Nutrient sensing pathways as therapeutic targets for healthy ageing.

INTRODUCTION: In the present paper, the authors have discussed anti-aging strategies which aim to slow the aging process and to delay the onset of age-related diseases, focusing on nutrient sensing pathways (NSPs) as therapeutic targets. Indeed, several studies have already demonstrated that both in animal models and humans, dietary interventions might have a positive impact on the aging process through the modulation of these pathways. Areas covered: Achieving healthy aging is the main challenge of the twenty-first century because lifespan is increasing, but not in tandem with good health. The authors have illustrated different approaches that can act on NSPs, modulating the rate of the aging process. Expert opinion: Humanity's lasting dream is to reverse or, at least, postpone aging. In recent years, increasing attention has been devoted to anti-aging therapies. The subject is very popular among the general public, whose imagination runs wild with all the possible tools to delay aging and to gain immortality. Some approaches discussed in the present review should be able to substantially slow down the aging process, extending our productive, youthful lives, without frailty.

Mediterranean nutraceutical foods: Strategy to improve vascular ageing.

Ageing is characterized by a decline in all systemic functions. A greater susceptibility to apoptosis and senescence may contribute to proliferative and functional impairment of endothelial progenitor cells. They play an important role in neo-angiogenesis and endothelial repair. Vascular ageing is associated with changes in the structure and functions of vessels' wall. There are many possible causes of this damage. For sure, inflammation and oxidative stress play a fundamental role in the pathogenesis of endothelial dysfunction, commonly attributed to a reduced availability of nitric oxide. Inflammageing, the chronic low-grade inflammation that characterizes elderly people, aggravates vascular pathology and provokes atherosclerosis, the major cardiovascular disease. Nutraceutical and molecular biology represent new insights in this field. In fact, the first could represent a possible treatment in the prevention or delay of vascular ageing; the second could offer new possible targets for potential therapeutic interventions. In this review, we pay attention on the causes of vascular ageing and on the effects of nutraceuticals on it.

Association of Klotho polymorphisms with healthy aging: a systematic review and meta-analysis.

Today it is clearly evident that genetic background constitutes an integral part of aging and longevity. Many studies on long-lived people have been conducted emphasizing the role of certain genes in long life. Classic case-control studies, genome-wide association studies, and high-throughput sequencing have permitted identification of a variety of genetic variants seemingly associated with longevity. Over the years, aging research has focused on the insulin/insulin-like growth factor-1 (IGF-1) signaling pathway because of its evolutionarily conserved correlation with life-span extension in model animals. Indeed, many single-nucleotide polymorphisms (SNPs) associated with longevity were identified in genes encoding proteins that take part in this metabolic pathway. Closely related to this pathway is the Klotho gene. It encodes a type-I membrane protein expressed in two forms, membrane and secreted. The latter form suppresses oxidative stress and growth factor signaling and regulates ion channels and transporters. In particular, its over-expression seems to be able to suppress insulin/IGF-1 signaling extending life span. Thus, our aim was to assemble the results in the literature concerning the association between the functional variant of the Klotho "KL-VS" stretch, which contains six polymorphisms in linkage disequilibrium, and successful aging to quantify the possible effect of the variants. The results of our systematic review indicate that the Klotho KL-VS variant is associated with healthy aging.

SHIP2: a "new" insulin pathway target for aging research.

Strong evidence suggests that systemic inflammation and central adiposity contribute to and perpetuate metabolic syndrome. All of these alterations predispose individuals to type 2 diabetes mellitus (T2DM), cardiovascular disease, as well as Alzheimer's disease (AD), all characterized by chronic inflammatory status. On the other hand, extensive abnormalities in insulin and insulin-like growth factor I (IGF-I) and IGF-II signaling mechanisms in brains with AD have been demonstrated, suggesting that AD could be a third form of diabetes. The Src homology domain-containing inositol 5-phosphatase 2 (SHIP2) has an important role in the insulin pathway because its over-expression causes impairment of insulin/IGF-1 signaling. Because some single-nucleotide polymorphisms (SNP) of the gene encoding SHIP2 were significantly associated in T2DM patients with metabolic syndrome and some related conditions, we decided to conduct a case-control study on this gene, analyzing AD and T2DM subjects as cases and young, old, and centenarians as controls. Our results suggest a putative correlation between the the rs144989913 SNP and aging, both successful and unsuccessful, rather than age-related diseases. Because this SNP is an insertion/deletion of 28 bp, it might cause an alteration in SHIP2 expression. It is noteworthy that SHIP2 has been demonstrated to be a potent negative regulator of insulin signaling and insulin sensitivity. Many studies demonstrated the association of the insulin/IGF1 pathway with aging and longevity, so it is tempting to speculate that the found association with SHIP2 and aging might depend on its effect on the insulin/IGF-1 pathway.

Nutraceutical properties of extra-virgin olive oil: a natural remedy for age-related disease?

The health benefits of the Mediterranean diet can be largely ascribed to the nutraceutical properties of extra-virgin olive oil (EVOO). Mono-unsaturated fatty acids and various phenolic compounds, such as oleocanthal, oleuropein, hydroxytyrosol, and tyrosol, are the main nutraceutical substances of EVOO. These substances have been suggested to have the ability to modulate aging-associated processes. In experimental models, it has been shown that EVOO with high concentrations of polyphenols has anti-inflammatory and anti-oxidant properties. Indeed, it was observed that hydroxytyrosol and oleocanthal inhibit the cyclooxygenases (COX-1 and -2) responsible for prostaglandin production; oleuropein is a radical scavenger that blocks the oxidation of low-density lipoproteins. Due to the relevance of olive oil in the economy of Sicily, our group has been funded to assess the nutraceutical properties of different kinds of olive oil. Indeed, the aim of the study is to evaluate effects of EVOOs, with low and high polyphenols content, on immuno-inflammatory and oxidative stress responses in young and old people. A further objective of our group is to evaluate effects of EVOO, with low and high polyphenol content, on the expression of genes encoding proteins that take part in the insulin/insulin-like growth factor-1 signaling pathway involved in longevity. The results of the study will be useful for producing olive oil enriched in nutraceutical properties that may be likely helpful in the prevention of age-related diseases.

Association between genetic variations in the insulin/insulin-like growth factor (Igf-1) signaling pathway and longevity: a systematic review and meta-analysis.

Some studies have shown that polymorphisms in the insulin growth factor-1 (IGF-1) signaling pathway genes could influence human longevity. However, the results of different studies are often inconsistent. Our aim was to investigate by systematic review and meta-analysis the association of the common polymorphisms defining the genetic variability of the IGF-1 signaling pathway associated with human longevity. Eleven studies investigating the association between the polymorphisms in the IGF-1 signaling pathway genes (IGF-1, IGF-1 receptor (IGF-1R), Forkhead box O3A (FOXO3A) and Silent mating type Information Regulation 1 (SIRT1) and longevity were found and analyzed. The modelfree approach was applied to meta-analyze these studies. No association was reported between the single nucleotide polymorphisms (SNPs) of IGF-1 and longevity in the only available study. The meta-analysis of available data from four studies, showed a significant association with the IGF-1R polymorphism rs2229765, suggesting that subjects with the Abearing genotype have a greater chance of longevity. Concerning the five studies on FOXO3A SNPs, for the rs2764264 a significant association with longevity was observed for C allele when only males were included in the analysis. Statistically significant results were obtained for other SNPs as well, i.e. rs2802292 (G allele), rs9400239 and rs479744 (T and A alleles, respectively). For rs9400239 the association was observed in long lived males with a lower odds ratio than in centenarians, while in rs479744 a significant association was highlighted in centenarians. Concerning SIRT1, no association between the SNPs under study and longevity was observed in the only available report. Current findings suggest that both IGF-1R and FOXO3A polymorphisms could be associated with longevity. The high degree of between-study heterogeneity and the low number of available studies underline the need for further methodologically adequate analyses to confirm this evidence.