Hypothesis

In aged somatic cells, supernumerary centrosomes are not merely clustered for survival; the intrinsic age difference between centrosomes creates a biased spindle that non‑randomly segregates chromosomes (and associated DNA damage) toward the daughter inheriting the older centrosome. This bias, amplified by KIFC1‑mediated clustering, fuels a gradual accumulation of damaged genomes in a subset of cells, driving senescence‑associated secretory phenotype (SASP) and tissue‑level decline. Consequently, inhibiting KIFC1 should (i) increase merotelic attachments specifically at old‑centrosome poles, (ii) exacerbate the segregation bias, and (iii) push damaged cells into apoptosis or senescence rather than allowing their survival through pseudo‑bipolar division.

Mechanistic Rationale

1. Centrosome age creates PCM asymmetry – older centrosomes (marked by cenexin‑Plk1) recruit more pericentrin, γ‑tubulin and Cdk5Rap2, generating a larger microtubule‑nucleating capacity 3.
2. Clustering forces the two pole‑like masses together – KIFC1 bundles microtubules from amplified centrosomes into a pseudo‑bipolar spindle 4. When the clustered mass contains a mix of old and new centrosomes, the stronger nucleation activity of the old centrosomes skews microtubule density toward that side of the spindle.
3. Merotelic attachments arise preferentially at the denser pole – higher microtubule density increases the chance that a kinetochore captures microtubules from both poles, producing merotelic configurations that lag during anaphase 2. Because the old‑centrosome side is denser, merotelic errors are biased toward chromosomes destined for the old‑centrosome daughter.
4. Non‑random segregation of damaged DNA – lagging chromosomes often suffer missegregation or micronucleus formation, which can trigger DNA‑sensing pathways (cGAS‑STING) and senescence. Thus, the old‑centrosome daughter inherits a higher load of DNA damage, reinforcing a senescent state and SASP.
5. p53 context – in non‑transformed cells p53 limits clonal expansion of centrosome‑amplified cells 1. However, p53‑dependent senescence can be exacerbated by the damage bias, while p53 loss would allow the damaged progeny to persist, potentially promoting oncogenesis.

Testable Predictions

• Prediction 1: In aged human fibroblasts, fluorescence‑labeling of old (cenexin‑Plk1 positive) vs new centrosomes will show a statistically significant enrichment of lagging chromosomes and micronuclei in the old‑centrosome daughter after nocodazole wash‑out, compared with young cells.
• Prediction 2: Treating aged cells with a KIFC1 inhibitor (e.g., SR31527) will increase the proportion of merotelic attachments specifically at old‑centrosome poles (detected by CREST‑staining and kinetochore‑microtubule co‑localization) and reduce the viability of old‑centrosome daughters (measured by live‑cell death reporters).
• Prediction 3: In p53‑wildtype aged cells, KIFC1 inhibition will shift the fate of damaged cells from senescence (SA‑β‑gal positive) toward apoptosis (caspase‑3 activation), whereas in p53‑null cells the same treatment will increase multinucleated, inviable progeny.
• Prediction 4: RNA‑seq of sorted old‑centrosome daughters will reveal upregulation of SASP cytokines (IL‑6, IL‑8) relative to new‑centrosome daughters, an effect amplified by KIFC1 inhibition.

Falsifiability

If any of the above measurements fail to show the predicted bias (e.g., lagging chromosomes distribute equally between daughters, or KIFC1 inhibition does not alter merotelic attachment polarity), the hypothesis would be falsified. Conversely, consistent support across multiple cell types and conditions would substantiate the model that centrosome age asymmetry, acting through KIFC1‑dependent clustering, directs non‑random chromosome segregation and promotes age‑related tissue dysfunction.

Broader Impact

Linking centrosome age to selective chromosome segregation provides a mechanistic bridge between cellular centrosome amplification, chromosomal instability, and organismal aging. It also suggests that therapeutic KIFC1 inhibition could be tuned to either eliminate damaged aged cells (by pushing them into apoptosis) or, in cancer contexts, to exacerbate CIN‑induced cell death, depending on the p53 status of the target tissue.