Rodella Luigi Fabrizio, Favero Gaia, Rossini Claudia, Foglio Eleonora, Bonomini Francesca, Reiter Russel J, Rezzani Rita
Department of Biomedical Sciences and Biotechnologies, Section of Human Anatomy, University of Brescia, Viale Europa 11, Brescia, Italy.
Age (Dordr). 2013 Feb;35(1):103-15. doi: 10.1007/s11357-011-9336-z. Epub 2011 Nov 23.
Aging is characterized by a progressive deterioration of physiological functions and metabolic processes. In aging and in diseases associated with the elderly, the loss of cells in vital structures or organs may be related to several factors. Sirtuin1 (SIRT1) is a member of the sirtuin family of protein deacetylases involved in life span extension; however, its involvement in the aging is not yet completely defined. Recently, melatonin, a pleiotropic molecule, shown to activate SIRT1 in primary neurons of young animals, as well as in aged neurons of a murine model of senescence. Melatonin is known to modulate oxidative stress-induced senescence and pro-survival pathways. We treated 6- and 15-week-old apolipoprotein E (APOE)-deficient mice (APOE 6w and 15w) with two melatonin formulations (FAST and RETARD) to evaluate their anti-aging effect. Morphological changes in vessels (aortic arch) of APOE mice were evaluated SIRT1, p53, endothelial nitric oxide synthase (eNOS), and endothelin-1 (ET-1) markers. We demonstrate that SIRT1 and eNOS decresed in APOE mice between 6 and 15 weeks and that aging induced an elevated expression of p53 and ET-1 in APOE animals. Melatonin improved the impairment of endothelial damage and reduced loss of SIRT1 and eNOS decreasing p53 and ET-1 expression. The RETARD melatonin preparation caused a greater improvement of vessel cytoarchitecture. In summary, we indicate that SIRT1-p53-eNOS axis as one of the important marker of advanced vascular dysfunctions linked to aging. Finally, we suggest that extended-release melatonin (RETARD) provides a more appropriate option for contrasting these dysfunctions compared with rapid release melatonin (FAST) administration.
衰老的特征是生理功能和代谢过程的逐渐衰退。在衰老以及与老年人相关的疾病中，重要结构或器官中的细胞丢失可能与多种因素有关。沉默调节蛋白1（SIRT1）是参与寿命延长的蛋白质去乙酰化酶沉默调节蛋白家族的成员；然而，其在衰老过程中的作用尚未完全明确。最近，褪黑素作为一种多效性分子，已被证明可在幼年动物的原代神经元以及衰老小鼠模型的老年神经元中激活SIRT1。已知褪黑素可调节氧化应激诱导的衰老和促生存途径。我们用两种褪黑素制剂（速释型和缓释型）处理6周龄和15周龄的载脂蛋白E（APOE）缺陷小鼠（APOE 6w和15w），以评估它们的抗衰老作用。通过SIRT1、p53、内皮型一氧化氮合酶（eNOS）和内皮素-1（ET-1）标志物评估APOE小鼠血管（主动脉弓）的形态学变化。我们证明，在6至15周龄的APOE小鼠中，SIRT1和eNOS减少，并且衰老诱导APOE动物中p53和ET-1的表达升高。褪黑素改善了内皮损伤的损害，并减少了SIRT1和eNOS的丢失，降低了p53和ET-1的表达。缓释型褪黑素制剂对血管细胞结构的改善更大。总之，我们指出SIRT1-p53-eNOS轴是与衰老相关的晚期血管功能障碍的重要标志物之一。最后，我们建议与速释型褪黑素（FAST）给药相比，缓释型褪黑素（RETARD）为对抗这些功能障碍提供了更合适的选择。
