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<p>In this study, we investigated the contribution of rare coding variants to human longevity by analyzing whole exome sequencing data from 1245 German long-lived individuals (LLI) and 4105 geographically matched younger controls. We identified novel exome-wide significant associations at both the single-variant and gene level, with a significant over-representation of genes involved in mechanistic target of rapamycin (mTOR) signaling. As such, three rare single variants in the mTOR-pathway genes <i>RPS6</i>,<i> FLCN</i>, and <i>SIK3</i> were enriched in LLI. Additionally, <i>RWDD1</i> emerged as a strong candidate gene for longevity, with LLI exhibiting a statistically significant burden of rare missense variants in this gene. Other associations involved <i>PRAC2</i>, <i>SLC16 A6</i>, <i>FOCAD</i>, <i>IHH</i>, <i>MESD</i>, <i>HOXA4</i>, and <i>DNAJB13</i>. Furthermore, we observed an enrichment of protein-truncating variants in the genes <i>ASXL1</i> and <i>TET2</i> amongst LLI, likely as a result of clonal haematopoiesis. The study emphasizes the role of rare variants in human longevity, particularly through mTOR signaling.</p>

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German longevity study reveals novel rare pro-longevity alleles clustering in mTOR signaling pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月15日

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  • Daniel Kolbe,
  • Janina Dose,
  • Pasquale Putter,
  • Malte Ziemann,
  • Matthias Laudes,
  • P. Eline Slagboom,
  • Andre Franke,
  • Joris Deelen,
  • Almut Nebel

摘要

In this study, we investigated the contribution of rare coding variants to human longevity by analyzing whole exome sequencing data from 1245 German long-lived individuals (LLI) and 4105 geographically matched younger controls. We identified novel exome-wide significant associations at both the single-variant and gene level, with a significant over-representation of genes involved in mechanistic target of rapamycin (mTOR) signaling. As such, three rare single variants in the mTOR-pathway genes RPS6, FLCN, and SIK3 were enriched in LLI. Additionally, RWDD1 emerged as a strong candidate gene for longevity, with LLI exhibiting a statistically significant burden of rare missense variants in this gene. Other associations involved PRAC2, SLC16 A6, FOCAD, IHH, MESD, HOXA4, and DNAJB13. Furthermore, we observed an enrichment of protein-truncating variants in the genes ASXL1 and TET2 amongst LLI, likely as a result of clonal haematopoiesis. The study emphasizes the role of rare variants in human longevity, particularly through mTOR signaling.