Abstract
Whether disc aging is influenced by factors beyond its local environment is an important unresolved question. Here we performed heterochronic parabiosis in mice to study the effects of circulating factors in young and old blood on age-associated intervertebral disc degeneration. Compared to young isochronic pairs (Y-Y), young mice paired with old mice (Y-O) showed significant increases in levels of disc MMP-13 and ADAMTS4, aggrecan fragmentation, and histologic tissue degeneration, but negligible changes in cellular senescence markers (p16INK4a, p21Cip1). Compared to old isochronic pairs (O-O), old mice paired with young mice (O-Y) exhibited a significant decrease in expression of cellular senescence markers (p16, p21, p53), but only marginal decreases in the levels of disc MMP-13 and ADAMTS4, aggrecan fragmentation, and histologic degeneration. Thus, exposing old mice to young blood circulation greatly suppressed disc cellular senescence, but only slightly decreased disc matrix imbalance and degeneration. Conversely, exposing young mice to old blood accelerated their disc matrix imbalance and tissue degeneration, with little effects on disc cellular senescence. Thus, non-cell autonomous effects of circulating factors on disc cellular senescence and matrix homeostasis are complex and suggest that disc matrix homeostasis is modulated by systemic factors and not solely through local disc cellular senescence.
Highlights
Intervertebral disc degeneration (IDD) contributes to biomechanical dysfunction of the spine commonly associated with low back pain, resulting in tremendous socioeconomic burden [1, 2]
No significant changes in disc TNFα or IL-6 expression were observed between the young mice paired with old mice (Y-O) and Y-Y mice. These findings suggest that exposure to an old environment only had modest influences on disc cellular senescence, and the differential effects of old blood on expression of different senescenceassociated secretory phenotype (SASP) factors in young mice highlight the complex interaction between the disc tissue and its surrounding systemic environment
Leveraging heterochronic parabiosis models, we demonstrated that exposure to old blood greatly accelerates disc matrix degeneration in young mice
Summary
Intervertebral disc degeneration (IDD) contributes to biomechanical dysfunction of the spine commonly associated with low back pain, resulting in tremendous socioeconomic burden [1, 2]. Aged discs exhibit many degenerative changes; most notably progressive loss of matrix proteoglycan (PG) leading to dehydration, tissue fibrosis, depressurization in the nucleus pulposus (NP), and decreased disc height [8]. Age-dependent loss of disc PG results from matrix homeostatic imbalance caused by increased matrix PG catabolism and decreased PG anabolism [8, 9]. Disc matrix imbalance is caused by the progressive loss of functional disc cells, likely stemming from increased apoptosis and cellular senescence during the course of aging. Growing evidence indicates that disc cellular senescence is a key factor responsible for disc PG loss and deterioration of the disc associated with aging. The causative role of cellular senescence in driving disc PG loss and disc aging was recently demonstrated whereby clearance of senescent cells ameliorated age-associated IDD using mice [12]
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