Department of Foundational Biomedical Sciences, College of Osteopathic Medicine, Touro University California, Vallejo, CA 94592, USA.
Int J Mol Sci. 2024 Sep 29;25(19):10493. doi: 10.3390/ijms251910493.
Stress resistance is highly associated with longer and healthier lifespans in various model organisms, including nematodes, fruit flies, and mice. However, we lack a complete understanding of stress resistance in humans; therefore, we investigated how stress resistance and longevity are interlinked in humans. Using more than 180 databases, we identified 541 human genes associated with stress resistance. The curated gene set is highly enriched with genes involved in the cellular response to stress. The Reactome analysis identified 398 biological pathways, narrowed down to 172 pathways using a medium threshold (-value < 1 × 10). We further summarized these pathways into 14 pathway categories, e.g., cellular response to stimuli/stress, DNA repair, gene expression, and immune system. There were overlapping categories between stress resistance and longevity, including gene expression, signal transduction, immune system, and cellular responses to stimuli/stress. The categories include the PIP3-AKT-FOXO and mTOR pathways, known to specify lifespans in the model systems. They also include the accelerated aging syndrome genes (WRN and HGPS/LMNA), while the genes were also involved in non-overlapped categories. Notably, nuclear pore proteins are enriched among the stress-resistance pathways and overlap with diverse metabolic pathways. This study fills the knowledge gap in humans, suggesting that stress resistance is closely linked to longevity pathways but not entirely identical. While most longevity categories intersect with stress-resistance categories, some do not, particularly those related to cell proliferation and beta-cell development. We also note inconsistencies in pathway terminologies with aging hallmarks reported previously, and propose them to be more unified and integral.
在各种模式生物中，包括线虫、果蝇和老鼠，应激抗性与更长和更健康的寿命高度相关。然而，我们对人类的应激抗性缺乏全面的了解；因此，我们研究了人类的应激抗性和寿命如何相互关联。我们使用了 180 多个数据库，鉴定出了 541 个人类与应激抗性相关的基因。经过精心整理的基因集高度富集了与细胞应激反应相关的基因。Reactome 分析确定了 398 个生物学途径，使用中等阈值 (-值 < 1 × 10) 进一步缩小到 172 个途径。我们进一步将这些途径总结为 14 个途径类别，例如，细胞对刺激/应激的反应、DNA 修复、基因表达和免疫系统。应激抗性和寿命之间存在重叠的类别，包括基因表达、信号转导、免疫系统和细胞对刺激/应激的反应。这些类别包括已知在模型系统中指定寿命的 PIP3-AKT-FOXO 和 mTOR 途径。它们还包括加速衰老综合征基因（WRN 和 HGPS/LMNA），而这些基因也参与了非重叠的类别。值得注意的是，核孔蛋白在应激抗性途径中丰富，并与多种代谢途径重叠。这项研究填补了人类知识的空白，表明应激抗性与长寿途径密切相关，但不完全相同。虽然大多数长寿类别与应激抗性类别相交，但有些则不然，特别是那些与细胞增殖和β细胞发育有关的类别。我们还注意到与之前报道的衰老标志不一致的途径术语，并提出将它们更加统一和完整。
