Aging and vascular dysfunction: beneficial melatonin effects

Abstract

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.

Sirtuins, aging, and cardiovascular risks

“…In a previous study, our research group indicated that the SIRT1-p53-NO axis may be one of the fundamental determinants of advancing endothelial dysfunction linked to aging and underlined the role of SIRT1 as a driver of cellular stress resistance and longevity. In particular, we observed that melatonin, pineal indoleamine which is known to be decreased during aging as well (Bubenik and Konturek 2011;Reiter et al 2002), increases SIRT1 expression and improves cellular survival at the aorta level of apolipoprotein E null mice, thereby reducing the progression of atherogenesis (Rodella et al 2013). SIRT1 may also prevent atherothrombosis by downregulating the endothelial expression of tissue factors; in fact, treatment of wild-type mice with the SIRT1 inhibitor in vivo enhanced tissue factor activity and markedly reduced the coagulation time in a photochemical vascular injury model (Breitenstein et al 2011).…”

“…SIRT1 may also prevent atherothrombosis by downregulating the endothelial expression of tissue factors; in fact, treatment of wild-type mice with the SIRT1 inhibitor in vivo enhanced tissue factor activity and markedly reduced the coagulation time in a photochemical vascular injury model (Breitenstein et al 2011). SIRT1 may be a potential target for the intervention on VSMC hypertrophy age-associated vascular disease, even if the mechanism are actually not well defined (Danz et al 2009;Guarani and Potente 2010;Li et al 2011;Rodella et al 2013).…”

“…Aging and atherosclerosis run along very similar pathways and determine many similar cardiovascular alterations; vessel aging may be viewed as representing the prodromal stage of atherosclerotic disease, or, conversely, atherosclerosis may be viewed as a form of accelerated arterial aging, probably favored by coexisting noxious stimuli, such as dyslipidemia, smoking, diabetes, and hypertension (Ferrari et al 2003;Ota et al 2010;Rivard et al 1999). Aging promotes also endothelial senescence and it is associated with pathways inducing atherosclerosis in humans (Rodella et al 2013). Indeed, atherosclerotic plaques show features of cellular senescence in terms of reduced cell proliferation, irreversible growth arrest, apoptosis, elevated DNA damage, epigenetic modifications, and telomere shortening and dysfunction (Wang and Bennett 2012).…”

Endothelial dysfunction and melatonin

“…These changes were not observed when the animals had been initially administrated (for 2-3 weeks) МТ (5 mg/kg) [42]. In a strain of mice with apolipoprotein E deficiency that simulated age-associated hypertension, a repeated use of МТ eliminated adverse hemodynamic changes, the metabolic dysfunction and other associated aberrations in the vessel cytoarchitectonics [69].…”

“…), accumulation of glutathione and so on. [38,58,70]. Actually, the limitation of oxidative stress that takes place actually under any cerebral and visceral pathology is viewed as the leading mechanism that lays the basis for both common and unique protective effects of MT [3,65].…”