Barger Jamie L, Anderson Rozalyn M, Newton Michael A, da Silva Cristina, Vann James A, Pugh Thomas D, Someya Shinichi, Prolla Tomas A, Weindruch Richard
LifeGen Technologies LLC, Madison, Wisconsin, United States of America.
Department of Medicine, SMPH, University of Wisconsin, Madison, Wisconsin, United States of America; Geriatric Research, Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, United States of America.
PLoS One. 2015 Apr 1;10(4):e0120738. doi: 10.1371/journal.pone.0120738. eCollection 2015.
Aging is the most significant risk factor for a range of diseases, including many cancers, neurodegeneration, cardiovascular disease, and diabetes. Caloric restriction (CR) without malnutrition delays aging in diverse species, and therefore offers unique insights into age-related disease vulnerability. Previous studies suggest that there are shared mechanisms of disease resistance associated with delayed aging, however quantitative support is lacking. We therefore sought to identify a common response to CR in diverse tissues and species and determine whether this signature would reflect health status independent of aging. We analyzed gene expression datasets from eight tissues of mice subjected to CR and identified a common transcriptional signature that includes functional categories of mitochondrial energy metabolism, inflammation and ribosomal structure. This signature is detected in flies, rats, and rhesus monkeys on CR, indicating aspects of CR that are evolutionarily conserved. Detection of the signature in mouse genetic models of slowed aging indicates that it is not unique to CR but rather a common aspect of extended longevity. Mice lacking the NAD-dependent deacetylase SIRT3 fail to induce mitochondrial and anti-inflammatory elements of the signature in response to CR, suggesting a potential mechanism involving SIRT3. The inverse of this transcriptional signature is detected with consumption of a high fat diet, obesity and metabolic disease, and is reversed in response to interventions that decrease disease risk. We propose that this evolutionarily conserved, tissue-independent, transcriptional signature of delayed aging and reduced disease vulnerability is a promising target for developing therapies for age-related diseases.
衰老是一系列疾病的最重要风险因素，包括许多癌症、神经退行性疾病、心血管疾病和糖尿病。无营养不良的热量限制（CR）可延缓多种物种的衰老，因此为了解与年龄相关的疾病易感性提供了独特的见解。先前的研究表明，存在与延缓衰老相关的共同抗病机制，但缺乏定量支持。因此，我们试图确定不同组织和物种对CR的共同反应，并确定这种特征是否能反映独立于衰老的健康状况。我们分析了接受CR的小鼠八个组织的基因表达数据集，确定了一个共同的转录特征，其中包括线粒体能量代谢、炎症和核糖体结构的功能类别。在接受CR的果蝇、大鼠和恒河猴中检测到了这种特征，表明CR的某些方面在进化上是保守的。在衰老减缓的小鼠遗传模型中检测到该特征，表明它并非CR所特有，而是延长寿命的一个共同方面。缺乏NAD依赖性脱乙酰酶SIRT3的小鼠在对CR的反应中无法诱导该特征的线粒体和抗炎成分，提示了一种涉及SIRT3的潜在机制。高脂肪饮食、肥胖和代谢疾病的摄入会检测到这种转录特征的相反情况，而对降低疾病风险的干预措施会使其逆转。我们认为，这种在进化上保守、与组织无关的延缓衰老和降低疾病易感性的转录特征是开发与年龄相关疾病疗法的一个有前景的靶点。
