Sirtuins

Brain aging is linked to certain types of neurodegenerative diseases and identifying new therapeutic targets has become critical. Melatonin, a pineal hormone, associates with molecules and signaling pathways that sense and influence energy metabolism, autophagy, and circadian rhythms, including insulin-like growth factor 1 (IGF-1), Forkhead box O (FoxOs), sirtuins and mammalian target of rapamycin (mTOR) signaling pathways. This review summarizes the current understanding of how melatonin, together with molecular, cellular and systemic energy metabolisms, regulates epigenetic processes in the neurons. This information will lead to a greater understanding of molecular epigenetic aging of the brain and anti-aging mechanisms to increase lifespan under healthy conditions.

Recent findings demonstrate that nutrition during the fetal and neonatal periods can affect the life span of an organism. Our previous studies in rodents using a maternal low protein diet have shown that limiting protein and growth during lactation [postnatal low protein (PLP group)] increases longevity, while in utero growth restriction (IUGR) followed by "catch up growth" (recuperated group) shortens life span. The aim of this study was to investigate mechanisms in early postnatal life that could underlie these substantial differences in longevity. At weaning, PLP animals had improved insulin sensitivity as suggested by lower concentrations of insulin required to maintain concentrations of glucose similar to those of the control group and significant upregulation of insulin receptor-beta, IGF-1 receptor, Akt1, Akt2, and Akt phosphorylated at Ser 473 in the kidney. These animals also had significantly increased SIRT1 (mammalian sirtuin) expression. Expression of the antioxidant enzymes catalase, CuZnSOD, and glutathione peroxidase-1 was elevated in these animals. In contrast, recuperated animals had a significantly increased fasting glucose concentration, while insulin levels remained comparable to those of the control group suggesting relative insulin resistance. MnSOD expression was increased in these animals. These data suggest that early nutrition can lead to alterations in insulin sensitivity and antioxidant capacity very early in life, which may influence life span.

Chromosome segregation is a crucial phenomenon in the cell cycle and defects in genome segregation result in an abnormality in various cellular events. Unlike higher eukaryotes, chromosome segregation and a number of cell cycle events are unusual in the protozoan parasite Entamoeba histolytica (E. histolytica). Characterization of Sir2 proteins from E. histolytica may reveal its unique cellular events as they play role in diverse cellular processes including chromosome segregation. E. histolytica has four homologs of Sir2 proteins. EhSir2a and EhSir2b show sequence similarity towards eukaryotic Sir2 homologs, whereas EhSir2c and EhSir2d are more like prokaryotic sirtuins. Using both computational and experimental methods, EhSir2c has been characterized in this study. The three-dimensional structure of EhSir2c is predicted by homology modelling. The protein interactors of EhSir2c have been identified by yeast-two-hybrid screening against the cDNA library of E. histolytica. We have identified a novel interactor, EhRAD23 which is a homolog of UV excision repair protein RAD23. The interaction of EhSir2c and EhRAD23 was validated by pull-down assay. UV-C irradiation up-regulates the relative expression of EhSir2c, suggesting the necessity of EhSir2c in UV-induced stress in this parasite.

The Silent Information Regulator (SIR2) family of genes have been cloned from a variety of species ranging from bacteria to man. In previous studies, we reported the characterization of a Leishmania major gene encoding a protein with extensive homology to yeast SIR2p and expressed by different Leishmania species and parasite developmental stages and thus termed LmSIR2. Unlike the yeast SIR2p, LmSIR2p is mainly localized within the cytoplasm. In the present study, sequencing of a homologue encoding gene in another Leishmania species, Leishmania infantum, revealed 93% overall amino acid identity with L. major SIR2 gene. Further, using L. infantum as a recipient for a plasmid vector (pTEX) which allows overexpression of LmSIR2p led to the accumulation of the protein in the parasite cytoplasm of both promastigote and amastigote forms and a striking increase in the survival of amastigotes, the vertebrate stage of the parasite, when maintained under normal axenic culture conditions. This ...