Spine Journal - 2026-06-09 - Journal Article
When aging becomes degeneration: Evidence from Metabolomics of Healthy Age-stratified organ-donor and degenerated lumbar discs.
Rajasekaran S, Tangavel C, Arunachalam D, Gurusamy G, Nayagam SM, Meena A, Anand SV
Topics
Key Takeaway
Untargeted UHPLC-MS/MS identified 831 significant metabolites (VIP >1) that distinguish physiological disc aging from degeneration, with degeneration specifically characterized by suppression of resolvins and disrupted sphingolipid metabolism rather than the oxidative drift seen in normal aging.
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Summary
This study compared untargeted metabolomic profiles of Pfirrmann grade I nucleus pulposus from 21 age-stratified organ donors (ages 20–30, 31–50, >50 years) against 40 degenerated discs (Pfirrmann grades III–V) from surgical specimens using UHPLC-MS/MS. Normal aging showed four sequential metabolic trends including progressive antioxidant decline, transient midlife antioxidant elevation, and sphingolipid accumulation with senescence markers in older discs. Degenerated discs exhibited a distinct profile: suppression of pro-resolving lipid mediators (resolvins, PGE2), disrupted sphingolipid metabolism, and reduced redox capacity, confirming degeneration as a pathobiological process separable from senescence.
Key Limitation
The cross-sectional design with only three age bins and no longitudinal sampling means the four metabolic trends in aging are inferred from between-subject comparisons rather than observed within individuals, making causal sequencing of metabolic events speculative.
Original Abstract
BACKGROUND
Aging and degeneration are biologically distinct processes in intervertebral discs, but are difficult to differentiate radiologically. Metabolomics reflects real-time biochemical activity, and age-stratified metabolomic profiling of normal and degenerated discs may identify preclinical degeneration and reveal molecular signatures distinguishing normal aging from degeneration.
PURPOSE
To characterize the metabolomic changes in the MRI-normal healthy lumbar intervertebral disc and compare them with degenerated discs to identify metabolomic signatures that differentiate normal aging from degeneration.
STUDY DESIGN AND SETTING
Comparative metabolomics study using human nucleus pulposus tissue from organ donors and surgical specimens, conducted at a tertiary spine care center and an affiliated research laboratory.
PATIENT SAMPLE
Nucleus pulposus tissue from 21 healthy organ donors (Pfirrmann grade I) was stratified by age: young (20-30 years), middle-aged (31-50 years), and old (>50 years), and compared with 40 degenerated discs (grades III-V) from surgical specimens.
OUTCOME MEASURES
Primary outcome measures included differential metabolite abundance (metabolites with Variable Importance in Projection [VIP] scores>1), pathway enrichment profiles, and identification of age-specific versus degeneration-specific metabolic signatures.
METHODS
Untargeted ultra-high performance liquid chromatography- tandem mass spectrometry (UHPLC-MS/MS) was performed in both positive and negative ionization modes. Metabolites were identified using Compound Discoverer v3.7, with reference to HMDB and KEGG. Statistical and pathway enrichment analyses were performed using MetaboAnalyst 6.0.
RESULTS
Untargeted UHPLC-MS/MS analysis revealed 831 significant metabolites (VIP >1), contributing to group separation in the partial least squares discriminant analysis (PLS-DA) model. Lipids and lipid-like molecules, especially sphingolipids, fatty acyls, and steroids, constituted 39%. MRI normal organ donor discs in progressive age periods demonstrated four distinct metabolic trends: (i) progressive decline of antioxidants (ubiquinone, glutathione, N-acetyl seretonin); (ii) increased oxidative/inflammatory markers (4-HNE, prostaglandin E₂ ethanolamide, N1-acetylspermidine); (iii) transient midlife antioxidant elevation; (4OH benozoic acid, 4OH phenylpyruvic acid); (iv) partial recovery in older discs (Hypoxanthine, Paraxanthine, CerP(d18:1/18:0)). In old-aged discs, accumulation of sphingolipids (sphingosine, ceramides) and redox drift indicated enhanced senescence and energy imbalance. Degenerated discs exhibited a different profile, characterized by the suppression of bioactive lipids, particularly resolvins, PGE2, and SOFAs, accompanied by disrupted sphingolipid metabolism and reduced redox capacity.
CONCLUSION
Distinct metabolomic signatures differentiate physiological aging from disc degeneration. Degeneration is characterized by disrupted sphingolipid and redox homeostasis, suggesting a pathobiological process beyond normal senescence. These data provide a metabolic framework for future translational studies to identify disc degeneration even at the preclinical stage and in therapeutic stratification.