The impact of LINE-1 retrotransposons on life span, SASP, and telomeres in vivo

LINE-1逆转录转座子对体内寿命、SASP和端粒的影响

基本信息

项目摘要

DNA damage accumulates with age in somatic tissues where it contributes to their dysfunction by causing mutations and cellular senescence. Senescent cells alter tissue microenvironment via secretion of proinflammatory molecules. DNA damage from endogenous or exogenous sources alone or in combination with defects in DNA repair pathways often decreases longevity. Long interspersed element-1, L1, an endogenous retrotransposon, contributes to genomic instability via retrotransposition and the induction of DNA double-strand breaks. Although endogenous L1 elements are expressed in normal human tissues and cause DNA damage and cellular senescence, whether L1 affects mammalian life span in vivo is unknown. Among the 500,000 L1 copies present in mammalian genomes only a few L1 loci are capable of causing further DNA damage. These L1 loci are often polymorphic for their presence in human genomes (pL1s) and are responsible for the bulk of L1-induced DNA damage. Although some individuals contain two or three times as many of these pL1 loci than others, the impact of this variation on human life span is not known. Our preliminary data generated using a transgenic rat model support that a functional L1 transgene increases levels of proinflammatory markers and shortens average and maximal lifespan in vivo. Our preliminary data also show that L1 endonuclease cuts telomeric sequences in vitro and may do so in vivo. We hypothesize that polymorphic L1 loci shorten mammalian lifespan in a dose-dependent manner by causing DNA damage that induces proinflammatory markers and/or telomere attrition. We will test this hypothesis by using custom transgenic rats to model variation in the number of functional L1s observed in the human population in order to study the effect of this variation on longevity in vivo. We will also use DNA samples collected from average and long-lived (>99 year old) individuals to determine their pL1 content and whether the number of pL1s per genome correlates with life span. We will use in vitro and tissue culture approaches to determine whether L1 contribution to an increase in SASP markers or telomere attrition could be a plausible mechanism(s) by which L1 may impact longevity. Combined our findings would provide a currently lacking experimental support for pL1 impact on longevity in vivo and novel mechanisms underlying this effect.
随着年龄的增长,DNA损伤在体细胞组织中积累,通过引起

项目成果

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Victoria Perepelitsa Belancio其他文献

Victoria Perepelitsa Belancio的其他文献

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{{ truncateString('Victoria Perepelitsa Belancio', 18)}}的其他基金

Polymorphic L1 transposons as a Genetic Variable Distinguishing Aggressive from Indolent Prostate Cancer
多态性 L1 转座子作为区分侵袭性前列腺癌和惰性前列腺癌的遗传变量
  • 批准号:
    10260721
  • 财政年份:
    2022
  • 资助金额:
    $ 33.31万
  • 项目类别:
Pilot Projects Program
试点项目计划
  • 批准号:
    10631210
  • 财政年份:
    2022
  • 资助金额:
    $ 33.31万
  • 项目类别:
Pilot Projects Program
试点项目计划
  • 批准号:
    10414533
  • 财政年份:
    2022
  • 资助金额:
    $ 33.31万
  • 项目类别:
FASEB's Mobile DNA: Evolution, Diversity, and Impact Conference.
FASEB 的移动 DNA:进化、多样性和影响会议。
  • 批准号:
    10317953
  • 财政年份:
    2021
  • 资助金额:
    $ 33.31万
  • 项目类别:
A Forgotten Connection: Retrotransposon contribution to Alzheimer's Disease
被遗忘的联系:逆转录转座子对阿尔茨海默病的贡献
  • 批准号:
    10288552
  • 财政年份:
    2018
  • 资助金额:
    $ 33.31万
  • 项目类别:
The impact of LINE-1 retrotransposons on life span, SASP, and telomeres in vivo
LINE-1逆转录转座子对体内寿命、SASP和端粒的影响
  • 批准号:
    10431860
  • 财政年份:
    2018
  • 资助金额:
    $ 33.31万
  • 项目类别:
The impact of LINE-1 retrotransposons on life span, SASP, and telomeres in vivo
LINE-1逆转录转座子对体内寿命、SASP和端粒的影响
  • 批准号:
    10212211
  • 财政年份:
    2018
  • 资助金额:
    $ 33.31万
  • 项目类别:
The impact of advanced parental age on genomic instability in offspring associated with retrotransposon-induced DNA damage
高龄父母对逆转录转座子诱导的 DNA 损伤相关后代基因组不稳定性的影响
  • 批准号:
    9277878
  • 财政年份:
    2017
  • 资助金额:
    $ 33.31万
  • 项目类别:
L 1 element as an inrinsic factor of mammalian aging
L 1 元素作为哺乳动物衰老的内在因素
  • 批准号:
    8032436
  • 财政年份:
    2008
  • 资助金额:
    $ 33.31万
  • 项目类别:
L 1 element as an inrinsic factor of mammalian aging
L 1 元素作为哺乳动物衰老的内在因素
  • 批准号:
    7384768
  • 财政年份:
    2008
  • 资助金额:
    $ 33.31万
  • 项目类别:

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激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
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