Inositol Polyphosphate Multikinase (IPMK), a Gene Coding for a Potential Moonlighting Protein, Contributes to Human Female Longevity

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.

Inositol Polyphosphate Multikinase Signaling: Multifaceted Functions in Health and Disease

“…Recently, genetic variations of human IPMK have been identified as potential factors involved in Alzheimer's disease, inflammation, and the control of longevity (Dato et al, 2021;De Rango et al, 2019;Yokoyama et al, 2016). Therefore, additional studies on Ipmk mutations and single-nucleotide polymorphisms will improve our understanding of the role of IPMK signaling.…”

IP6K3 and IPMK variations in LOAD and longevity: Evidence for a multifaceted signaling network at the crossroad between neurodegeneration and survival

“…A panel of 17 SNPs within approximately 30 kb encompassing the entire IP6K3 gene and its 5′ and 3′ flanking regions were genotyped in all subjects included in the study and chosen based on those genotyped in the previous study by Crocco et al (2016). Similarly, 14 SNPs were investigated for IPMK, mapping within and nearby the gene and prioritized by a tagging approach (De Rango et al, 2019). Genotyping was performed by iPlex Gold Genotyping Assay and Sequenom MassArray (Sequenom, San Diego, CA, USA) technology, following the manufacturer's instructions.…”

“…We then investigated the IPMK variants previously studied in relation to longevity (De Rango et al, 2019), in patients affected by LOAD. In consideration of the sex-specific effect of IPMK SNPs on longevity, the data were analysed according to gender.…”

“…We recently demonstrate that the genetic variability of IPMK affect human longevity, by reporting a six-SNPs haplotype that significantly influences female longevity (De Rango et al, 2019). Additionally, a study by Crocco et al (2016) showed that the variability of IP6K3, which is highly expressed in the brain, is associated with increased risk of late onset Alzheimer's disease (LOAD).…”

Untangling the Genetics of Human Longevity—A Challenging Quest

“…The papers by De Rango et al and Crocco et al highlight the complexity of longevity, a highly dynamic phenotype influenced by internal and external stresses, that makes the identification of genes robustly associated with it very challenging. De Rango’s paper investigated for the first time the contribution to the longevity phenotype of the genetic variability of IPMK (Inositol Polyphosphate Multikinase), a potential moonlighting protein performing multiple functions in pathways affecting the aging process, from nutrient-sensing to oxidative stress and telomere maintenance [5]. This paper supports this gene as a novel gender-specific determinant of human longevity on one hand, and on the other hand promotes pleiotropic proteins like IPMK, able to integrate cellular activities in space and time, as crucial determinants of the complex connections among aging, health, and longevity.…”