a central sensor of cytosolic DNA, plays a critical role in mediating innate immune responses."
- "Unexpectedly, we found that cGAS KO mice exhibit an accelerated-aging phenotype, with induction of inflammation in multiple organs."
- "EDB treatment notably decreased the expression of senescence markers (p16/p21/p53). Mechanistic studies revealed that EDB not only alleviated oxidative stress but also inhibited the cGAS-STING-mediated innate immune signaling pathway."
- "CCND1 and its kinase partner CDK6 drive SASP and ISG expression in senescent cells by promoting DNA damage accumulation. This leads to the formation of cytoplasmic chromatin fragments that activate pro-inflammatory cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling."
- "The accumulation of senescent cells drives age-related diseases, and their removal (senolysis) has been reported to ameliorate pathological aging phenotypes."
- "Pharmacological blockade of individual nodes within this signaling cascade significantly reversed 6-shogaol-induced senescence and blunted its anti-activation effect in LX-2 cells."
- "Targeting the PRELP-HDAC2 axis may represent a potential therapeutic strategy for COPD-related SMD."
- "Knockdown of GPR81 in young healthy myoblasts led to an increase in senescence hallmarks such as DNA damage, accumulation of reactive oxygen species (ROS), impaired mitochondrial activity, and autophagy."
- "This study demonstrates that GRo targets the pathological mechanisms underlying age-related muscle degeneration by regulating oxidative stress, inflammatory responses, metabolic processes, and gut microbiota homeostasis."
- "R527C pathogenic variant disrupted the interaction between Lamin A and DNA-binding proteins, causing abnormal protein aggregation and hyperactivation of the cGAS-STING."
- "Mechanistically, IL-35 signaled through the glycoprotein 130 (GP130) receptor to activate the cGAS-STING-TBK1-IRF3 pathway, leading to upregulated senescence markers (p16, p21, p53)."
- "The principal accounting identity states that coupled repair reserve equals material-repair closure plus regulatory-interface closure minus cross-hallmark obstruction rank."
- "The release of mitochondrial DNA into the cytoplasm activated the cGAS-STING signaling pathway. The subsequent oxidative stress-inflammatory cascade drove ovarian cellular senescence."
- "LCCPs induce excessive mitochondrial fission by blocking the interaction between Drp1 and Parkin, leading to the leakage of mitochondrial DNA into the cytoplasm, which in turn activates the cGAS-STING pathway and ultimately drives granulosa cell senescence."
- "The functional significance of this pathway was confirmed, as the STING agonist DMXAA abolished the polarizing effects of CTSB silencing."
- "Senolytics, NAD⁺ replenishment, SIRT1 activators, mitophagy inducers, anti-myostatin medicines, and exosome-based therapies shift metabolic care towards senescence."
- "TRF2 also inhibited activation of the cGAS/STING pathway by increasing mitophagy during H/Post in aged myocardiocytes."
- "Single-nucleus analysis of 97,154 nuclei from 17 donors showed broad TPT1 expression across myonuclear, satellite-cell, stromal, endothelial, and immune compartments, with lower expression in older muscle."
- "FMN alleviates age-related sarcopenia by targeting mitochondrial function and ferroptosis, providing potential targets for sarcopenia treatment."
- "Molecular analyses suggested activation of the FOXO1-MuRF-1/Atrogin-1 pathway and changes consistent with ferroptosis-related signaling."
- "In aged diabetic rats, vitamin D deficiency aggravated hyperglycemia, insulin resistance, intramuscular lipid accumulation, and muscle senescence, whereas vitamin D3 supplementation improved muscle strength, myofiber cross-sectional area, and lipid infiltration."
- "JTG benefits for alleviating aging conditions of skeletal muscle by maintaining mitochondrial homeostasis, thus, effectively ameliorates age-related sarcopenia by blocking the cGAS-STING signaling pathway."
- "Senolytic treatment reduced overall senescent cell burden, attenuated macrophage accumulation, and restored muscle mass and function in aged mice following disuse."
- "Pretreatment with the STING agonist DMXAA exacerbated cisplatin-induced body weight loss and skeletal muscle atrophy. In contrast, genetic deletion of cGAS or STING attenuated the loss of gastrocnemius and tibialis anterior muscle mass."
- "Notably, pharmacological blockade of STING by H-151 partially phenocopied the protective effects of RLX-2, suggesting a coordinated regulation of fibrosis and senescence."
- "The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway, a central sensor of cytosolic DNA, plays a critical role in mediating innate immune responses."
- "In this study, it was found that microgravity simulated by Rotating Flat Chamber induced MSC senescence and promoted the expression of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING), and C176, a STING inhibitor, alleviated the rotating culture-induced MSC senescence."
- "Mechanistically, LINE-1-derived cytoplasmic DNA activates the cGAS-STING innate immune pathway in post-mitotic neurons, and inhibition of cGAS phenocopies the effects of LINE-1 suppression."
- "Ginkgetin-mediated cyclic GMP-AMP-synthase-stimulator of interferon genes (cGAS-STING) inhibition was identified as a mechanistically novel target within natural senotherapy."
- "Unexpectedly, we found that cGAS KO mice exhibit an accelerated-aging phenotype, with induction of inflammation in multiple organs."
- "EDB treatment notably decreased the expression of senescence markers (p16/p21/p53). Mechanistic studies revealed that EDB not only alleviated oxidative stress but also inhibited the cGAS-STING-mediated innate immune signaling pathway."
- "CCND1 and its kinase partner CDK6 drive SASP and ISG expression in senescent cells by promoting DNA damage accumulation. This leads to the formation of cytoplasmic chromatin fragments that activate pro-inflammatory cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling."
- "The accumulation of senescent cells drives age-related diseases, and their removal (senolysis) has been reported to ameliorate pathological aging phenotypes."
- "Pharmacological blockade of individual nodes within this signaling cascade significantly reversed 6-shogaol-induced senescence and blunted its anti-activation effect in LX-2 cells."
- "Targeting the PRELP-HDAC2 axis may represent a potential therapeutic strategy for COPD-related SMD."
- "Knockdown of GPR81 in young healthy myoblasts led to an increase in senescence hallmarks such as DNA damage, accumulation of reactive oxygen species (ROS), impaired mitochondrial activity, and autophagy."
- "This study demonstrates that GRo targets the pathological mechanisms underlying age-related muscle degeneration by regulating oxidative stress, inflammatory responses, metabolic processes, and gut microbiota homeostasis."
- "R527C pathogenic variant disrupted the interaction between Lamin A and DNA-binding proteins, causing abnormal protein aggregation and hyperactivation of the cGAS-STING."
- "Mechanistically, IL-35 signaled through the glycoprotein 130 (GP130) receptor to activate the cGAS-STING-TBK1-IRF3 pathway, leading to upregulated senescence markers (p16, p21, p53)."
- "The principal accounting identity states that coupled repair reserve equals material-repair closure plus regulatory-interface closure minus cross-hallmark obstruction rank."
- "The release of mitochondrial DNA into the cytoplasm activated the cGAS-STING signaling pathway. The subsequent oxidative stress-inflammatory cascade drove ovarian cellular senescence."
- "LCCPs induce excessive mitochondrial fission by blocking the interaction between Drp1 and Parkin, leading to the leakage of mitochondrial DNA into the cytoplasm, which in turn activates the cGAS-STING pathway and ultimately drives granulosa cell senescence."
- "The functional significance of this pathway was confirmed, as the STING agonist DMXAA abolished the polarizing effects of CTSB silencing."
- "Senolytics, NAD⁺ replenishment, SIRT1 activators, mitophagy inducers, anti-myostatin medicines, and exosome-based therapies shift metabolic care towards senescence."
- "TRF2 also inhibited activation of the cGAS/STING pathway by increasing mitophagy during H/Post in aged myocardiocytes."
- "Single-nucleus analysis of 97,154 nuclei from 17 donors showed broad TPT1 expression across myonuclear, satellite-cell, stromal, endothelial, and immune compartments, with lower expression in older muscle."
- "FMN alleviates age-related sarcopenia by targeting mitochondrial function and ferroptosis, providing potential targets for sarcopenia treatment."
- "Molecular analyses suggested activation of the FOXO1-MuRF-1/Atrogin-1 pathway and changes consistent with ferroptosis-related signaling."
- "In aged diabetic rats, vitamin D deficiency aggravated hyperglycemia, insulin resistance, intramuscular lipid accumulation, and muscle senescence, whereas vitamin D3 supplementation improved muscle strength, myofiber cross-sectional area, and lipid infiltration."
- "These effects were associated with inhibition of the cGAS-STING pathway, as indicated by reduced 2',3'-cGAMP and HMGB1 levels."
- "Western blotting further confirmed that KSZZP dose-dependently suppressed the expression of key cGAS-STING pathway proteins (cGAS, STING) and downstream proteins associated with M1 polarization (iNOS, TNF-α, COX-2)."
- "Together, these findings define an mtDNA-driven pathogenic mechanism in autoimmune thyroiditis and identify STING as a potential therapeutic target."
- "This STING activation was essential, as its inhibition abolished the pro-senescent effect."
- "Hepatocyte-specific Ccnd1 knockout or treatment with the clinical grade CDK4/6 inhibitor palbociclib reduces DNA damage and ISGs in aged mouse liver."
- "Spatial transcriptomic analysis of human AD brain tissue further supports that senescent neurons with high LINE-1 expression are localized to inflammatory niches in the brain."
- "Mitochondrial dysfunction serves as a fundamental driver of the aging process, precipitating progressive functional decline through complex molecular cascades."
- "TRF2 improved myocardial I/Post protection in vivo."
- "Morphological analysis confirmed this protective effect, showing that treated myotubes maintained greater thickness and exhibited a larger cross-sectional area despite exposure to the sarcopenic stimulus."
- "We conclude that the exosome couples RNA decay to epigenetic state across the lifespan, positioning RNA surveillance as an emerging therapeutic target."
- "The study supports KDM4C inhibition as a potential therapeutic strategy for TP53-mutated AML, particularly in patients receiving NK cell-based immunotherapy or undergoing allo-HSCT."
- "Piroxicam's protection of mitochondrial function and suppression of oxidative stress was also abolished upon blocking ERα by tamoxifen."
- "We propose that targeting the bimodal SkM-EV axis will accelerate the development of EV-based liquid biopsies for sarcopenic cardiomyopathy and pioneer cell-free "exercise mimetics" for frail, exercise-intolerant aging populations."
- "Among the candidate biomarkers, GDF-15, FGF-21, IL-6, TNF-α, CAF22, p16INK4a, p21/CDKN1A, IGF-1, and myostatin appear particularly promising for characterizing the biological heterogeneity of sarcopenia."
- "Reducing TRM EP2 signaling in aged mice preserved youthful mitochondrial fitness and prevented cognitive decline, frailty, sarcopenia, adiposity, cardiac impairment, and systemic inflammation."
- "MC1 significantly extends the lifespan of Caenorhabditis elegans, accompanied by an improvement in muscle strength and physiological functions."
- "These senescent features may exert both detrimental and beneficial effects on tissue homeostasis and systemic physiological integrity."
- "These genes were mainly primarily found to be associated with oxygen and hypoxia response, energy metabolism, peptide hormone signaling, protein phosphorylation regulation, growth factor activity, insulin receptor binding, PI3K-Akt signaling, MAPK signaling, AGE-RAGE signaling in diabetic complications, FoxO signaling, HIF-1 signaling, diabetic cardiomyopathy, and cellular senescence."
- "JTG benefits for alleviating aging conditions of skeletal muscle by maintaining mitochondrial homeostasis, thus, effectively ameliorates age-related sarcopenia by blocking the cGAS-STING signaling pathway."
- "Pretreatment with the STING agonist DMXAA exacerbated cisplatin-induced body weight loss and skeletal muscle atrophy. In contrast, genetic deletion of cGAS or STING attenuated the loss of gastrocnemius and tibialis anterior muscle mass."
- "Notably, pharmacological blockade of STING by H-151 partially phenocopied the protective effects of RLX-2, suggesting a coordinated regulation of fibrosis and senescence."
- "The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway, a central sensor of cytosolic DNA, plays a critical role in mediating innate immune responses."
- "In this study, it was found that microgravity simulated by Rotating Flat Chamber induced MSC senescence and promoted the expression of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING), and C176, a STING inhibitor, alleviated the rotating culture-induced MSC senescence."
- "Mechanistically, LINE-1-derived cytoplasmic DNA activates the cGAS-STING innate immune pathway in post-mitotic neurons, and inhibition of cGAS phenocopies the effects of LINE-1 suppression."
- "Ginkgetin-mediated cyclic GMP-AMP-synthase-stimulator of interferon genes (cGAS-STING) inhibition was identified as a mechanistically novel target within natural senotherapy."
- "Unexpectedly, we found that cGAS KO mice exhibit an accelerated-aging phenotype, with induction of inflammation in multiple organs."
- "EDB treatment notably decreased the expression of senescence markers (p16/p21/p53). Mechanistic studies revealed that EDB not only alleviated oxidative stress but also inhibited the cGAS-STING-mediated innate immune signaling pathway."
- "CCND1 and its kinase partner CDK6 drive SASP and ISG expression in senescent cells by promoting DNA damage accumulation. This leads to the formation of cytoplasmic chromatin fragments that activate pro-inflammatory cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling."
- "The accumulation of senescent cells drives age-related diseases, and their removal (senolysis) has been reported to ameliorate pathological aging phenotypes."
- "Pharmacological blockade of individual nodes within this signaling cascade significantly reversed 6-shogaol-induced senescence and blunted its anti-activation effect in LX-2 cells."
- "Targeting the PRELP-HDAC2 axis may represent a potential therapeutic strategy for COPD-related SMD."
- "Knockdown of GPR81 in young healthy myoblasts led to an increase in senescence hallmarks such as DNA damage, accumulation of reactive oxygen species (ROS), impaired mitochondrial activity, and autophagy."
- "This study demonstrates that GRo targets the pathological mechanisms underlying age-related muscle degeneration by regulating oxidative stress, inflammatory responses, metabolic processes, and gut microbiota homeostasis."
- "R527C pathogenic variant disrupted the interaction between Lamin A and DNA-binding proteins, causing abnormal protein aggregation and hyperactivation of the cGAS-STING."
- "Mechanistically, IL-35 signaled through the glycoprotein 130 (GP130) receptor to activate the cGAS-STING-TBK1-IRF3 pathway, leading to upregulated senescence markers (p16, p21, p53)."
- "The principal accounting identity states that coupled repair reserve equals material-repair closure plus regulatory-interface closure minus cross-hallmark obstruction rank."
- "The release of mitochondrial DNA into the cytoplasm activated the cGAS-STING signaling pathway. The subsequent oxidative stress-inflammatory cascade drove ovarian cellular senescence."
- "LCCPs induce excessive mitochondrial fission by blocking the interaction between Drp1 and Parkin, leading to the leakage of mitochondrial DNA into the cytoplasm, which in turn activates the cGAS-STING pathway and ultimately drives granulosa cell senescence."
- "The functional significance of this pathway was confirmed, as the STING agonist DMXAA abolished the polarizing effects of CTSB silencing."
- "Senolytics, NAD⁺ replenishment, SIRT1 activators, mitophagy inducers, anti-myostatin medicines, and exosome-based therapies shift metabolic care towards senescence."
- "TRF2 also inhibited activation of the cGAS/STING pathway by increasing mitophagy during H/Post in aged myocardiocytes."
- "Single-nucleus analysis of 97,154 nuclei from 17 donors showed broad TPT1 expression across myonuclear, satellite-cell, stromal, endothelial, and immune compartments, with lower expression in older muscle."
- "FMN alleviates age-related sarcopenia by targeting mitochondrial function and ferroptosis, providing potential targets for sarcopenia treatment."
- "Molecular analyses suggested activation of the FOXO1-MuRF-1/Atrogin-1 pathway and changes consistent with ferroptosis-related signaling."
- "In aged diabetic rats, vitamin D deficiency aggravated hyperglycemia, insulin resistance, intramuscular lipid accumulation, and muscle senescence, whereas vitamin D3 supplementation improved muscle strength, myofiber cross-sectional area, and lipid infiltration."
- "These effects were associated with inhibition of the cGAS-STING pathway, as indicated by reduced 2',3'-cGAMP and HMGB1 levels."
- "Western blotting further confirmed that KSZZP dose-dependently suppressed the expression of key cGAS-STING pathway proteins (cGAS, STING) and downstream proteins associated with M1 polarization (iNOS, TNF-α, COX-2)."
- "Together, these findings define an mtDNA-driven pathogenic mechanism in autoimmune thyroiditis and identify STING as a potential therapeutic target."
- "This STING activation was essential, as its inhibition abolished the pro-senescent effect."
- "Hepatocyte-specific Ccnd1 knockout or treatment with the clinical grade CDK4/6 inhibitor palbociclib reduces DNA damage and ISGs in aged mouse liver."
- "Spatial transcriptomic analysis of human AD brain tissue further supports that senescent neurons with high LINE-1 expression are localized to inflammatory niches in the brain."
- "Mitochondrial dysfunction serves as a fundamental driver of the aging process, precipitating progressive functional decline through complex molecular cascades."
- "TRF2 improved myocardial I/Post protection in vivo."
- "Morphological analysis confirmed this protective effect, showing that treated myotubes maintained greater thickness and exhibited a larger cross-sectional area despite exposure to the sarcopenic stimulus."
- "We conclude that the exosome couples RNA decay to epigenetic state across the lifespan, positioning RNA surveillance as an emerging therapeutic target."
- "The study supports KDM4C inhibition as a potential therapeutic strategy for TP53-mutated AML, particularly in patients receiving NK cell-based immunotherapy or undergoing allo-HSCT."
- "Piroxicam's protection of mitochondrial function and suppression of oxidative stress was also abolished upon blocking ERα by tamoxifen."
- "We propose that targeting the bimodal SkM-EV axis will accelerate the development of EV-based liquid biopsies for sarcopenic cardiomyopathy and pioneer cell-free "exercise mimetics" for frail, exercise-intolerant aging populations."
- "Among the candidate biomarkers, GDF-15, FGF-21, IL-6, TNF-α, CAF22, p16INK4a, p21/CDKN1A, IGF-1, and myostatin appear particularly promising for characterizing the biological heterogeneity of sarcopenia."
- "Reducing TRM EP2 signaling in aged mice preserved youthful mitochondrial fitness and prevented cognitive decline, frailty, sarcopenia, adiposity, cardiac impairment, and systemic inflammation."
- "MC1 significantly extends the lifespan of Caenorhabditis elegans, accompanied by an improvement in muscle strength and physiological functions."
- "These senescent features may exert both detrimental and beneficial effects on tissue homeostasis and systemic physiological integrity."
- "These genes were mainly primarily found to be associated with oxygen and hypoxia response, energy metabolism, peptide hormone signaling, protein phosphorylation regulation, growth factor activity, insulin receptor binding, PI3K-Akt signaling, MAPK signaling, AGE-RAGE signaling in diabetic complications, FoxO signaling, HIF-1 signaling, diabetic cardiomyopathy, and cellular senescence."
- "Clearance of senescent cells using the senolytic dasatinib and quercetin (D + Q) mitigated injury-induced muscle atrophy and cartilage degradation, with greater senescent cell clearance within muscle compared with cartilage."
- "BIA-derived phase angle constitutes a macroscopic electrobiological correlate of inflammaging: low phase angle values in visceral obese subjects overlap with those of frail elderly individuals, reflecting impaired membrane integrity, loss of active cell mass, and altered ICW/ECW balance."
- "SLC25A12 expression ameliorates myoblast senescence and mitochondrial dysfunction, while also attenuating cuproptosis-related changes under copper stress."
- "Sesamin bound STING with high affinity, inhibited cGAS-STING activation, restored insulin signaling, improved glucose uptake, and enhanced mitochondrial respiratory function."