Work in the Lombard laboratory focuses on sirtuin proteins, NAD+-dependent deacetylases/ADP-ribosyltransferases/deacylases that promote longevity in budding yeast and other invertebrates, and numerous aspects of healthspan in mammals.
Our current efforts focus primarily on two mammalian sirtuins, SIRT5 and SIRT6. SIRT5, unlike other sirtuins, is a desuccinylase/demalonylase/deglutarylase. We recently carried out a large-scale proteomics survey to identify novel succinylated SIRT5 substrates (Park et al., Mol Cell 2013). In these studies, we found that SIRT5 negatively regulates the activities of two major cellular metabolic enzyme complexes, pyruvate dehydrogenase and succinate dehydrogenase. SIRT5 deficiency leads to greatly increased cellular respiration. Ongoing work in the lab focuses on assessing whether SIRT5 inhibition could potentially be of therapeutic utility to boost mitochondrial respiration in metabolic dysfunction or cancer.
Our other area of interest is the chromatin deacetylase SIRT6. Among the seven mammalian sirtuins, SIRT6 is of particular interest, as it is the only one shown to increase longevity when overexpressed in mice. We previously showed that mice lacking SIRT6 develop a degenerative/metabolic disorder, dying before one month of age (Mostoslavsky et al., Cell 2006). More recently, our lab has initiated work to test whether SIRT6 might affect specific age-associated diseases, using tissue-specific SIRT6 knockouts. Via this approach, we recently showed that SIRT6 functions as a tumor suppressor in the intestines in mice, and likely in humans as well (Sebastian et al., Cell 2012). Ongoing studies focus on the role of SIRT6 in modulating chromatin structure to promote genomic stability, a SIRT6 function relevant for tumor suppression and maintenance of overall organismal health.