Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages

Covarrubias, Anthony J.; Kale, Abhijit; Perrone, Rosalba; López-Domínguez, José A; Pisco, Angela Oliveira; Kasler, Herbert G.; Schmidt, Mark S.; Heckenbach, Indra; Kwok, Ryan T. K.; Wiley, Christopher D.; Wong, Hoi Shan; Gibbs, Eddy; Iyer, Shankar S.; Basisty, Nathan; Wu, Qiuxia; Kim, Ik Jung; Silva, Elena; Vitangcol, Kaitlyn; Shin, Kyong‐Oh; Lee, Yong Moon; Riley, Rebeccah; Ben-Sahra, Issam; Ott, Mélanie; Schilling, Birgit; Scheibye‐Knudsen, Morten; Ishihara, Katsuhiko; Quake, Stephen R.; Newman, John C.; Brenner, Charles; Campisi, Judith; Verdin, Eric

doi:10.1038/s42255-020-00305-3

Cited by 258 publications

(246 citation statements)

References 74 publications

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“…In mice, high cGAMP correlated with high anti-tumor activity, by a direct triggering of the STING-dependent pathway. Consequently, inhibitors of CD203a/ENPP1 (26) could have anti-tumor activity by inhibiting the conversion of extracellular b-NAD + to ADO and by inhibiting cGAMP degradation and, therefore, the secretion of SASP (senescent-associated secretory phenotype) factors which were found to increase CD38 expression (27,28). All these findings are schematized in Figure 1.…”

Section: Inhibition Of Anti-tumor Immunitymentioning

confidence: 99%

The Key Role of NAD+ in Anti-Tumor Immune Response: An Update

2021

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Nicotinamide adenine dinucleotide (NAD+) is an important molecule that functions as a co-enzyme in numerous metabolic processes. Generated both through de novo synthesis and via salvage pathways, NAD+ is the substrate for a variety of NAD+-consuming enzymes. Among them is CD38, a cell surface ecto-enzyme widely expressed on different types of cells and endowed with the function of cADP-ribose synthases/NAD+ glycohydrolase. Surface CD38 expression is increased in different hematological and solid tumors, where it cooperates with other ecto-enzymes to produce the immunosuppressive molecule adenosine (ADO). Few studies have explored the correlation of NAD+ levels with T-cell mediated anti-tumor response in preclinical models. We therefore discuss these novel findings, examining the possible contribution of NAD+ depletion, along with ADO production, in the immunosuppressive activities of CD38 in the context of human tumors. Lastly, we discuss the use of pharmacological inhibitors of CD38 and supplementation of different NAD+ precursors to increase NAD+ levels and to boost T cell responses. Such molecules may be employed as adjuvant therapies, in combination with standard treatments, for cancer patients.

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Section: Inhibition Of Anti-tumor Immunitymentioning

confidence: 99%

The Key Role of NAD+ in Anti-Tumor Immune Response: An Update

2021

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“…Recent studies showed that inflammation increases CD38-mediated NAD + degradation activity, which decreases NAD + . The increase in CD38 in metabolic tissues during aging is likely mediated by accumulation of pro-inflammatory M1-like macrophages that also express CD38 ( Chini et al, 2020 ; Covarrubias et al, 2020 ).…”

Section: Immunity Kyn Pathway Metabolites and De Novo Nad + Metabolismmentioning

confidence: 99%

“…Consequently, NAD + has a multifarious and highly important influence on cellular health, affecting an extensive suite of processes, including: DNA repair, central metabolism, circadian rhythms, meiosis and lifespan ( Imai and Guarente, 2014 ; Kato and Lin, 2014 ; Nikiforov et al, 2015 ; Chini et al, 2016 ; Yoshino et al, 2018 ; Okabe et al, 2019 ; Castro-Portuguez and Sutphin, 2020 ). Owing to its centrality in cellular homeostasis, defects in NAD + metabolism are often associated with a variety of disease states, seen in diabetes, neurological disorders, and various cancers ( Schwarcz et al, 2012 ; Imai and Guarente, 2014 ; Cantó et al, 2015 ; Garten et al, 2015 ; Nikiforov et al, 2015 ; Verdin, 2015 ; Cheng et al, 2016 ; Chini et al, 2016 ; Yang and Sauve, 2016 ; Williams et al, 2017 ; Liu et al, 2018 ; Poyan Mehr et al, 2018 ; Yaku et al, 2018 ; Yoshino et al, 2018 ; Okabe et al, 2019 ; Chini et al, 2020 ; Covarrubias et al, 2020 ; Katsyuba et al, 2020 ; Covarrubias et al, 2021 ). Administration of NAD + precursors such as nicotinamide mononucleotide (NMN), nicotinamide (NAM), nicotinic acid riboside (NaR), nicotinamide riboside (NR), and dihydronicotinamide riboside (NRH) has been shown to increase NAD + levels and ameliorate associated deficiencies in various model systems and in humans ( Belenky et al, 2007 ; Brown et al, 2014 ; Cantó et al, 2015 ; Edwards et al, 2015 ; Garten et al, 2015 ; Verdin, 2015 ; Chini et al, 2016 ; Lin et al, 2016 ; Ryu et al, 2016 ; Yang and Sauve, 2016 ; Zhang et al, 2016 ; Williams et al, 2017 ; Katsyuba et al, 2018 ; Liu et al, 2018 ; Meng et al, 2018 ; Mitchell et al, 2018 ; Poyan Mehr et al, 2018 ; Rajman et al, 2018 ; Yoshino et al, 2018 ; Sambeat et al, 2019 ; Vannini et al, 2019 ; ...…”

Section: Introductionmentioning

confidence: 99%

NAD+ Metabolism, Metabolic Stress, and Infection

Groth

Venkatakrishnan

Lin

2021

Front. Mol. Biosci.

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Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite with wide-ranging and significant roles in the cell. Defects in NAD+ metabolism have been associated with many human disorders; it is therefore an emerging therapeutic target. Moreover, NAD+ metabolism is perturbed during colonization by a variety of pathogens, either due to the molecular mechanisms employed by these infectious agents or by the host immune response they trigger. Three main biosynthetic pathways, including the de novo and salvage pathways, contribute to the production of NAD+ with a high degree of conservation from bacteria to humans. De novo biosynthesis, which begins with l-tryptophan in eukaryotes, is also known as the kynurenine pathway. Intermediates of this pathway have various beneficial and deleterious effects on cellular health in different contexts. For example, dysregulation of this pathway is linked to neurotoxicity and oxidative stress. Activation of the de novo pathway is also implicated in various infections and inflammatory signaling. Given the dynamic flexibility and multiple roles of NAD+ intermediates, it is important to understand the interconnections and cross-regulations of NAD+ precursors and associated signaling pathways to understand how cells regulate NAD+ homeostasis in response to various growth conditions. Although regulation of NAD+ homeostasis remains incompletely understood, studies in the genetically tractable budding yeast Saccharomyces cerevisiae may help provide some molecular basis for how NAD+ homeostasis factors contribute to the maintenance and regulation of cellular function and how they are regulated by various nutritional and stress signals. Here we present a brief overview of recent insights and discoveries made with respect to the relationship between NAD+ metabolism and selected human disorders and infections, with a particular focus on the de novo pathway. We also discuss how studies in budding yeast may help elucidate the regulation of NAD+ homeostasis.

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“…It is plausible that declining NAD levels in aged macrophages could also compromise SIRT activity that may negatively impact inflammatory homeostasis during aging (He et al, 2020). Interestingly, senescent macrophages have recently been implicated in the immunometabolism of NAD (Covarrubias et al, 2020). It was observed that NAD consuming CD38+ M1 macrophages with upregulated markers of senescence (p16/p21) and inflammation accumulated in adipose tissue which were primarily responsible for decreased NAD availability in tissues during aging, suggesting a causative relationship between CD38+ macrophages, NAD consumption, Sirtuins and aging (Covarrubias et al, 2020).…”

Section: Immunometabolism and Macrophage Senescencementioning

confidence: 99%

“…Interestingly, senescent macrophages have recently been implicated in the immunometabolism of NAD (Covarrubias et al, 2020). It was observed that NAD consuming CD38+ M1 macrophages with upregulated markers of senescence (p16/p21) and inflammation accumulated in adipose tissue which were primarily responsible for decreased NAD availability in tissues during aging, suggesting a causative relationship between CD38+ macrophages, NAD consumption, Sirtuins and aging (Covarrubias et al, 2020). In addition, M2 phenotype macrophages were identified as novel sources of IGF1, and ablation of IGF1 receptors from myeloid cells reduced phagocytosis, increased macrophages in adipose tissue, elevated adiposity, lowered energy expenditure, and led to insulin resistance in mice fed a high-fat diet indicating that IGF1 signaling shapes the macrophage-activation phenotype (Spadaro et al, 2017).…”

Section: Immunometabolism and Macrophage Senescencementioning

confidence: 99%

Emerging Dynamics of Macrophage Cellular Senescence and Immunosenescence in Governing Organismal Aging and Disease: Concepts and Opportunities

Sharma¹

2021

Preprint

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An intricate relationship between impaired immune functions and the age-related accumulation of tissue senescent cells (SC) is rapidly emerging. The immune system is unique as it undergoes mutually inclusive and deleterious processes of immunosenescence and cellular senescence with advancing age. While factors inducing immunosenescence and cellular senescence may be shared, however, both these processes are fundamentally different which holistically influence the aging immune system. Immunosenescence is a well-characterized phenomenon, but our understanding and biological impact of cellular senescence in immune cells, especially in the innate immune cells such as macrophages, is only beginning to be understood. Tissue-resident macrophages are long-lived, and while functioning in tissue-specific and niche-specific microenvironments, senescence in macrophages can be directly influenced by senescent host cells which may impact organismal aging. In addition, evidence of age-associated immunometabolic changes as drivers of altered macrophage phenotype and functions such as inflamm-aging is also emerging. The present review describes the emerging impact of cellular senescence vis-à-vis immunosenescence in aging macrophages, its biological relevance with other senescent non-immune cells, and known immunometabolic regulators. Gaps in our present knowledge, as well as strategies aimed at understanding cellular senescence and its therapeutics in the context of macrophages, have been reviewed.

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Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages

Cited by 258 publications

References 74 publications

The Key Role of NAD+ in Anti-Tumor Immune Response: An Update

The Key Role of NAD+ in Anti-Tumor Immune Response: An Update

NAD+ Metabolism, Metabolic Stress, and Infection

Emerging Dynamics of Macrophage Cellular Senescence and Immunosenescence in Governing Organismal Aging and Disease: Concepts and Opportunities

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