Summary The overarching goal of our funded program project grant (PPG) is to understand the mechanisms of longevity that evolved in long-lived mammalian species. Project 2 led by Dr. Andrei Seluanov focuses on the mechanisms of longevity and cancer resistance of the naked mole rat. Naked mole rat is the longest-lived rodent with the maximum lifespan of 32 years. Naked mole rats are a model of healthy aging as they do not display age-related pathologies almost until death. Remarkably, naked mole rats brains contain high levels of Aβ, similar to what is found in 3xTg Alzheimer’s disease (AD) model mice, but they do not form plaques and do not show any signs of neurodegeneration. Our group has found that naked mole rat tissues, including brain, contain very high levels of high molecular weight hyaluronan (HA). HA is a linear polysaccharide that is the main non-protein component of extracellular matrix. HA has potent cytoprotective, anti-inflammatory and antioxidant properties, and, as we discovered, plays important role in cancer resistance and longevity of naked mole rat. Core B of the PPG maintains colonies of naked mole rats at the University of Rochester and recently developed transgenic mouse model that overexpresses naked mole rat hyaluronan synthase 2 gene. In this Administrative supplement we propose to expand our research into the field of AD. We hypothesize that HA protects naked mole rat brain from AD by counteracting aging related neurodegeneration, inflammatory processes and neuropathology triggered by Aβ. To test this hypothesis, we propose the following three aims: (1) Test whether high molecular weight HA is protective against aging related phenotypic and morphological changes in mice over 2 years of age. We will test for signs of neurodegeneration, aging-related inflammation and age-related degradation in central nervous system (CNS) of our transgenic mice overexpressing naked mole rat hyaluronic acid synthase 2 (nmrHAS2). (2) Assess the effect of endogenous high molecular weight HA on acute and chronic neuroinflammation in young mice. By subjecting mice to LPS induced inflammation we will be able to assess whether HA is protective against acute and chronic states of inflammation in nmrHAS2 mice. (3) Test the protective effect of high molecular weight HA in transgenic AD mouse models expressing nmrHAS2. We will develop a transgene of nmrHAS2 and AD mice model, MAPT and 5xFAD, in order to test if endogenous HA is protective against AD pathologies in these models. This work will be conducted by Project 2 and supported by the Animal Core. In addition, the proposed work will facilitate Projects 3 and 4 of the PPG that analyze the effects of HA on mutagenesis and on global transcriptome changes triggered by HA. The proposed studies will open new avenues for developing drugs for AD. If HA is protective, small molecule inhibitors of hyaluronan degrading enzymes could be developed to increase the levels of HA in the brains.