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

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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