Anti‐aging properties of melatonin in an in vitro murine senescence model: involvement of the sirtuin 1 pathway

Abstract

Sirtuin 1 is a member of the sirtuin family of protein deacetylases, which have attracted considerable attention as mediators of lifespan extension in several model organisms. Induction of sirtuin 1 expression also attenuates neuronal degeneration and death in animal models of Alzheimer's disease and Huntington's disease. In this study, an in vitro model of neuronal aging was used to test in several ways whether melatonin acts as a sirtuin 1 inducer and if this effect could be neuroprotective. It is shown that melatonin is able to increase the level of this deacetylase in young primary neurons, as well as in aged neurons. We also observed an increase in the deacetylation of several substrates of sirtuin 1, such as p53, PGC-1alpha, FoxO1, ADAM10 and NFkappaB. In addition, there was a reduction in its nuclear translocation and, subsequently, an improvement in transcriptional activity. Sirtinol, a sirtuin 1 inhibitor, was used to correlate these effects with sirtuin. It is shown that sirtinol reduces sirtuin 1 expression and impairs the beneficial action of melatonin on cell viability and apoptosis prevention. Moreover, some of the sirtuin 1 substrates studied also reversed the melatonin effect when sirtinol is added to the cells, mainly p53. Globally, these results add weight to the findings of previous reports, indicating a new role for melatonin in improving cell function gated to an increased neuroprotective role for the sirtuin 1 pathway.

Caloric restriction, resveratrol and melatonin: Role of SIRT1 and implications for aging and related-diseases

“…Focusing on neuroprotective effects in aging, in neuronal cultures from cerebellum, melatonin also enhanced the deacetylation of various SIRT1 substrates, such as PGC-1␣, FOXO1, NF-B and p53, effects which were largely reversed by the SIRT1 inhibitor sirtinol (Tajes et al, 2009). This suggests that pretreatment with melatonin partially prevents neuronal disturbances associated with aging.…”

Melatonin and ubiquitin: what’s the connection?

“…they point out that PGC-1a also stimulated the expression of rOS-detoxifying enzymes and hence is a major regulator of free radical removal. In neuronal cell cultures, melatonin has been shown to stimulate the deacetylation of PGC-1a [73]. Hardeland and colleagues [74] interpret this as evidence that mitochondrial biogenesis is stimulated by melatonin.…”

Melatonin plus physical exercise are highly neuroprotective in the 3xTg-AD mouse

“…Exercise, particularly aerobic exercise, has been reported to increase mitochondrial biogenesis in experimental animals through activation of PGC1 (Viña et al, 2009). Activation of PGC1 by melatonin has been demonstrated in aged cultured neurons (Tajes et al, 2009). Therefore, this and other pathways probably contributed to the healthy status of mitochondria in the 3xTg-AD mice treated with the combination of melatonin and exercise.…”