#1

It would seem that we could use the AI software from this new startup mentioned here: Chat GPT and AI in Healthcare Thread - #215 by RapAdmin to evaluate the prevalence in our own genome of these longevity associated SNPs.

ChatGPT Image Oct 21, 2025 at 09_46_36 AM
ChatGPT Image Oct 21, 2025 at 09_46_36 AM1024×1024 81.2 KB

Centenarians and supercentenarians serve as models for studying exceptional longevity, offering insights into the aging process and resistance to age-related diseases. This research investigates common genetic variations (SNPs) shared among 3 centenarians and 18 supercentenarians, individuals aged 110 years or older. 754,520 SNPs were found to be common among all the 21 samples.

… research on the whole genome sequences of male and female supercentenarians who are both older than 114 years has revealed that the remarkable longevity is probably caused by a genetic predisposition involving both common and uncommon genetic variants. [14]. Besides, in 2013, comparing 6 supercentenarians, a total of 89 novel non-synonymous SNPs (nsSNPs) and already reported 51 nsSNPs were found among them. [15] Garagnani P, 2021 reported that DNA repair and clonal hematopoiesis as vital players for healthy aging and defense from cardiovascular events by analyzing the genome of semi-supercentenarians (105–110 older) and supercentenarians.

Full (Open access) Paper here: Genetic signatures of exceptional longevity: a comprehensive analysis of coding region single nucleotide polymorphisms (SNPs) in centenarians and supercentenarians | Human Genomics | Full Text

AI Summary of paper:

Here’s a detailed summary of the paper “Genetic signatures of exceptional longevity” (Raj et al., 2025) including all reported longevity-associated and deleterious SNPs with their known or predicted biological functions:

:small_blue_diamond: Study Overview

  • Cohort: 21 individuals (3 centenarians, 18 supercentenarians, ages 106–119).
  • SNP count: 754,520 shared → 11,348 coding → 4,980 non-synonymous → 110 predicted deleterious (SIFT ≤ 0.05).
  • Databases used: SNPnexus, Ensembl (GRCh37), 1000 Genomes, gnomAD.
  • Top enriched pathways: ECM remodeling, signal transduction, immune defense, sensory processing, protein/RNA metabolism.

:small_blue_diamond: Longevity-Associated SNPs (previously reported + confirmed here)

SNP Gene Function / Process Notes
rs412051 APOE (proximal region) Lipid transport, neuroprotection Recurrent in long-lived cohorts; associated with APOE ε2 haplotype longevity bias
rs9885916 FOXO3A intronic Stress resistance, insulin/IGF signaling Classical longevity SNP, replicates across multiple populations
rs575564328 KMT2C Histone H3K4 methyltransferase, epigenetic regulation Predicted deleterious; rare variant (<1 % MAF) linked to transcriptional resilience
rs75029097 NEMF Ribosome-associated quality control (mitochondrial UPR) Maintains proteostasis; may confer mitochondrial stress tolerance
rs11228733 MAP2K3 p38-MAPK signaling, oxidative stress response Involved in nutrient sensing, cell survival under stress
rs61849494 TIMM23 Mitochondrial protein import translocase Supports mitochondrial integrity; low MAF < 1 %
rs150316320 MDM1 Cell-cycle and DNA-damage regulation May affect senescence suppression
rs141207681 ESPL1 Separase enzyme, chromosomal stability Absent in gnomAD; protects genomic fidelity in dividing cells

:small_blue_diamond: Novel Deleterious SNPs (16 variants across 9 genes)

Gene Function Associated process in aging/longevity
TIMM23 Mitochondrial inner-membrane import Bioenergetic maintenance, ROS control
NEMF Ribosomal rescue complex Protein quality control, mitochondrial UPR
KMT2C (MLL3) Histone methylation (H3K4me1/3) Epigenetic rejuvenation, chromatin plasticity
MAP2K3 p38 MAPK kinase Stress signaling, hormetic adaptation
ZNF214 / ZNF534 Zinc-finger transcription factors DNA repair regulation, telomere maintenance
MDM1 Centrosome/DNA-damage regulator Anti-senescence, tumor suppression
ESPL1 Chromosome segregation enzyme Genomic stability, mitotic fidelity
CDK11A/B Cyclin-dependent kinase family Cell-cycle control, apoptosis modulation
PDE4DIP / PRIM2 cAMP metabolism / DNA replication primase Signaling and genome maintenance

:small_blue_diamond: Functional Themes of Deleterious SNPs

  1. Mitochondrial protection: TIMM23, NEMF → support mitochondrial protein import & UPR.
  2. Epigenetic homeostasis: KMT2C → histone-methylation balance influencing stress-response genes.
  3. Genomic stability: ESPL1, MDM1 → limit aneuploidy & DNA damage.
  4. Signal transduction & stress adaptation: MAP2K3, CDK11 → p38 MAPK, apoptotic control.
  5. Transcriptional regulation: ZNF family → broad transcriptional fine-tuning.
  6. Protein metabolism: NEMF → proteostasis and resilience to proteotoxic stress.

:small_blue_diamond: Pathway Enrichment Highlights

  • Extracellular matrix (ECM) remodeling: COL, MMP, LOX genes—tissue integrity.
  • Signal transduction: MAPK, PI3K-AKT, RAS pathways—metabolic resilience.
  • Sensory perception: GPCR genes—maintaining neural/cognitive sensitivity.
  • Protein/RNA metabolism: ribosomal, spliceosomal genes—translation accuracy.
  • Immune regulation: HLA, interferon pathways—immunosenescence resistance.

:small_blue_diamond: Summary Interpretation

  • The 110 deleterious SNPs cluster in 79 genes, many tied to mitochondrial function, chromatin regulation, and DNA repair—core hallmarks of aging.
  • Several rare or novel variants (< 1 % MAF or absent in gnomAD) suggest private protective genotypes.
  • Notably, FOXO3A and APOE longevity SNPs co-appear with new candidates like TIMM23 and KMT2C, pointing to a multi-system genetic architecture underlying exceptional human lifespan.