Saturday, December 21, 2024
12/21/2024
Project Summary Aging is a major risk factor for many chronic diseases including diabetes, cardiovascular disease, cancer, and neurodegenerative diseases, as well as for geriatric syndromes including frailty and sarcopenia. Therapeutics that delay and/or slow the progression of aging, and thereby increase healthspan and longevity, have remained elusive. Over the past several decades, genetic studies in model organisms and humans have identified and validated a number of longevity-associated genes. A notable subset of these genes function in the somatotropic axis that signals nutrient status and thereby regulates growth and metabolism. Together, these findings strongly suggest that modest changes in the expression levels and/or activities of these genes can have significant impact on healthspan and lifespan. Despite this strong genetic basis, how to pharmacologically modulate levels of these genes in vivo has been a major challenge. Fortunately, antisense oligonucleotides (ASOs) are emerging as a promising therapeutic modality, and they enable highly specific modulation of target protein levels in vivo. Leveraging recent advances in ASO technology, we are now well poised to target longevity-associated genes in vivo. In this project, we will: 1) design and test ASOs to modulate the levels of four longevity-associated genes, and 2) test if the ASOs can extend lifespan and improve healthspan using a mouse model of accelerated aging. Completion of these studies will provide important insights into the utility of ASO-based therapeutic approaches for modulating levels of longevity- associated genes to improve healthspan and increase longevity.
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