For instance, increasing AGE content has been correlated to reduced bone toughness and increased fracture risk, a relationship that has been demonstrated experimentally and through numerical modeling. The goal of the present investigation was to more directly quantify the mechanical consequences of AGEs on collagen fibril failure behavior and viscoelasticity. This study employed synchrotron small-angle X-ray scattering and mechanical testing to reveal how collagen fibril deformations are altered by MGO induced AGEs in rat tail tendon fascicles. The rat tail tendon fascicle is a widely employed experimental model to study collagen structurefunction, and was previously employed by us to characterize the effects of AGEs on collagen fiber kinematics at the cellular scale using multiphoton confocal microscopy. In this earlier work, we observed drastically diminished tendon NSC-718781 viscoelasticity in MGO treated tendons and a corresponding loss of collagen fiber sliding. The mechanisms behind this potentially critical functional loss remained unclear. The intent of the present study was to focus on the underlying molecular effects of AGEs, hoping to gain mechanistic insight into these functional deficits that may underlie loss of tissue homeostasis and play a central role in tissue disease. In control tendons the diffraction pattern could not be decomposed to the sum of two different Bragg reflections, indicating a characteristically less abrupt mode of fibril damage, characterized by a respective loss of the quarter-staggered molecular arrangement. Collagen cross-linking by AGEs has been increasingly implicated as a central factor in the onset and progression of connective tissue disease. For the first time we report the physical effects of AGEs on collagen molecular and supramolecular deformations under load. We identify and describe altered damage mechanisms that could play a central role in connective tissue disease processes. Our data provide evidence that accumulation of AGEs dramatically affects collagen fibril failure behavior and stress relaxation. These functional parameters strongly reflect how collagen structures accommodate mechanical load and overload. Because the temporal and spatial dynamics of connective tissue damage and repair involve an intricate balance of mechanically driven catabolic and anabolic processes, even slight changes in collagen mechanics or patterns of damage accumulation may detrimentally affect tissue homeostasis. Such changes in extracellular matrix mechanics are likely to be exacerbated by resistance of AGE modified substrates to proteolytic enzymes that drive and regulate balanced matrix remodeling, or by chronic activation of inflammatory mediators that drive fibrosis. Another important finding was the characterization of distinctly different failure behavior in MGO treated specimens, with dramatically increased collagen fibril strength and a shift to an abrupt mode of failure.