Role of rare damaging mutations in aging

罕见的破坏性突变在衰老中的作用

• 批准号: 10669699
• 负责人: Vadim N. Gladyshev
• 金额: $ 55.52万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669699
• 关键词: Affect; Age; Aging; Alleles; Centenarian; Cessation of life; Complex; Data Set; Development; Disease; Elderly; Exhibits; Frequencies; Future; Gender; Genes; Genetic; Genomics; Genotype; Genotype-Tissue Expression Project; Germ-Line Mutation; Human; Human Genome; Incidence; Individual; Initiator Codon; Intervention; Intervention Studies; Length; Life; Longevity; Methods; Mus; Mutation; Organism; Pathway interactions; Pattern; Phenotype; Protein Truncation; RNA Splicing; Risk; Role; Sampling; Schedule; Stochastic Processes; Technology; Terminator Codon; Testing; Time; Twin Studies; Variant; Woman; age related; biobank; cohort; comparative; disorder risk; early onset; exome; exome sequencing; genetic variant; genome wide association study; healthspan; human mortality; improved; intervention effect; loss of function; men; middle age; mortality; mouse model; negative affect; programs; rare variant; trait

Aging is associated with a continuous accumulation of deleterious changes, consequential loss of function, and development of age-related diseases. The length of time organisms live is a complex trait, influenced by genetic, environmental and stochastic processes. Much effort has been placed at defining the genetic basis of lifespan variation. However, common genetic variants have low effect size and are responsible only for a fraction of human lifespan variation. On the other hand, human genomes also harbor highly damaging variants, such as highly deleterious alleles represented by loss-of-function variants in important genes. These damaging mutations are rare or ultra-rare, but they often have strong effect sizes. While these variants are missed by genotyping, they can be easily detected by exome sequencing, providing an opportunity to quantify their role in age-related diseases, mortality and longevity, if information on these phenotypes is available together with exome sequences. We hypothesize that burden of rare damaging variants influences lifespan and that this effect can be quantified. This would mean that long-lived individuals, especially centenarians, on average are depleted of these mutations, whereas mid-life mortality may be associated with their increased burden. To test this hypothesis, we propose the following: (1) Quantify the impact of burden of rare damaging mutations on human mortality and healthspan. We will examine if higher burden of damaging mutations is associated with increased mortality and an early onset of age-related diseases. To test this possibility, we will determine if longer life is associated with lower burden of rare variants that lead to stop or start codon gain/loss, frameshifting and splicing aberrations. We will apply the methods we developed in preliminary studies to larger cohorts, quantifying the role of rare mutation burden in men and women, determining their effect on the incidence of various age-related diseases as well as on healthspan, assessing the effect of mutation frequency, and identifying genes and pathways affected by damaging mutations. We will further determine if centenarians and other long-lived individuals are depleted of damaging mutations, whereas earlier mortality is associated with them. (2) Examine the association of burden of rare damaging variants with mouse lifespan. We will take advantage of genetically heterogeneous UM-HET3 mice with the known age at death. We will sequence their exomes and determine the effect of rare damaging mutations on longevity. As in humans, we hypothesize that burden of these variants negatively affects mouse lifespan. Comparative analysis of human and mouse damaging mutations will allow us to uncover common features at the level of mutations, genes and pathways. We will further characterize exomes of mice subjected to interventions that extend lifespan. Using this dataset, we will determine if adjusting for mutation burden offers a better statistical support for the observed effect of these interventions.

衰老与有害变化的连续积累，功能丧失以及 与年龄有关的疾病的发展。生物的生物长度是一个复杂的特征，受遗传影响， 环境和随机过程。在定义寿命的遗传基础上已付出了很多努力 变化。但是，常见的遗传变异具有较低的效果大小，并且仅对一小部分负责 人类的寿命变化。另一方面，人类基因组还具有高度破坏性的变体，例如 重要基因中功能丧失变体代表的高度有害等位基因。这些破坏性突变 是罕见的或超稀有的，但通常具有很强的效果大小。尽管这些变体被基因分型遗漏，但 可以通过外显子组测序轻松检测它们，提供了量化其在与年龄相关的角色的机会 疾病，死亡率和寿命，如果有关这些表型的信息与外显子类 序列。我们假设稀有破坏性变体的负担会影响寿命，并且这种影响可以 被量化。这意味着平均而言，长寿的人，尤其是百岁老人 这些突变，而中年死亡率可能与增加的负担有关。测试这个 假设，我们提出以下提议：（1）量化稀有破坏突变对人的负担的影响 死亡率和健康范围。我们将检查损坏突变的较高负担是否与增加有关 死亡率和与年龄有关的疾病的早期发作。为了测试这种可能性，我们将确定寿命是否更长 与导致停止或启动密码子增益/丢失，框架和剪接的稀有变体负担较低相关 畸变。我们将将我们在初步研究中开发的方法应用于较大的队列，从而量化 稀有突变负担在男性和女性中的作用，确定其对各种年龄相关的发生率的影响 疾病和健康范围，评估突变频率的效果，并识别基因和 受破坏突变影响的途径。我们将进一步确定百岁老人和其他长寿的 个体耗尽了破坏性突变，而较早的死亡率与之相关。 （2）检查 稀有破坏性变体的负担与小鼠寿命的关联。我们将利用遗传 异质的UM-HET3小鼠死亡时年龄已知。我们将对它们的外来序列进行测序，并确定 罕见破坏突变对寿命的影响。就像在人类中一样，我们假设这些变体的负担 负面影响小鼠寿命。人类和小鼠破坏突变的比较分析将使我们 在突变，基因和途径的水平上发现共同特征。我们将进一步描述Exomes 受到延长寿命的干预措施的小鼠。使用此数据集，我们将确定是否调整 突变负担为观察到的这些干预措施的影响提供了更好的统计支持。

项目成果

Maintenance of genome sequence integrity in long- and short-lived rodent species.

• DOI: 10.1126/sciadv.abj3284
• 发表时间: 2021-10-29
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Zhang L;Dong X;Tian X;Lee M;Ablaeva J;Firsanov D;Lee SG;Maslov AY;Gladyshev VN;Seluanov A;Gorbunova V;Vijg J
• 通讯作者: Vijg J

Molecular Damage in Aging.

• DOI: 10.1038/s43587-021-00150-3
• 发表时间: 2021-12
• 期刊: NATURE AGING
• 作者: Gladyshev, Vadim N.;Kritchevsky, Stephen B.;Clarke, Steven G.;Cuervo, Ana Maria;Fiehn, Oliver;de Magalhaes, Joao Pedro;Mau, Theresa;Maes, Michal;Moritz, Robert L.;Niedernhofer, Laura J.;Van Schaftingen, Emile;Tranah, Gregory J.;Walsh, Kenneth;Yura, Yoshimitsu;Zhang, Bohan;Cummings, Steven R.
• 通讯作者: Cummings, Steven R.

Epigenetic aging of the demographically non-aging naked mole-rat.

• DOI: 10.1038/s41467-022-27959-9
• 发表时间: 2022-01-17
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Kerepesi C;Meer MV;Ablaeva J;Amoroso VG;Lee SG;Zhang B;Gerashchenko MV;Trapp A;Yim SH;Lu AT;Levine ME;Seluanov A;Horvath S;Park TJ;Gorbunova V;Gladyshev VN
• 通讯作者: Gladyshev VN

Emerging rejuvenation strategies-Reducing the biological age.

• DOI: 10.1111/acel.13538
• 发表时间: 2022-01
• 期刊: Aging cell
• 影响因子: 7.8
• 作者: Zhang B;Trapp A;Kerepesi C;Gladyshev VN
• 通讯作者: Gladyshev VN

Ectopic cervical thymi and no thymic involution until midlife in naked mole rats.

• DOI: 10.1111/acel.13477
• 发表时间: 2021-10
• 期刊: Aging cell
• 影响因子: 7.8
• 作者: Emmrich S;Tolibzoda Zakusilo F;Trapp A;Zhou X;Zhang Q;Irving EM;Drage MG;Zhang Z;Gladyshev VN;Seluanov A;Gorbunova V
• 通讯作者: Gorbunova V