A novel approach to high‐throughput discovery of anti‐aging drugs identifies lithocholic acid as a longevity‐extending compound
Bibliographic record
Abstract
Caloric restriction (CR) and dietary restriction (DR) extend life span across species and improve health by delaying the onset of age‐related diseases. All currently known anti‐aging drugs: 1) mimic numerous life‐extending and health‐improving effects of CR and DR without restricting caloric and nutrient intake; and 2) target two signaling pathways that are under the stringent control of calorie and/or nutrient availability. It was believed therefore that all longevity pathways are “adaptable” by nature because they modulate longevity only in response to certain changes in the extracellular and intracellular nutrient and energy status of an organism. However, it is possible that that some longevity pathways could be “constitutive” or “housekeeping” because they control longevity irrespective of calorie and/or nutrient availability. We designed a novel high‐throughput chemical genetic screen for drugs that increase the life span of yeast under CR by modulating such housekeeping longevity pathways and targeting lipid metabolism. Our screen identified lithocholic acid as one of such molecules. We revealed that this bile acid delays aging by suppressing lipid‐induced necrosis, attenuating mitochondrial fragmentation, altering oxidation‐reduction processes in mitochondria, enhancing resistance to oxidative and thermal stresses, suppressing mitochondria‐controlled apoptosis, and enhancing stability of nuclear and mitochondrial DNA. Supported by CIHR and NSERC of Canada.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".