Background

Aged somatic cells frequently exhibit centrosome amplification yet avoid p53‑mediated arrest, suggesting a tolerance mechanism that permits survival with extra centrosomes.Chronic centrosome amplification through elevated PLK4 does not initiate tumorigenesis in mice with intact p53 Tumor‑suppressor p53 eliminates cells with severe centrosome defects, but chronic low‑level amplification persists in aging tissues.Cellular aging is associated with both centrosome aberrations and increased chromosomal instability Cells cope by clustering supernumerary centrosomes into a bipolar spindle, a process that nonetheless generates merotelic attachments and chromosome mis‑segregation.Cells with supernumerary centrosomes avoid lethal multipolar divisions by clustering them into a bipolar arrangement, but this adaptation promotes chromosome mis‑segregation through merotelic kinetochore attachments during transient multipolar states Extra centrosomes exert unequal pulling forces on chromosomes, leading to aneuploidy even when cells divide bipolar The E3 ubiquitin ligase TRIM37 restrains centrosome over‑duplication by degrading Centrobin and blocking PLK4 condensates,TRIM37 controls stability of centrosomal proteins like Centrobin and prevents assembly of inactive PLK4 into protein condensates that recruit other centrosomal proteins and is required for growth arrest after PLK4 perturbation, partly independent of its ubiquitin activity.TRIM37 is required for growth arrest in response to PLK4 inhibition that causes either centrosome loss or amplification, and this occurs through mechanisms partially independent of its E3 ligase activity

Hypothesis

We propose that progressive loss of TRIM37 function during aging diminishes the fidelity of centrosome clustering, allowing transient multipolar spindle states that increase merotelic kinetochore attachments and thus chromosomal instability, even when the average centrosome number remains below the p53 activation threshold. In this model, TRIM37 decline does not raise centrosome number per se but worsens the quality of clustering, linking PLK4‑driven centrosome dynamics to age‑related aneuploidy without triggering p53‑dependent cell‑cycle arrest.

Testable Predictions

1. TRIM37 protein levels decline with age in multiple somatic tissues (e.g., liver, brain, muscle) and correlate inversely with the frequency of cells displaying lagging chromosomes or micronuclei, independent of centrosome number.
2. Acute knockdown of TRIM37 in young cells phenocopies the aged clustering defect, producing increased multipolar intermediates and higher rates of chromosome mis‑segregation, while centrosome number remains unchanged.
3. Restoring TRIM37 expression in aged cells rescues clustering fidelity and reduces aneuploidy, despite persistent PLK4 activity.
4. PLK4 inhibition in TRIM37‑deficient cells fails to induce growth arrest, confirming that the arrest pathway is uncoupled from centrosome number when clustering is defective.

Experimental Approach

• Quantify TRIM37 by immunoblot and immunofluorescence in young (3‑mo) versus aged (24‑mo) mouse tissues; correlate with centrosome number (pericentrin staining) and clustering metrics (percentage of cells with bipolar vs. multipolar spindle poles) using live‑cell imaging of centrin‑GFP.
• Induce TRIM37 loss via siRNA or CRISPRi in cultured fibroblasts; assess spindle morphology, kinetochore‑microtubule attachment errors (CREST staining), and chromosomal instability (micronucleus assay) after a brief PLK4 overexpression pulse.
• Rescue experiments: overexpress wild‑type TRIM37 (or a ligase‑dead mutant) in aged primary cells; measure whether clustering errors and aneuploidy revert.
• Functional readout: assess tissue‑level functional decline (e.g., hepatocyte proliferation capacity, neuronal electrophysiology) to link clustering defects to physiological aging.

If TRIM37 loss drives clustering‑dependent chromosomal instability without elevating centrosome number beyond the p53 checkpoint, this hypothesis reframes centrosome amplification in aging as a quality‑control problem rather than a quantity problem, offering a target for mitigating age‑related genomic instability.