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.

Radiation induces stress and transgenerational impacts in the cricket, Acheta domesticus.

PURPOSE: Radiation exposure of crickets during their fourth juvenile molt inflicted ionizing radiation damage and altered growth rate, adult size at sexual maturity. High levels of ionizing radiation also impacted the subsequent generation, likely via heritable epigenetic mechanisms. Using radiation as a proxy for external stress, we aim to understand the transgenerational impacts of stress on non-irradiated offspring. METHODS AND MATERIALS: We assess the impacts of ionizing radiation on maturation mass and growth rate in F0 male and female house crickets (Acheta domesticus). We also assessed trans-generational impacts of irradiation on growth rate and maturation mass on non-irradiated offspring of irradiated parents compared to non-irradiated controls. RESULTS: Early-life exposure to high levels of ionizing radiation-induced lower growth rate and maturation mass compared to controls (p < .0001). Non-irradiated male F1 offspring of irradiated parents demonstrated significantly lower mass at maturation (p = .0012) and significantly faster time of maturation (p < .0001) compared to F1 non-irradiated controls. CONCLUSION: Our results show that a single early-life exposure to ionizing radiation can alter male offspring development through accelerated maturation and reduced maturation mass.

Age-related expression of prominent regulatory elements in mouse brain: catastrophic decline of FOXO3a.

Aging is associated with changes in regulation, particularly among diverse regulators in the brain. We assayed prominent regulatory elements in mouse brain to explore their relationship to one another, stress, and aging. Notably, unphosphorylated (activated) forkhead transcription factor 3a (uFOXO3a) expressed exponential decline congruent with increasing age-related mortality. Decline in uFOXO3a would impact homeostasis, aging rate, stress resistance, and mortality. We also examined other regulators associated with aging and FOXO3a: protein kinase B (PKB), the mechanistic target of rapamycin (mTOR), 70 kDa ribosomal S6 kinase (P70S6K), and 5' AMP-activated protein kinase (AMPK). It would require powerful regulatory distortion, conflicting tradeoffs and/or significant damage to inflict exponential decline of a transcription factor as crucial as FOXO3a. No other regulator examined expressed an exponential pattern congruent with aging. PKB was strongly associated with decreases in uFOXO3a, but the aging pattern of PKB did not support a causal linkage. Although mTOR expressed a trend for age-related increase, this was not significant. We considered that the mTOR downstream element, P70S6K, might suppress FOXO3a, but remarkably, it expressed a strong positive association. The age-related pattern of AMPK was also incompatible. Literature suggested the immunological regulator NFĸB (nuclear factor kappa-light-chain-enhancer of activated B cells) increases with age and suppresses FOXO3a. This would inhibit apoptosis, autophagy, mitophagy, proteostasis, detoxification, antioxidants, chaperones, and DNA repair, thus exacerbating aging. We conclude that a key aspect of aging involves distortion of key regulators in the brain.

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.

Histone 3 lysine 9 acetylation is a biomarker of the effects of culture on zygotes.

Acetylation of histone proteins is a major determinant of chromatin structure and function. Fertilisation triggers a round of chromatin remodelling that prepares the genome for the first round of transcription from the new embryonic genome. In this study we confirm that fertilisation leads to a marked progressive increase in the level of histone 3 lysine 9 acetylation in both the paternally and maternally derived genomes. The culture of zygotes in simple defined media caused a marked increase in the global level of acetylation and this affected the male pronucleus more than the female. The culture created a marked asymmetry in staining between the two pronuclei that was not readily detected in zygotes collected directly from the reproductive tract and was ameliorated to some extent by optimized culture media. The increased acetylation caused by culture resulted in increased transcription of Hspa1b, a marker of embryonic genome activation. Pharmacological analyses showed the hyperacetylation of H3K9 and the increased expression of Hspa1b caused by culture were due to the altered net activity of a range of histone acetylases and deacetylases. The marked hyperacetylation of histone 3 lysine 9 caused by culture of zygotes may serve as an early biomarker for the effects of culture on the normal function of the embryo. The results also provide further evidence for an effect of the stresses associated with assisted reproductive technologies on the normal patterns of epigenetic reprogramming in the early embryo.

A multi-ingredient dietary supplement abolishes large-scale brain cell loss, improves sensory function, and prevents neuronal atrophy in aging mice.

Transgenic growth hormone mice (TGM) are a recognized model of accelerated aging with characteristics including chronic oxidative stress, reduced longevity, mitochondrial dysfunction, insulin resistance, muscle wasting, and elevated inflammatory processes. Growth hormone/IGF-1 activate the Target of Rapamycin known to promote aging. TGM particularly express severe cognitive decline. We previously reported that a multi-ingredient dietary supplement (MDS) designed to offset five mechanisms associated with aging extended longevity, ameliorated cognitive deterioration and significantly reduced age-related physical deterioration in both normal mice and TGM. Here we report that TGM lose more than 50% of cells in midbrain regions, including the cerebellum and olfactory bulb. This is comparable to severe Alzheimer's disease and likely explains their striking age-related cognitive impairment. We also demonstrate that the MDS completely abrogates this severe brain cell loss, reverses cognitive decline and augments sensory and motor function in aged mice. Additionally, histological examination of retinal structure revealed markers consistent with higher numbers of photoreceptor cells in aging and supplemented mice. We know of no other treatment with such efficacy, highlighting the potential for prevention or amelioration of human neuropathologies that are similarly associated with oxidative stress, inflammation and cellular dysfunction. Environ. Mol. Mutagen. 57:382-404, 2016. © 2016 Wiley Periodicals, Inc.

Synergistic effects of diet and exercise on hippocampal function in chronically stressed mice.

Severe chronic stress can have a profoundly negative impact on the brain, affecting plasticity, neurogenesis, memory and mood. On the other hand, there are factors that upregulate neurogenesis, which include dietary antioxidants and physical activity. These factors are associated with biochemical processes that are also altered in age-related cognitive decline and dementia, such as neurotrophin expression, oxidative stress and inflammation. We exposed mice to an unpredictable series of stressors or left them undisturbed (controls). Subsets of stressed and control mice were concurrently given (1) no additional treatment, (2) a complex dietary supplement (CDS) designed to ameliorate inflammation, oxidative stress, mitochondrial dysfunction, insulin resistance and membrane integrity, (3) a running wheel in each of their home cages that permitted them to exercise, or (4) both the CDS and the running wheel for exercise. Four weeks of unpredictable stress reduced the animals' preference for saccharin, increased their adrenal weights and abolished the exercise-induced upregulation of neurogenesis that was observed in non-stressed animals. Unexpectedly, stress did not reduce hippocampal size, brain-derived neurotrophic factor (BDNF), or neurogenesis. The combination of dietary supplementation and exercise had multiple beneficial effects, as reflected in the number of doublecortin (DCX)-positive immature neurons in the dentate gyrus (DG), the sectional area of the DG and hippocampal CA1, as well as increased hippocampal BDNF messenger ribonucleic acid (mRNA) and serum vascular endothelial growth factor (VEGF) levels. In contrast, these benefits were not observed in chronically stressed animals exposed to either dietary supplementation or exercise alone. These findings could have important clinical implications for those suffering from chronic stress-related disorders such as major depression.

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.

Elevated DNA damage in a mouse model of oxidative stress: impacts of ionizing radiation and a protective dietary supplement.

Transgenic growth hormone (Tg) mice express elevated free radical processes and a progeroid syndrome of accelerated ageing. We examined bone marrow cells of Tg mice and their normal (Nr) siblings for three markers of DNA damage and assessed the impact of free radical stress using ionizing radiation. We also evaluated the radiation protection afforded by a dietary supplement that we previously demonstrated to extend longevity and reduce cognitive ageing of Nr and Tg mice. Spectral karyotyping revealed few spontaneous chromosomal aberrations in Nr or Tg. Tg mice, however, had significantly greater constitutive levels of both gammaH2AX and 8-hydroxy-deoxyguanosine (8-OHdG) compared to Nr. When exposed to a 2-Gy whole-body dose of ionizing radiation, both Nr and Tg mice showed significant increases in DNA damage. Compared to Nr mice, irradiated Tg mice had dramatically higher levels of gammaH2AX foci and double the levels of chromosomal aberrations. In unirradiated mice, the dietary supplement significantly reduced constitutive gammaH2AX and 8-OHdG in both Nr and Tg mice (normalizing both gammaH2AX and 8-OHdG in Tg), with little difference in gammaH2AX and 8-OHdG over constitutive levels. Induced chromosomal aberrations were also reduced, and in Nr mice, virtually absent. Remarkably, supplemented mice expressed 6-fold lower levels of radiation-induced chromosomal aberrations compared to unsupplemented Nr or Tg mice. Based on our data, the dietary supplement appeared to scavenge free radicals before they could cause damage. This study validates Tg mice as an exemplary model of oxidative stress and radiation hypersensitivity and documents unprecedented radioprotection by a dietary supplement comprised of ingredients available to the general public.