Abstract 376: Downregulation of Endogenous Apelinergic Axis Mediates Endothelial and Organismal Senescence
Bibliographic record
Abstract
Background: Apelinergic signaling is a recently discovered GPCR mediated pathway. Endothelial cells are the main source of endogenous apelin (apln) while apelin receptor (aplnr) is present on multiple cell types. Since the role of endogenous apelinergic pathway within the context of senescence is largely unknown, we ask if levels of apln- aplnr vary with aging. We also investigate the effects of downregulated apln- aplnr on cellular and organismal aging. Approach and Results: To assess variations in endogenous apln- aplnr with aging, we compared their levels in 1 month (young) and 1 year old (old) WT mice. We noticed significant downregulation of apln- aplnr with chronological senescence in multiple tissues. Expression of apelin was also reduced with replicative senescence of endothelial cells. L-NAME administration, a model of stress induced senescence, also repressed aortic and cardiac apln. To address the mechanism involved in downregulation of apln- aplnr, we administered young wild type mice with Ang II. After a week of Ang II, there was significant downregulation of aortic apln and aplnr. Ang II and TGF-β also repressed apln and aplnr in vitro . Next we investigated the effects of downregulated apln on endothelial cells. In response to shRNA mediated apelin knockdown, cells exhibited slower proliferation and upregulated senescence associated markers. We observed similar results when endothelial aplnr was blocked with an antagonist, ML221. In addition, apln and aplnr deficient mice also exhibited features of cardiovascular aging, including ventricular hypertrophy and lower EF. Importantly, aplnr deficient mice at eight months of age were also hypertensive. Conclusion: We provide a systematic assessment of senescence associated variation in levels of apln- aplnr. We demonstrate the role of Ang II- TGF-β axis in downregulating apln- aplnr during chronological and stress induced senescence in vivo and in vitro . We propose a novel model of Ang II- TGF-β induced senescence. Where in, with aging Ang II and TGF-β repress endogenous apln- aplnr. Downregulation of endogenous apln- aplnr axis decreases beneficial “youthful” effects of apelin, resulting in endothelial dysfunction and accelerated organismal aging.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".