Xq22 deletions and correlation with distinct neurological disease traits in females: Further evidence for a contiguous gene syndrome.

Xq22 deletions that encompass PLP1 (Xq22-PLP1-DEL) are notable for variable expressivity of neurological disease traits in females ranging from a mild late-onset form of spastic paraplegia type 2 (MIM# 312920), sometimes associated with skewed X-inactivation, to an early-onset neurological disease trait (EONDT) of severe developmental delay, intellectual disability, and behavioral abnormalities. Size and gene content of Xq22-PLP1-DEL vary and were proposed as potential molecular etiologies underlying variable expressivity in carrier females where two smallest regions of overlap (SROs) were suggested to influence disease. We ascertained a cohort of eight unrelated patients harboring Xq22-PLP1-DEL and performed high-density array comparative genomic hybridization and breakpoint-junction sequencing. Molecular characterization of Xq22-PLP1-DEL from 17 cases (eight herein and nine published) revealed an overrepresentation of breakpoints that reside within repeats (11/17, ~65%) and the clustering of ~47% of proximal breakpoints in a genomic instability hotspot with characteristic non-B DNA density. These findings implicate a potential role for genomic architecture in stimulating the formation of Xq22-PLP1-DEL. The correlation of Xq22-PLP1-DEL gene content with neurological disease trait in female cases enabled refinement of the associated SROs to a single genomic interval containing six genes. Our data support the hypothesis that genes contiguous to PLP1 contribute to EONDT.

The prevalence and pattern of chemotherapy-induced peripheral neuropathy among women with breast cancer receiving care in a large community oncology practice.

PURPOSE: To describe the prevalence, severity, and risk factors of chemotherapy-induced peripheral neuropathy (CIPN) and its impact on function and quality of life (QOL) among women treated for breast cancer in a large U.S. Community Oncology practice. METHODS: Women previously treated with taxane-based chemotherapy for early-stage breast cancer completed the EORTC QLQ-C30, QLQ-BR23, and QLQ-CIPN20. Subscales are scored 0-100; higher scores indicate greater symptom severity. Pre-specified hypotheses were tested. RESULTS: 126 women with mean age 56.7 years (SD 11.8) were stage I-II (79.4%) or stage III (20.6%) at the time of the survey; 65.1% were White and 27.8% were Black or African American. The mean time since last taxane chemotherapy cycle was 144.9 weeks (SD 112.9). 73.0% reported having CIPN. QLQ-CIPN20 mean scores for the sensory, motor, and autonomic subscales were 18.9 (SD 23.1), 18.6 (SD 18.7), and 17.1 (SD 21.8), respectively. CIPN symptom severity was negatively correlated with global health status/QOL and physical and role functioning (range of r = -0.46 to -0.72). It was not associated with age, body mass index, diabetes, or cumulative taxane dosage, but was greater for Black or African American women (e.g., sensory, p < 0.002). CIPN sensory impairment was marginally greater for patients treated with paclitaxel compared to docetaxel (p < 0.064). CONCLUSIONS: CIPN was prevalent in this community oncology practice and significantly impacts function and QOL. These data highlight the importance of developing methods to mitigate CIPN, and for screening for CIPN particularly among Black or African American women.

A mitochondrial ATP synthase subunit interacts with TOR signaling to modulate protein homeostasis and lifespan in Drosophila.

Diet composition is a critical determinant of lifespan, and nutrient imbalance is detrimental to health. However, how nutrients interact with genetic factors to modulate lifespan remains elusive. We investigated how diet composition influences mitochondrial ATP synthase subunit d (ATPsyn-d) in modulating lifespan in Drosophila. ATPsyn-d knockdown extended lifespan in females fed low carbohydrate-to-protein (C:P) diets but not the high C:P ratio diet. This extension was associated with increased resistance to oxidative stress; transcriptional changes in metabolism, proteostasis, and immune genes; reduced protein damage and aggregation, and reduced phosphorylation of S6K and ERK in TOR and mitogen-activated protein kinase (MAPK) signaling, respectively. ATPsyn-d knockdown did not extend lifespan in females with reduced TOR signaling induced genetically by Tsc2 overexpression or pharmacologically by rapamycin. Our data reveal a link among diet, mitochondria, and MAPK and TOR signaling in aging and stresses the importance of considering genetic background and diet composition in implementing interventions for promoting healthy aging.

Lifespan extension by cranberry supplementation partially requires SOD2 and is life stage independent.

Many nutraceuticals and pharmaceuticals have been shown to promote healthspan and lifespan. However, the mechanisms underlying the beneficial effects of prolongevity interventions and the time points at which interventions should be implemented to achieve beneficial effects are not well characterized. We have previously shown that a cranberry-containing nutraceutical can promote lifespan in worms and flies and delay age-related functional decline of pancreatic cells in rats. Here we investigated the mechanism underlying lifespan extension induced by cranberry and the effects of short-term or life stage-specific interventions with cranberry on lifespan in Drosophila. We found that lifespan extension induced by cranberry was associated with reduced phosphorylation of ERK, a component of oxidative stress response MAPK signaling, and slightly increased phosphorylation of AKT, a component of insulin-like signaling. Lifespan extension was also associated with a reduced level of 4-hydroxynonenal protein adducts, a biomarker of lipid oxidation. Moreover, lifespan extension induced by cranberry was partially suppressed by knockdown of SOD2, a major mitochondrial superoxide scavenger. Furthermore, cranberry supplementation was administered in three life stages of adult flies, health span (3-30 days), transition span (31-60 days) and senescence span (61 days to the end when all flies died). Cranberry supplementation during any of these life stages extended the remaining lifespan relative to the non-supplemented and life stage-matched controls. These findings suggest that cranberry supplementation is sufficient to promote longevity when implemented during any life stage, likely through reducing oxidative damage.

Cranberry interacts with dietary macronutrients to promote healthy aging in Drosophila.

Botanicals possess numerous bioactivities, and some promote healthy aging. Dietary macronutrients are major determinants of life span. The interaction between botanicals and macronutrients that modulates life span is not well understood. Here, we investigated the effect of a cranberry-containing botanical on life span and the influence of macronutrients on the longevity-related effect of cranberry in Drosophila. Flies were supplemented with cranberry on three dietary conditions: standard, high sugar-low protein, and low sugar-high protein diets. We found that cranberry slightly extended life span in males fed with the low sugar-high protein diet but not with other diets. Cranberry extended life span in females fed with the standard diet and more prominently the high sugar-low protein diet but not with the low sugar-high protein diet. Life-span extension was associated with increased reproduction and higher expression of oxidative stress and heat shock response genes. Moreover, cranberry improved survival of sod1 knockdown and dfoxo mutant flies but did not increase wild-type fly's resistance to acute oxidative stress. Cranberry slightly extended life span in flies fed with a high-fat diet. These findings suggest that cranberry promotes healthy aging by increasing stress responsiveness. Our study reveals an interaction of cranberry with dietary macronutrients and stresses the importance of considering diet composition in designing interventions for promoting healthy aging.

The effect of resveratrol on lifespan depends on both gender and dietary nutrient composition in Drosophila melanogaster.

Resveratrol, a polyphenolic compound, has been shown to extend lifespan in different organisms. Emerging evidence suggests that the prolongevity effect of resveratrol depends on dietary composition. However, the mechanisms underlying the interaction of resveratrol and dietary nutrients in modulating lifespan remain elusive. Here, we investigated the effect of resveratrol on lifespan of Drosophila melanogaster fed diets differing in the concentrations of sugar, yeast extract, and palmitic acid representing carbohydrate, protein, and fat, respectively. Resveratrol at up to 200 µM in diets did not affect lifespan of wild-type female flies fed a standard, restricted or high sugar-low protein diet, but extended lifespan of females fed a low sugar-high protein diet. Resveratrol at 400 µM extended lifespan of females fed a high-fat diet. Lifespan extension by resveratrol was associated with downregulation of genes in aging-related pathways, including antioxidant peroxiredoxins, insulin-like peptides involved in insulin-like signaling and several downstream genes in Jun-kinase signaling involved in oxidative stress response. Furthermore, resveratrol increased lifespan of superoxide dismutase 1 (sod1) knockdown mutant females fed a standard or high-fat diet. No lifespan extension by resveratrol was observed in wild-type and sod1 knockdown males under the culture conditions in this study. Our results suggest that the gender-specific prolongevity effect of resveratrol is influenced by dietary composition and resveratrol promotes the survival of flies by modulating genetic pathways that can reduce cellular damage. This study reveals the context-dependent effect of resveratrol on lifespan and suggests the importance of dietary nutrients in implementation of effective aging interventions using dietary supplements.

Nutrient-dependent requirement for SOD1 in lifespan extension by protein restriction in Drosophila melanogaster.

Reactive oxygen species (ROS) modulate aging and aging-related diseases. Dietary composition is critical in modulating lifespan. However, how ROS modulate dietary effects on lifespan remains poorly understood. Superoxide dismutase 1 (SOD1) is a major cytosolic enzyme responsible for scavenging superoxides. Here we investigated the role of SOD1 in lifespan modulation by diet in Drosophila. We found that a high sugar-low protein (HS-LP) diet or low-calorie diet with low-sugar content, representing protein restriction, increased lifespan but not resistance to acute oxidative stress in wild-type flies, relative to a standard base diet. A low sugar-high protein diet had an opposite effect. Our genetic analysis indicated that SOD1 overexpression or dfoxo deletion did not alter lifespan patterns of flies responding to diets. However, sod1 reduction blunted lifespan extension by the HS-LP diet but not the low-calorie diet. HS-LP and low-calorie diets both reduced target of rapamycin (TOR) signaling and only the HS-LP diet increased oxidative damage. sod1 knockdown did not affect phosphorylation of S6 kinase, suggesting that SOD1 acts in parallel with or downstream of TOR signaling. Surprisingly, rapamycin decreased lifespan in sod1 mutant but not wild-type males fed the standard, HS-LP, and low-calorie diets, whereas antioxidant N-acetylcysteine only increased lifespan in sod1 mutant males fed the HS-LP diet, when compared to diet-matched controls. Our findings suggest that SOD1 is required for lifespan extension by protein restriction only when dietary sugar is high and support the context-dependent role of ROS in aging and caution the use of rapamycin and antioxidants in aging interventions.

Gender-specific prandial response to dietary restriction and oxidative stress in Drosophila melanogaster.

Drosophila melanogaster is ideal for studying lifespan modulated by dietary restriction (DR) and oxidative stress, and also for screening prolongevity compounds. It is critical to measure food intake in the aforementioned studies. Current methods, however, overlook the amount of the food excreted out of the flies as feces or deposited in eggs. Here we describe a feeding method using a radioactive tracer to measure gender-specific food intake, retention and excretion in response to DR and oxidative stress to account for all the ingested food. Flies were fed a full, restricted or paraquat-containing diet. The radioactivity values of the food in fly bodies, feces and eggs were measured separately after a 24-hr feeding. Food intake was calculated as the sum of these measurements. We found that most of the tracer in the ingested food was retained in the fly bodies and < 8% of the tracer was excreted out of the flies as feces and eggs in the case of females during a 24-hr feeding. Under a DR condition, flies increased food intake in volume to compensate for the reduction of calorie content in the diet and also slightly increased excretion. Under an oxidative stress condition, flies reduced both food intake and excretion. Under all the tested dietary conditions, males ingested and excreted 3-5 fold less food than females. This study describes an accurate method to measure food intake and provides a basis to further investigate prandial response to DR and prolongevity interventions in invertebrates.

Nectarine promotes longevity in Drosophila melanogaster.

Fruits containing high antioxidant capacities and other bioactivities are ideal for promoting longevity and health span. However, few fruits are known to improve the survival and health span in animals, let alone the underlying mechanisms. Here we investigate the effects of nectarine, a globally consumed fruit, on life span and health span in Drosophila melanogaster. Wild-type flies were fed standard, dietary restriction (DR), or high-fat diet supplemented with 0-4% nectarine extract. We measured life span, food intake, locomotor activity, fecundity, gene expression changes, and oxidative damage indicated by the level of 4-hydroxynonenal-protein adduct in these flies. We also measured life span, locomotor activity, and oxidative damage in sod1 mutant flies on the standard diet supplemented with 0-4% nectarine. Supplementation with 4% nectarine extended life span, increased fecundity, and decreased expression of some metabolic genes, including a key gluconeogenesis gene, PEPCK, and oxidative stress-response genes, including peroxiredoxins, in female wild-type flies fed the standard, DR, or high-fat diet. Nectarine reduced oxidative damage in wild-type females fed the high-fat diet. Moreover, nectarine improved the survival of and reduced oxidative damage in female sod1 mutant flies. Together, these findings suggest that nectarine promotes longevity and health span partly by modulating glucose metabolism and reducing oxidative damage.

Açai palm fruit (Euterpe oleracea Mart.) pulp improves survival of flies on a high fat diet.

Reducing oxidative damage is thought to be an effective aging intervention. Açai, a fruit indigenous to the Amazon, is rich in phytochemicals that possesses high anti-oxidant activities, and has anti-inflammatory, anti-cancer and anti-cardiovascular disease properties. However, little is known about its potential anti-aging properties especially at the organismal level. Here we evaluated the effect of açai pulp on modulating lifespan in Drosophila melanogaster. We found that açai supplementation at 2% in the food increased the lifespan of female flies fed a high fat diet compared to the non-supplemented control. We measured transcript changes induced by açai for age-related genes. Although transcript levels of most genes tested were not altered, açai increased the transcript level of l(2)efl, a small heat-shock-related protein, and two detoxification genes, GstD1 and MtnA, while decreasing the transcript level of phosphoenolpyruvate carboxykinase (Pepck), a key gene involved in gluconeogenesis. Furthermore, açai increased the lifespan of oxidative stressed females caused by sod1 RNAi. This suggests that açai improves survival of flies fed a high fat diet through activation of stress response pathways and suppression of Pepck expression. Açai has the potential to antagonize the detrimental effect of fat in the diet and alleviate oxidative stress in aging.