Amino acids and amino acid sensing: implication for aging and diseases.

Biogerontological research indicates nutrition as one of the major determinants of healthy aging, due to the role of nutrients in maintaining the dynamic-homeostasis of the organism. In this frame, the importance of proteins and constitutive amino acids (AAs), and in particular of functional AAs is emerging. The ability to sense and respond to changes in AAs availability is mediated by a complex network of dynamic players, crucial for an efficient regulation of their downstream effects. Here, we reviewed the current knowledge about the involvement of AA sensing mechanisms in aging and age-related diseases, focusing our attention on mTORC1 and AA transporters. In this context it is of note that alterations in AA sensors have been reported to be directly implicated in age-related phenotypes, suggesting that their modulation can represent a possible strategy for modulating (and possibly delaying) aging decline. Furthermore, these alterations may influence the effects of AA supplementation, by influencing the individual answer to AA availability. On the whole, evidences support the hypothesis that the efficiency of components of AA sensing network may have important implications for therapy, and their knowledge may be crucial for programming AA supplementation for contrasting age-related phenotypes, opening new opportunities for therapeutic interventions aimed to promote human health span.

Physical decline and survival in the elderly are affected by the genetic variability of amino acid transporter genes.

Amino acid (AA) availability is a rate-limiting factor in the regulation of muscle protein metabolism and, consequently, a risk factor for age-related decline in muscle performance. AA transporters are emerging as sensors of AA availability and activators of mTORC1 signalling, acting as transceptors. Here, we evaluated the association of 58 single nucleotide polymorphisms (SNPs) in 10 selected AA transporter genes with parameters of physical performance (Hand Grip, Activity of Daily Living, Walking time). By analysing a sample of 475 subjects aged 50-89 years, we found significant associations with SLC7A5/LAT1, SLC7A8/LAT2, SLC36A1/PAT1, SLC38A2/SNAT2, SLC3A2/CD98, SLC38A7/SNAT7 genes. Further investigation of the SNPs in a cross-sectional study including 290 subjects aged 90-107 years revealed associations of SLC3A2/CD98, SLC38A2/SNAT2, SLC38A3/SNAT3, SLC38A9/SNAT9 variability with longevity. Finally, a longitudinal study examining the survival rate over 10 years showed age-dependent complexity due to possible antagonistic pleiotropic effects for a SNP in SLC38A9/SNAT9, conferring a survival advantage before 90 years of age and a disadvantage later, probably due to the remodelling of AA metabolism. On the whole, our findings support the hypothesis that AA transporters may impact on the age-related physical decline and survival at old age in a complex way, likely through a mechanism involving mTORC1 signalling.

Reduction of Syndecan Transcript Levels in the Insulin-Producing Cells Affects Glucose Homeostasis in Adult Drosophila melanogaster.

Signaling by direct cell-matrix interactions has been shown to impact the transcription, secretion, and storage of insulin in mammalian ß cells. However, more research is still needed in this area. Syndecans are transmembrane heparan sulfate proteoglycans that function independently and in synergy with integrin-mediated signaling to mediate cell adhesion to the extracellular matrix. In this study, we used the model organism Drosophila melanogaster to determine whether knockdown of the Syndecan (Sdc) gene expression specifically in the insulin-producing cells (IPCs) might affect insulin-like peptide (ILP) production and secretion. IPCs of adult flies produce three ILPs (ILP2, ILP3, and ILP5), which have significant homology to mammalian insulin. We report that flies with reduced Sdc expression in the IPCs did not show any difference in the expression of ilp genes compared to controls. However, they had significantly reduced levels of the circulating ILP2 protein, higher circulating carbohydrates, and were less glucose tolerant than control flies. Finally, we found that IPCs-specific Sdc knockdown led to reduced levels of head Glucose transporter1 gene expression, extracellular signal-regulated kinase phosphorylation, and reactive oxygen species. Taken together, our findings suggest a cell autonomous role for Sdc in insulin release in D. melanogaster.