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.