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Preprint WatchModerateOctober 12th, 2026

The Onset of Breathing at Birth Switches Off Regenerative Capacity

Song, X.; Cai, X.; Hegarty, S.; Speri, D.; Yasuda, M.; Donahue, R.; Stanicka, J.; Yan, T.; Mao, S.; Yang, S.; Chen, J.; Zhu, J.; Kiraly, J.; Chien, C.-H.; Kegeles, E.; Feng, D.; Stieger, K.; Yang, Z.; Zhang, Y.; Yellen, G.; Umemori, H.; Williams, P.; He, Z.

mTOR signaling in CNS neurons declines within minutes of birth, driven by CO2 exhalation and intracellular alkalinization acting through the AMPK-family kinase SNRK, and CO2 inhalation or Snrk deletion restores mTOR activity and enables axon regeneration in adult retinal ganglion cells.

Moderate contradiction

1 prior failure

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

The preprint makes a gain-of-function claim for mTOR activity in a regenerative setting, which is the opposite direction of travel from the single Claidex MTOR entry, an everolimus and erlotinib combination in metastatic pancreatic cancer stopped for futility (everolimus-erlotinib-mtor-egfr-pancreatic-cancer-phase2-futility-termination). The flag is raised because the shared target has a recorded efficacy failure, not because the two findings conflict. What transfers is the preprint's demonstration that mTOR output is set by an upstream physiological input, SNRK activity downstream of intracellular pH, which implies that pharmacological mTOR modulation is competing with a regulated set point rather than a fixed one.

Abstract excerpt

Many mammalian tissues, including the central nervous system (CNS), lose regenerative capacity in adulthood, but when and how this transition is initiated remains unclear. By monitoring mTOR activity, an evolutionarily conserved readout of cellular growth and intrinsic regenerative potential, we found that mTOR signaling declines within minutes after birth in murine CNS neurons and in other organs such as the heart and skeletal muscles. Focusing on retinal ganglion cells (RGCs), we show that this abrupt decline is driven primarily by CO2 exhalation following the onset of breathing after birth. Using real-time in vivo imaging of RGCs during the earliest postnatal period, we further discover that breathing-induced CO2 exhalation rapidly causes intracellular alkalinization, activates an AMPK-family kinase, SNF-related kinase (SNRK), which in turn suppresses mTOR signaling. Importantly, this process remains reversible in adulthood: CO2 inhalation or Snrk deletion restores mTOR activity in RGCs and enables robust regeneration of their axons after injury. Similar CO2 inhalation-induced mTOR reactivation occurs across multiple cell types and organs, suggesting a general mechanism by which breathing-associated CO2/pH signaling shapes the regenerative capacity across life and pointing to a potential CO2-based strategy for promoting tissue regeneration.

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This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.