High-throughput sequencing analysis of nuclear-encoded mitochondrial genes reveals a genetic signature of human longevity
Why this work is in the frame
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Bibliographic record
Abstract
Mitochondrial dysfunction is a well-known contributor to aging and age-related diseases. The precise mechanisms through which mitochondria impact human lifespan, however, remain unclear. We hypothesize that humans with exceptional longevity harbor rare variants in nuclear-encoded mitochondrial genes (mitonuclear genes) that confer resistance against age-related mitochondrial dysfunction. Here we report an integrated functional genomics study to identify rare functional variants in ~ 660 mitonuclear candidate genes discovered by target capture sequencing analysis of 496 centenarians and 572 controls of Ashkenazi Jewish descent. We identify and prioritize longevity-associated variants, genes, and mitochondrial pathways that are enriched with rare variants. We provide functional gene variants such as those in MTOR (Y2396Lfs*29), CPS1 (T1406N), and MFN2 (G548*) as well as LRPPRC (S1378G) that is predicted to affect mitochondrial translation. Taken together, our results suggest a functional role for specific mitonuclear genes and pathways in human longevity.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.001 |
| 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) | 0.000 | 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 it