Project summary
Intervertebral disc degeneration (IDD) underlies many spinal disorders resulting in debilitating back
pain, disability, and tremendous economic loss. Aging is the greatest risk factor for IDD and yet the biology of
disc aging is still poorly understood. Our prior research demonstrated that persistent DNA damage promotes
senescent cells resulting in their acquisition of the senescence-associated secretory phenotype (SASP) that
produces copious inflammatory and catabolic factors that promote disc matrix loss, a universal feature of disc
aging and degeneration. While these findings greatly advance our understanding of disc aging, they also raise
important questions. Does cellular senescence mainly drive disc aging locally, systemically, or both? In other
words, do senescent disc cells with tissue-destroying SASP locally drive disc aging in a cell-autonomous
manner, or do senescent cells from other tissues systemically promote disc aging through the endocrine action
of their SASP and signaling factors through non-cell autonomous mechanisms? Moreover, which of the two
major cellular senescence pathways, p16INK4a or p21Cip1, predominantly drive the local cell-autonomous effects
and the systemic non-cell autonomous effects on disc aging? Based on our preliminary data, we hypothesize
that local effects of p21-mediated disc cellular senescence are only partially responsible for driving age
dependent IDD, and that contribution from p16-mediated systemic cellular senescence is necessary to
fully account for the observed disc aging phenotype. We propose three specific aims to test this
hypothesis using several innovative transgenic mouse strains: (1) Determine the relative contributions of local
(cell autonomous) and systemic (non-cell autonomous) processes in driving disc cellular senescence and age-
dependent IDD; (2) Determine the relative contributions of p21CIP1 and p16INK4a -mediated cellular senescence
on age-dependent IDD; and (3) Test whether senolytic treatment can slow age-dependent IDD. Completion of
the proposed studies will determine whether disc aging is driven predominantly by local or systemic processes
and whether these processes are mediated primarily through the p21Cip1 or p16INK4a cellular senescence
pathway. Finally, our proposed studies will identify novel senolytic drugs for treating and slowing age-
dependent IDD.
