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Insulin resistance and neurodegenerative diseases such as Alzheimer s disease are considered part of the main threats to health in old age. In light of the high numbers of overweight/obese and diabetic individuals, there is a clear need to better understand the pathophysiological mechanisms underpinning insulin resistance/obesity and the accompanying impact on cognitive function. The aim of the present study was to investigate the missing link between aging, insulin resistance and cognitive decline as aging and insulin resistance are both risk factors for Alzheimer s disease. TMA is a gut metabolite which proceeds from the bacterial synthesis of substrates such as L-carnitine and choline. TMA is then rapidly further oxidized by hepatic flavin monooxygenases FMO3 and FMO1 to form TMAO. At first, TMAO was thought to be a waste product of choline metabolism without action in our organism, but nowadays, there is emerging evidence linking TMAO to atherosclerosis, systemic inflammation, type 2 diabetes mellitus and even neuropathologies. Plasma TMAO levels show wide inter- and intra-individual variations. These levels are influenced by several factors but the main factor influencing TMAO levels is aging. Some studies performed in human and rats have revealed that plasma TMAO levels are closely related to aging showing increasing levels with age. In this context, we have investigated if TMAO could be the link between metabolic diseases and cognitive deficiencies. In vitro studies showed that TMAO was able to raise the differentiation of mature adipocytes from preadipocytes, increase expression of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) from macrophages and neurons and reduce expression of tight junction proteins in blood brain barrier cells. Moreover, TMAO was able to activate microglia and raise the expression of the pro-inflammatory marker CD16/CD32, increasing aberrantly myelin phagocytosis. SAMP8 a senescence accelerated mouse model was used to study the effect of aging (the main risk factor for AD) in peripheral inflammation and neuroinflammation. Studies were performed at three different ages: 2-months-old SAMP8 (young mice), 6-months-old SAMP8 (adult mice) and 10-month-old SAMP8 (old mice). Aging altered peripheral insulin sensitivity and glucose homeostasis in SAMP8 mice but not brain insulin signaling. Moreover, aging induced cognitive deficiencies and promoted peripheral and central inflammation. Finally, aging also induced gut dysbiosis, showing reduced diversity and changes in gut microbiota composition with enterotypes that could be associated to higher TMAO levels. This fact was further contrasted using LC-SM/SM what showed greater TMAO levels in serum of SAMP8 mice. Brain TMAO levels also increased with age in mice and humans. Treatment with 3,3-dimethyl-1-butanol (DMB), which is a choline TMA lyase enzyme inhibitor that decreases TMAO serum levels, restored peripheral inflammation reducing fat adipose tissue and reversing insulin and glucose alterations. Moreover, DMB also restored neuroinflammation decreasing expression of pro-inflammatory cytokines in hippocampus, reducing gliosis and restoring GFAP levels back to normal. Finally, SAMP8 performance in behavioral test was improved after DMB treatment ameliorating and restoring cognitive dysfunction.

[EN] The present invention describes a transgenic plant resistant to cold and to saline stress based on the use of a new gene, gene RCI5, encoding a monooxygenase enzyme which induces the appearance of TMAO. Moreover, the invention provides a sequence of nucleotides, vectors and cells necessary to carry out the procedure for the obtainment of said transgenic plants. Finally, there is added the use of compositions containing TMAO to improve the tolerance to saline stress of affected plants by means of exogenous application of said solutions onto the plant or seed, for example spraying or injection., [ES] La presente invención describe una planta transgénica resistente al frió y al estrés salino basada en el uso de un nuevo gen, el gen RCI5, codificante de una enzima monoxigenasa que induce la aparición de TMAO. Además la invención proporciona secuencia de nucleótidos, vectores y células necesarias para llevar a cabo el procedimiento para obtener dichas plantas transgénicas. Finalmente, se añade el uso de composiciones que contienen TMAO para la mejora de la tolerancia al estrés salino de las plantas afectadas mediante la aplicación exógena de dichas soluciones sobre la planta o semilla, por ejemplo pulverización o inyección., Consejo Superior de Investigaciones Científicas (España), Instituto Nacional de Investigación, Tecnología Agraria Alimentaria (INIA), A1 Solicitud de patentes con informe sobre el estado de la técnica