Anti-senescence therapy for the treatment of age-associated cardiovascular and metabolic diseases

流行病学研究表明，年龄是动脉粥样硬化性心血管疾病的主要危险因素。然而，这类疾病风险增加的分子机制仍不清楚。体外培养的血管细胞寿命有限，最终进入不可逆转的生长停滞，称为“细胞衰老”。从患有早衰综合征（如Werner综合征和Bloom综合征）的患者身上提取的人类原代培养物，已知比从年龄匹配的健康人群中提取的培养物寿命短，这表明细胞衰老与衰老之间存在关系。我们证明在人类动脉粥样硬化病变中存在衰老血管细胞，但在非动脉粥样硬化病变中没有。此外，这些细胞表达的促炎分子水平升高，内皮一氧化氮合酶水平降低，表明体内细胞衰老参与了人类动脉粥样硬化和血管衰老的发病机制。我们发现了端粒功能在调节血管功能和血管细胞寿命方面的关键作用。我们还发现端粒独立通路，如AngII/Ras和胰岛素/Akt通路，对血管细胞衰老和与衰老相关的血管并发症至关重要。衰老改变了广泛的生理、内分泌和行为节律。我们在这里报告细胞衰老损害昼夜节律在体外和体内。血清刺激的衰老细胞中生物钟基因的昼夜节律表达明显弱于年轻细胞。端粒酶的引入完全阻止了与衰老相关的时钟基因表达的减少。当年轻细胞被植入幼鼠或老年小鼠体内时，被植入的细胞被受体的昼夜节律有效地引导。相反，植入的衰老细胞的夹带明显受损。这些结果表明，衰老降低了细胞向生物钟传递昼夜节律信号的能力，调节生物钟基因表达可能是治疗与年龄相关的昼夜节律障碍的一种新策略。少

Epidemiological studies have shown that age is the dominant risk factor for atherosclerotic cardiovascular diseases. However, the molecular mechanisms underlying the increased risk of such diseases that is conferred by aging remain unclear. Vascular cells have a finite lifespan when cultured in vitro and eventually enter an irreversible growth arrest called "cellular senescence." Human primary cultures derived from the patients with premature aging syndromes, such as Werner syndrome and Bloom syndrome, are known to have shorter lifespan than the cultures from age-matched healthy populations, suggesting a relationship between cellular senescence and aging. We demonstrated the presence of senescent vascular cells in human atherosclerotic lesions but not non-atherosclerotic lesions. Moreover, these cells expressed increased levels of proinflammatory molecules and decreased levels of endothelial nitric oxide synthase, suggesting that cellular senescence in vivo contributes to the pathogene … More sis of human atherosclerosis and vascular aging. We showed a critical role of telomere function in regulating vascular function as well as lifespan of vascular cells. We also found that telomere-independent pathways, such as AngII/Ras and insulin/Akt pathways, were crucial for vascular cell senescence and vascular complication associated with aging.Aging alters a broad spectrum of physiological, endocrine, and behavioral rhythms. We report here that cellular senescence impairs circadian rhythmicity both in vitro and in vivo. Circadian expression of clock genes in serum-stimulated senescent cells was significantly weaker compared with that in young cells. Introduction of telomerase completely prevented this reduction of clock gene expression associated with senescence. When young cells were implanted into young mice or old mice, the implanted cells were effectively entrained by the circadian rhythm of the recipients. In contrast, the entrainment of implanted senescent cells was markedly impaired. These results suggest that senescence decreases the ability of cells to transmit circadian signals to their clocks and that regulation of clock gene expression may be a novel strategy for the treatment of age-associated impairment of circadian rhythmicity. Less