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 previously have identified hundreds of genes showing significant changes at the transcript level in aging in seven different tissues, including brain, muscle and tissues in the digestive and reproductive systems, which represent different physiological functions. This survey has provided us a foundation to address several basic questions in aging. First, we have started to address the mechanisms of lifespan extension by the longevity genes at the tissue and molecular levels. We have identified hundreds of genes showing tissue-specific changes between the wild type and a long-lived fly strain, methuselah. This assessment elucidates molecular and cellular mechanisms on how the methuselah gene regulates lifespan at the tissue level. Second, we have investigated what are the common and different changes in aging among different tissues. Using a machine learning algorithm, we have found that most of the age-related changes are tissue-specific. The mitochondrial energy production is the only biological process showing significant changes with age in all the tissues, further confirming the current view on the importance of mitochondrial functions in aging. Similar approaches will be applied to study mechanisms by which prolongevity interventions extend lifespan at the tissue levels in the future. We will further investigate which age-related genes and pathways are important in regulating lifespan in D. melanogaster. ? ? 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 several prolongevity screen systems and have assessed the effects of supplementation of more than a dozen of compounds on lifespan in the mexfly. This screen has been conducted in the Moscafrut mass-rearing facility at Tapachula, Chiapas, Mexico. We have shown that resveratrol can extend lifespan of the mexflies only under certain nutritional conditions, suggesting the prolongevity effect of resveratrol depends on dietary composition and content. ? ? Consumption of cranberry has been shown to have a numerous health benefits, especially on fighting against urinary tract infection. However, not much is known about anti-aging effects of cranberry. Therefore, we have decided to assess the anti-aging effects of cranberry extracts in rats. We have found that long-term supplementation of cranberry can delay some age-related decline of physiological functions, including glucose metabolism. This result encourages us to investigate additional health benefits of cranberry consumption related to aging, which will provide scientific guidance to cranberry consumption.? ? In summary, we have utilized multi-species to address issues related to lifespan regulation 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 the mexflies to identify effective prolongevity interventions, which will be further assessed in rodents. This multi-species approach should prove valuable to advance the objective of Laboratory of Experimental Gerontology to investigate and develop aging interventions in mammals. Identification of the conserved features in aging and efficient prolongevity interventions are clearly valuable for understanding human aging and more importantly for developing efficient aging intervention strategies for humans.
