Blanka Rogina

Sirtuin activators mimic caloric restriction and delay ageing in metazoans.

Caloric restriction extends lifespan in numerous species. In the budding yeast Saccharomyces cerevisiae this effect requires Sir2 (ref. 1), a member of the sirtuin family of NAD+-dependent deacetylases. Sirtuin activating compounds (STACs) can promote the survival of human cells and extend the replicative lifespan of yeast. Here we show that resveratrol and other STACs activate sirtuins from Caenorhabditis elegans and Drosophila melanogaster, and extend the lifespan of these animals without reducing fecundity. Lifespan extension is dependent on functional Sir2, and is not observed when nutrients are restricted. Together these data indicate that STACs slow metazoan ageing by mechanisms that may be related to caloric restriction.

Conditional tradeoffs between aging and organismal performance of Indy long-lived mutant flies

Alterations that extend the life span of animals and yeast typically involve decreases in metabolic rate, growth, physical activity, and/or early-life fecundity. This negative correlation between life span and the ability to assimilate and process energy, to move, grow, and reproduce, raises questions about the potential utility of life span extension. Tradeoffs between early-life fitness and longevity are central to theories of the evolution of aging, which suggests there is necessarily a price to be paid for reducing the rate of aging. It is not yet clear whether life span can be extended without undesirable effects on metabolism and fecundity. Here, we report that the long-lived Indy mutation in Drosophila causes a decrease in the slope of the mortality curve consistent with a slowing in the rate of aging without a concomitant reduction in resting metabolic rate, flight velocity, or age-specific fecundity under normal rearing conditions. However, Indy mutants on a decreased-calorie diet have reduced fecundity, suggesting that a tradeoff between longevity and this aspect of performance is conditional, i.e., the tradeoff can occur in a stressful environment while being absent in a more favorable environment. These results provide evidence that there do exist mechanisms, albeit conditional, that can extend life span without significant reduction in fecundity, metabolic rate, or locomotion.

Behavioral, physical, and demographic changes in Drosophila populations through dietary restriction

Dietary restriction (DR) is a valuable experimental tool for studying the aging process. Primary advancement of research in this area has relied on rodent models, but attention has recently turned toward Drosophila melanogaster. However, little is known about the baseline effects of DR on wild‐type Drosophila and continued experimentation requires such information. The findings described here survey the effects of DR on inbred, wild‐type populations of Canton‐S fruit flies and demonstrate a robust effect of diet on longevity. Over a circumscribed range of dietary conditions, healthy lifespan varies by as much as 121% for wild‐type Drosophila females. Significant differences are also observed for male flies, but the magnitude of the DR effect is less robust. Mortality analyses of the survivorship data reveal that this variation in lifespan can be attributed to a modulation of the rate parameter for the mortality function – a change in the demographic rate of aging. Since the feeding of fruit flies is less easily controlled than that of rodents, this research also addresses the validity of applying a DR model to Drosophila populations. Feeding and body weight data for flies given the various dietary conditions surveyed indicate that Drosophila on higher‐calorie diets consume a similar volume of food to those on a low‐calorie diet, resulting in different levels of calorie intake. Fertility and activity levels demonstrate that the diets surveyed are comparable, and that increasing the calorie content of laboratory food up to twice the normal concentration is not pathologic for experimental fly populations.

Long-lived Indy induces reduced mitochondrial reactive oxygen species production and oxidative damage

Decreased Indy activity extends lifespan in D. melanogaster without significant reduction in fecundity, metabolic rate, or locomotion. To understand the underlying mechanisms leading to lifespan extension in this mutant strain, we compared the genome-wide gene expression changes in the head and thorax of adult Indy mutant with control flies over the course of their lifespan. A signature enrichment analysis of metabolic and signaling pathways revealed that expression levels of genes in the oxidative phosphorylation pathway are significantly lower in Indy starting at day 20. We confirmed experimentally that complexes I and III of the electron transport chain have lower enzyme activity in Indy long-lived flies by Day 20 and predicted that reactive oxygen species (ROS) production in mitochondria could be reduced. Consistently, we found that both ROS production and protein damage are reduced in Indy with respect to control. However, we did not detect significant differences in total ATP, a phenotype that could be explained by our finding of a higher mitochondrial density in Indy mutants. Thus, one potential mechanism by which Indy mutants extend life span could be through an alteration in mitochondrial physiology leading to an increased efficiency in the ATP/ROS ratio.

Distinct biological epochs in the reproductive life of female Drosophila melanogaster

Mating alters the physiology and behavior of female Drosophila melanogaster resulting in a surge of egg laying, a decrease in receptivity to other males, and a decrease in life span. Here, we show striking differences in patterns of Drosophila egg laying and mortality rate dependent upon mating history. Our data reveal previously unreported epochs in the reproductive life of females: optimal, vulnerable and declining-terminal. During the optimal period, mating induces females to respond with a surge in egg laying and has a reversible effect on mortality rate. In contrast, during the vulnerable period, mating does not induce females to respond with a surge in egg laying and causes an irreversible increase in mortality rate. The terminal period was always observed several days before death, irrespective of the chronological age, and is marked by sharp reductions in egg laying. The presence of these distinctive biological epochs may reflect increased female sensitivity to mating due to age-related decline.

dSir2 and longevity in Drosophila

The silent information regulator 2 (Sir2 or Sirtuin) family of proteins is highly conserved and has been implicated in the extension of longevity for several species. Mammalian Sirtuins have been shown to affect various aspects of physiology including metabolism, the stress response, cell survival, replicative senescence, inflammation, the circadian rhythm, neurodegeneration, and even cancer. Evidence in Drosophila implicates Sir2 in at least some of the beneficial effects of caloric restriction (CR). CR delays age-related pathology and extends life span in a wide variety of species. Here we will review the evidence linking Drosophila Sir2 (dSir2) to longevity regulation and the pathway associated with CR in Drosophila, as well as the effects of the Sir2 activator resveratrol and potential interactions between dSir2 and p53.

From Genes to Aging in Drosophila

Despite the intimate nature of the aging process we actually know little about it. In more recent years, work on a variety of organisms, utilizing approaches including demography, molecular genetics, and epidemiology, have challenged some of the more commonly held assumptions about the aging process. These studies have served to reinvigorate the field of aging research and are beginning to lead the way in a renaissance in aging research (Helfand and Inouye, 2002). Invertebrate model systems such as Drosophila and Caenorhabditis elegans that permit extensive genetic analysis are at the forefront of this renaissance.

Cu, Zn superoxide dismutase deficiency accelerates the time course of an age-related marker in Drosophila melanogaster.

In the oxidative stress hypothesis of aging therandom accumulation of oxidative damage over time ispostulated to cause aging. The pace at whichoxidative damage accrues determines the rate of aging,but it is less clear how the accumulation of randomdamage could cause the stereotypic pattern of aging. It has been proposed that oxidative damage induceschanges in gene expression, translating a random inputof damage into a patterned output. In support of thiswe show that in adult Drosophila melanogaster,with a deficiency in the anti-oxidant enzyme Cu, Znsuperoxide dismutase (Sod), an increase in oxidativestress, and a shortened life span, there isacceleration in the normal age-related temporalpattern of wingless gene expression. Theacceleration in the temporal pattern of winglessgene expression is proportional to the shortened lifespan suggesting that the shortened life span of Soddeficient animals is due, not to an abnormalpathological process, but to an increase in the rateof aging.

Regulation of gene expression is preserved in aging Drosophila melanogaster

Aging, and the deterioration of biological performance that characterizes it, are routinely assumed to be due to a progressive global loss of homeostasis and a general increase in dysregulation [1-4] . We tested this hypothesis directly by measuring age-specific variability in gene expression. Analysis of the transcriptional activity of six genes in various inbred lines of Drosophila melanogaster unexpectedly failed to show an increase in variability among individuals as they age and die. Although regulation of gene expression is a central feature of life, a global decline in the control of gene expression does not appear to be either a cause or a consequence of the process of aging.

The Effects of Age on Radiation Resistance and Oxidative Stress in Adult Drosophila melanogaster

Abstract Parashar, V., Frankel, S., Lurie, A. G. and Rogina, B. The Effects of Age on Radiation Resistance and Oxidative Stress in Adult Drosophila melanogaster. Radiat. Res. 169, 707–711 (2008). Drosophila melanogaster (fruit fly) is a well-established model organism for genetic studies of development and aging. We examined the effects of lethal ionizing radiation on male and female adult Drosophila of different ages, using doses of radiation from 200 to 1500 Gy. Fifty percent lethality 2 days postirradiation (LD50/2) in wild-type 1-day-old adult fruit flies was ∼1238 Gy for males and 1339 Gy for females. We observed a significant age-dependent decline in the radiation resistance of both males and females. Radiation damage is postulated to occur by the generation of oxygen radicals. An age-related decline in the ability of flies to resist an agent that induces oxygen radicals, paraquat, was observed when comparing 10- and 20-day adults. Female flies are more resistant to paraquat than male flies. Oxidative stress mediated by paraquat was additive with sublethal exposures to radiation in young adults. Therefore, the ability to repair the damage caused by oxygen radicals seems to decline with the age of the flies. Because Drosophila adults are largely post-mitotic, our data suggest that adult Drosophila melanogaster can serve as an excellent model to study the factors responsible for radiation resistance in post-mitotic tissue and age-dependent changes in this resistance.