Genetic basis of enhanced stress resistance in long-lived mutants highlights key role of innate immunity in determining longevity
Bibliographic record
Abstract
ABSTRACT Mutations that extend lifespan are associated with enhanced resistance to stress. To better understand the molecular mechanisms underlying this relationship, we studied nine long-lived C. elegans mutants representative of different pathways of lifespan extension. We directly compared the magnitude of their lifespan extension and their ability to resist various external stressors (heat, oxidative stress, bacterial pathogens, osmotic stress, and anoxia). Furthermore, we analysed gene expression in each of these mutants to identify genes and pathways responsible for the enhanced resistance to stress. All of the examined long-lived mutants have increased resistance to one or more type of stress. Resistance to each of the examined types of stress had a significant, positive correlation with lifespan, with bacterial pathogen resistance showing the strongest relationship. All of the examined long-lived mutants have significant upregulation of multiple stress response pathways but differ in which stress response pathway has the greatest enrichment of genes. We used RNA sequencing data to identify which genes are most highly correlated with each type of stress resistance. There was a highly significant overlap between genes highly correlated with stress resistance, and genes highly correlated with longevity, suggesting that the same genetic pathways drive both phenotypes. This was especially true for genes correlated with bacterial pathogen resistance, which showed an 84% overlap with genes correlated with lifespan. Overall, our results demonstrate a strong correlation between stress resistance and longevity that results from the high degree of overlap in genes contributing to each phenotype. SIGNIFICANCE STATEMENT While increased resistance to stress has been correlated with longevity, the genetic basis for this relationship is incompletely understood. To advance our understanding of the relationship between stress resistance and lifespan, we measured lifespan, stress resistance and gene expression in a panel of nine long-lived mutants in C. elegans . All of the long-lived mutants exhibit enhanced resistance to at least one external stressor resulting from significant upregulation of multiple stress response pathways. Importantly, our data indicates that the same genetic pathways control stress resistance and lifespan, thereby accounting for the strong correlation between these two phenotypes. This work demonstrates the importance of innate immune signaling and other stress response pathways in determining longevity.
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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 | 0.001 |
| 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".