Abstract
Biogerontological research highlighted a complex and dynamic connection between aging, health and longevity, partially determined by genetic factors. Multifunctional proteins with moonlighting features, by integrating different cellular activities in the space and time, may explain part of this complexity. Inositol Polyphosphate Multikinase (IPMK) is a potential moonlighting protein performing multiple unrelated functions. Initially identified as a key enzyme for inositol phosphates synthesis, small messengers regulating many aspects of cell physiology, IPMK is now implicated in a number of metabolic pathways affecting the aging process. IPMK regulates basic transcription, telomere homeostasis, nutrient-sensing, metabolism and oxidative stress. Here, we tested the hypothesis that the genetic variability of IPMK may affect human longevity. Single-SNP (single nuclear polymorphism), haplotype-based association tests as well as survival analysis pointed to the relevance of six out of fourteen genotyped SNPs for female longevity. In particular, haplotype analysis refined the association highlighting two SNPs, rs2790234 and rs6481383, as major contributing variants for longevity in women. Our work, the first to investigate the association between variants of IPMK and longevity, supports IPMK as a novel gender-specific genetic determinant of human longevity, playing a role in the complex network of genetic factors involved in human survival.
Highlights
In the last few decades, research on aging has seen progressive growth due to the social and medical burden correlated to the increase of the elderly population in developed countries
In order to evaluate if the detected effect of the polymorphisms on longevity may result in differential patterns of survival of the different relevant genotypes, we evaluated survival after 10 years from the baseline visit
Fourteen single nuclear polymorphism (SNP) from about 76 kb genomic sequences spanning the Inositol Polyphosphate Multikinase (IPMK) gene were selected for examination by a tagging approach
Summary
In the last few decades, research on aging has seen progressive growth due to the social and medical burden correlated to the increase of the elderly population in developed countries. These efforts point towards a better understanding of the connections between aging, health, and longevity as they may provide useful insights for strategies to improve the wellbeing of the elderly. The results obtained in different research areas underscored the dynamic complexity of such connections [1] These studies often identify genes involved in the regulation of the aging process that are susceptibility loci of one or multiple age-related diseases. The same variant exhibits opposite effects on the development of different diseases, with potential differential impact
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