Insulin pathway and its correlation with ageing and longevity

Ageing is unavoidable and leads to the reduction of the ability to adapt to the environment, involving the organism at all levels. Approximately 25% of the overall variation in human lifespan can be attributed to genetic factors, which become more relevant for extreme longevity. A “favourable” genetic background is essential to live longer. Longevity depends on the survival after reproduction and genes that lead to longevity are “survival genes” rather than “longevity genes”. But human population is very heterogeneous because of the different genetic background and different environmental stimuli thus it has not been yet possible to identify a clear panel of biomarkers of ageing and longevity. However, the correlation between nutritional, hormonal and immune-inflammatory pathways is particularly evident. The aim of my PhD was to explore the mechanisms that drive ageing and longevity focusing the attention on the role of insulin/IGF-1 pathway and of inflammatory mechanisms. In particular, the attention was focused on IGF-1, IGF-1 receptor, Forkhead box O (FOXO) 3A, Silent mating type information regulation 1, KLOTHO and SHIP2, all molecules directly or indirectly involved in the above mentioned pathway. Through reviews we explored the literature to summarize the existing data up to date. With systematic reviews and meta-analyses we identified some genetic variants associated with ageing and longevity . Moreover, we conducted a case-control study to verify the association of two SNPs of SHIP2 with T2DM and AD. The results confirmed previous studies about the association between FOXOA3A, IGF-1R and longevity but no association was reported between IGF-1 and SIRT1 (for the analyzed SNPs). This would be consistent with the hypothesis that most longevity genes have modest or small effect sizes. Moreover, we observed sex-specific differences in the association of the genetic variation with survival during old age. About KLOTHO, the KL-VS variant was associated with healthy ageing and longevity. This association was limited to KL-VS heterozygous people because the KL-VS homozygous undergoes to a detrimental effect of the polymorphism indicating a possible association mechanism not related to the gene dose. We also found an association of an insertion/deletion of 28 base pairs in INPPL1 that encodes for SHIP2 with ageing, both successfully and unsuccessfully. Moreover, it could be speculated that a reduction in insulin signaling may reduce the activation of NF-kB thus slow down the transcription of inflammatory genes. Hence, we agreed that a down regulation of this pathway can increase lifespan in human leading to “healthspan” and healthy longevity. Moreover, we agreed that inflammatory pathways have a crucial role, as well. Indeed, as previously discussed for the Sicilian population, there was an association between SNPs responsible for a low production of inflammatory mediators and longevity.