Mutation in IR or IGF1R produces features of long-lived mice while maintaining metabolic health
Bibliographic record
Abstract
Insulin/insulin growth factor signaling is a conserved pathway that regulates lifespan. However, long-lived loss-of-function mutants often produce insulin resistance, slow growth, and impair reproduction. Recently, a gain-of-function mutation in the kinase insert domain (KID) of the Drosophila insulin/IGF receptor was seen to dominantly extend lifespan without impairing insulin sensitivity, growth, or reproduction. This substitution occurs within residues conserved in mammalian insulin receptor (IR) and insulin growth factor-1 receptor (IGF-1R). We produced 2 knock-in mouse strains that carry the homologous KID Arg/Cys substitution in murine IR or IGF-1R, and we replicated these genotypes in human cells. Cells with heterodimer receptors of IR or IGF-1R induce receptor phosphorylation and phospho-Akt when stimulated with insulin or IGF. Heterodimer receptors of IR fully induce pERK, but ERK was less phosphorylated in cells with IGF-1R heterodimers. Adults with a single KID allele (producing heterodimer receptors) have normal growth and glucose regulation. At 4 months, these mice variably display hormonal markers that associate with successful aging counteraction, including elevated adiponectin and FGF21, as well as reduced leptin and IGF-1. Livers of IGF-1R females show decreased transcriptome-based biological age, which may point toward delayed aging and warrants an actual lifespan experiment. These data suggest that KID mutants may slow mammalian aging while they avoid the complications of insulin resistance.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.006 | 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".