A novel anti‐aging compound extends longevity by remodeling neutral lipid metabolism
Bibliographic record
Abstract
We use yeast as a model to understand a mechanism linking longevity and lipid metabolism. Caloric restriction (CR) extends lifespan across species. We examined 1) the effect of CR and numerous mutations extending yeast lifespan on the spatiotemporal dynamics of the proteomes and lipidomes of organelles involved in neutral lipid metabolism, including the endoplasmic reticulum (ER), peroxisomes, and lipid droplets; and 2) the chronology of hallmark events of apoptotic and necrotic cell death pathways in various long‐lived yeast mutants impaired in neutral lipid metabolism. Our findings revealed that a calorie‐rich diet suppresses peroxisomal oxidation of fatty acids (FFA) that originate from neutral lipids synthesized in the ER and deposited within lipid droplets. The resulting age‐related accumulation of arrays of FFA within lipid droplets triggers a programmed necrotic cell death pathway. We designed a chemical genetic screen for small molecules that extend yeast longevity by altering neutral lipid metabolism. Our screen identified lithocholic acid (LCA) as one of such novel anti‐aging compounds. Using a combination of proteomic, lipidomic, metabolomic, and systems biological approaches, we established the mechanism underlying its life‐extending ability. We found that this bile acid remodels neutral lipid metabolism in the ER, lipid droplets, and peroxisomes, thereby postponing age‐related necrosis caused by the buildup of FFA. Our findings revealed two different ways for delaying aging by altering neutral lipid metabolism and thereby impairing the age‐related programmed necrotic death pathway. Supported by 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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".