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Cited by 15Alzheimer's disease research and treatmentsGenetics, Aging, and Longevity in Model OrganismsGenetic Associations and Epidemiology

IP6K3 and IPMK Variations in LOAD and Longevity: Evidence for a Multifaceted Signaling Network at the Crossroad between Neurodegeneration and Survival

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Dato, Serena, Crocco, Paolina, De Rango, Francesco, Iannone, Francesca, Maletta, Raffaele, Bruni, Amalia C., Saiardi, Adolfo, Rose, Giuseppina +1 more·2021·Mechanisms of Ageing and Development
DOI 10.1016/j.mad.2021.111439
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Abstract

Several studies reported that genetic variants predisposing to neurodegeneration were at higher frequencies in centenarians than in younger controls, suggesting they might favor also longevity. IP6K3 and IPMK regulate many crucial biological functions by mediating synthesis of inositol poly- and pyrophosphates and by acting non-enzymatically via protein-protein interactions. Our previous studies suggested they affect Late Onset Alzheimer Disease (LOAD) and longevity, respectively. Here, in the same sample groups, we investigated whether variants of IP6K3 also affect longevity, and variants of IPMK also influence LOAD susceptibility. We found that: i) a SNP of IP6K3 previously associated with increased risk of LOAD increased the chance to become long-lived, ii) SNPs of IPMK, previously associated with decreased longevity, were protective factors for LOAD, as previously observed for UCP4. SNP-SNP interaction analysis, including our previous data, highlighted phenotype-specific interactions between sets of alleles. Moreover, linkage disequilibrium and eQTL data associated to analyzed variants suggested mitochondria as crossroad of interconnected pathways crucial for susceptibility to neurodegeneration and/or longevity. Overall, data support the view that in these traits interactions may be more important than single polymorphisms. This phenomenon may contribute to the non-additive heritability of neurodegeneration and longevity and be part of the missing heritability of these traits.

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  • Certain IPMK SNPs, previously associated with decreased longevity, are protective factors for Late Onset Alzheimer's Disease.

    “Another study investigating the relationship between Late Onset Alzheimer’s Disease (LOAD) and longevity found that certain IPMK SNPs, previously associated with decreased longevity, were protective factors for LOAD [91].”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [91]

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Authors
Dato, S., Crocco, P., De Rango, F., Iannone, F., Maletta, R., Bruni, A. C., Saiardi, A., Rose, G., & Passarino, G.
Affiliations
  • University of Calabria (IT)
  • MRC Laboratory for Molecular Cell Biology (GB)
Corresponding author
  • Rose, Giuseppina
  • Passarino, Giuseppe
ORCID
Venue
Mechanisms of Ageing and Development
Publisher
Elsevier BV
Published
2021-04
Volume
195
Pages
111439
ISSN
0047-6374 (ISSN-L)
DOI
10.1016/j.mad.2021.111439
OpenAlex
W3123229164
Cited by
15
References
2
Citations by year
2026: 2 · 2025: 4 · 2023: 6 · 2021: 3
FWCI
1.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Mechanisms of Ageing and Development (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Archive of Doctoral Theses and Digital Collections (University of Calabria) (submittedVersion)
Funders
  • Medical Research Council
  • Ministero dell’Istruzione, dell’Università e della Ricerca
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
inositol polyphosphate multikinase, inositol polyphosphates, inositol pyrophosphates, late-onset Alzheimer's disease, longevity, centenarians, single nucleotide polymorphisms, gene-gene interaction, linkage disequilibrium, expression quantitative trait loci, mitochondria, missing heritability, neurodegeneration, UCP4
MeSH terms
Aged, Aging, Alzheimer Disease, Female, Humans, Italy, Longevity, Male, Mitochondria, Signal Transduction, Phosphotransferases (Alcohol Group Acceptor), Phosphotransferases (Phosphate Group Acceptor), Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Protein Interaction Mapping

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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