Mahadev Murthy

Cognitive deficits in docosahexaenoic acid-deficient rats.

This study investigated the influence of brain docosahexaenoic acid (DHA) deficiency on simple and complex olfactory-based learning and memory in 2nd generation (F2) adult male rats. Rats raised and maintained on either an n-3-adequate or an n-3-deficient diet were tested for acquisition of an olfactory learning set and an olfactory memory task, and for motivation to obtain a water reward. Despite a 76% decrease in brain DHA, n-3-deficient rats were able to acquire most simple 2-odor discrimination tasks but were deficient in the acquisition of a 20-problem olfactory learning set. This deficit could not be attributed to changes in sensory capacity but, instead, appeared to represent a deficit in higher order learning.

Acute Kidney Injury in Older Adults

Aging kidneys undergo structural and functional changes that decrease autoregulatory capacity and increase susceptibility to acute injury. Acute kidney injury associates with duration and location of hospitalization, mortality risk, progression to chronic kidney disease, and functional status in daily living. Definition and diagnosis of acute kidney injury are based on changes in creatinine, which is an inadequate marker and might identify patients when it is too late. The incidence of acute kidney injury is rising and increases with advancing age, yet clinical studies have been slow to address geriatric issues or the heterogeneity in etiologies, outcomes, or patient preferences among the elderly. Here we examine some of the current literature, identify knowledge gaps, and suggest potential research questions regarding acute kidney injury in older adults. Answering these questions will facilitate the integration of geriatric issues into future mechanistic and clinical studies that affect management and care of acute kidney injury.

A decrease in cell size accompanies a loss of docosahexaenoate in the rat hippocampus.

Rats raised on n-3 essential fatty acid deficient diets demonstrate spatial memory deficits. To investigate neuroanatomical correlates of these deficits, morphological analysis of the hippocampus were carried out. Adult, female rats were raised for three generations on n-3 deficient or n-3 supplemented diets. Two n-3 deficient diets contained adequate linoleic acid (LA), or high linoleic acid (high LA), and two supplemented diets contained LA supplemented with alpha-linolenic acid (+LNA), or linoleic supplementation with alpha- linolenic and docosahexaenoic acids (+LNA/DHA). The total fatty acid composition of the hippocampus revealed a profound loss (90%) in docosahexaenoic acid (DHA) in the hippocampi of LA and high LA animals compared to those on +LNA and +LNA/DHA diets with a reciprocal increase in docosapentaenoic acid (DPAn-6) in all phospholipid species. The volume, density; total number, and cell body size of neurons in CA1-3, granular and hilar layers of the hippocampus were measured at septal and temporal locations using unbiased stereology. No differences were detected in any of these measures except for in cell body size; CA1 pyramidal neurons in the LA group were significantly (p < 0.04) smaller than neurons in the +LNA/DHA group at the septal location.

Blue Journal Conference Aging and Susceptibility to Lung Disease

The aging of the population in the United States and throughout the developed world has increased morbidity and mortality attributable to lung disease, while the morbidity and mortality from other prevalent diseases has declined or remained stable. Recognizing the importance of aging in the development of lung disease, the American Thoracic Society (ATS) highlighted this topic as a core theme for the 2014 annual meeting. The relationship between aging and lung disease was discussed in several oral symposiums and poster sessions at the annual ATS meeting. In this article, we used the input gathered at the conference to develop a broad framework and perspective to stimulate basic, clinical, and translational research to understand how the aging process contributes to the onset and/or progression of lung diseases. A consistent theme that emerged from the conference was the need to apply novel, systems-based approaches to integrate a growing body of genomic, epigenomic, transcriptomic, and proteomic data and elucidate the relationship between biologic hallmarks of aging, altered lung function, and increased susceptibility to lung diseases in the older population. The challenge remains to causally link the molecular and cellular changes of aging with age-related changes in lung physiology and disease susceptibility. The purpose of this review is to stimulate further research to identify new strategies to prevent or treat age-related lung disease.

Alcohol Consumption in Pregnant, Black Women Is Associated With Decreased Plasma and Erythrocyte Docosahexaenoic Acid

BACKGROUND Inner-city, black women are among those groups that are at higher risk for having infants with fetal alcohol spectrum disorders that can include life-long neurobehavioral and cognitive impairments. Chronic alcohol consumption can decrease amounts of docosahexaenoic acid (DHA), a fatty acid that is essential for optimal infant neural and retinal development in a variety of tissues. METHODS Black women who presented at an inner-city antenatal clinic for their first prenatal visit were recruited into a longitudinal, observational study. Alcohol intake was determined by a structured interview. Participants provided blood specimens and completed food frequency surveys at 24 weeks of gestation, infant delivery, and 3 months postpartum. Fatty acid composition analyses were completed on 307, 260, and 243 for plasma and 278, 261, and 242 erythrocyte specimens at 24 weeks of gestation, delivery, and 3 months postpartum, respectively. RESULTS Proportion of drinking days at the first prenatal visit was associated with decreased DHA in plasma and erythrocytes throughout the study. This association was the strongest at 24 weeks of gestation. In addition, an interaction between proportion of drinking days at the time of conception and ounces of absolute alcohol per drinking day at the time of conception was detected and demonstrated that, in daily drinkers, high intakes of alcohol are associated with decreased DHA and arachidonic acid (AA) concentrations in plasma. CONCLUSIONS Frequent and high intakes of alcohol that have been previously associated with fetal alcohol spectrum disorders are also associated with decreased maternal DHA and AA plasma concentrations. The present findings indicate that maternal DHA deficiency is associated with high-risk drinking and may contribute to the mechanism(s) of alcohol-related neurodevelopmental disorders.

Effects of Alcohol Intake During Pregnancy on Docosahexaenoic Acid and Arachidonic Acid in Umbilical Cord Vessels of Black Women

Objective. Alcohol influences the intake and metabolism of several nutrients including long-chain polyunsaturated fatty acids (LC-PUFAs). The LC-PUFAs docosahexaenoic acid (DHA) and arachidonic acid (AA) are particularly crucial for intrauterine growth and brain development. We hypothesized that alcohol consumption adversely affects LC-PUFA levels in pregnant women and their newborn infants. Methods. Pregnant black women (N = 208) presenting at a core city antenatal clinic were screened and recruited. Shortly before delivery, maternal plasma was collected. After delivery, umbilical arteries and veins were dissected from the cords, total lipids were extracted from the vessel tissues and maternal plasma, and fatty acid levels were assayed by gas chromatography. For statistical analysis, subjects were categorized according to absolute alcohol intake per day (AAD) and absolute alcohol intake per drinking day (AADD) around the time of conception, with smoking and other potential confounders included in the analyses. Results. Significant differences in fatty acid composition of total lipid extracts were detected in umbilical cord vessels among the AADD groups: abstainers (AADD = 0), moderate drinkers (AADD < 130 g), and heavy drinkers (AADD ≥ 130 g). DHA and AA content in the arterial umbilical vessel wall was ∼14% and ∼10% higher in the moderate (n = 127) and heavy (n = 32) alcohol groups, respectively, than in abstainers (n = 49). A small, nonsignificant increase (∼3%) was seen in the umbilical vein for AA but not for DHA. Alcohol intake was positively correlated to both DHA and AA concentrations in the arterial vessel wall but to neither in the venous wall nor maternal plasma. Maternal plasma DHA was positively correlated with both umbilical arteries and vein DHA, but there were no significant correlations for AA between maternal plasma and either umbilical vessel. Conclusions. Our findings indicate that alcohol intake during pregnancy is associated with altered DHA and AA status in fetal tissues. Although differences may be due to either metabolism and/or distribution, it is most likely a result of a direct influence of alcohol on fetal metabolism.

Invertebrates as model organisms for research on aging biology

Invertebrate model systems, such as nematodes and fruit flies, have provided valuable information about the genetics and cellular biology involved in aging. However, limitations of these simple, genetically tractable organisms suggest the need for other model systems, some of them invertebrate, to facilitate further advances in the understanding of mechanisms of aging and longevity in mammals, including humans. This paper introduces 10 review articles about the use of invertebrate model systems for the study of aging by authors who participated in an ‘NIA-NIH symposium on aging in invertebrate model systems’ at the 2013 International Congress for Invertebrate Reproduction and Development. In contrast to the highly derived characteristics of nematodes and fruit flies as members of the superphylum Ecdysozoa, cnidarians, such as Hydra, are more ‘basal’ organisms that have a greater number of genetic orthologs in common with humans. Moreover, some other new model systems, such as the urochordate Botryllus schlosseri, the tunicate Ciona, and the sea urchins (Echinodermata) are members of the Deuterostomia, the same superphylum that includes all vertebrates, and thus have mechanisms that are likely to be more closely related to those occurring in humans. Additional characteristics of these new model systems, such as the recent development of new molecular and genetic tools and a more similar pattern to humans of regeneration and stem cell function suggest that these new model systems may have unique advantages for the study of mechanisms of aging and longevity.

Biomarker Validation for Aging: Lessons from mtDNA Heteroplasmy Analyses in Early Cancer Detection

The anticipated biological and clinical utility of biomarkers has attracted significant interest recently. Aging and early cancer detection represent areas active in the search for predictive and prognostic biomarkers. While applications differ, overlapping biological features, analytical technologies and specific biomarker analytes bear comparison. Mitochondrial DNA (mtDNA) as a biomarker in both biological models has been evaluated. However, it remains unclear whether mtDNA changes in aging and cancer represent biological relationships that are causal, incidental, or a combination of both. This article focuses on evaluation of mtDNA-based biomarkers, emerging strategies for quantitating mtDNA admixtures, and how current understanding of mtDNA in aging and cancer evolves with introduction of new technologies. Whether for cancer or aging, lessons from mtDNA based biomarker evaluations are several. Biological systems are inherently dynamic and heterogeneous. Detection limits for mtDNA sequencing technologies differ among methods for low-level DNA sequence admixtures in healthy and diseased states. Performance metrics of analytical mtDNA technology should be validated prior to application in heterogeneous biologically-based systems. Critical in evaluating biomarker performance is the ability to distinguish measurement system variance from inherent biological variance, because it is within the latter that background healthy variability as well as high-value, disease-specific information reside.