Advanced science (Weinheim, Baden-Wurttemberg, Germany)Oct 28, 2026

Serine Metabolism Controlled by PHGDH in Spine Disc Cells May Be a Treatment Target for Disc Degeneration

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Oct 29, 2026

Abstract

The serine synthesis rate limiting enzyme PHGDH is markedly reduced in senescent nucleus pulposus cells during intervertebral disc degeneration.

Transcriptomic profiling indicates downregulation of the glycine-serine-threonine pathway in senescent nucleus pulposus cells.
Single cell RNA sequencing confirms decreased intracellular serine in aged rat tissues and degenerated human samples.
Silencing PHGDH or depriving serine leads to inhibited proliferation, increased senescence, and reduced matrix production in nucleus pulposus cells.
PHGDH deficiency is associated with lower levels of alpha-ketoglutarate, impacting histone modifications that silence Rap1b and activate mTORC1.
Serine starvation results in glutathione depletion, elevated reactive oxygen species, and increased apoptosis.
In vivo experiments show that PHGDH overexpression mitigates disc degeneration, while a diet lacking serine worsens the condition.

Simplified

Intervertebral disc degeneration (IVDD) is a major cause of low back pain, driven largely by nucleus pulposus cell (NPC) senescence under chronic hypoxia and nutrient stress. Serine metabolism regulates senescence, but its role in IVDD remains unclear. Here, transcriptomic profiling reveals that the glycine-serine-threonine pathway is downregulated in senescent NPCs, with marked reduction of the serine synthesis rate limiting enzyme PHGDH. This is confirmed by single cell RNA sequencing of human discs, aged rat tissues, and degenerated human samples, accompanied by decreased intracellular serine. PHGDH silencing or serine deprivation inhibits NPC proliferation, induces senescence, and suppresses matrix anabolism. Mechanistically, PHGDH deficiency lowers α ketoglutarate, impairing histone demethylation and increasing H3K27me3 occupancy at the Rap1b promoter, which silences Rap1b and activates mTORC1, thereby blocking autophagic flux. Additionally, serine starvation depletes glutathione, elevates ROS, and promotes apoptosis. In vivo, AAV mediated PHGDH overexpression alleviates puncture induced IVDD, while a serine deficient diet exacerbates degeneration. Collectively, we uncover a PHGDH/Rap1b/mTORC1/autophagy cascade linking serine deprivation to NPC senescence, and propose that restoring PHGDH or serine availability may be a viable strategy to combat age related disc degeneration.

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Serine Metabolism Controlled by PHGDH in Spine Disc Cells May Be a Treatment Target for Disc Degeneration

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