Jaba Tkemaladze
The mother centriole does two things. In mitosis it builds the microtubule-organising centre — recruiting pericentriolar material, nucleating spindle microtubules, anchoring poles. In interphase it builds the primary cilium, the cell’s antenna for Hedgehog, Wnt and PDGF. Both jobs depend on the same scaffold: a microtubule barrel whose subunits, once incorporated, show almost no turnover. This scaffold accumulates damage with time. Carbonyl groups appear on lysine and arginine residues. 4-hydroxynonenal forms bulky adducts on cysteines and histidines. Asparagine and glutamine residues spontaneously deamidate. Because the scaffold does not renew, these modifications are not diluted. They build up. I argue that this accumulation progressively degrades both centriole functions, and that the degradation follows two paths depending on the cell. In quiescent stem cells, cilia shorten with centriole age, and the cell goes deaf to niche signals — Hedgehog fades, Wnt weakens, and the stem cell exhausts itself without ever receiving the command to divide. In proliferating cells, the same damage impairs the machinery that resorbs the cilium before mitosis; the cilium persists, the centrosome cannot mature, the spindle fails, and the cell senesces through AURKA-dependent arrest, as shown by Jeffries and colleagues. These are not competing mechanisms. They are two exits from the same process. A damaged centriole produces both outcomes; which one dominates depends on whether the cell spends more of its life in G0 or in cycle. I propose that the centriole is best understood not as a division organelle but as a physical ratchet of irreversible differentiation. Its state reflects how many asymmetric divisions a lineage has passed through. Its decay progressively narrows what a cell can become. Because centrioles are inherited asymmetrically in stem cell lineages, the damage burden of the older centriole functions as a clock that counts divisions independently of telomeres. No other organelle couples division fidelity to environmental sensing from a single, ageing-prone scaffold. This coupling, I suggest, makes centriole aging a substantial contributor to stem cell exhaustion — alongside telomere attrition, mitochondrial decline, and epigenetic drift — and a candidate driver of the tissue-level failures that define organismal aging.