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Age-related pathway signatures – relevance for treating aging disorders

T. Shavlakadze, G. A. Joseph, M. Morris, J. Zhu, S. Wang, W. Zhou, H. Tse, R. Mondragon Gonzalez and D. J. Glass

Novartis Institutes for Biomedical Research, Cambridge, MA, USA

Aging occurs in a regulated manner and the gene expression changes associated with aging could contribute to the onset of many diseases, either by creating a permissive environment for pathology, or by directly inducing these conditions. We identified an Age-related Gene Expression Signature (AGES) in kidney, liver, skeletal muscle and hippocampus in rats, by studying a time course of gene expression throughout the life of the animal. Examining multiple tissues in rats aged 6, 9, 12, 18, 21, 24 and 27 months, we demonstrated tissue-specific and common gene pathway changes. Pathways up-regulated by age in all four tissues were related to apoptosis, innate immune and inflammatory response, interferon signaling and complement signaling. The most down-regulated pathways were related to metabolism, with oxidative metabolism being the most suppressed with age. Since AGES are shared by multiple tissues, it is plausible that perturbation of discrete cell signaling pathways can extend life span and delay age-related diseases and co-morbidities. We thus asked, what is the impact of clinically-relevant low doses of rapalog on age-related pathway changes? Rapamycin or rapalogs (e.g. RAD001), inhibitors of mTORC1 (mammalian target of rapamycin complex 1), have been shown to increase lifespan and forestall age-related morbid phenotypes in multiple species, including humans. Interestingly, the effect of RAD001 on age-related gene pathways was the most pronounced in old kidneys. The majority of the age-related pathways in the kidney were counter-regulated by a low dose of RAD001, and this was accompanied by the reduction of age-related renal histo-pathology. We also examined the impact of RAD001 on molecular pathways implicated in skeletal muscle aging (sarcopenia). Partial inhibition of the mTORC1 pathway counteracted several genes related to senescence, muscle atrophy and deteriortaion of neuromuscular junctions. In addition, prevention of muscle mass loss was observed for select muscles.