Vadim Aksenov

The Ancient Chemistry of Avoiding Risks of Predation and Disease

Illness, death, and costs of immunity and injury strongly select for avoidance of predators or contagion. Ants, cockroaches, and collembola recognize their dead using unsaturated fatty acids (e.g., oleic or linoleic acid) as “necromone” cues. Ants, bees, and termites remove dead from their nests (necrophoric behavior) whereas semi-social species seal off corpses or simply avoid their dead or injured (necrophobic behavior). Alarm and avoidance responses to exudates from injured conspecifics are widespread. This involves diverse pheromones, complex chemistry and learning. We hypothesized that necromones are a phylogenetically ancient class of related signals and predicted that terrestrial Isopoda (that strongly aggregate and lack known dispersants) would avoid body fluids and corpses using fatty acid “necromones.” Isopods were repelled by crushed conspecifics (blood), intact corpses, and alcohol extracts of bodies. As predicted, the repellent fraction contained oleic and linoleic acids and authentic standards repelled several isopod species. We further predicted a priori that social caterpillars (lacking known dispersants) would be repelled by their own body fluids and unsaturated fatty acids. Both tent caterpillars and fall webworms avoided branches treated with conspecific body fluid. Oleic and linoleic acids were also strongly avoided by both species. Necromone signaling appears widespread and likely traces to aquatic ancestors pre-dating the divergence of the Crustacea and Hexapoda at least 420 million years ago.

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 ∼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.

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.

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 multi-ingredient athletic supplement disproportionately enhances hind leg musculature, jumping performance, and spontaneous locomotion in crickets (Acheta domesticus)

Nutrition is a key component of life‐history theory with profound impacts on fitness traits. We examined lifetime impacts of a multi‐ingredient athletic supplement (MAS) on physical performance, anatomical morphology, survivorship, and general life‐history features in the house cricket, Acheta domesticus (L.) (Orthoptera: Gryllidae). The MAS was formulated using 13 nutraceutical supplements that are commonly used by human athletes specifically to improve athletic performance. Cricket doses were based on human doses adjusted for body size and metabolic rate. Markers of athletic performance included: jumping distance, spontaneous locomotor activity, and morphology of the hind legs (femurs). Supplemented adult crickets jumped ca. 25% further and expressed elevated spontaneous locomotion relative to controls. The MAS disproportionately increased hind leg femur length and width. Life‐history endpoints included survivorship, juvenile growth rate, maturation age, and mature body size. Supplemented crickets showed faster juvenile growth and earlier maturation, but no change in final adult size. A 20% increase in mean survivorship (extending into older ages) was also documented. Crickets represent an excellent new model for assessing athletic diets and associated performance criteria. Finally, as experimental animals were untrained, we argue that our supplement may represent a novel ‘exercise mimetic’ that impacts both performance and survivorship.

Trojan Genes or Transparent Genomes? Sexual Selection and Potential Impacts of Genetically Modified Animals in Natural Ecosystems

Introgression of genetically engineered modifications (GMs) into natural populations represents a new realm for mutation theory. GMs, like mutations, have direct and pleiotropic impacts that can disrupt evolved adaptive suites. If GM males are more competitive or attractive mates, the “Trojan Gene Hypothesis” predicts potentially drastic impacts. We examined sexual selection in transgenic growth hormone (Tg) mice that are strong Trojan candidates given their exceptional size and extensive pleiotropic deficits. We hypothesized that the sophisticated olfactory abilities of females would recognize dysregulation of Tg males (the Transparent Genome Hypothesis). Females expressed interest in Tg males and their volatile scent, but when allowed nasal contact with urine (critical to mate choice) they preferred normal males. Tg male urine had reduced major urinary proteins (important in social signaling) and contained albumin and transferrin indicative of pathology. Novel Tg males failed to elicit pregnancy block in recently inseminated females (the “Bruce Effect”) whereas normal males were highly effective. Normal males expressed high aggression but Tg males were placid, non-aggressive and were largely ignored by normal males. Female mice also strongly preferred normal males over p53± knockout males in response to volatiles, contact with urine and male presence. This study suggests that conspecific discrimination of fitness may be more powerful than generally appreciated. This has great implications for introductions of GM animals and sexual selection generally.

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.