Selective Segregation of Damaged Molecules Is the Universal Rule of Cellular Rejuvenation, and Centriolar Retention in Stem Cells Is Its Exception

Abstract

The hypothesis that centrioles function as division counters in replicative aging predicts that aging driven by centriolar damage requires (i) a population of dividing cells whose centrioles are propagated through mitosis and (ii) a somatic self-renewal system in which such propagation persists. Adult Caenorhabditis elegans violates both conditions: its soma is eutelic (a fixed ~959-cell count), somatic cells are essentially post-mitotic, and the soma does not regenerate whole tissues. Concurrently, centrioles are extensively and programmatically eliminated from most somatic cells during embryogenesis, persisting chiefly in the germline, in ciliated sensory neurons as basal bodies, and in a small number of mitotic cells. Nevertheless, C. elegans unambiguously ages. This natural experiment constitutes a falsification-tier observation for the strong version of the centriolar-counter hypothesis: centriole-based division counting cannot be the necessary or universal driver of organismal aging, because an aging organism exists that lacks both the counting substrate (propagated somatic centrioles) and the permissive architecture (somatic self-renewal). In mammals, by contrast, tissues are maintained by asymmetric stem-cell divisions in which the mother centriole is non-randomly inherited and retained by the self-renewing cell; this is precisely the configuration in which damage-accumulating centrioles could serve as a counter. We propose that the centriole is an organelle of irreversible differentiation whose preferential retention of the older centriole in the self-renewing daughter makes the stem-cell niche a local entropy sink—concentrating irreversible centriolar information against a background of organism-wide entropy export. We formalize the “renewal-gated centriolar counter” hypothesis, specify its falsifiable predictions, and identify the regenerating versus post-mitotic boundary as the variable that discriminates organisms and tissues in which centriolar counting can operate from those in which it cannot. Because post-mitotic neurons inactivate their centrioles, the mammalian brain behaves as a C. elegans-like compartment that ages by diffuse molecular accumulation—protein aggregates, oxidative and glycative damage, lipofuscin, mitochondrial dysfunction—rather than by centriolar counting. We explain what such compartments accumulate that ultimately proves lethal. We further unify these observations under a universal “red thread”: across prokaryotes and eukaryotes, dividing cells selectively segregate damaged molecules to one daughter and renew from low-entropy components in the other—this is the engine of rejuvenation in bacteria, yeast, and acentriolar planarians. The centriole is the singular exception—retained, accumulating, and non-exchangeable in the self-renewing stem cell—which converts an otherwise-renewable centriole-based lineage into an aging one.