Naomi Dirckx, Ph.D.

ABSTRACT

Age-related skeletal fragility is a leading cause of disability and death in older adults — one-year mortality after hip fracture approaches 20–40% — yet current therapies focus almost entirely on bone mineral density, even though most fractures occur in people who do not meet densitometric criteria for osteoporosis. This project targets “bone quality,” the tissue-level material properties that determine fracture resistance, through the sodium-citrate transporter SLC13A5. Citrate is a structural component of hydroxyapatite that governs crystal morphology and mechanical strength, and SLC13A5 also intersects conserved longevity pathways: reduced activity of its orthologue INDY extends lifespan in flies and worms, and Slc13a5 deletion improves metabolic health in mice. The team’s UK Biobank Mendelian randomization analyses link reduced SLC13A5 function to lower osteoporosis risk, and their preliminary data show that inhibiting SLC13A5 suppresses osteoblast senescence and improves skeletal mechanical properties with age. Aim 1 defines the metabolic, mitochondrial ROS, and senescence mechanisms downstream of reduced SLC13A5 activity using integrated transcriptomics, metabolomics, and flux analysis in aged wild-type and Slc13a5-deficient mice. Aim 2 tests the selective inhibitor PF-06761281 in middle-aged (12-month, prevention) and old (20-month, reversal) mice, evaluating bone structure, material quality, and fracture resistance after 8 weeks. Because SLC13A5 is a druggable transporter with inhibitors already in hand, the work is positioned for rapid translation and will support planned NIH R01 applications.
Lay Summary:
As we age, our bones become weaker and more likely to break. Fractures — especially hip fractures — can be devastating for older adults, bringing chronic pain, loss of mobility, loss of independence, and even death. Today’s osteoporosis treatments mainly work by increasing bone density, but density alone does not explain fracture risk: most fractures happen in people whose bone density looks normal.
This research focuses on something different, called “bone quality” — how strong and resilient bone tissue is at the microscopic level. Dr. Dirckx discovered that a naturally occurring molecule called citrate helps maintain healthy bone structure, and that its availability is controlled by a transporter protein, SLC13A5. Intriguingly, this same protein is tied to aging pathways across species: lowering its activity has been linked to better metabolic health and longer lifespan in animal studies, and human genetic data connect reduced activity to lower osteoporosis risk. Preliminary work suggests that blocking SLC13A5 protects bone cells from aging-related stress and makes bone stronger. This project will test a drug that blocks SLC13A5 in aged mice, with the goal of a completely new approach to preventing fractures — by improving the health and resilience of bone tissue itself rather than simply adding density — and preserving the mobility and independence that matter most in later life.