Functional Genomic Study of Aging and Aging Interventions

衰老是一个受遗传和环境因素影响的基本生物学过程。寿命是衡量衰老速度的少数可靠参数之一。模式生物的遗传分析揭示了一些影响寿命的基因突变。在许多生物体中，包括蠕虫、苍蝇、啮齿动物、灵长类动物和人类，都观察到了衰老过程中基因表达的变化。然而，对于不同的组织如何衰老，以及长寿基因和延长寿命的干预措施如何影响衰老，人们知之甚少。为了解决组织特异性衰老问题，我们系统地研究了影响寿命和衰老过程的组织特异性因素。我们测量了果蝇大脑、肌肉、消化系统和生殖系统等7个组织的衰老表达谱，这些组织代表着不同的生理功能。数百个基因已被确定，在每个组织的衰老过程中，在转录水平上显示出显著的变化。这为我们在组织和分子水平上研究长寿基因延长寿命的机制提供了基础。为了解决这个问题，我们选择了研究玛土撒拉突变蝇，它们比对照蝇活得更长。我们已经测量了上述七种组织中这种突变体在不同年龄的分子变化。我们在分子和组织水平上将这些变化与野生型蝇株进行了比较。数百个基因已经被确定在野生型和玛士撒拉蝇之间有组织特异性的变化。这一评估阐明了甲基撒拉基因如何在组织水平上调控寿命的分子和细胞机制。类似的方法将应用于研究机制，通过延长寿命的干预措施延长寿命在组织水平在未来。

Aging is a fundamental biological process that is influenced by a number of genetic and environmental factors. Lifespan is one of the few reliable parameters to measure the rate of aging. Genetic analyses of model organisms have uncovered mutations in a number of genes that can affect lifespan. Changes in gene expression in aging have been observed in a number of organisms, including worms, flies, rodents, primates and human beings. However, little is known about how different tissues age, and how longevity genes and prolongevity interventions influence aging. To address tissue-specific aging, we have systematically investigated tissue-specific factors that affect lifespan and aging processes. We have measured the expression profile of aging for seven tissues from fly, including brain, muscle and tissues in the digestive and reproductive systems, which represent different physiological functions. Hundreds of genes have been identified to show significant changes at the transcript level in aging in each tissue. This survey has provided us a foundation to study the mechanisms of lifespan extension by the longevity genes at the tissue and molecular levels. To address this question, we have chosen to study the methuselah mutant flies, which live longer than control flies. We have measured molecular changes of this mutant across age for the seven tissues described above. We have compared these changes to those in the wild type fly strain at the molecular and tissue levels. Several hundreds of genes have been identified to have tissue-specific changes between wild type and methuselah flies. This assessment elucidates molecular and cellular mechanisms on how the methuselah gene regulates lifespan at the tissue level. Similar approaches will be applied to study mechanisms by which prolongevity interventions extend lifespan at the tissue levels in the future. A robust environmental manipulation of lifespan is dietary restriction (DR), which has been shown to extend lifespan in many species, ranging from invertebrates to mammals. However, it would be challenging to impose long-term DR in humans. An alternative strategy would be to apply pharmaceutical or nutraceutical compounds to induce responses that would mimic DR. A few compounds have been shown to have this effect in model organisms. However, the number is still small and little is known about mechanisms by which these compounds extend lifespan. Dietary supplements are widely used with the belief that they can forestall disease and increase longevity. Few systematic attempts have been made to confirm prolongevity claims made or to investigate potentially effective interventions. We have developed a screen system by using mexfly in the Moscafrut mass-rearing facility at Tapachula, Chiapas, Mexico. We have assessed the effects of supplementation of more than a dozen of compounds ranging from antioxidants, DR mimetics, fruit extracts and anticonvulsants. We have found that most of these compounds have marginal effects on lifespan extension. However, we have shown that resveratrol can extend lifespan of mexflies only under certain nutritional conditions and some cranberry compounds appears to have positive effects on lifespan. Utilization of the high-throughput system will provide reliable and statistically convincing results on the effects of aging interventions. Systematic evaluation of prolongevity interventions will not only allow identification of effective anti-aging compounds but also uncover mechanisms of lifespan extension by dietary supplementation. This approach should prove valuable to advance the objective of experimental gerontology to investigate and develop aging interventions in mammals. Our understanding of molecular mechanisms of DR comes primarily from studies of genetically amenable systems including yeast, worms, and flies, where DR has been imposed by either diluting the food source or by using genetic mutations that reduce feeding efficiency. However, a major drawback of these approaches is that there remains substantial uncertainty in determining the exact caloric intake of individuals under these DR paradigms, unlike this ability in studies of higher organisms. We have developed an alternative dietary paradigm that can extend lifespan in C. elegans. We have found that a dietary deprivation (DD) regimen, in which the food source is completely removed from adults, can prolong adult lifespan by 45%. Since this regimen involves complete removal of the food source, the problem of controlling food intake, which has hampered interpretation of past studies, is alleviated. Using this unambiguous method, we have investigated the genetic pathways necessary for lifespan extension by diet. We have measured genome-wide transcript profiles of DD response and have identified hundreds of candidates for further genetic studies. In addition, we have conducted a small scale genetic screen to identify which genes are required for DD response. This analysis should reveal mechanisms governing longevity under different environmental especially dietary conditions. Considering the similarities between DD and DR, some of the DD mechanisms should be evolutionarily conserved, which will advance knowledge about effects of diet on aging and longevity in mammals. In summary, we have applied three different invertebrate species to address issues related to dietary regulation of lifespan by taking advantage of unique features of each system. With D. melanogaster, we are studying mechanisms by which prolongevity interventions and longevity genes extend lifespan at molecular and tissue levels. We are using mexflies to identify effective prolongevity interventions, which should provide guidance for further investigation of aging interventions in mammals. By utilizing a unique and robust dietary regimen in C. elegans, we are dissecting molecular mechanisms of dietary regulation of lifespan. Identification of the conserved features in aging and efficient prolongevity interventions are clearly critical for us understand human aging and more importantly to develop efficient aging intervention strategies for humans.