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Healthspan science aims to add healthy, functional years to human life. Many different methods of improving healthspan have been investigated, chiefly focusing on just one aspect of an organism's health such as survival. Studies in Drosophila melanogaster have demonstrated that a reversal to a long-abandoned ancestral diet results in improved functional health, particularly at later ages. Meanwhile, pharmaceutical studies have demonstrated that botanical extracts have potent antiaging properties, capable of extending the mean lifespan of D. melanogaster by up to 25%, without a decrease in early fecundity. In this study, we combine these two different approaches to healthspan extension to examine whether a combination of such treatments results in a synergistic or antagonistic effect on Drosophila healthspan. One botanical extract, derived from Rhodiola rosea, mimicked the effects of the ancestral apple diet with better performance at later ages compared with the control. Another extract, derived from Rosa damascena, decreased age-specific survivorship when combined with the apple diet providing support for the "Poisoned Chalice" hypothesis that combinations of various supplements or diets can elicit adverse physiological responses. More experiments in model organisms should be completed researching the effects of combining healthspan-extending substances in various diet backgrounds.

Our intuitive understanding of adaptation by natural selection is dominated by the power of selection at early ages in large populations. Yet, as the forces of natural selection fall with adult age, we expect adaptation to be attenuated with age. Explicit simulations of age-dependent adaptation suggest that populations adapt to a novel environment quickly at early ages, but only slowly and incompletely at later adult ages. Experimental tests for age-dependent adaptation to a novel diet were performed on populations of Drosophila melanogaster. The results support the prediction that populations should perform better on an ancestral, long-abandoned diet, compared to an evolutionarily recent diet, only at later ages. D. melanogaster populations also perform poorly on a novel diet compared to an evolutionarily recent diet that has been sustained for hundreds of generations, particularly at earlier ages. Additional experiments demonstrate that the timing of the shift to better performance in our populations on the long-abandoned diet is dependent on when the forces of natural selection weaken in the evolutionary history of experimental populations. Taken together, these experimental findings suggest that the forces of natural selection scale the rate of adaptation to novel environments.

BackgroundStudies combining experimental evolution and next-generation sequencing have found that adaptation in sexually reproducing populations is primarily fueled by standing genetic variation. Consequently, the response to selection is rapid and highly repeatable across replicate populations. Some studies suggest that the response to selection is highly repeatable at both the phenotypic and genomic levels, and that evolutionary history has little impact. Other studies suggest that even when the response to selection is repeatable phenotypically, evolutionary history can have significant impacts at the genomic level. Here we test two hypotheses that may explain this discrepancy. Hypothesis 1: Past intense selection reduces evolutionary repeatability at the genomic and phenotypic levels when conditions change. Hypothesis 2: Previous intense selection does not reduce evolutionary repeatability, but other evolutionary mechanisms may. We test these hypotheses using D. melanogaster populations that were subjected to 260 generations of intense selection for desiccation resistance and have since been under relaxed selection for the past 230 generations.ResultsWe find that, with the exception of longevity and to a lesser extent fecundity, 230 generations of relaxed selection has erased the extreme phenotypic differentiation previously found. We also find no signs of genetic fixation, and only limited evidence of genetic differentiation between previously desiccation resistance selected populations and their controls.ConclusionOur findings suggest that evolution in our system is highly repeatable even when populations have been previously subjected to bouts of extreme selection. We therefore conclude that evolutionary repeatability can overcome past bouts of extreme selection in Drosophila experimental evolution, provided experiments are sufficiently long and populations are not inbred.

Insects and vertebrates have multiple major physiological systems, each species having a circulatory system, a metabolic system, and a respiratory system that enable locomotion and survival in stressful environments, among other functions. Broadening our understanding of the physiology of Drosophila melanogaster requires the parsing of interrelationships among such major component physiological systems. By combining electrical pacing and flight exhaustion assays with manipulative conditioning, we have started to unpack the interrelationships between cardiac function, locomotor performance, and other functional characters such as starvation and desiccation resistance. Manipulative sequences incorporating these four physiological characters were applied to five D. melanogaster lab populations that share a common origin from the wild and a common history of experimental evolution. While exposure to starvation or desiccation significantly reduced flight duration, exhaustion due to flight only affected subsequent desiccation resistance. A strong association was found between flight duration and desiccation resistance, providing additional support for the hypothesis that these traits depend on glycogen and water content. However, there was negligible impact on rate of cardiac arrests from exhaustion by flight or exposure to desiccant. Brief periods of starvation significantly lowered the rate of cardiac arrest. These results provide suggestive support for the adverse impact of lipids on Drosophila heart robustness, a parallel result to those of many comparable studies in human cardiology. Overall, this study underscores clear distinctions among the connections between specific physiological responses to stress and specific types of physiological performance.

Drosophila melanogaster is a good model species for the study of heart function. However, most previous work on D. melanogaster heart function has focused on the effects of large-effect genetic variants. We compare heart function among 18 D. melanogaster populations that have been selected for altered development time, aging, or stress resistance. We find that populations with faster development and faster aging have increased heart dysfunction, measured as percentage heart failure after electrical pacing. Experimental evolution of different triglyceride levels, by contrast, has little effect on heart function. Evolved differences in heart function correlate with allele frequency changes at many loci of small effect. Genomic analysis of these populations produces a list of candidate loci that might affect cardiac function at the intersection of development, aging, and metabolic control mechanisms.

The relative impact of selection, chance and history will determine the predictability of evolution. There is a lack of empirical research on this subject, particularly in sexual organisms. Here we use experimental evolution to test the predictability of evolution. We analyse the real-time evolution of Drosophila subobscura populations derived from contrasting European latitudes placed in a novel laboratory environment. Each natural population was sampled twice within a three-year interval. We study evolutionary responses at both phenotypic (life-history, morphological and physiological traits) and karyotypic levels for around 30 generations of laboratory culture. Our results show (1) repeatable historical effects between years in the initial state, at both phenotypic and karyotypic levels; (2) predictable phenotypic evolution with general convergence except for body size; and (3) unpredictable karyotypic evolution. We conclude that the predictability of evolution is contingent on the trait and level of organization, highlighting the importance of studying multiple biological levels with respect to evolutionary patterns.

Experimental evolutionary genomics now allows biologists to test fundamental theories concerning the genetic basis of adaptation. We have conducted one of the longest laboratory evolution experiments with any sexually-reproducing metazoan, Drosophila melanogaster. We used next-generation resequencing data from this experiment to examine genome-wide patterns of genetic variation over an evolutionary time-scale that approaches 1,000 generations. We also compared measures of variation within and differentiation between our populations to simulations based on a variety of evolutionary scenarios. Our analysis yielded no clear evidence of hard selective sweeps, whereby natural selection acts to increase the frequency of a newly-arising mutation in a population until it becomes fixed. We do find evidence for selection acting on standing genetic variation, as independent replicate populations exhibit similar population-genetic dynamics, without obvious fixation of candidate alleles under selection. A hidden-Markov model test for selection also found widespread evidence for selection. We found more genetic variation genome-wide, and less differentiation between replicate populations genome-wide, than arose in any of our simulated evolutionary scenarios.

Drosophila research has identified a new feature of aging that has been called the death spiral. The death spiral is a period prior to death during which there is a decline in life-history characters, such as fecundity, as well as physiological characters. First, we review the data from the Drosophila and medfly literature that suggest the existence of death spirals. Second, we re-analyze five cases with such data from four laboratories using a generalized statistical framework, a re-analysis that strengthens the case for the salience of the death spiral phenomenon. Third, we raise the issue whether death spirals need to be taken into account in the analysis of functional characters over age, in aging research with model species as well as human data.

Pathogenic mitochondrial tRNA (mt-tRNA) gene mutations represent a prominent cause of primary mitochondrial DNA (mtDNA)-related disease despite accounting for only 5%-10% of the mitochondrial genome.(1,2) Although some common mt-tRNA mutations, such as the m.3243A>G mutation, exist, the majority are rare and have been reported in only a small number of cases.(3) The MT-TP gene, encoding mt-tRNA(Pro), is one of the less polymorphic mt-tRNA genes, and only 5 MT-TP mutations have been reported as a cause of mitochondrial muscle disease to date (table e-1 at Neurology.org/ng, P6-10). We report 5 patients with myopathic phenotypes, each harboring different pathogenic mutations in the MT-TP gene, highlighting the importance of MT-TP mutations as a cause of mitochondrial muscle disease and the requirement to study clinically relevant tissue.

IntroductionInclusion-body myositis (IBM) is a late-onset idiopathic inflammatory myopathy associated with selective and progressive muscle weakness and atrophy. Current clinical management of IBM is largely supportive due to its uncertain etiology and lack of effective treatment. Establishing a consensus of opinion on questions relating to diagnosis and management of IBM is expected to help reduce inconsistencies in the care and resources allocated to those living with this condition.MethodsA protocol has been developed to produce best practice clinical guidelines for IBM based on a combination of published research and expert consensus.ConclusionsIn this study we describe the proposed protocol for developing methods for producing robust and transparent clinical guidance on aspects of diagnosis, drug treatment, physical and practical management, respiration, nutrition and cardiac management, psychosocial management, and multidisciplinary care.

BackgroundNormal swallowing function is divided into oral, pharyngeal, and oesophageal phases. The anatomy and physiology of the oral cavity facilitates an oral preparatory phase of swallowing, in which food and liquid are pushed towards the pharynx by the tongue. During pharyngeal and oesophageal phases of swallowing, food and liquid are moved from the pharynx to the stomach via the oesophagus. Our understanding of swallowing function in health and disease has informed our understanding of how muscle weakness can disrupt swallowing in people with muscle disease. As a common complication of long-term, progressive muscle disease, there is a clear need to evaluate the current interventions for managing swallowing difficulties (dysphagia). This is an update of a review first published in 2004.ObjectivesTo assess the effects of interventions for dysphagia in people with long-term, progressive muscle disease.Search methodsOn 11 January 2016, we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, AMED, LILACS, and CINAHL. We checked references in the identified trials for additional randomised and quasi-randomised controlled trials. We also searched ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform on 12 January 2016 for ongoing or completed but unpublished clinical trials.Selection criteriaWe included randomised and quasi-randomised controlled trials that assessed the effect of interventions for managing dysphagia in adults and children with long-term, progressive muscle disease, compared to other interventions, placebo, no intervention, or standard care. Quasi-randomised controlled trials are trials that used a quasi-random method of allocation, such as date of birth, alternation, or case record number. Review authors previously excluded trials involving people with muscle conditions of a known inflammatory or toxic aetiology. In this review update, we decided to include trials of people with sporadic inclusion body myositis (IBM) on the basis that it presents as a long-term, progressive muscle disease with uncertain degenerative and inflammatory aetiology and is typically refractory to treatment.Data collection and analysisWe applied standard Cochrane methodological procedures.Main resultsThere were no randomised controlled trials (RCTs) that reported results in terms of the review's primary outcome of interest, weight gain or maintenance. However, we identified one RCT that assessed the effect of intravenous immunoglobulin on swallowing function in people with IBM. The trial authors did not specify the number of study participants who had dysphagia. There was also incomplete reporting of findings from videofluoroscopic investigations, which was one of the review's secondary outcome measures. The study did report reductions in the time taken to swallow, as measured using ultrasound. No serious adverse events occurred during the study, although data for the follow-up period were lacking. It was also unclear whether the non-serious adverse events reported occurred in the treatment group or the placebo group. We assessed this study as having a high risk of bias and uncertain confidence intervals for the review outcomes, which limited the overall quality of the evidence. Using GRADE criteria, we downgraded the quality of the evidence from this RCT to 'low' for efficacy in treating dysphagia, due to limitations in study design and implementation, and indirectness in terms of the population and outcome measures. Similarly, we assessed the quality of the evidence for adverse events as 'low'. From our search for RCTs, we identified two other non-randomised studies, which reported the effects of long-term intravenous immunoglobulin therapy in adults with IBM and lip-strengthening exercises in children with myotonic dystrophy type 1. Headaches affected two participants treated with long-term intravenous immunoglobulin therapy, who received a tailored dose reduction; there were no adverse events associated with lip-strengthening exercises. Both non-randomised studies identified improved outcomes for some participants following the intervention, but neither study specified the number of participants with dysphagia or demonstrated any group-level treatment effect for swallowing function using the outcomes prespecified in this review.Authors' conclusionsThere is insufficient and low-quality RCT evidence to determine the effect of interventions for dysphagia in long-term, progressive muscle disease. Clinically relevant effects of intravenous immunoglobulin for dysphagia in inclusion body myositis can neither be confirmed or excluded using the evidence presented in this review. Standardised, validated, and reliable outcome measures are needed to assess dysphagia and any possible treatment effect. Clinically meaningful outcomes for dysphagia may require a shift in focus from measures of impairment to disability associated with oral feeding difficulties.

BackgroundInclusion body myositis (IBM) is a late-onset inflammatory muscle disease (myopathy) associated with progressive proximal and distal limb muscle atrophy and weakness. Treatment options have attempted to target inflammatory and atrophic features of this condition (for example with immunosuppressive and immunomodulating drugs, anabolic steroids, and antioxidant treatments), although as yet there is no known effective treatment for reversing or minimising the progression of inclusion body myositis. In this review we have considered the benefits, adverse effects, and costs of treatment in targeting cardinal effects of the condition, namely muscle atrophy, weakness, and functional impairment.ObjectivesTo assess the effects of treatment for IBM.Search methodsOn 7 October 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, the Cochrane Central Register for Controlled Trials (CENTRAL), MEDLINE, and EMBASE. Additionally in November 2014 we searched clinical trials registries for ongoing or completed but unpublished trials.Selection criteriaWe considered randomised or quasi-randomised trials, including cross-over trials, of treatment for IBM in adults compared to placebo or any other treatment for inclusion in the review. We specifically excluded people with familial IBM and hereditary inclusion body myopathy, but we included people who had connective tissue and autoimmune diseases associated with IBM, which may or may not be identified in trials. We did not include studies of exercise therapy or dysphagia management, which are topics of other Cochrane systematic reviews.Data collection and analysisWe used standard Cochrane methodological procedures.Main resultsThe review included 10 trials (249 participants) using different treatment regimens. Seven of the 10 trials assessed single agents, and 3 assessed combined agents. Many of the studies did not present adequate data for the reporting of the primary outcome of the review, which was the percentage change in muscle strength score at six months. Pooled data from two trials of interferon beta-1a (n = 58) identified no important difference in normalised manual muscle strength sum scores from baseline to six months (mean difference (MD) -0.06, 95% CI -0.15 to 0.03) between IFN beta-1a and placebo (moderate-quality evidence). A single trial of methotrexate (MTX) (n = 44) provided moderate-quality evidence that MTX did not arrest or slow disease progression, based on reported percentage change in manual muscle strength sum scores at 12 months. None of the fully published trials were adequately powered to detect a treatment effect. We assessed six of the nine fully published trials as providing very low-quality evidence in relation to the primary outcome measure. Three trials (n = 78) compared intravenous immunoglobulin (combined in one trial with prednisone) to a placebo, but we were unable to perform meta-analysis because of variations in study analysis and presentation of trial data, with no access to the primary data for re-analysis. Other comparisons were also reported in single trials. An open trial of anti-T lymphocyte immunoglobulin (ATG) combined with MTX versus MTX provided very low-quality evidence in favour of the combined therapy, based on percentage change in quantitative muscle strength sum scores at 12 months (MD 12.50%, 95% CI 2.43 to 22.57). Data from trials of oxandrolone versus placebo, azathioprine (AZA) combined with MTX versus MTX, and arimoclomol versus placebo did not allow us to report either normalised or percentage change in muscle strength sum scores. A complete analysis of the effects of arimoclomol is pending data publication. Studies of simvastatin and bimagrumab (BYM338) are ongoing. All analysed trials reported adverse events. Only 1 of the 10 trials interpreted these for statistical significance. None of the trials included prespecified criteria for significant adverse events.Authors' conclusionsTrials of interferon beta-1a and MTX provided moderate-quality evidence of having no effect on the progression of IBM. Overall trial design limitations including risk of bias, low numbers of participants, and short duration make it difficult to say whether or not any of the drug treatments included in this review were effective. An open trial of ATG combined with MTX versus MTX provided very low-quality evidence in favour of the combined therapy based on the percentage change data given. We were unable to draw conclusions from trials of IVIg, oxandrolone, and AZA plus MTX versus MTX. We need more randomised controlled trials that are larger, of longer duration, and that use fully validated, standardised, and responsive outcome measures.

There is not one systems biology of aging, but two. Though aging can evolve in either sexual or asexual species when there is asymmetric reproduction, the evolutionary genetics of aging in species with frequent sexual recombination are quite different from those arising when sex is rare or absent. When recombination is rare, selection is expected to act chiefly on rare large-effect mutations, which purge genetic variation due to genome-wide hitchhiking. In such species, the systems biology of aging can focus on the effects of large-effect mutants, transgenics, and combinations of such genetic manipulations. By contrast, sexually outbreeding species maintain abundant genetic polymorphism within populations. In such species, the systems biology of aging can examine the genome-wide effects of selection and genetic drift on the numerous polymorphic loci that respond to laboratory selection for different patterns of aging. An important question of medical relevance is to what extent insights derived from the systems biology of aging in model species can be applied to human aging.

The roles of history, chance and selection have long been debated in evolutionary biology. Though uniform selection is expected to lead to convergent evolution between populations, contrasting histories and chance events might prevent them from attaining the same adaptive state, rendering evolution somewhat unpredictable. The predictability of evolution has been supported by several studies documenting repeatable adaptive radiations and convergence in both nature and laboratory. However, other studies suggest divergence among populations adapting to the same environment. Despite the relevance of this issue, empirical data is lacking for real-time adaptation of sexual populations with deeply divergent histories and ample standing genetic variation across fitness-related traits. Here we analyse the real-time evolutionary dynamics of Drosophila subobscura populations, previously differentiated along the European cline, when colonizing a new common environment. By analysing several life-history, physiological and morphological traits, we show that populations quickly converge to the same adaptive state through different evolutionary paths. In contrast with other studies, all analysed traits fully converged regardless of their association with fitness. Selection was able to erase the signature of history in highly differentiated populations after just a short number of generations, leading to consistent patterns of convergent evolution.

Census population size, sex-ratio and female reproductive success were monitored in 10 laboratory populations of Drosophila melanogaster selected for different ages of reproduction. With this demographic information, we estimated eigenvalue, variance and probability of allele loss effective population sizes. We conclude that estimates of effective size based on genefrequency change at a few loci are biased downwards. We analysed the relative roles of selection and genetic drift in maintaining genetic variation in laboratory populations of Drosophila. We suggest that rare, favourable genetic variants in our laboratory populations have a high chance of being lost if their fitness effect is weak, e.g. 1% or less. However, if the fitness effect of this variation is 10% or greater, these rare variants are likely to increase to high frequency. The demographic information developed in this study suggests that some of our laboratory populations harbour more genetic variation than expected. One explanation for this finding is that part of the genetic variation in these outbred laboratory Drosophila populations may be maintained by some form of balancing selection. We suggest that, unlike bacteria, medium-term adaptation of laboratory populations of fruit flies is not primarily driven by new mutations, but rather by changes in the frequency of preexisting alleles.

In a variety of organisms, adulthood is divided into aging and late life, where aging is a period of exponentially increasing mortality rates and late life is a period of roughly plateaued mortality rates. In this study we used ∼57,600 Drosophila melanogaster from six replicate populations to examine the physiological transitions from aging to late life in four functional characters that decline during aging: desiccation resistance, starvation resistance, time spent in motion, and negative geotaxis. Time spent in motion and desiccation resistance declined less quickly in late life compared to their patterns of decline during aging. Negative geotaxis declined at a faster rate in late life compared to its rate of decline during aging. These results yield two key findings: (1) Late-life physiology is distinct from the physiology of aging, in that there is not simply a continuation of the physiological trends which characterize aging; and (2) late life physiology is complex, in that physiological characters vary with respect to their stabilization, deceleration, or acceleration in the transition from aging to late life. These findings imply that a correct understanding of adulthood requires identifying and appropriately characterizing physiology during properly delimited late-life periods as well as aging periods.

Aging is not simply an accumulation of damage or inappropriate higher-order signaling, though it does secondarily involve both of these subsidiary mechanisms. Rather, aging occurs because of the extensive absence of adaptive genomic information required for survival to, and function at, later adult ages, due to the declining forces of natural selection during adult life. This absence of information then secondarily leads to misallocations and damage at every level of biological organization. But the primary problem is a failure of adaptation at later ages. Contemporary proposals concerning means by which human aging can be ended or cured which are based on simple signaling or damage theories will thus reliably fail. Strategies based on reverse-engineering age-extended adaptation using experimental evolution and genomics offer the prospect of systematically greater success.

In the late 19th century, the evolutionary approach to the problem of ageing was initiated by August Weismann, who argued that natural selection was more important for ageing than any physiological mechanism. In the mid-twentieth century, J. B. S. Haldane, P. B. Medawar and G. C. Williams informally argued that the force of natural selection falls with adult age. In 1966, W. D. Hamilton published formal equations that showed mathematically that two' forces of natural selection' do indeed decline with age, though his analysis was not genetically explicit. Brian Charlesworth then developed the required mathematical population genetics for the evolution of ageing in the 1970's. In the 1980's, experiments using Drosophila showed that the rate of ageing evolves as predicted by Hamilton's' forces of natural selection'. The discovery of the cessation of ageing late in life in the 1990's was followed by its explanation in terms of evolutionary theory based on Hamilton's forces. Recently, it has been shown that the cessation of ageing can also be manipulated experimentally using Hamilton's' forces of natural selection'. Despite the success of evolutionary research on ageing, mainstream gerontological research has largely ignored both this work and the opportunity that it provides for effective intervention in ageing.

An important aspect of the aging process in Drosophila melanogaster is the natural loss of antennae, legs, bristles, and parts of wings with age. These injuries lead to a loss of hemolymph, which contains water and nutrients. Stress-resistant lines of D. melanogaster are sometimes longer-lived than the populations from which they are derived. One hypothesis tested here is that increased stress-resistance fosters longevity because it allows fruit flies to cope with the loss of hemolymph due to injury to the aging fly. We tested the effects of surgically induced injury on the aging and reproduction of five replicate populations. We then tested the effects of injury on populations that had been selected for different levels of stress resistance and on control populations. Injury affected aging more in males than in females, in part because of a counter-balancing reduction in female reproduction brought about by injury. More specifically, injury reduced female fecundity and male virility. Injury significantly reduced the starvation resistance in some groups of flies, but not in others. These findings undermine any simple interpretation of the interactions between injury, reproduction, and aging based on stress resistance. But they do indicate the existence of significant interactions between these biological processes, interactions that should be resolved in greater mechanistic detail than has been managed here.

BackgroundNatural selection and genetic drift are major forces responsible for temporal genetic changes in populations. Furthermore, these evolutionary forces may interact with each other. Here we study the impact of an ongoing adaptive process at the molecular genetic level by analyzing the temporal genetic changes throughout 40 generations of adaptation to a common laboratory environment. Specifically, genetic variability, population differentiation and demographic structure were compared in two replicated groups of Drosophila subobscura populations recently sampled from different wild sources.ResultsWe found evidence for a decline in genetic variability through time, along with an increase in genetic differentiation between all populations studied. The observed decline in genetic variability was higher during the first 14 generations of laboratory adaptation. The two groups of replicated populations showed overall similarity in variability patterns. Our results also revealed changing demographic structure of the populations during laboratory evolution, with lower effective population sizes in the early phase of the adaptive process. One of the ten microsatellites analyzed showed a clearly distinct temporal pattern of allele frequency change, suggesting the occurrence of positive selection affecting the region around that particular locus.ConclusionGenetic drift was responsible for most of the divergence and loss of variability between and within replicates, with most changes occurring during the first generations of laboratory adaptation. We also found evidence suggesting a selective sweep, despite the low number of molecular markers analyzed. Overall, there was a similarity of evolutionary dynamics at the molecular level in our laboratory populations, despite distinct genetic backgrounds and some differences in phenotypic evolution.

Using the fruit fly, Drosophila melanogaster, we investigated the effects of Rhodiola on life-span. Rhodiola is a plant root used in traditional Chinese medicine that may increase an organism's resistance to stress. It has been proposed that Rhodiola can extend longevity and improve health span by alleviating oxidative stress. Rhodiola supplied every other day at 30 mg/mL significantly increased the lifespan of Drosophila melanogaster. When comparing the distribution of deaths between Rhodiola-supplemented and control flies, Rhodiola-fed flies exhibited decelerated aging. Although the observed extension in lifespan was associated with statistically insignificant reductions in fecundity, correcting for a possible dietary restriction effect still did not eliminate the difference between supplemented and control flies, nor does the effect of Rhodiola depend on dietary manipulation, strongly suggesting that Rhodiola is not a mere dietary restriction mimetic. Although this study does not reveal the causal mechanism behind the effect of Rhodiola, it does suggest that the supplement is worthy of continued investigation, unlike the other Chinese herbals, Lu Duo Wei (LDW), Bu Zhong Yi Qi Tang (BZYQT), San Zhi Pian (SZP, Three Imperial Mushrooms), Hong Jing Tian (Rhodiola) that were evaluated in this study.

Insulin and Insulin-Growth-Factor-like (IGF) signaling pathways are well known longevity pathways in nematodes, insects and mammals. To our knowledge, there are no systematic pharmacological studies evaluating the anti-aging properties of medications that target this pathway in Drosophila. Although there are no published data implicating an anti-aging role for these compounds in Drosophila, we hypothesized that their promising pharmacological profile might decrease mortality. However, the decrease in mortality could be due to a number of potential artifacts and confounds such as fecundity depression, decrease in metabolic rate, or CNS depression. Therefore, the mere finding that a compound decreases mortality does not qualify it as an anti-aging compound. In this study, we evaluated the anti-aging properties of four compounds that might target the insulin signaling pathway in Drosophila. Once it was established that the compound decreased mortality, we proceeded to evaluate possible confounding factors that could have contributed to the mortality reduction. We show that only piolglitazone displayed anti-aging properties. At present, we do not have a mechanistic explanation for this pharmacological disparity.

BackgroundThe last third of the 20th Century featured an accumulation of research findings that severely challenged the assumptions of the "Modern Synthesis" which provided the foundations for most biological research during that century. The foundations of that "Modernist" biology had thus largely crumbled by the start of the 21st Century. This in turn raises the question of foundations for biology in the 21st Century.ConclusionLike the physical sciences in the first half of the 20th Century, biology at the start of the 21st Century is achieving a substantive maturity of theory, experimental tools, and fundamental findings thanks to relatively secure foundations in genomics. Genomics has also forced biologists to connect evolutionary and molecular biology, because these formerly Balkanized disciplines have been brought together as actors on the genomic stage. Biologists are now addressing the evolution of genetic systems using more than the concepts of population biology alone, and the problems of cell biology using more than the tools of biochemistry and molecular biology alone. It is becoming increasingly clear that solutions to such basic problems as aging, sex, development, and genome size potentially involve elements of biological science at every level of organization, from molecule to population. The new biology knits together genomics, bioinformatics, evolutionary genetics, and other such general-purpose tools to supply novel explanations for the paradoxes that undermined Modernist biology.Open Peer ReviewersThis article was reviewed by W.F. Doolittle, E.V. Koonin, and J.M. Logsdon. For the full reviews, please go to the Reviewers' Comments section.

An intensive study of longevity, female fecundity, and male reproductive behavior in Drosophila melanogaster was undertaken in order to establish whether late-life fitness characters in short-lived populations might be affected by the increase in deleterious alleles due to random genetic drift. We also sought to determine whether selection for late-life fertility could eliminate alleles that produce a decline in later fitness components in short-lived populations, as predicted by the mutation accumulation hypothesis for the evolution of aging. These experiments employed long-lived (O) populations, short-lived (B) populations, and hybrids made from crosses of independent lines from within the O and B populations. No detectable longevity differences were seen between hybrid B males and females and purebred B males and females. Reproduction in aged B purebred females was significantly less than in hybrid females at 3 wk of age only. A full diallel cross of the five replicate B lines showed a steady increase in hybrid male reproductive performance after the first week of adult life, relative to the parental lines. A full diallel cross of the five replicate O lines revealed no significant increase in hybrid O age-specific male reproductive success compared with the purebred O lines when assayed over the first 5 wk of adult life. The results on male reproductive behavior are consistent with the idea that relaxed age-specific selection in the B populations has been accompanied by an increase in deleterious, recessive traits that exhibit age-specific expression. Consequently, we conclude that a mutation accumulation process has been at least partly responsible for the age-specific decline in male B virility relative to that of the O populations.

Data from populations undergoing experimental evolution can be used to make comparisons between physiologically differentiated populations and to determine evolutionary trajectories. Comparisons of long-established laboratory populations of Drosophila melanogaster that are strongly differentiated with respect to desiccation resistance are used to test alternative hypotheses concerning the mechanisms that fruit flies use to survive bouts of extreme desiccation. This comparative study supports the hypothesis that, in at least one case, D. melanogaster can evolve increased resistance to desiccation by decreasing water loss rates and by increasing bulk water content but not by increasing metabolic water content or dehydration tolerance. While glycogen was involved in water storage, its primary role was in water binding, not the production of metabolic water. Measurement of the trajectories of these component mechanisms during selection for desiccation resistance is used to demonstrate that water loss rate quickly plateaus in response to selection, while water content continues to improve. This disparity reveals the value of studying evolutionary trajectories and the need for longer-term selection studies in evolutionary physiology.

There is now a significant body of research that establishes the deceleration of mortality rates in late life and their ultimate leveling off on a late-life plateau. Natural selection has been offered as one mechanism responsible for these plateaus. The force of natural selection should also exert such effects on female fecundity. We have already developed a model of female fecundity in late life that incorporates the general predictions of the evolutionary model. The original evolutionary model predicts a decline in fecundity from a peak in early life, followed by a plateau with non-zero fecundity in late life. However, in Drosophila there is also a well-defined decline in fecundity among dying flies, here called the "death spiral". This effect produces heterogeneity between dying and non-dying flies. Here a hybrid evolutionary heterogeneity model is developed to accommodate both the evolutionary plateau prediction and the death spiral. It is shown that this evolutionary heterogeneity model gives a much better fit to late-life fecundity data.

Recent research indicates that aging is affected by many genes and thus many biochemical pathways. This has led to a failure to find pharmaceuticals that significantly ameliorate the human aging process. Progress in evolutionary and genetic research, however, suggests the possibility of combining experimental evolution, genomic analysis, and mass screening of pharmaceuticals and botanicals to produce effective therapeutics for human aging. The starting point for this strategy is model systems that have outbred populations with substantially increased lifespan. These are easily produced by tuning the force of natural selection in the laboratory. Such biological material is then a good candidate for genomic analysis, leading to the identification of numerous biochemical pathways involved in increased lifespan, in the model system. These biochemical pathways would then be available for pharmaceutical development, first in fruit flies, then in rodents, and eventually in a clinical human population. We include a discussion of the pharmacological methods appropriate to this strategy of drug discovery.

In the year 1992, two publications on age-specific mortality rates revealed a cessation of demographic aging at later ages in very large cohorts of two dipteran species reared under a variety of conditions. Despite some initial concerns about possible artifacts, these findings have now been amply corroborated in the experimental literature. The eventual cessation of aging undermines the credibility of simple Gompertzian aging models based on a protracted acceleration in age-specific mortality during adulthood. The first attempt to explain the apparent cessation of aging was extreme lifelong heterogeneity among groups with respect to frailty. This lifelong heterogeneity theory assumes an underlying Gompertzian aging affecting every member of an adult cohort, with a merely apparent cessation of aging explained in terms of the increasing domination of a slowly aging group among the survivors to late ages. This theory has received several experimental refutations. The second attempt to explain the cessation of aging applied force of natural selection theory. This explanation of the cessation of aging has been corroborated in several Drosophila experiments. In particular, this theory requires that both age-specific survival and age-specific fecundity cease declining in late life, which has now been experimentally established. This theory also predicts that the timing of the cessation of aging should depend on the last age of reproduction in a population's evolutionary history, a prediction that has been corroborated. While lifelong heterogeneity should reduce average age-specific mortality in late life whenever it is pronounced, the cessation of aging in late life can be explained by plateaus in the forces of natural selection whether lifelong heterogeneity is present or not. The discovery that aging ceases is one of the most significant discoveries in recent aging research, with potentially revolutionary scientific implications.