Cancer treatment-induced NAD+ depletion in premature senescence and late cardiovascular complications

Abstract

Numerous studies have revealed the critical role of premature senescence induced by various cancer treatment modalities in the pathogenesis of aging-related diseases. Senescence-associated secretory phenotype (SASP) can be induced by telomere dysfunction. Telomeric DNA damage response induced by some cancer treatments can persist for months, possibly accounting for long-term sequelae of cancer treatments. Telomeric DNA damage-induced mitochondrial dysfunction and increased reactive oxygen species production are hallmarks of premature senescence. Recently, we reported that the nucleus-mitochondria positive feedback loop formed by p90 ribosomal S6 kinase (p90RSK) and phosphorylation of S496 on ERK5 (a unique member of the mitogen-activated protein kinase family that is not only a kinase but also a transcriptional co-activator) were vital signaling events that played crucial roles in linking mitochondrial dysfunction, nuclear telomere dysfunction, persistent SASP induction, and atherosclerosis. In this review, we will discuss the role of NAD+ depletion in instigating SASP and its downstream signaling and regulatory mechanisms that lead to the premature onset of atherosclerotic cardiovascular diseases in cancer survivors.

The significance of ERK5 catalytic-independent functions in disease pathways

“…We have observed the formation of a nucleus-mitochondria positive feedback loop that links mitochondrial dysfunction with nuclear telomere dysfunction, resulting in sustained dysfunctions and their associated biological consequences. This intricate feedback loop is primarily regulated by the signaling pathway involving p90RSK-mediated ERK5 S496 phosphorylation (Le et al, 2013;Kotla et al, 2021), as extensively discussed elsewhere (Le et al, 2012;Le et al, 2013;Vu et al, 2018;Singh et al, 2019;Banerjee et al, 2021;Kotla et al, 2021;Banerjee et al, 2022;Abe et al, 2023). Our key finding stems from evidence that demonstrates the occurrence of late cardiovascular complications in cancer survivors following cancer treatments (Yeh et al, 2004).…”

Metabolic regulation of endothelial senescence

“…SIPS is characterized by the upregulation of the p53/p21 Cip1/Waf1 , p16I NK4a /pRB pathways, positive staining for SA-β-gal, and, in some cases, telomere shortening (77). Unlike RS, SIPS can occur even in the absence of significant telomere shortening, as we (63,64,91) and others (77,92) have discussed previously.…”

Premature senescence and cardiovascular disease following cancer treatments: mechanistic insights

“…Activation of the p53/p21 Cip1/Waf1 and p16I NK4a /pRB pathways plays a central role in regulating senescence ( 132 ). Unlike RS, SIPS can occur without significant telomere shortening, as we ( 106 , 116 , 117 ) and others ( 132 , 136 ) have previously reviewed. Senescent cells secrete SASP factors, including various cytokines, growth factors, and proteases contributing to chronic inflammation and senescence-associated phenotypes ( 115 – 122 ).…”