Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
Department of Genetics, Albert Einstein College of Medicine, New York, New York.
Aging Cell. 2020 Mar;19(3):e13121. doi: 10.1111/acel.13121. Epub 2020 Feb 19.
A key goal of aging research was to understand mechanisms underlying healthy aging and develop methods to promote the human healthspan. One approach is to identify gene regulations unique to healthy aging compared with aging in the general population (i.e., "common" aging). Here, we leveraged Genotype-Tissue Expression (GTEx) project data to investigate "healthy" and "common" aging gene expression regulations at a tissue level in humans and their interconnection with diseases. Using GTEx donors' disease annotations, we defined a "healthy" aging cohort for each tissue. We then compared the age-associated genes derived from this cohort with age-associated genes from the "common" aging cohort which included all GTEx donors; we also compared the "healthy" and "common" aging gene expressions with various disease-associated gene expressions to elucidate the relationships among "healthy," "common" aging and disease. Our analyses showed that 1. GTEx "healthy" and "common" aging shared a large number of gene regulations; 2. Despite the substantial commonality, "healthy" and "common" aging genes also showed distinct function enrichment, and "common" aging genes had a higher enrichment for disease genes; 3. Disease-associated gene regulations were overall different from aging gene regulations. However, for genes regulated by both, their regulation directions were largely consistent, implying some aging processes could increase the susceptibility to disease development; and 4. Possible protective mechanisms were associated with some "healthy" aging gene regulations. In summary, our work highlights several unique features of GTEx "healthy" aging program. This new knowledge could potentially be used to develop interventions to promote the human healthspan.
衰老研究的一个主要目标是了解健康衰老的机制，并开发促进人类健康寿命的方法。一种方法是识别与普通人群衰老相比，健康衰老所特有的基因调控（即“普通”衰老）。在这里，我们利用基因型组织表达（GTEx）项目数据，在人类组织水平上研究“健康”和“普通”衰老的基因表达调控及其与疾病的相互关系。利用 GTEx 供体的疾病注释，我们为每个组织定义了一个“健康”衰老队列。然后，我们将从这个队列中得出的与年龄相关的基因与包含所有 GTEx 供体的“普通”衰老队列中的与年龄相关的基因进行比较；我们还将“健康”和“普通”衰老基因的表达与各种与疾病相关的基因的表达进行了比较，以阐明“健康”、“普通”衰老和疾病之间的关系。我们的分析表明：1. GTEx“健康”和“普通”衰老共享大量的基因调控；2. 尽管有很大的共性，但“健康”和“普通”衰老基因也表现出明显不同的功能富集，而且“普通”衰老基因富集了更多的疾病基因；3. 与疾病相关的基因调控总体上与衰老基因调控不同。然而，对于受两者共同调控的基因，其调控方向在很大程度上是一致的，这意味着一些衰老过程可能会增加疾病发展的易感性；4. 与某些“健康”衰老基因调控相关的可能存在保护机制。总之，我们的工作突出了 GTEx“健康”衰老计划的几个独特特征。这些新知识可能被用于开发促进人类健康寿命的干预措施。
