Inducible muscle-specific deletion of Depdc5 in 27-month-old mice produced constitutive mTORC1 activation and a pronounced upregulation of inflammatory and immune-related transcripts alongside elevated TNF-α protein, without accompanying shifts in macrophage phenotype or capillary density. Dietary rapamycin partially normalized mTORC1 signaling and angiogenic gene expression but left the inflammatory signature intact. Sustained mTORC1 activity is therefore sufficient to add inflammatory burden to already-aged muscle, and suppressing the kinase late does not reliably remove it.
Key Points
- Constitutive mTORC1 activation drove inflammatory gene expression in aged muscle
- Rapamycin restored signaling partially but failed to suppress inflammation
- TNF-α rose without macrophage phenotype or capillary density changes
Longevity Analysis
Muscle is not a passive casualty of age-related inflammation; it can generate inflammatory signaling itself when nutrient-sensing pathways remain chronically switched on. The failure of late rapamycin to reverse the inflammatory transcripts, despite correcting the upstream signal, indicates that persistent overactivation leaves changes that outlast the stimulus — an argument for limiting chronic anabolic signaling early rather than attempting pharmacological correction after decades of excess. For anyone tracking muscle quality as a longevity metric, the relevant levers sit upstream in feeding patterns, protein timing, and loading that cycle mTORC1 rather than hold it open, with immune and vascular readouts interpreted alongside strength and mass.
Original published by Wiley Aging Cell, by Erik D. Marchant, Hanna Kalenta, Jacquelyn May, Zhao Lai, Adam B. Salmon, Blake B. Rasmussen .