Sirtuins and nuclear receptors in aging and age-associated diseases

National Institute Of Environmental Health Sciences

Investigators

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Abstract

In the past year, we have been working on several projects on host-microbe interaction in regulation of host gut tissue stress response, inflammation, and tumorigenesis as well as metabolic and epigenetic regulation of stem cells and cancer cells. Paneth cells, intestine-originated innate immune-like cells, are important for maintenance of the intestinal stem cell niche, gut microbiota, and gastrointestinal barrier. Dysfunctional Paneth cells under pathological conditions are a site of origin for intestinal inflammation. However, mechanisms underlying stress-induced Paneth cell dysregulation remains unclear. In one of our studies, we show that SIRT1, the most conserved mammalian NAD+-dependent protein deacetylase and a well-known genetic repressor of inflammation, cell-autonomously suppresses Paneth cell function and sensitizes the gut epithelium to environmental stress. Specifically, deletion of Paneth cell SIRT1 in mice elevates Wnt signaling and ATF4/endoplasmic reticulum stress pathway in Paneth cells. These molecular alterations are coupled with increased Paneth cell abundance and enhanced anti-microbial peptide production in young mice, improved protection against intraepithelial immune cell expansion in aged mice, and increased resistance to chemically induced colitis. Using microbiota-depleted mice with or without fecal transplantation, we further demonstrate that Paneth cell SIRT1 deficiency ameliorates colitis by interacting with the gut microbiota. Collectively, our findings uncover an unanticipated function of Paneth cell SIRT1 in conferring stress sensitivity in the gut epithelium, and further suggest that early activation of Paneth cell by SIRT1 inhibition and/or microbiome manipulation might offer a novel strategy against intestinal disorders. A paper describing this study is currently under revision (Garcia-Peterson et al., 2025). Homeostasis of nicotinamide adenine dinucleotide (NAD), an essential electron carrier for hundreds of biochemical reactions in all living cells, is tightly maintained by various NAD biosynthesis pathways and consuming enzymes in response to environmental signals. Dysregulation of this balance by aging and environmental stresses is associated with numerous human diseases, ranging from cancer and metabolic syndromes to inflammatory and neurodegenerative diseases. Particularly, NAD and its biosynthesis are currently believed to be tumor-promoting, as the highly proliferative cancer cells have a high demand on NAD for its energy metabolism and growth. We have previously discovered that deamidated NAD biosynthesis catalyzed by nicotinic acid phosphoribosyl transferase (NAPRT) mediates the impact of gut microbiota and dietary NAD precursors on tissue NAD synthesis in mice (Shats et al., Cell Metabolism, 2020). However, in contrast to the well-studied nicotinamide phosphoribosyl transferase (NAMPT)-mediated amidated NAD salvage pathway, the (patho)physiological importance of this microbiota-enabled highly efficient NAD biosynthesis pathway is largely understudied, and the functional difference between different NAD biosynthesis pathways remains unknown. In this study, we investigated the functional impacts of this pathway on animal (patho)physiology and stress response in both mice and humans and identified an unexpected suppressive role of this pathway in both cancer and inflammation. Specifically, in contrast to the ubiquitous expression of the key enzyme in the amidated NAD salvage pathway, NAPRT is specifically enriched in gut epithelial cells, where it maintains the NAD pool for an efficient response to stress-induced acute NAD depletion. Consequently, NAPRT deficiency impairs the activity of poly-(ADP-ribose) polymerases and DNA repair, sensitizes mice to chemical-induced colitis and tumorigenesis as well as to age-associated spontaneous tumor development. In several human cancer types, low NAPRT expression is associated with poor prognosis. Therefore, endogenous deamidated NAD biosynthesis suppresses tumorigenesis, and its boosting may be beneficial for tumor prevention and treatment. A paper describing this study is currently under revision (Wu et al., 2025). Two new manuscripts regarding metabolic regulation of ES cell maintenance and differentiation, and the impact of prolonged methionine restriction on cancer cell persistence are currently in preparation. Additionally, we published one invited review articles (Wu et al., Trends in Molecular Medicine, 2025) and two collaborative articles (Colasante et al., Plos One, 2024; Rungratanawanich et al., Journal of Pineal Research, 2024).