Ablation of Sirtuin 1 Deacetylase Activity Induces Pulmonary Emphysema by Inducing Cellular Senescence and Disrupting Circadian Clock in Mice (P01-022-19)
Bibliographic record
Abstract
Sirtuin 1 (SIRT1), a NAD+-dependent protein/histone deacetylase has the capability to extend life span, delay aging, and prevent aging-related diseases. There are several reports showing that there is no significant decline in SIRT1 protein with age, indicating that SIRT1 protein levels alone may not reflect its deacetylase activity. We investigated the causal effect of systemic ablation of SIRT1 deacetylase activity on aging-related pulmonary disease development in mice. We used Sirt1y/y homozygous male mice carrying a point mutation (H355Y) that ablates the deacetylase activity, along with their wild type littermates (Sirt1+/+), and followed them for 6, 10 and 18 months of age. Sirt1y/y homozygous mice developed severe pulmonary emphysema at the ages of 6, 10 and 18 months, with the respective incidences of 33%, 100% and 100%, while the Sirt1+/+wild-type mice only developed emphysema (13% incidence) at 18 months of age. The development of emphysema in Sirt1y/y mice was accompanied with higher protein levels of matrix metalloproteinase (MMP)-2, MMP9, and tissue inhibitor of metalloproteinase-1, and ratio of cleaved/total anti-poly (ADP-ribose) polymerase. The ablation of SIRT1 activity significantly up-regulated mRNA expression of hypoxia-inducible factor-1α and retinoic acid receptor-b, while p21 protein and phosphorylated AMPK increased and phosphorylated ribosomal S6 decreased, suggesting the association of ablation of SIRT1 activity with cellular quiescence and senescence. Additionally, the lack of SIRT1 activity down-regulated the mRNA expression of circadian clock genes (BMAL1, NPAS2, CRY1, CRY2) in the lungs of Sirt1y/y mice, as compared with that of Sirt1+/+ mice. There were no inflammatory responses in the lungs (e.g., inflammatory cell infiltrations, mRNA expressions of IL-6 and TNFα) in Sirt1y/y homozygous mice compared to Sirt1+/+ mice. The lacking of SIRT1 enzymatic activity plays a major role in the susceptibility of organs to aging and pulmonary emphysema development by inducing cellular senescence and disrupting circadian clock genes. USDA/ARS (58-1950-0074) and NIFA/AFRI (2017-67017-26363).
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".