RESUMEN
Aging leads to a gradual decline in physical activity and disrupted energy homeostasis. The NAD+-dependent SIRT6 deacylase regulates aging and metabolism through mechanisms that largely remain unknown. Here, we show that SIRT6 overexpression leads to a reduction in frailty and lifespan extension in both male and female B6 mice. A combination of physiological assays, in vivo multi-omics analyses and 13C lactate tracing identified an age-dependent decline in glucose homeostasis and hepatic glucose output in wild type mice. In contrast, aged SIRT6-transgenic mice preserve hepatic glucose output and glucose homeostasis through an improvement in the utilization of two major gluconeogenic precursors, lactate and glycerol. To mediate these changes, mechanistically, SIRT6 increases hepatic gluconeogenic gene expression, de novo NAD+ synthesis, and systemically enhances glycerol release from adipose tissue. These findings show that SIRT6 optimizes energy homeostasis in old age to delay frailty and preserve healthy aging.
Asunto(s)
Metabolismo Energético/genética , Fragilidad/metabolismo , Envejecimiento Saludable/metabolismo , Longevidad/genética , Sirtuinas/metabolismo , Animales , Modelos Animales de Enfermedad , Femenino , Fragilidad/genética , Regulación de la Expresión Génica/fisiología , Gluconeogénesis/genética , Glucosa/metabolismo , Envejecimiento Saludable/genética , Humanos , Hígado/metabolismo , Masculino , Ratones , Ratones Transgénicos , Sirtuina 1/genética , Sirtuina 1/metabolismo , Sirtuinas/genéticaRESUMEN
Recent studies from our laboratory have revealed that basic fibroblast growth factor (bFGF) selectively inhibits the proliferation of human MCF-7 breast cancer cells. It has also been shown to enhance cis-platinum-induced apoptosis, decrease levels of the anti-apoptotic gene product bcl-2, and increase levels of the cyclin-dependent protein kinase inhibitor p21/WAF1/Cip1. Transforming growth factor beta-1 (TGFbeta1), a cell growth regulator has been found to have an inhibitory effect on breast cancer cells. The aim of the present study was to evaluate the possible role of TGFbeta1 in the antiproliferative effects of bFGF in MCF-7 breast cancer cells. We found that exogenous, as well as endogenous (overexpressed) bFGF increased TGFbeta1 mRNA expression in the cells and enhanced the secretion of TGFbeta1 into culture medium. However, exogenous addition of TGFbeta1 neither led to a decrease in bcl-2 nor induced an increase in the levels of p21/WAF1/Cip1 and neutralizing antibodies to TGFbeta1, did not reverse bFGF-induced G1 arrest northe increase in p21/WAF1/Cip1 level. In contrast, antisense oligonucleotides to TGFbeta1 abrogated the antiproliferative effects and inhibited the induction of p21/WAF1/Cip1 by bFGF in MCF-7 cells. These data suggest that the anti-proliferative effects of bFGF in human MCF-7 breast cancer cells are mediated by endogenous TGFbeta1, while exogenous TGFbeta1 does not mimic all the effects of bFGF on these breast cancer cells. These findings provide an important basis for further investigations into the autocrine and paracrine processes that control the growth of breast cancer cells.
