Modulation of Lifespan and Healthspan by Meiosis Genes

减数分裂基因对寿命和健康寿命的调节

基本信息

  • 批准号:
    10724491
  • 负责人:
  • 金额:
    $ 23.85万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-09-01 至 2025-05-31
  • 项目状态:
    未结题

项目摘要

ABSTRACT: Modulation of Lifespan and Healthspan by Meiosis Genes The impact of advanced maternal age on fertility decline is well established, but how germline fitness influ- ences organismal health and aging remains unclear. It is known that reproductive defects augur detrimental long-term consequences in both sexes. For instance, early age-at-natural-menopause (ANM) has been linked to greater risk of mortality. Women with late ANM exhibit younger ‘epigenetic aging’ profiles and brothers of women with prolonged reproductive longevity show extended lifespan. Menopause itself triggers susceptibility to a host of comorbidities unrelated to reproduction such as cardiovascular disease and dementia, as does tes- tosterone decline in men. Thus, a compelling body of clinical and epidemiological evidence indicates that germline status influences overall organismal health and aging. However, human studies do not address cau- sality nor reveal the mechanisms by which the immortal germline may influence aging of the mortal somatic tissues. We have utilized the unique strengths of Caenorhabditis elegans to assess how perturbing meiosis, a pro- cess that occurs exclusively in germ cells, impacts the length of life and rate of aging of the animal. This pro- posal is based on our discovery that disruption of meiosis accelerates somatic aging. We found that mutations in C. elegans genes operating at different steps of meiosis shortened lifespan, impaired healthspan and desta- bilized protein homeostasis. Importantly, meiotic mutants exhibited prematurely aged transcriptional profiles reminiscent of old C. elegans and aging human tissues, suggesting that germline dysfunction triggers a con- served molecular-aging signature. Thus, we hypothesize that genes that govern meiotic fidelity in germ cells influence organismal lifespan and healthspan. Our study has revealed a hitherto unknown link between the nuclear events of meiosis in germ cells and the aging of both the gonadal tissue and the organism. This exploratory study aims to find the missing links in this pathway: what are the signals between the germ line and soma that lead to organismal aging (Aim 1), does the meiotic nuclear dysfunction lead to aging of the gonad as well and how is this connected to somatic aging (Aim 2). Notably, many of the genes we studied have human homologs with roles in mammalian meiosis and have been implicated in reproductive senescence. The transcriptional similarities we identified between meiosis mutants and aging human tissues suggest avenues to unravel potential evolutionarily conserved mechanisms underpinning the meiotic control of health and longevity. This study will establish the foundation for future mechanistic- and conservational- studies.
文摘:减数分裂基因对寿命和健康寿命的调节 高龄孕妇对生育率下降的影响是公认的,但生殖系健康如何影响生育。 目前尚不清楚机体的健康和衰老情况。众所周知,生殖缺陷是有害的预兆 对两性都有长期影响。例如,绝经早期自然年龄(ANM)与 导致更大的死亡风险。患有晚期ANM的女性表现出更年轻的“表观遗传衰老”特征和兄弟 生育寿命延长的女性表现出更长的寿命。更年期本身会触发易感性 一系列与生殖无关的并发症,如心血管疾病和痴呆症,就像TES一样- 男性的睾酮水平下降。因此,令人信服的临床和流行病学证据表明 生殖系状态会影响整体的生物体健康和衰老。然而,人体研究并没有解决病因-- 也没有揭示不朽生殖系可能影响死亡体细胞衰老的机制 纸巾。 我们利用秀丽线虫的独特优势来评估如何干扰减数分裂,一种促进减数分裂的过程。 仅发生在生殖细胞中的卵裂会影响动物的寿命和衰老速度。这位亲王- POSAL是基于我们的发现,即减数分裂中断会加速体细胞衰老。我们发现突变 在线虫减数分裂的不同阶段操作的基因缩短了寿命,损害了健康寿命和寿命- 胆汁化的蛋白质动态平衡。重要的是,减数分裂突变体表现出过早老化的转录特征。 这让人想起古老的线虫和老化的人体组织,表明生殖系功能障碍引发了一种慢性疾病-- 提供分子老化的签名。因此,我们假设控制生殖细胞减数分裂保真度的基因 影响生物寿命和健康寿命。 我们的研究揭示了迄今为止未知的生殖细胞减数分裂核事件与 性腺组织和生物体的衰老。这项探索性研究旨在找到 这条途径:胚系和胞体之间的信号是什么导致生物衰老(目标1), 减数分裂核功能障碍是否也会导致性腺老化?这与体细胞有何关系? 老龄化(目标2)。值得注意的是,我们研究的许多基因与人类在哺乳动物减数分裂中的作用有同源关系。 并与生殖衰老有关。我们发现的转录相似之处 减数分裂突变体和老化的人类组织暗示了解开进化上保守的潜力的途径 减数分裂控制健康和长寿的机制。这项研究将为今后的研究奠定基础 用于未来的机械论和保守主义研究。

项目成果

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Arjumand Ghazi其他文献

Arjumand Ghazi的其他文献

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{{ truncateString('Arjumand Ghazi', 18)}}的其他基金

A Pipeline for Research, Education and Mentoring in Reproductive Aging
生殖衰老研究、教育和指导渠道
  • 批准号:
    10663641
  • 财政年份:
    2023
  • 资助金额:
    $ 23.85万
  • 项目类别:
Role of the transcription elongation and splicing factor TCER-1 in repressing immunity and promoting fertility
转录延伸和剪接因子TCER-1在抑制免疫和促进生育力中的作用
  • 批准号:
    10358251
  • 财政年份:
    2021
  • 资助金额:
    $ 23.85万
  • 项目类别:
The Coordination of Lipid Synthesis and Breakdown in Metabolism and Aging
代谢和衰老中脂质合成和分解的协调
  • 批准号:
    9173620
  • 财政年份:
    2016
  • 资助金额:
    $ 23.85万
  • 项目类别:

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