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

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健康的调节 高龄产妇对生育率下降的影响是众所周知的，但生殖系健康如何影响生育率？ 生物体健康和衰老仍然不清楚。众所周知，生殖缺陷预示着有害的 对两性的长期影响。例如，自然绝经年龄（ANM）与 死亡的风险更大。晚期ANM女性表现出更年轻的“表观遗传衰老”特征， 生育寿命延长的妇女寿命延长。更年期本身会引发易感性 许多与生殖无关的合并症，如心血管疾病和痴呆症，以及tes- 男性睾酮下降。因此，大量令人信服的临床和流行病学证据表明， 生殖系状态影响整体有机体健康和衰老。然而，人类研究并没有解决原因- 也没有揭示永生生殖系可能影响致命躯体衰老的机制。 组织中 我们已经利用秀丽隐杆线虫的独特优势来评估如何干扰减数分裂，一个亲- 只发生在生殖细胞中的癌症，影响动物的寿命和衰老速度。这个亲- 这是基于我们的发现，即减数分裂的破坏加速身体衰老。我们发现突变 in C.在减数分裂的不同阶段运作的线虫基因缩短了寿命，损害了健康寿命和目的地， 胆汁化蛋白质稳态重要的是，减数分裂突变体表现出过早老化的转录谱 让人想起老C。elegans和老化的人体组织，这表明生殖细胞功能障碍引发了一个骗局， 分子老化特征因此，我们假设，在生殖细胞中，控制减数分裂保真度的基因 影响生物体寿命和健康。 我们的研究揭示了生殖细胞减数分裂的核事件与 性腺组织和机体的老化。这项探索性研究的目的是找到缺失的环节， 这条途径：什么是生殖细胞和索马之间的信号，导致有机体老化（目标1）， 减数分裂核功能障碍是否也会导致性腺衰老，以及这与体细胞衰老有何联系？ 老化（目标2）。值得注意的是，我们研究的许多基因与人类同源，在哺乳动物减数分裂中发挥作用 并与生殖衰老有关。我们发现的转录相似性 减数分裂突变体和老化的人类组织表明， 减数分裂控制健康和长寿的基本机制。这项研究将奠定基础 用于未来的机械和保护研究。