Downregulation of Sirt6 by CD38 promotes cell senescence and aging

Abstract

Decreased nicotinamide adenine dinucleotide (NAD+) levels accompany aging. CD38 is the main cellular NADase. Cyanidin-3-O-glucoside (C3G), a natural inhibitor of CD38, is a well-known drug that extends the human lifespan. We investigated mechanisms of CD38 in cell senescence and C3G in antiaging. Myocardial H9c2 cells were induced to senescence with D-gal. CD38 siRNA, C3G and UBCS039 (a chemical activator of Sirt6) inhibited D-gal-induced senescence by reducing reactive oxygen species, hexokinase 2 and SA--galactosidase levels. These activators also stimulated cell proliferation and telomerase reverse transcriptase levels, while OSS-128167 (a chemical inhibitor of Sirt6) and Sirt6 siRNA exacerbated the senescent process. H9c2 cells that underwent D-gal-induced cell senescence increased CD38 expression and decreased Sirt6 expression; CD38 siRNA and C3G decreased CD38 expression and increased Sirt6 expression, respectively; and Sirt6 siRNA stimulated cell senescence in the presence of C3G and CD38 siRNA. In D-gal-induced acute aging mice, CD38 and Sirt6 exhibited increased and decreased expression, respectively, in myocardial tissues, and C3G treatment decreased CD38 expression and increased Sirt6 expression in the tissues. C3G also reduced IL-1, IL-6, IL-17A, TNF-α levels and restored NAD+ and NK cell levels in the animals. We suggest that CD38 downregulates Sirt6 expression to promote cell senescence and C3G exerts an antiaging effect through CD38-Sirt6 signaling.

Hepatic Sirt6 protects against cholestatic liver disease primarily via inhibiting bile acid synthesis rather than antioxidation or triggering mitochondrial biogenesis

“…Hence, there is a requirement for safer and more efficient therapeutic solutions. Sirt6 agonist doesn't just address cholestasis by blocking CYP7A1 expression; it also offers additional benefits like slowing aging, reducing liver damage and scarring, and dampening inflammation and oxidative stress [40][41][42]. Moreover, Sirt6 agonist regulates CYP7A1 expression in distinct pathway compared to obeticholic acid, cilofexor, alafermin or fibrates, thus its combination with those old medicines may enhance overall efficacy and minimize potential toxicity.…”

NAD metabolism: Role in senescence regulation and aging

“…SIRT6 has been shown to regulate multiple senescence‐associated biological processes, including oxidative stress, glucose and fat homeostasis, inflammatory responses, autophagy, genome integrity, and telomeres homeostasis (Li et al, 2021 ). SIRT6 deficiency induces endothelial and myocardial cellular senescence (Lee et al, 2020 ; Zhou et al, 2022 ), and SIRT6 knockout mice have premature aging and hyperinflammation (Mostoslavsky et al, 2006 ). Studies also show that SIRT3 is involved in the development of senescence.…”