The Effects of NAD-Boosting Therapies on Sirtuin Activity and DNA Repair Capacity
CitationKelley, Colleen. 2020. The Effects of NAD-Boosting Therapies on Sirtuin Activity and DNA Repair Capacity. Master's thesis, Harvard Extension School.
AbstractAs we age, we accumulate DNA damage that results in the chronic activation of PARP, a critical enzyme involved in the DNA repair process (Mouchiroud et al. 2013; Gomes et al. 2013; Yoshino et al. 2013). Chronic activation of PARP leads to an age-associated decline of nicotinamide adenine dinucleotide (NAD) and an increase in nicotinamide (NAM), which inhibits critical enzymes such as the sirtuins, nicotinamide phosphoribosyl transferase (NAMPT), and even PARP itself (Gomes et al. 2013; Zhu et al. 2015; Zhang et. al. 2016). As a result, increased levels of PARP have been observed in many chronic diseases such as diabetes, cancer, and neurodegenerative diseases (Love et al. 1999; Kauppin and Swanson 2007; Pacher and Szabo 2005; Peralta-Leal et al. 2009). We were able to detect the upregulation of PARP and inhibition of the sirtuins in the tissues of aged mouse kidneys. We then developed a DNA damage in vitro model that mimics the increase of DNA damage markers that we observed in aged animals. In this model, we were able to demonstrate that DNA damage drives an increase in markers associated with senescence, inflammation, and fibrosis. This correlates with published literature surrounding the development of age-associated diseases as well as the occurrence of radiation-induced fibrosis in cancer patients (Serrano et al. 2014; Straub et al. 2016). Recent studies in mouse in vivo models have shown the benefits of using NAD-boosting therapies to improve or delay the onset of many age-associated diseases (Belenky et al. 2007; Balan et al. 2008; Mouchiroud et al. 2013). We were able to compare supplementation of a NAD precursor, Nicotinamide Riboside (NR), with P7C3, a known NAMPT activator, in our in vitro DNA damage model. We observed that P7C3 was superior to NR to alleviate markers associated with DNA damage, senescence, inflammation and fibrosis in the context of increased DNA damage.
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