mTOR Inhibition by Rapamycin Restores Mechanical Properties and Mineral Homeostasis in Aged Non-Human Primate Dental Tissues

Abstract

Aging is the primary risk factor for functional decline and chronic conditions, including disorders of the oral cavity. Teeth are essential for mastication, speech, facial esthetics, and quality of life. With advancing age, dental tissues undergo structural, compositional, and biological changes, including enamel wear, dentin sclerosis, altered mineral homeostasis, and reduced cellular activity. These changes increase susceptibility to cracked tooth syndrome, periodontal disease, and eventual tooth loss. Despite the high prevalence of age-associated dental pathology in older people, the biological mechanisms that contribute to deterioration of tooth structure and mechanical integrity remain incompletely understood.Geroscience focuses on targeting fundamental mechanisms of aging to delay, prevent, or restore age-related dysfunction. Among these pathways, mammalian target of rapamycin (mTOR) signaling is a central regulator of cellular metabolism, autophagy, inflammation, and tissue homeostasis. Modulation of mTOR signaling can extend healthspan and improve tissue function in multiple organ systems. However, the relevance of mTOR signaling to dental tissue aging, tooth biomechanics, and mineral balance has been largely unexplored. This dissertation integrates geroscience with oral health science to test whether dental structural aging is biologically modifiable and whether mTOR inhibition can restore age-associated declines in tooth integrity. Chapter 1 reviews age-related changes in enamel and dentin in the context of cracked tooth syndrome, establishing structural fatigue and altered material properties as key contributors to tooth fracture. Chapter 2 reviews mTOR signaling in dental tissues, with emphasis on odontoblast function, mineralization, periodontal homeostasis, and age-related oral pathology. Chapter 3 explains the limitations of traditional animal models and establishes nonhuman primates as a biologically and mechanically relevant model for dental aging and systemic pharmacologic intervention. Chapter 4 describes fracture resistance testing, nanoindentation, and field-emission electron probe microanalysis as complementary approaches for evaluating whole-tooth mechanical performance, microscale material properties, and mineral composition. Chapter 5 presents experimental findings showing that aging significantly reduces tooth fracture resistance and disrupts dentin mineral balance, whereas rapamycin treatment restores mechanical integrity, enhances dentin material properties, and normalizes the calcium-to-phosphorus ratio in aged teeth. Chapter 6 integrates these biological, mechanical, and compositional findings to interpret how mTOR inhibition may restore a favorable balance between stiffness and fracture resistance in aging nonhuman primate dental tissues. In summary, this research demonstrates that dental aging is not solely a passive degenerative process but may be biologically modifiable. By linking aging biology to tooth biomechanics and mineral homeostasis, this dissertation identifies mTOR signaling as a potential regulator of age-associated tooth fragility. These findings establish mTOR inhibition as a promising conceptual strategy for preserving tooth structure and reducing risk for cracked tooth syndrome, while also providing a foundation for future translational studies in geriatric oral health.