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

• 批准号: 10724491
• 负责人: Arjumand Ghazi
• 金额: $ 23.85万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10724491
• 关键词: Acceleration; Address; Age; Aging; Animals; Biological Assay; Brothers; Caenorhabditis elegans; Cardiovascular Diseases; Clinical; Coal; Data; Defect; Dementia; Disease; Elderly; Epidemiology; Epigenetic Process; Etiology; Exhibits; Fertility; Foundations; Functional disorder; Future; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genome; Germ Cells; Germ Lines; Gonadal structure; Health; Homologous Gene; Human; Impairment; Individual; Knowledge; Lead; Ligands; Link; Longevity; Mediating; Meiosis; Menopause; Modeling; Molecular; Molecular Genetics; Mutation; Nematoda; Nuclear; Nuclear Accidents; Organism; Outcome; Pathway interactions; Predisposition; Pregnancy; Premature aging syndrome; Process; Public Health; Regulatory Pathway; Reproduction; Reproductive Health; Reproductive system; Research; Role; SPO11 gene; Serinus; Signal Pathway; Signal Transduction; Sterility; Testing; Testosterone; Tissues; WNT Signaling Pathway; Woman; Work; advanced maternal age; age related; aged; beta catenin; comorbidity; fitness; genetic approach; healthspan; human tissue; in vivo; insight; member; men; mortality; mortality risk; mutant; neuronal cell body; novel; premature; programs; proteostasis; receptor; reproductive; reproductive fitness; reproductive longevity; reproductive senescence; response; sex; therapy design; transcription factor; transcriptome; transcriptome sequencing; transmission process; trend; young adult; Acceleration; Address; Age; Aging; Animals; Biological Assay; Brothers; Caenorhabditis elegans; Cardiovascular Diseases; Clinical; Coal; Data; Defect; Dementia; Disease; Elderly; Epidemiology; Epigenetic Process; Etiology; Exhibits; Fertility; Foundations; Functional disorder; Future; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genome; Germ Cells; Germ Lines; Gonadal structure; Health; Homologous Gene; Human; Impairment; Individual; Knowledge; Lead; Ligands; Link; Longevity; Mediating; Meiosis; Menopause; Modeling; Molecular; Molecular Genetics; Mutation; Nematoda; Nuclear; Nuclear Accidents; Organism; Outcome; Pathway interactions; Predisposition; Pregnancy; Premature aging syndrome; Process; Public Health; Regulatory Pathway; Reproduction; Reproductive Health; Reproductive system; Research; Role; SPO11 gene; Serinus; Signal Pathway; Signal Transduction; Sterility; Testing; Testosterone; Tissues; WNT Signaling Pathway; Woman; Work; advanced maternal age; age related; aged; beta catenin; comorbidity; fitness; genetic approach; healthspan; human tissue; in vivo; insight; member; men; mortality; mortality risk; mutant; neuronal cell body; novel; premature; programs; proteostasis; receptor; reproductive; reproductive fitness; reproductive longevity; reproductive senescence; response; sex; therapy design; transcription factor; transcriptome; transcriptome sequencing; transmission process; trend; young adult

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.

摘要：减数分裂基因对寿命和保健的调节 晚期生物年龄对生育能力下降的影响已经确定，但是种系健身如何影响 - 加密有机健康和衰老尚不清楚。众所周知，生殖缺陷augur有害 两性的长期后果。例如，已链接到自然的年龄段（ANM） 更大的死亡风险。 ANM晚期的妇女展示了年轻的“表观遗传衰老”概况和兄弟 长期繁殖寿命的妇女表明寿命延长。更年期本身会触发易感性 对于与繁殖无关的合并症，例如心血管疾病和痴呆症，TES-也是如此 男性的丁香酮下降。这是一个令人信服的临床和流行病学证据的体系，表明 种系状态影响整体有机健康和衰老。但是，人类研究并未解决 sality也不揭示不朽种系可能影响凡人的衰老的机制 组织。 我们利用了秀丽隐杆线虫的独特优势来评估减数分裂的扰动，这是一种促进 仅发生在生殖细胞中的刚刚影响动物衰老的寿命和速度。这个亲 Posal是基于我们发现的，即减数分裂的破坏会加速体细胞衰老。我们发现突变 在秀丽隐杆线虫基因以减数分裂的不同步骤工作的寿命缩短的情况下，HealthSpan和Desta- 双蛋白稳态。重要的是，暴露于先前老化的转录曲线的减数分裂突变体 让人想起旧的秀丽隐杆线虫和衰老的人体组织，这表明种系功能障碍会触发 使用的分子签名。这是我们假设控制生殖细胞减少忠诚度的基因 影响有机寿命和健康范围。 我们的研究揭示了生殖细胞中减数分裂的核事件与 性腺组织和生物体的衰老。这项探索性研究旨在在 这条途径：导致有机衰老的种系和躯体之间的信号是什么（AIM 1）， 减数分裂的核功能障碍也会导致性腺衰老吗？ 衰老（目标2）。值得注意的是，我们研究的许多基因具有人类同源物在哺乳动物的Meiossis中具有角色 并在生殖感应中隐含。我们确定的转录相似性 减数分裂突变体和衰老的人体组织提出了阐明潜力在进化上的途径 基于健康和寿命的减数分裂控制的机制。这项研究将建立基础 用于未来的机械和保护研究。