Differential impacts of ionizing radiation on a sexually dimorphic trait in male and female Acheta domesticus.

PURPOSE: In many Orthopteran species, including crickets, forewings exhibit substantial sexual dimorphism driven by sexual selection. In the cricket, Acheta domesticus, females are the 'choosy' sex and males exhibit multiple sexual signals to attract and successfully mate. Male forewings have highly specialized structures critical for acoustic signaling and mating. In contrast, female forewings currently serve no known purpose in this flightless species. Forewings also differ morphologically with male forewings containing complex acoustic producing and resonating regions and females lacking any defined structures. Due to their importance to mating as well as their structural complexity, impacts of environmental stress that target cricket forewing development may therefore have more severe consequences in males than females. Here, we investigate the sensitivity of a sexually dimorphic trait, forewing morphology, to an early life environmental stressor. MATERIALS AND METHODS: We applied ionizing radiation (0--27.8 Gy) as a stressor as dose can be precisely applied as well as its relevance in both environmental contamination and use in the Sterile Insect Technique. RESULTS: A canonical variate analysis indicated that wing shape was significantly altered in males at all doses; .58 Gy, 2.3 Gy, 4.6 Gy, 16.2 Gy, and 23.2 Gy. In females, shape was significantly altered at 27.8 Gy and 23.2 Gy groups and to a lesser extent at .58 Gy and 16.2 Gy. Linear regression analysis of centroid size indicated a dose dependent decline in wing size in both sexes, with males exhibiting more decline. Fluctuating asymmetry, a measure of environmental sensitivity, revealed that males were more sensitive to shape changes due to stress than females. This difference in sensitivity is likely due to the complexity of male forewings. CONCLUSION: These results expand understanding of sex dimorphism in stress responses and sensitivity to ionizing radiation.

Investigation of presence and impact of radiation-induced bystander effect in Acheta domesticus.

PURPOSE: Radiation-induced bystander effect (RIBE), a non-targeted effect of ionizing radiation in which non-irradiated individuals behave as if they have been irradiated after interactions with irradiated individuals, has been well documented in vertebrates. However, little research has been done investigating RIBE in terrestrial insects, this paucity of invertebrate RIBE leads to lack of knowledge on invertebrates living in fallout and exclusion zones. This paper aims to better understand the impacts of RIBE on terrestrial insects.Methods and materials: House crickets who have interacted with irradiated crickets were examined to investigate population effects of ionizing radiation exposure to better understand RIBE in insects. RESULTS: The results demonstrated RIBE in crickets and found that cohabitated males had higher growth rate (mg/day) when compared to non-cohabitated males. Further, cohabitated males and females matured significantly faster with no significant difference in maturation weight than non-cohabitated populations. Experiment with adult irradiated crickets found saturability of bystander signals and similar shifts in maturation parameters. These results highlight that bystander signals can impacted development and maturation in crickets. CONCLUSION: Given long-term impacts of RIBE in insects, these results may have significant implications for interactions between insects inhabiting fringe nuclear exclusion zones and those outside of it.

Impacts of ionization radiation on the cuticular hydrocarbon profile and mating success of male house crickets (Acheta domesticus).

PURPOSE: Ionizing radiation is well known to have drastic impacts on major life history features including survivorship, growth, fertility, and longevity. What is much less appreciated is how radiation stress can cause changes to more subtle traits, such as those associated with sexual signaling, an underappreciated but vital aspect of insect reproduction. In the House Cricket (Acheta domesticus) cuticular hydrocarbons are vital for sex and species recognition, as well as a possible indicator of stress, making them crucial for successful mating and reproduction. MATERIALS AND METHODS: Here, we analyze the impacts of ionizing radiation on the cuticular hydrocarbons of male crickets and its subsequent impacts on mating success. We exposed juvenile (14-day, 4th instar) male crickets to a broad range of radiation doses (2 Gy - 2 Gy). RESULTS: We detected significant changes in individual cuticular hydrocarbons across a broad range of doses in mature male crickets using gas-liquid chromatography. Specifically, dose was identified as a significant contributing factor to hydrocarbon increases p < .0001. Mating success was significantly reduced in 12 Gy (p < .0001), 10 Gy (0.0001), and 7 Gy (0.0060) groups compared to non-irradiated controls. CONCLUSION: Insect chemical communication can be species specific, and functionally specialized. Here, we show that radiation can alter the chemical signals used to attract mates in a large bodied insect and this may be a contributing factor to the described reduction in male mating success. Further research should be conducted to further analyze the various modes of communication employed by male crickets to attract mates i.e. acoustic signaling, and how this may also contribute to the reduction in mating success seen in irradiated males.

Trans-Generational Impacts of Paternal Irradiation in a Cricket: Damage, Life-History Features and Hormesis in F1 Offspring.

Animals exposed to significant stress express multi-modal responses to buffer negative impacts. Trans-generational impacts have been mainly studied in maternal lines, with paternal lines having received less attention. Here, we assessed paternal generational effects using irradiated male crickets (Acheta domesticus), and their F1 offspring (irradiated males mated to unirradiated females). Paternal transmission of radiation impacts emerged in multiple life history traits when compared to controls. Irradiated males and their F1 offspring expressed hormetic responses in survivorship and median longevity at mid-range doses. For F0 males, 7 Gy & 10 Gy doses extended F0 longevity by 39% and 34.2% respectively. F1 offspring of 7 Gy and 10 Gy sires had median lifespans 71.3% and 110.9% longer, respectively. Survivorship for both F0 7 Gy (p < 0.0001) and 10 Gy (p = 0.0055) males and F1 7 Gy and 10 Gy (p < 0.0001) offspring significantly surpassed that of controls. Irradiated F0 males and F1 offspring had significantly reduced growth rates. For F0 males, significant reductions were evident in 4Gy-12 Gy males and F1 offspring in 4 Gy (p < 0.0001), 7 Gy (p < 0.0001), and 10 Gy (p = 0.017). Our results indicate paternal effects; that irradiation directly impacted males but also mediated diverse alterations in the life history features (particularly longevity and survivorship) of F1 offspring.

Hormetic Effects of Early Juvenile Radiation Exposure on Adult Reproduction and Offspring Performance in the Cricket (Acheta domesticus).

Exposure to low-dose ionizing radiation can have positive impacts on biological performance-a concept known as hormesis. Although radiation hormesis is well-documented, the predominant focus has been medical. In comparison, little research has examined potential effects of early life radiation stress on organismal investment in life history traits that closely influence evolutionary fitness (eg, patterns of growth, survival, and reproduction). Evaluating the fitness consequences of radiation stress is important, given that low-level radiation pollution from anthropogenic sources is considered a major threat to natural ecosystems. Using the cricket (Acheta domesticus), we tested a wide range of doses to assess whether a single juvenile exposure to radiation could induce hormetic benefits on lifetime fitness measures. Consistent with hormesis, we found that low-dose juvenile radiation positively impacted female fecundity, offspring size, and offspring performance. Remarkably, even a single low dose of radiation in early juvenile development can elicit a range of positive fitness effects emerging over the life span and even into the next generation.

Early Intervention with a Multi-Ingredient Dietary Supplement Improves Mood and Spatial Memory in a Triple Transgenic Mouse Model of Alzheimer's Disease.

The increasing global burden of Alzheimer's disease (AD) and failure of conventional treatments to stop neurodegeneration necessitates an alternative approach. Evidence of inflammation, mitochondrial dysfunction, and oxidative stress prior to the accumulation of amyloid-ß in the prodromal stage of AD (mild cognitive impairment; MCI) suggests that early interventions which counteract these features, such as dietary supplements, may ameliorate the onset of MCI-like behavioral symptoms. We administered a polyphenol-containing multiple ingredient dietary supplement (MDS), or vehicle, to both sexes of triple transgenic (3xTg-AD) mice and wildtype mice for 2 months from 2-4 months of age. We hypothesized that the MDS would preserve spatial learning, which is known to be impaired in untreated 3xTg-AD mice by 4 months of age. Behavioral phenotyping of animals was done at 1-2 and 3-4 months of age using a comprehensive battery of tests. As previously reported in males, both sexes of 3xTg-AD mice exhibited increased anxiety-like behavior at 1-2 months of age, prior to deficits in learning and memory, which did not appear until 3-4 months of age. The MDS did not reduce this anxiety or prevent impairments in novel object recognition (both sexes) or on the water maze probe trial (females only). Strikingly, the MDS specifically prevented 3xTg-AD mice (both sexes) from developing impairments (exhibited by untreated 3xTg-AD controls) in working memory and spatial learning. The MDS also increased sucrose preference, an indicator of hedonic tone. These data show that the MDS can prevent some, but not all, psychopathology in an AD model.

Impacts of metformin and aspirin on life history features and longevity of crickets: trade-offs versus cost-free life extension?

We examined the impacts of aspirin and metformin on the life history of the cricket Acheta domesticus (growth rate, maturation time, mature body size, survivorship, and maximal longevity). Both drugs significantly increased survivorship and maximal life span. Maximal longevity was 136 days for controls, 188 days (138 % of controls) for metformin, and 194 days (143 % of controls) for aspirin. Metformin and aspirin in combination extended longevity to a lesser degree (163 days, 120 % of controls). Increases in general survivorship were even more pronounced, with low-dose aspirin yielding mean longevity 234 % of controls (i.e., health span). Metformin strongly reduced growth rates of both genders (<60 % of controls), whereas aspirin only slightly reduced the growth rate of females and slightly increased that of males. Both drugs delayed maturation age relative to controls, but metformin had a much greater impact (>140 % of controls) than aspirin (~118 % of controls). Crickets maturing on low aspirin showed no evidence of a trade-off between maturation mass and life extension. Remarkably, by 100 days of age, aspirin-treated females were significantly larger than controls (largely reflecting egg complement). Unlike the reigning dietary restriction paradigm, low aspirin conformed to a paradigm of "eat more, live longer." In contrast, metformin-treated females were only ~67 % of the mass of controls. Our results suggest that hormetic agents like metformin may derive significant trade-offs with life extension, whereas health and longevity benefits may be obtained with less cost by agents like aspirin that regulate geroprotective pathways.

Impact of a complex nutraceutical supplement on primary tumour formation and metastasis in Trp53+/- cancer-prone mice.

A complex dietary supplement designed to impact multiple mechanisms associated with aging and cancer reduced overall tumorigenesis in cancer-prone heterozygous Trp53+/- mice by ~30% (P < 0.018). Carcinomas were reduced by 67% (P < 0.006). Remarkably, metastasis (a leading cause of cancer mortality) was undetectable in treated animals (P < 0.004), and the occurrence of multiple primary tumours was reduced by 74% (P < 0.012). Reduction of pulmonary adenocarcinoma by 62% (P < 0.021) was of particular note given that lung cancer is the second leading cause of death in humans. Tumours showed pronounced age-related expression in untreated animals older than 600 days. Benefits of treatment only emerged in these later ages, suggesting that the supplement acted on mechanisms common to aging and cancer. The supplement was administered daily on bagel bits that were usually eaten within minutes by the mice. Although longevity was not statistically different between treatments, longevity was strongly related to the compliance of mice in eating the supplement. Linear regression revealed a strong positive relationship between the proportion of supplement eaten and the longevity of mice within the treatment group (P < 0.0001).

A complex dietary supplement augments spatial learning, brain mass, and mitochondrial electron transport chain activity in aging mice.

We developed a complex dietary supplement designed to offset five key mechanisms of aging and tested its effectiveness in ameliorating age-related cognitive decline using a visually cued Morris water maze test. All younger mice (<1 year old) learned the task well. However, older untreated mice (>1 year) were unable to learn the maze even after 5 days, indicative of strong cognitive decline at older ages. In contrast, no cognitive decline was evident in older supplemented mice, even when ∼2 years old. Supplemented older mice were nearly 50% better at locating the platform than age-matched controls. Brain weights of supplemented mice were significantly greater than controls, even at younger ages. Reversal of cognitive decline in activity of complexes III and IV by supplementation was significantly associated with cognitive improvement, implicating energy supply as one possible mechanism. These results represent proof of principle that complex dietary supplements can provide powerful benefits for cognitive function and brain aging.

A complex dietary supplement modulates nitrative stress in normal mice and in a new mouse model of nitrative stress and cognitive aging.

We examined whether transgenic growth hormone mice (Tg) that exhibit accelerated cognitive aging and exceptional free radical damage also express elevated nitrative stress. We characterized age-related patterns of 3-nitrotyrosine (3-NT) in brain homogenate and mitochondria of Tg and normal (Nr) mice as modulated by a complex anti-aging dietary supplement. Levels of 3-NT rose rapidly with age in Tg brain homogenate whereas normal controls maintained constant lower levels. The age-related slope for 3-NT was 3.6-fold steeper in untreated Tg compared to treated Tg (p<0.009), although treated Tg showed elevation in youth. Opposite to Tg, treated Nr mice had reduced 3-NT in youth (p<0.02). The age-related pattern of mitochondrial 3-NT in Nr mice was parabolic (p<0.005). Remarkably, levels in treated Nr were reduced by ~50% (p<0.0007). Untreated Tg showed strongly increasing mitochondrial 3-NT with higher mitochondrial activity (p<0.01) whereas treated Tg showed lower nitrosylation at higher levels of mitochondrial activity. Tg mice also expressed a postural abnormality that is a biomarker of neurodegeneration and/or nitrative stress. Tg represent a promising new model of nitrative stress associated with brain deterioration and results provide proof of principle that complex dietary supplements may be ameliorating.

Influence of two methods of dietary restriction on life history features and aging of the cricket Acheta domesticus.

Studying aging is constrained using vertebrates by their longevity, size, ethical restrictions, and expense. The key insect model, Drosophila melanogaster, is holometabolous. Larvae feed on yeast in moist media and adults sponge food. Most aging studies are restricted to adults. Another key model, the nematode Caenorhabditis elegans, feeds on bacteria in moist media. For either invertebrate refreshing test materials, preventing degradation and obtaining accurate dosing are difficult even with synthetic media. The cricket Acheta domesticus has a short lifespan (∼120 days at 30°C) and is omnivorous. Age-matched cohorts are easily obtained from eggs. The life cycle is hemimetabolous and nymphs eat the same foods as adults. Growth is easily monitored, gender can be differentiated before maturity, and maturation is indicated by wings and mature genitalia. Crickets can be reared in large numbers at low cost. Test materials can be mixed into food and ingestion rates or mass budgets easily assessed. Here, we validate the cricket as a model of aging by testing two fundamental methods of restricting food intake: time-restricted access to food and dietary dilution. Growth, maturation, survivorship, and longevity varied with treatments and genders. Intermittent feeding (which is ineffective in flies) significantly extended longevity of crickets. Dietary dilution also extended longevity via remarkable prolongation of the juvenile period.

Dietary amelioration of locomotor, neurotransmitter and mitochondrial aging.

Aging degrades motivation, cognition, sensory modalities and physical capacities, essentially dimming zestful living. Bradykinesis (declining physical movement) is a highly reliable biomarker of aging and mortality risk. Mice fed a complex dietary supplement (DSP) designed to ameliorate five mechanisms associated with aging showed no loss of total daily locomotion compared with >50% decrement in old untreated mice. This was associated with boosted striatal neuropeptide Y, reversal of age-related declines in mitochondrial complex III activity in brain and amelioration of oxidative stress (brain protein carbonyls). Supplemented mice expressed approximately 50% fewer mitochondrial protein carbonyls per unit of complex III activity. Reduction of free radical production by mitochondria may explain the exceptional longevity of birds and dietary restricted animals and no DSP is known to impact this mechanism. Functional benefits greatly exceeded the modest longevity increases documented for supplemented normal mice. Regardless, for aging humans maintaining zestful health and performance into later years may provide greater social and economic benefits than simply prolonging lifespan. Although identifying the role of specific ingredients and interactions remains outstanding, results provide proof of principle that complex dietary cocktails can powerfully ameliorate biomarkers of aging and modulate mechanisms considered ultimate goals for aging interventions.

Aging and the Mammalian regulatory triumvirate.

A temporal framework linking circadian rhythms and clocks to aging rates identifies a specific window of target of rapamycin (TOR) signaling associated with growth hormone (GH) and insulin-like growth factor (IGF-1) (largely exclusive of insulin) in early sleep. IGF-1 signaling is released by growth hormone secretory peaks and downregulation of IGF-1 binding protein-1 resulting in activation of the mitogen activated protein kinase/extracellular signal response kinase (MAPK/ERK) and phosphoinositide 3-kinase-protein kinase B (PI3K-PKB/Akt) signaling pathways. Phosphorylation of Akt activates TOR which mediates the protein synthesis and growth functions of the GH axis. TOR activity is also associated with downregulated stress resistance, faster aging and reduced lifespan. IGF-1 signaling is terminated by falling GH and upregulation of IGF-1 binding proteins mediated by somatostatin and rising corticosteroids in later sleep. This suppresses PI3K-Akt signaling, thus activating the forkhead transcription factors (FOXOs) and stress-resistance pathways involved in promoting longevity. Thus, sleep appears to encompass both pathways currently identified as most relevant to aging and they toggle successively on the phosphorylation status of Akt. I propose a modified version of Pearl's rate of living theory emphasizing the hard-wired antagonism of growth (TOR) and stress resistance (FOXO). The sleep association of TOR and FOXO in temporally separated windows and their sequential temporal deployment may change much of the way we think about aging and how to manipulate it.

Dopamine and aging: intersecting facets.

Aging encompasses life itself so understanding requires frameworks that forge unity amidst complexity. The free radical theory of aging is one example. The original focus on damage was augmented recently by appreciation that reactive oxygen and nitrogen species are essential to normal signaling and cell function. This paradigm is currently undergoing an explosive expansion fueled by the discovery that regulatory organization is a merry-go-round of redox cycling seamlessly fused to endogenous clocks. This might best be described as an "Electroplasmic Cycle." This is certainly applicable to dopaminergic neurons with their exceptional metabolic, electrical and rhythmic properties. Here I review normal aging of dopamine systems to highlight them as a valuable model. I then examine the possible integration of free radical and ion channel theories of aging. Finally, I incorporate clocks and explore the multifaceted implications of electroplasmic cycles with special emphasis on dopamine.

Radiation-induced apoptosis in mouse lymphocytes is modified by a complex dietary supplement: the effect of genotype and gender.

This study examined whether radiation sensitivity measured by lymphocyte apoptosis could be ameliorated by a complex anti-oxidant/anti-ageing dietary supplement. We also examined lymphocytes from both genders of normal (Nr) mice as well as transgenic growth hormone (Tg) mice that express strongly elevated reactive oxygen species processes and a progeroid syndrome of accelerated ageing. We introduce Tg mice as a potentially valuable new model to study radiation sensitivity. Isolated lymphocytes from all experimental groups were exposed to gamma radiation and the time course of apoptosis was measured in vitro. Kinetics of radiation-induced apoptosis was similar among groups, which peaked at 8 h, but maximal levels differed significantly between groups. Nr male mice had 60% lower levels of radiation-induced apoptosis than Tg males, supporting our hypothesis that Tg mice would be radiation sensitive. The dietary supplement protected lymphocytes in male mice of both strains, with proportionally greater reductions in Tg mice. Lymphocytes from female mice (both Nr and Tg) were highly radiation resistant compared to males and the supplement provided no additional benefit at the doses used in this study. These results highlight that radiation-induced apoptosis is complex and is modified by genotype, dietary supplements and gender.

Radiation and the regulatory landscape of neo2-Darwinism.

Several recently revealed features of eukaryotic genomes were not predicted by earlier evolutionary paradigms, including the relatively small number of genes, the very large amounts of non-functional code and its quarantine in heterochromatin, the remarkable conservation of many functionally important genes across relatively enormous phylogenetic distances, and the prevalence of extra-genomic information associated with chromatin structure and histone proteins. All of these emphasize a paramount role for regulatory evolution, which is further reinforced by recent perspectives highlighting even higher-order regulation governing epigenetics and development (EVO-DEVO). Modern neo2-Darwinism, with its emphasis on regulatory mechanisms and regulatory evolution provides new vision for understanding radiation biology, particularly because free radicals and redox states are central to many regulatory mechanisms and free radicals generated by radiation mimic and amplify endogenous signalling. This paper explores some of these aspects and their implications for low-dose radiation biology.

A complex dietary supplement extends longevity of mice.

Key factors implicated in aging include reactive oxygen species, inflammatory processes, insulin resistance, and mitochondrial dysfunction. All are exaggerated in transgenic growth hormone mice (TGM), which display a syndrome resembling accelerated aging. We formulated a complex dietary supplement containing 31 ingredients known to ameliorate all of the above features. We previously showed that this supplement completely abolished the severe age-related cognitive decline expressed by untreated TGM. Here we report that longevity of both TGM and normal mice is extended by this supplement. Treated TGM showed a 28% increase (p < .00008) in mean longevity. An 11% increase in mean longevity was also significant (p < .002093) for treated normal mice, compared to untreated normal mice. These data support the hypothesis that TGM are a model of accelerated aging, and demonstrate that complex dietary supplements may be effective in ameliorating aging or age-related pathologies where simpler formulations have generally failed.

Growth negatively impacts the life span of mammals.

A negative intraspecific relationship between growth and longevity was proposed in the early 20th century. Indeed, stunting the growth of rodents by restricting their food dramatically extended life span. Subsequently, however, the hypothesis that growth exacerbates aging rates fell into disfavor. Contributing to this was (a) the establishment of a positive relationship between body size and longevity interspecifically, (b) purported antiaging impacts of growth hormone, and (c) the fact that the longevity of even mature rodents that had completed growth was extended by dietary restriction. Furthermore, intraspecific analytical studies failed to provide any clear resolution. This article presents the first global analyses of maximal longevity versus maximum mature mass for laboratory rats and mice, based on a relatively comprehensive compilation of research across the 20th century. Peak body mass (which reflects juvenile growth rates) was negatively associated with longevity within both species. Proximal mechanisms for impacts of growth on longevity appear congruent with the free radical and immunological theories of aging.