The NADase CD38 is induced by factors secreted from senescent cells providing a potential link between senescence and age-related cellular NAD+ decline

Chini, Claudia C.S.; Hogan, Kelly A.; Warner, Gina M.; Tarragó, Mariana G.; Peclat, Thais; Tchkonia, Tamar; Kirkland, James L.; Chini, Eduardo N.

doi:10.1016/j.bbrc.2019.03.199

Cited by 98 publications

(95 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Low levels of NAD + were also reported in several tissues (Massudi et al, 2012;Zhu et al, 2015), and supplementation of NAD + precursors increased life span in different species (Fang et al, 2016;Zhang et al, 2016). Interestingly, SCs were shown to induce the SASP-mediated expression of CD38 -an ectoenzyme with a high NADase activity -in non-senescent cells, such as endothelial cells and bone marrow-derived macrophages (Chini et al, 2019;Covarrubias et al, 2019). CD38 inhibitors rescued NAD + decline and ameliorated a number of age-related metabolic outcomes in mice (Tarrago et al, 2018).…”

Section: Me1mentioning

confidence: 93%

Where Metabolism Meets Senescence: Focus on Endothelial Cells

et al. 2019

View full text Add to dashboard Cite

Despite the decline in their proliferative potential, senescent cells display a high metabolic activity. Senescent cells have been shown to acquire a more glycolytic state even in presence of high oxygen levels, in a way similar to cancer cells. The diversion of pyruvate, the final product of glycolysis, away from oxidative phosphorylation results in an altered bioenergetic state and may occur as a response to the enhanced oxidative stress caused by the accumulation of dysfunctional mitochondria. This metabolic shift leads to increased AMP/ATP and ADP/ATP ratios, to the subsequent AMPK activation, and ultimately to p53-mediated growth arrest. Mounting evidences suggest that metabolic reprogramming is critical to direct considerable amounts of energy toward specific activities related to the senescent state, including the senescence-associated secretory phenotype (SASP) and the modulation of immune responses within senescent cell tissue microenvironment. Interestingly, despite the relative abundance of oxygen in the vascular compartment, healthy endothelial cells (ECs) produce most of their ATP content from the anaerobic conversion of glucose to lactate. Their high glycolytic rate further increases during senescence. Alterations in EC metabolism have been identified in age-related diseases (ARDs) associated with a dysfunctional vasculature, including atherosclerosis, type 2 diabetes and cardiovascular diseases. In particular, higher production of reactive oxygen species deriving from a variety of enzymatic sources, including uncoupled endothelial nitric oxide synthase and the electron transport chain, causes DNA damage and activates the NAD +-consuming enzymes polyADP-ribose polymerase 1 (PARP1). These non-physiological mechanisms drive the impairment of the glycolytic flux and the diversion of glycolytic intermediates into many pathological pathways. Of note, accumulation of senescent ECs has been reported in the context of ARDs. Through their pro-oxidant, pro-inflammatory, vasoconstrictor, and prothrombotic activities, they negatively impact on vascular physiology, promoting both the onset and development of ARDs. Here, we review the current knowledge on the cellular senescence-related metabolic changes and their contribution to the mechanisms underlying the pathogenesis of ARDs, with a particular focus on ECs. Moreover, current and potential interventions aimed at modulating EC metabolism, in order to prevent or delay ARD onset, will be discussed.

show abstract

Section: Me1mentioning

confidence: 93%

Where Metabolism Meets Senescence: Focus on Endothelial Cells

et al. 2019

View full text Add to dashboard Cite

show abstract

“…The mechanisms that underlie NAD + level decrease remain a fundamental question. A recent report from Chini et al 19 suggests that SASP from senescent cells can induce CD38 in endothelial cells and bone marrow-derived macrophages. CD38 is a major consumer of NAD + .…”

Section: Senescent State Can Reduce Nad +mentioning

confidence: 99%

Interacting NAD⁺ and Cell Senescence Pathways Complicate Antiaging Therapies

Mendelsohn

Larrick

2019

Rejuvenation Research

View full text Add to dashboard Cite

During human aging, decrease of NAD + levels is associated with potentially reversible dysfunction in the liver, kidney, skeletal and cardiac muscle, endothelial cells, and neurons. At the same time, the number of senescent cells, associated with damage or stress that secretes proinflammatory factors (SASP or senescence-associated secretory phenotype), increases with age in many key tissues, including the kidneys, lungs, blood vessels, and brain. Senescent cells are believed to contribute to numerous age-associated pathologies and their elimination by senolytic regimens appears to help in numerous preclinical aging-associated disease models, including those for atherosclerosis, idiopathic pulmonary fibrosis, diabetes, and osteoarthritis. A recent report links these processes, such that decreased NAD + levels associated with aging may attenuate the SASP potentially reducing its pathological effect. Conversely, increasing NAD + levels by supplementation or genetic manipulation, which may benefit tissue homeostasis, also may worsen SASP and encourage tumorigenesis at least in mouse models of cancer. Taken together, these findings suggest a fundamental trade-off in treating aging-related diseases with drugs or supplements that increase NAD +. Even more interesting is a report that senescent cells can induce CD38 on macrophages and endothelial cells. In turn, increased CD38 expression is believed to be the key modulator of lowered NAD + levels with aging in mammals. So, accumulation of senescent cells may itself be a root cause of decreased NAD + , which in turn could promote dysfunction. On the contrary, the lower NAD + levels may attenuate SASP, decreasing the pathological influence of senescence. The elimination of most senescent cells by senolysis before initiating NAD + therapies may be beneficial and increase safety, and in the best-case scenario reduce the need for NAD + supplementation.

show abstract

“…CD38 expression was recently found to be driven by a cocktail of cytokines and chemokines secreted by senescent cells. Cellular senescence is a cell fate in which cells cease to divide and adopt a senescent-associated secretory phenotype (SASP) characterized by the secretion of factors (including proinflammatory cytokines and chemokines) that promote chronic "sterile" inflammation and fibrosis [68]. Several studies found that senescent cells accumulate with age, including in the brain [69].…”

Section: Aging the Missing Link Between Cd38 And Neurodegeneration/imentioning

confidence: 99%

CD38 in Neurodegeneration and Neuroinflammation

Guerreiro¹,

Privat²,

Bressac³

et al. 2020

Cells

103

View full text Add to dashboard Cite

Neurodegenerative diseases are characterized by neuronal degeneration as well as neuroinflammation. While CD38 is strongly expressed in brain cells including neurons, astrocytes as well as microglial cells, the role played by CD38 in neurodegeneration and neuroinflammation remains elusive. Yet, CD38 expression increases as a consequence of aging which is otherwise the primary risk associated with neurodegenerative diseases, and several experimental data demonstrated that CD38 knockout mice are protected from neurodegenerative and neuroinflammatory insults. Moreover, nicotinamide adenine dinucleotide, whose levels are tightly controlled by CD38, is a recognized and potent neuroprotective agent, and NAD supplementation was found to be beneficial against neurodegenerative diseases. The aims of this review are to summarize the physiological role played by CD38 in the brain, present the arguments indicating the involvement of CD38 in neurodegeneration and neuroinflammation, and to discuss these observations in light of CD38 complex biology.

show abstract

The NADase CD38 is induced by factors secreted from senescent cells providing a potential link between senescence and age-related cellular NAD+ decline

Cited by 98 publications

References 36 publications

Where Metabolism Meets Senescence: Focus on Endothelial Cells

Where Metabolism Meets Senescence: Focus on Endothelial Cells

Interacting NAD⁺ and Cell Senescence Pathways Complicate Antiaging Therapies

CD38 in Neurodegeneration and Neuroinflammation

Contact Info

Product

Resources

About

The NADase CD38 is induced by factors secreted from senescent cells providing a potential link between senescence and age-related cellular NAD+ decline

Cited by 98 publications

References 36 publications

Where Metabolism Meets Senescence: Focus on Endothelial Cells

Where Metabolism Meets Senescence: Focus on Endothelial Cells

Interacting NAD+ and Cell Senescence Pathways Complicate Antiaging Therapies

CD38 in Neurodegeneration and Neuroinflammation

Contact Info

Product

Resources

About

Interacting NAD⁺ and Cell Senescence Pathways Complicate Antiaging Therapies