Omics approaches for discovery of natural anti‐aging and anti‐cancer compounds and defining mechanisms of their action
Bibliographic record
Abstract
Caloric restriction (CR) and dietary restriction (DR) extend lifespan across species and improve health by delaying the onset of age‐related diseases. All currently known anti‐aging chemical compounds (1) mimic lifespan‐extending and health‐improving effects of CR and DR without restricting caloric and nutrient intake; and (2) target 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 high‐throughput chemical genetic screen for compounds that increase the lifespan of yeast under CR by modulating such housekeeping pathways. Our screen identified lithocholic acid (LCA) as one of them. Using proteomics, lipidomics, metabolomics and cell biological approaches, we found that LCA delays aging by: (1) remodeling lipid metabolism in the endoplasmic reticulum, lipid droplets and peroxisomes ‐ thereby preventing liponecrotic programmed cell death caused by the age‐related accumulation of fatty acids; (2) remodeling the repertoire of mitochondrial membrane lipids ‐ thereby reducing the number of mitochondria, increasing their size, expanding their cristae, elevating the abundance of respiratory supercomplexes in the inner mitochondrial membrane, and altering the age‐related dynamics of changes in mitochondrial respiration, membrane potential and reactive oxygen species; (3) attenuating age‐related mitochondrial fragmentation ‐ thereby suppressing mitochondria‐controlled apoptosis; and (4) promoting “mitohormesis” through the activation of several stress response‐related processes in mitochondria. Our findings also imply that, in addition to its robust anti‐aging effect, LCA exhibits a potent and selective anti‐tumor effect in cultured human neuroblastoma, glioma, breast cancer and prostate cancer cells by activating both the intrinsic and extrinsic pathways of apoptotic death. Support or Funding Information 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 | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.003 | 0.003 |
| Bibliometrics | 0.003 | 0.003 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.003 | 0.002 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.005 | 0.002 |
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".