Lipid peroxides in brain during aging and vitamin E deficiency: Possible relations to changes in neurotransmitter indices

Lipid peroxide levels, were found to be significantly higher in brains of 18 month old as compared to 4 month old rats, with particularly large increases occuring in the olfactory bulb, globus pallidus, cerebral cortex and caudate-putamen (CP). Eighteen month old rats fed a vitamin E deficient diet for 9 months before sacrifice had lipid peroxide levels significantly higher than age-matched controls in the cerebral cortex, hippocampus and hypothalamus. Age-related decreases were seen in choline acetyltransferase, acetylcholinesterase and ³H-QNB binding in some but not all brain regions, while GABA transaminase and MAO showed age-related increases. No age-related change was seen in tyrosine hydroxylase in the CP or in ³H-dihydroalprenol (DHA) or ³H-spiroperidol binding in the cortex. As compared with controls, vitamin E deficient rats showed decreases of 38% in cortical ³H-DHA binding, of 3 in ³H-QNB binding in the CP and of 23% and 12% in choline acetyltransferase in the CP and cerebellum, respectively. There were no completely consistent regional correlations between significant changes in lipid peroxidase levels and any neurotransmitter indices studied except for MAO which was only measured in the caudate-putamen.     

Effect of chronic vitamin E deficiency on the synapses of cerebellar glomeruli in young rats

A morphometric investigation has been carried out on the synaptic junctions in the cerebellar glomeruli of young-adult rats chronically deprived of vitamin E for 10 months and control animals of the same age. The following parameters were evaluated: the average length of the synapses (L), the numerical (NV) as well as the surface (SV) density of the synaptic contact zones. The results from these experimental groups were compared with data from young, adult and old rats. The results obtained show a significant decrease of the surface density of the synaptic contact zones in old and alpha-tocopherol deprived young-adult (11-month-old) rats as compared to younger and normally fed animals. This reduction of the synaptic contact area seems to be due to the marked decline in the number of synapses found in both cases. The average size (L) of the synaptic junctions, on the other hand, was increased in alpha-tocopherol deficient rats as compared to normally fed littermates. The significant reduction of the synaptic contact area in old and vitamin E deprived young rats supports the hypothesis that a common denominator may be responsible to explain this alteration. Because of the recognized protective role of alpha-tocopherol against free radical attacks on plasma membranes, the present findings support an involvement of membrane structural alterations in aging as well as in vitamin E deficiency.     

A genetic program theory of aging using an RNA population model

Aging is a common characteristic of multicellular eukaryotes. Copious hypotheses have been proposed to explain the mechanisms of aging, but no single theory is generally acceptable. In this article, we refine the RNA population gene activating model (Lv et al., 2003) based on existing reports as well as on our own latest findings. We propose the RNA population model as a genetic theory of aging. The new model can also be applied to differentiation and tumorigenesis and could explain the biological significance of non-coding DNA, RNA, and repetitive sequence DNA. We provide evidence from the literature as well as from our own findings for the roles of repetitive sequences in gene activation. In addition, we predict several phenomena related to aging and differentiation based on this model.     

Non-coding RNA regulation of synaptic plasticity and memory: Implications for aging

Advancing age is associated with the loss of cognitive ability and vulnerability to debilitating mental diseases. Although much is known about the development of cognitive processes in the brain, the study of the molecular mechanisms governing memory decline with aging is still in its infancy. Recently, it has become apparent that most of the human genome is transcribed into non-coding RNAs (ncRNAs) rather than protein-coding mRNAs. Multiple types of ncRNAs are enriched in the central nervous system, and this large group of molecules may regulate the molecular complexity of the brain, its neurons, and synapses. Here, we review the current knowledge on the role of ncRNAs in synaptic plasticity, learning, and memory in the broader context of the aging brain and associated memory loss. We also discuss future directions to study the role of ncRNAs in the aging process.     

Vitamin E deficiency induced neurological disease in common variable immunodeficiency: two cases and a review of the literature of vitamin E deficiency

Vitamin E deficiency causes a neurological disorder characterised by sensory loss, ataxia and retinitis pigmentosa due to free radical mediated neuronal damage. Symptomatic vitamin E deficiency has been reported in genetic defects of the vitamin E transport protein and in malabsorption complicating cholestasis, abetalipoproteinaemia, celiac disease, cystic fibrosis and small bowel resection. There are no reports to date of vitamin E deficiency in patients with primary immunodeficiencies. We describe two CVID patients with the associated enteropathy who developed neurological disease because of vitamin E deficiency, suggesting a possible predisposition to developing this complication. We recommend that all CVID patients with evidence of an enteropathy be screened for vitamin E deficiency, as early detection and consequent treatment may prevent, halt or reverse the neurological sequelae.     

The critical impacts of small RNA biogenesis proteins on aging,longevity and age-related diseases

Small RNAs and enzymes that provide their biogenesis and functioning are involved in the organism development and coordination of biological processes, including metabolism, maintaining genome integrity, immune and stress responses. In this review, we focused on the role of small RNA biogenesis proteins in determining the aging and longevity of animals and human. A number of studies have revealed that changes in expression profiles of key enzymes, in particular proteins of the Drosha, Dicer and Argonaute families, are associated with the aging process, as well as with some age-related diseases and progeroid syndromes. Down-regulation of small RNA biogenesis proteins leads to global alterations in the expression of regulatory RNAs, disruption of key molecular, cellular and systemic processes, which leads to a lifespan shortening. In contrast, overexpression of Dicer prolongs lifespan and improves cellular defense. Additionally, the role of small RNA biogenesis proteins in the pathogenesis of age-related diseases, including cancer, inflammaging, neurodegeneration, cardiovascular, metabolic and immune disorders, has been conclusively evidenced. Recent advances in biomedicine allow using these proteins as diagnostic and prognostic biomarkers and therapeutic targets.     

脂质过氧化在老化大鼠急性胆源性肝细胞线粒体损害中的作用及维生素E的影响

目的：探讨脂质过氧化在老化大鼠胆源性肝细胞线粒体受损中及维生素Ｅ（ＶＥ）的保护作用。结果：老化大鼠非ＶＥ处理组（ＮＶＥＧ）肝细胞线粒体丙二醛（ＭＤＡ）含量明显高于非老化组，超氧化物歧化酶（ＳＯＤ）和谷胱甘肽过氧化物酶（ＧＰＤ）活性明显低于非老化组，过氧化氢酶（ＣＡＴ）无明显变化。１８和２４月龄ＶＥ处理组（ＶＥＧ）ＭＤＡ显著低于ＮＶＥＧ，ＳＯＤ和ＧＰＤ显著高于ＮＶＥＧ，并以１８月龄组为明显。急性梗阻性左肝胆管炎（ＡＯＬＨ）后ＭＤＡ水平明显高于对照组，间接致伤肝叶（ＩＡＬ）较直接致伤肝叶（ＤＡＬ）为明显；ＩＡＬ线粒体ＳＯＤ和ＣＡＴ活性均显著高于对照组，ＤＡＬ显著降低；各叶ＧＰＤ活性均显著低于对照组，ＩＡＬ和ＤＡＬ均无显著差别；以上改变以２４月龄组为明显。各月龄ＶＥＧＡＯＬＨ２４ｈ时ＩＡＬＭＤＡ含量明显低于ＮＶＥＧ；１８月龄ＶＥＧＡＯＬＨ后ＳＯＤ水平均明显高于ＮＶＥＧ；各月龄ＶＥＧ组ＡＯＰＨ后ＧＰＤ和ＣＡＴ活性与ＮＶＥＧ比较均无明显差异。结论：脂质过氧化是老化大鼠胆源性肝细胞线粒体受损的重要机制，ＶＥ具有明显的保护作用。     

Exercise-induced muscle damage in the rat: the effect of vitamin E deficiency

Rats, fed a vitamin-E-deficient diet for 6 weeks, performed treadmill exercise for 2 h. Muscle damage was assessed by measuring the creatine kinase (CK) activity in plasma before and after exercise, and by studying semithin longitudinal sections of the soleus muscle 48 h after running. Vitamin-E-deficient male and female rats showed an increased post-exercise CK activity when compared to matched controls, but male rats showed a larger CK response than females. This rise in plasma CK activity was caused mainly by an increased activity of the muscle-specific CK-isoenzyme, CK-MM (males + 1238%; females + 540%, P<0.05). In a parallel histological study we observed in vitamin-E-deficient male rats a dramatic and significant disturbance of the normal cyto-architecture of the muscle fibres after exercise (focal necrosis, phagocytosis and cellular infiltrates), whereas in females only minor, non-significant, changes were seen. We conclude that vitamin E deficiency enhances the susceptibility to exercise-induced muscle damage in male rats more than in female rats. This difference between the sexes is attributed to the protective effect of oestradiol that remains operative in female rats when the vitamin E status is disturbed: male rats lack such hormonal protection.     

Endotoxin induced production of interleukin-6 is enhanced by vitamin E deficiency and reduced by black tea extract

Studies were performed to investigate the effect of a polyphenol rich extract from black tea and vitamin E on bacterial lipopolysaccharide (endotoxin) induced IL-6 production, alterations in liver glutathione and antioxidant acute phase protein (caeruloplasmin) concentration, in rats fed on a synthetic diet for 21 days. In the vitamin E sufficient group a significantly lower IL-6 concentration than in vitamin E deficient animals was observed. Addition of tea extract to the diet produced a similar reduction in IL-6, but no synergism occurred in the presence of both vitamin E and tea extract. However, a significantly lower caeruloplasmin and a significantly higher liver glutathione concentration was observed in rats fed both substances. It is suggested that consideration of dietary components which alter antioxidant/oxidant status may contribute towards treatment of inflammatory/autoimmune diseases.     

Evaluation of vitamin E status in the institutionalized Japanese elderly with respect to tocopherol levels in plasma, blood cells, and buccal mucosal cells

The vitamin E status of elderly Japanese individuals was investigated in the population of two institutions at Osaka and Kyoto. We determined α- and γ-tocopherol levels in red blood cells, platelets, mononuclear cells, polymorphonuclear cells, and buccal mucosal cells as well as plasma to assess the vitamin E status. Plasma α-tocopherol levels in the elderly were similar to those in young adult controls, while γ-tocopherol levels were significantlower in the elderly than in the young adults. Both α- and γ-tocopherol levels in the cells examined were significantly lower in the elederly than in the young adults. Analysis of the fatty acid composition of red cell ghost membranes revealed a higher peroxidizability index and a lower α-tocopherol to peroxidizability index ratio in the elderly as compared with the young adults, suggesting that the elderly had a higher susceptibility to oxidant stress. The daily intake of vitamin E was calculated from the menus of the two institutions, and was found to be lower than the Japanese recommended dietary allowance. These findings indicate that these institutionalized elderly in Japan have an inadequate vitamin E status.     

Effect of vitamin E deficiency on the growth and secretory function of the rat prostatic complex

Increased intake of vitamin E has been suggested to be protective against prostate cancer in men, but the effects of vitamin E on prostate growth and function remain poorly defined. The purpose of this study was to determine the effects of vitamin E deficiency on pubertal growth and maturation of the prostate in the rat. Animals were placed on a vitamin E deficient diet at 28 days of age and were followed for 15 and 26 weeks. Vitamin E deficient rats had a circulating vitamin E level of less than 1% of control animals and experienced a decrease in body and testis weight. The deficiency did not alter the weights of the ventral and dorsal lobes of the prostate. However, there was an increase in weight, DNA, and protein contents of the lateral lobe in control and vitamin E deficient rats from 15 to 26 weeks of treatment, but these increases were significantly lower in vitamin E deficient 26-week treated rats. The volume of secretion per milligram tissue was greater in the ventral than lateral or dorsal lobes. The volume of secretion and activity of the secretory 26 kDa protease in the ventral prostate was lower in vitamin E deficient rats at 15 weeks, but not at 26 weeks of treatment. In contrast, the relative protein content of lateral lobe secretion increased in both control and vitamin E deficient rats from 15 to 26 weeks of treatment. The lateral, but not ventral or dorsal, lobes of both control and vitamin E deficient rats were affected by chronic prostatitis as evidenced by infiltration of inflammatory cells. The lateral lobes also showed markedly elevated activities of the matrix metalloproteinases gelatinase A (MMP-2) and gelatinase B (MMP-9). These data indicate that vitamin E deficiency does not alter the growth of the prostatic lobes, nor the onset and extent of lateral lobe specific prostatitis, but it may delay some differentiated functions such as secretion of specific proteins in the ventral lobe. Thus, the effects of vitamin E in the prostate of the rat appear to be selective.     

Vitamin D and aging: beyond calcium and bone metabolism

Background

Low serum 25-hydroxyvitamin D (25[OH]D) levels are common and may be associated with morbidity and mortality (and indeed with frailty more generally). This association is not restricted to the links between vitamin D and calcium and bone metabolism.

Objective

To review the influences of vitamin D on the aging process other than those related to bone and calcium. Its effect on mortality is also assessed.

Methods

The PubMed database was searched for English-language articles relating to vitamin D, using the following MeSH terms: vitamin D, mortality, cardiovascular diseases, and frailty. In addition, searches were carried out with Google.

Results

Although some of the reported results have proved controversial, overall the evidence seems to support an association between low serum 25[OH]D levels and mortality rates (all-cause and cardiovascular). Frailty is a condition frequently associated with low serum 25[OH]D levels.

Conclusion

The aging process and mortality are associated with low vitamin D levels. Prospective controlled trials are warranted to determine whether vitamin D supplements can increase longevity and reduce the incidence of certain conditions.     

Altered Ca2+ sparks in aging skeletal and cardiac muscle

Ca²⁺ sparks are the fundamental units that comprise Ca²⁺-induced Ca²⁺ release (CICR) in striated muscle cells. In cardiac muscle, spontaneous Ca²⁺ sparks underlie the rhythmic CICR activity during heart contraction. In skeletal muscle, Ca²⁺ sparks remain quiescent during the resting state and are activated in a plastic fashion to accommodate various levels of stress. With aging, the plastic Ca²⁺ spark signal becomes static in skeletal muscle, whereas loss of CICR control leads to leaky Ca²⁺ spark activity in aged cardiomyocytes. Ca²⁺ spark responses reflect the integrated function of the intracellular Ca²⁺ regulatory machinery centered around the triad or dyad junctional complexes of striated muscles, which harbor the principal molecular players of excitation-contraction coupling. This review highlights the contribution of age-related modification of the Ca²⁺ release machinery and the effect of membrane structure and membrane cross-talk on the altered Ca²⁺ spark signaling during aging of striated muscles.     

Low molecular weight fluorescent probes with good photostability for imaging RNA-rich nucleolus and RNA in cytoplasm in living cells

We have synthesized two low molecular weight organic molecules, PY and IN successfully, which selectively stain nucleolus and cytoplasm of living cells in 30 min, with a much lower uptake in the nucleus. Nucleic acids electrophoresis and digest test of ribonuclease indicate their markedly higher affinity for RNA, especially PY. Moreover their RNA localization in cells is further supported by digest test of ribonuclease, namely, the nucleolar fluorescence signal is distinctly lost upon treatment with RNase. And, the fact that live cells stained by PY and IN still possess physiological function can be confirmed: 1) MTT assay demonstrates that the mitochondria of cells stained remains its electron mediating ability, 2) Double assay of PY/IN and propidium iodide as well as trypan blue testing show that the membrane of cells stained still is intact. Importantly, compared with the only commercial RNA probe, SYTO RNA-Select, PY and IN exhibit much better photostability when continuously illuminated with 488 nm laser and mercury lamp. These results prove that PY and IN are very attractive staining reagents for visualizing RNA in living cells.     

Non-specific immunity in aging: deficiency of monocyte and polymorphonuclear cell-mediated functions

Peripheral blood monocytes obtained from 55 aged donors were evaluated for their chemotactic and phagocytic capacity. In the same subjects, polymorphonuclear cell-mediated functions were studied by chemotaxis, phagocytosis, nylon fiber adherence and nitroblue-tetrazolium reduction assay. Monocytes showed a normal chemotactic responsiveness to zymosan-activated serum, while the chemotactic activity induced by leukocyte-derived chemotactic factor and phagocytosis were rather depressed. A dramatic impairment of polymorphonuclear cell-mediated immune response was also observed. In fact, in spite of a normal nylon fiber adherence, chemotaxis, phagocytosis and nitroblue-tetrazolium reduction capacity were significantly depressed by the aging process. These data suggest that the deficiency of non-specific immunity may play an important role in the increased susceptibility to infections in aged donors.     

Changes in lymphoid organs and blood lymphocytes induced by vitamin A deficiency and Newcastle disease virus infection in chickens

The effect of vitamin A deficiency in the presence or absence of Newcastle disease virus infection (NDV, La Sota strain) on weight of lymphoid organs and on the number and type of circulating white blood cells (WBC) was investigated in chickens. Day-old chickens with limited vitamin A reserves were fed purified diets containing either marginal (ad libitum) or adequate (pair-fed) levels of vitamin A and at 21–28 days of age; half the chickens in each group were infected with NDV. Vitamin A deficiency resulted only in significantly lower absolute and relative weights of bursa of Fabricius and after infection both weights of bursa and thymus were significantly lower. Relative weight of spleen was significantly higher after infection irrespective of vitamin A status. Liver weights were not affected by vitamin A status and/or NDV infection. Both vitamin A deficiency and NDV infection resulted in lymphopenia, while the lowest number of WBC were observed in vitamin A-deficient chickens during the acute phase of NDV (5 days after infection). Subsequent to lymphopenia due to NDV infection, a marked lymphocytosis was observed in controls and to a lesser extent in vitamin A-deficient birds. These results indicate that vitamin A deficiency, which is aggravated by concomitant NDV infection, affects lymphoid cell systems.     

Protective role of melatonin and a combination of vitamin C and vitamin E on lung toxicity induced by chlorpyrifos-ethyl in rats

The ameliorating effects of melatonin and vitamin C plus vitamin E were examined histologically and biochemically in lung tissues in rats exposed to chlorpyriphos-ethyl (CE). Experimental groups were as follows: Control group (C), CE treated group (CE), vitamin C plus vitamin E treated group (Vit), melatonin treated group (Mel), vitamin C plus vitamin E plus CE treated group (Vit + CE), and melatonin plus CE treated group (Mel + CE). Vitamin E and vitamin C were administered intramuscularly at the rates of 150 and 200 mg per kg body weight, respectively, in Vit and Vit + CE groups, once a day for 6 consecutive days. Melatonin was administered intramuscularly at the rate of 10 mg per kg body weight in Mel and Mel + CE groups, once a day for 6 consecutive days. At the end of the fifth day, the rats of CE, Vit + CE and Mel + CE groups were treated orally with CE dissolved in corn oil with two equal doses of 41 mg CE per kg body weight at zero and twenty-first hours. Tissue samples of lungs were taken by using appropriate techniques for biochemical and histological examinations under anesthesia at the twenty-fourth hours of CE administration, at the end of the sixth day of the experiment. In tissue homogenates, the level of thiobarbituric acid reactive substances (TBARS), antioxidant potential (AOP), and the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) were determined. TBARS was significantly high (p < 0.05) in CE group compared to control group, while TBARS was found to significantly decrease (p < 0.05) with Vit and Mel groups compared to control. On the other hand, TBARS was seen to significantly decrease (p < 0.05) in both groups of Vit + CE and Mel + CE compared to CE group. In comparison with CE group, SOD activity was significantly high (p < 0.05) with the groups of Vit, Mel, Vit + CE and Mel + CE. GSH-Px activity was found to significantly decrease (p < 0.05) with CE group, compared with both C and Vit groups. AOP was significantly lower (p < 0.01) in CE group than C group. Although there was an increased AOP with Vit + CE and Mel + CE groups compared to CE group, the increase in AOP was only seen to be significant (p < 0.05) in Mel + CE group. In comparison with C group, AOP significantly (p < 0.05) increased with Vit group. There was also a significant (p < 0.05) increase in AOP with Mel + CE group, compared with CE group. Additionally, AOP was significantly lower (p < 0.05) in Vit + CE group than Mel + CE group. Lungs were examined histologically at the end of sixth day. There were remarkable changes in the histomorphology of peribronchial and perivascular area in the lung of rats treated with CE. These were infiltration of mononuclear cells (such as lymphocytes, plasmocytes, macrophages), hyperplasia of type II pneumocyte, and thickened and increased connective tissue. Damage to the lung tissue such as increased inflammatory mononuclear cells in peribronchial and perivascular areas were more pronounced for the CE group than Vit + CE and Mel + CE groups in which these changes were higher than C, Vit and Mel groups. These results suggest that CE increases lipid peroxidation and decreases antioxidant enzymes activities and AOP due to increasing oxidative stress induced by CE, and high doses of vitamin C plus vitamin E and melatonin considerably reduce CE toxicity in lung tissues of rats.     

Morphometry of nuclei, nuclear envelopes and nucleoli in aging hamster cerebrum

The neuronal nucleus and nucleolus undergo extensive dimensional and configurational changes during maturation and aging, as shown in this study of pyramidal cells of the hamster motor cortex. With maturation, the increase in nuclear perimeter length per unit nuclear area was associated with an increased amount of nuclear invaginations. With maturation and aging, there was a change in nuclear caliper shape, from spherical to very nonspherical. The number of nucleoli containing microbodies peaked first at 15 days and again at 600 days. It is concluded that area, perimeter and form factor relate to nuclear caliper shape and the presence of nucleolar microbodies. The correlated changes in these parameters appear to differentially reflect stage-specific metabolic conditions related to two critical phases: (1) an early phase (10-15 days) at the inception of configurational changes leading to maturity, and (2) a late phase (600-700 days) at the inception of configurational changes leading to old age.     

Muscle pathology in Bassen-Kornzweig syndrome and vitamin E deficiency

A constellation of histologic abnormalities was demonstrated in the quadriceps femoris muscle of a 29-year-old man with Bassen-Kornzweig syndrome. The abnormalities consisted of fibers containing dense lipid inclusions ceroid and lipofuscin, a spectrum of fiber size, architectural changes, and an increase in central nuclei. A dramatic shift of fiber type predominance, from type I to type II, was demonstrated in the myosin ATPase reactions one year after vitamin E therapy. Despite an apparent reduction in the number of fibers containing lipid and ceroid granules in the second biopsy, neuromyopathic changes worsened. The relationship of these findings to vitamin E therapy is discussed.