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ObjectivesDiabetes leads to cognitive impairment and is associated with age-related neurodegenerative diseases including Alzheimer's disease (AD). Thus, understanding diabetes-induced alterations in brain function is important for developing early interventions for neurodegeneration. Low-capacity runner (LCR) rats are obese and manifest metabolic risk factors resembling human “impaired glucose tolerance” or metabolic syndrome. We examined hippocampal function in aged LCR rats compared to their high-capacity runner (HCR) rat counterparts.MethodsHippocampal function was examined using proton magnetic resonance spectroscopy and imaging, unbiased stereology analysis, and a Y maze. Changes in the mitochondrial respiratory chain function and levels of hyperphosphorylated tau and mitochondrial transcriptional regulators were examined.ResultsThe levels of glutamate, myo-inositol, taurine, and choline-containing compounds were significantly increased in the aged LCR rats. We observed a significant loss of hippocampal neurons and impaired cognitive function in aged LCR rats. Respiratory chain function and activity were significantly decreased in the aged LCR rats. Hyperphosphorylated tau was accumulated within mitochondria and peroxisome proliferator-activated receptor-gamma coactivator 1α, the NAD+-dependent protein deacetylase sirtuin 1, and mitochondrial transcription factor A were downregulated in the aged LCR rat hippocampus.InterpretationThese data provide evidence of a neurodegenerative process in the hippocampus of aged LCR rats, consistent with those seen in aged-related dementing illnesses such as AD in humans. The metabolic and mitochondrial abnormalities observed in LCR rat hippocampus are similar to well-described mechanisms that lead to diabetic neuropathy and may provide an important link between cognitive and metabolic dysfunction.

Aging is a risk factor for progressive fibrotic disorders involving diverse organ systems, including the lung. Idiopathic pulmonary fibrosis, an age-associated degenerative lung disorder, is characterized by persistence of apoptosis-resistant myofibroblasts. Here we demonstrate that sirtuin 3 (SIRT3), a mitochondrial deacetylase, is downregulated in the lungs of humans with idiopathic pulmonary fibrosis and in mice subjected to lung injury. Overexpression of Sirt3 cDNA via airway delivery restored the capacity for fibrosis resolution in aged mice, in association with activation of the forkhead box transcription factor FoxO3a in fibroblasts, upregulation of pro-apoptotic members of the Bcl2 family and recovery of apoptosis susceptibility. While transforming growth factor-β1 reduced levels of SIRT3 and FOXO3A in lung fibroblasts, cell non-autonomous effects involving macrophage-secreted products were necessary for SIRT3-mediated activation of FOXO3A. Together, these findings reveal a novel role of SIRT3 in pro-resolution macrophage functions that restore susceptibility to apoptosis in fibroblasts via a FOXO3A-dependent mechanism.