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The intervertebral disc is the largest avascular organ in the body, and degeneration is suspected to be linked to nutritional deficiencies. Autophagy, the process through which cells self\u2010digest and recycle damaged components, is an important cell survival mechanism under stress conditions, especially nutrient deprivation. Autophagy is negatively controlled by the mammalian target of rapamycin (mTOR) signaling pathway. mTOR is a serine\/threonine kinase that detects nutrient availability to trigger the activation of cell growth and protein synthesis pathways. Thus, resident disc cells may utilize autophagy and mTOR signaling to cope with harsh low\u2010nutrient conditions, such as low glucose, low oxygen, and low pH. We performed rabbit and human disc cell and tissue studies to elucidate the involvement and roles played by autophagy and mTOR signaling in the intervertebral disc. In vitro serum and nutrient deprivation studies resulted in decreased disc cell proliferation and metabolic activity and increased apoptosis and senescence, in addition to increased autophagy. The selective RNA interference\u2010mediated and pharmacological inhibition of mTOR complex 1 (mTORC1) was protective against inflammation\u2010induced disc cellular apoptosis, senescence, and extracellular matrix catabolism, through the induction of autophagy and the activation of the Akt\u2010signaling network. Although temsirolimus, a rapamycin derivative with improved water solubility, was the most effective mTORC1 inhibitor tested, dual mTOR inhibitors, capable of blocking multiple mTOR complexes, did not rescue disc cells. In vivo, high levels of mTOR\u2010signaling molecule expression and phosphorylation were observed in human intermediately degenerated discs and decreased with age. A mechanistic understanding of autophagy and mTOR signaling can provide a basis for the development of biological therapies to treat degenerative disc disease.<\/jats:p>","DOI":"10.1002\/jsp2.1082","type":"journal-article","created":{"date-parts":[[2020,2,18]],"date-time":"2020-02-18T14:08:40Z","timestamp":1582034920000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":80,"title":["Autophagy and mTOR signaling during intervertebral disc aging and degeneration"],"prefix":"10.1002","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3007-361X","authenticated-orcid":false,"given":"Takashi","family":"Yurube","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery Kobe University Graduate School of Medicine  Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaaki","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Kobe 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