Biomedical subjects

Christopher A Jolly

Publications and source records attributed to Christopher A Jolly.

10 recordsLinked to original sources

PubMed2007

Is dietary restriction beneficial for human health, such as for immune function?

PURPOSE OF REVIEW: The impact of dietary restriction on physiologic function in humans is now beginning to be examined. The clinical trials are fueled by decades of animal experiments showing that dietary restriction delays the aging process and decreases the incidence of many age-associated diseases. The critical issue addressed in this article is whether or not dietary restriction long term is feasible or beneficial in humans. RECENT FINDINGS: Short-term dietary restriction in humans does appear to have beneficial effects at lowering metabolism, especially when examining carbohydrates and weight loss. Dietary restriction long term does, however, have detrimental psychological effects in humans, making its feasibility questionable. Even short-term dietary restriction can negatively impact physical activity and potentially some aspects of immunity. The best avenue for humans to benefit from dietary restriction would be for pharmacological or bioactive food ingredient mimetics to be developed which would be more applicable for long-term use. SUMMARY: Dietary restriction per se is unlikely to emerge as a feasible long-term strategy to improve human health. Developing dietary restriction mimetics targeting energy metabolism may prove beneficial, not only in aging, but also in diabetes and obesity.

Animals↗

PubMed2006

Phosphorylation regulates mitochondrial glycerol-3-phosphate-1 acyltransferase activity in T-lymphocytes.

Recently, we have shown that stimulation and recombinant ACBP increase mitochondrial glycerol-3-phosphate acyltransferase (mtGPAT) activity in rat splenic T-lymphocytes and that this effect is blunted in aged T-lymphocytes. In addition to decreased mtGPAT activity, aged T-lymphocytes also have altered membrane lipid composition and decreased proliferation in response to antigen. Therefore, we wanted to determine the mechanism by which mtGPAT activity is regulated in aged T-lymphocytes. We show that aged T-lymphocyte mtGPAT activity is not increased by ex vivo stimulation or in vitro phosphorylation with casein kinase II and protein kinase C theta as is seen in young T-lymphocytes. However, other factors that might impact mtGPAT activity such as reduced mtGPAT protein levels, gene expression or alterations in the soluble acyl-CoA pool were not affected by age or stimulation. The age effect was also not compensated for by increased acyl-CoA binding protein expression in aged T-lymphocytes. Currently, two mitochondrial GPAT (mtGPAT) isoforms (mtGPAT1 and mtGPAT2) have been identified. We found that T-lymphocytes express mtGPAT1, but not mtGPAT2, suggesting that at least mtGPAT1 is sensitive to phosphorylation in vitro. Support for direct phosphorylation of mtGPAT1 in young T-lymphocytes is shown by mtGPAT1 immunoprecipitation where a phosphoprotein band was detected migrating at the same molecular weight (85 kDa) as mtGPAT1. This is significant because we also show that T-lymphocytes from mtGPAT1 KO mice have reduced proliferation ex vivo as is seen in aged T-lymphocytes. These data provide evidence for a novel mechanism by which T-lymphocyte proliferation may be regulated and, for the first time, give a potential mechanistic explanation for the correlation between reduced proliferation and membrane lipid changes seen in aged T-lymphocytes.

Animals↗

PubMed2005

Aging reduces glycerol-3-phosphate acyltransferase activity in activated rat splenic T-lymphocytes.

T-lymphocyte proliferation declines with age. Phosphatidic acid (PA) is the precursor to all glycerophospholipids, which serve as important membrane structural components and signaling molecules. Therefore, we tested the hypothesis that aged T-lymphocyte proliferation may be reduced, in part, suppressing phosphatidic acid (PA) biosynthesis. We showed, for the first time, that anti-CD3 stimulation in rat splenic T-lymphocytes selectively increased mitochondrial glycerol-3-phosphate acyltransferase (GPAT) activity. GPAT activity could be further increased by the addition of recombinant acyl-CoA binding protein (rACBP), but the amplification of GPAT activity was blunted by aging. This is important because PA is the precursor lipid for phospholipid synthesis and GPAT is the rate-limiting enzyme in PA biosynthesis. The mechanism by which stimulation and rACBP increased GPAT activity may involve phosphorylation since incubating Jurkat T-lymphocyte mitochondria with casein kinase 2 in vitro significantly increased GPAT activity. The data presented here suggest a novel mechanism by which aging may reduce activation-dependent mitochondrial GPAT activity. This age-induced alteration would result in reduced PA biosynthesis and could explain, in part, the diminished phospholipid content of the membrane and subsequent loss of proliferative capacity in the aged T-lymphocyte.

Aging↗

PubMed2005

Dietary n-3 polyunsaturated fatty acids increase T-lymphocyte phospholipid mass and acyl-CoA binding protein expression.

Dietary flaxseed oil, which is enriched in alpha-linolenic acid, and fish oil, which is enriched in EPA and DHA, possess anti-inflammatory properties when compared with safflower oil, which is enriched in linoleic acid. The influence of flaxseed oil and fish oil feeding on lipid metabolism in T-lymphocytes is currently unknown. This study directly compared the effects of feeding safflower oil, flaxseed oil, and fish oil for 8 wk on splenic T-lymphocyte proliferation, phospholipid mass, and acyl-CoA binding protein expression in the rat. The data show that both flaxseed oil and fish oil increased acyl-CoA binding protein expression and phosphatidic acid mass in unstimulated T-lymphocytes when compared with safflower oil feeding. Fish oil feeding increased cardiolipin mass, whereas flaxseed oil had no effect. After stimulation, flaxseed oil and fish oil blunted T-lymphocyte interleukin-2 production and subsequent proliferation, which was associated with the lack of increased acyl-CoA binding protein expression. The results reported show evidence for a novel mechanism by which dietary flaxseed oil and fish oil suppress T-lymphocyte proliferation via changes in acyl-CoA binding protein expression and phospholipid mass.

Animals↗

PubMed2005

Dietary alpha-linolenic acid increases brain but not heart and liver docosahexaenoic acid levels.

Fish oil-enriched diets increase n-3 FA in tissue phospholipids; however, a similar effect by plant-derived n-3 FA is poorly defined. To address this question, we determined mass changes in phospholipid FA, individual phospholipid classes, and cholesterol in the liver, heart, and brain of rats fed diets enriched in flax oil (rich in 18:3n-3), fish oil (rich in 22:6n-3 and 20:5n-3), or safflower oil (rich in 18:2n-6) for 8 wk. In the heart and liver phospholipids, 22:6n-3 levels increased only in the fish oil group, although rats fed flax oil accumulated 20:5n-3 and 22:5n-3. However, in the brain, the flax and fish oil diets increased the phospholipid 22:6n-3 mass. In all tissues, these diets decreased the 20:4n-6 mass, although the effect was more marked in the fish oil than in the flax oil group. Although these data do not provide direct evidence for 18:3n-3 elongation and desaturation by the brain, they demonstrate that 18:3n-3-enriched diets reduced tissue 20:4n-6 levels and increased cellular n-3 levels in a tissue-dependent manner. We hypothesize, based on the lack of increased 22:6n-3 but increased 18:3n-3 in the liver and heart, that the flax oil diet increased circulating 18:3n-3, thereby presenting tissue with this EFA for further elongation and desaturation.

Animals↗

PubMed2005

Diet manipulation and prevention of aging, cancer and autoimmune disease.

PURPOSE OF REVIEW: Dietary supplementation and other dietary regimens have become increasingly popular in the US population. Information regarding how different dietary constituents interact when consumed simultaneously is needed. This review examines the recent literature on how different dietary constituents may interact physiologically when consumed in combination. Furthermore, the potential human relevance of calorie restriction and nonclassical function of vitamin E is discussed. RECENT FINDINGS: Long-term calorie restriction in monkeys has shown similar beneficial effects as has been shown in rodents. Limited calorie restriction studies in humans have shown promise in reducing the incidence of heart disease and breast cancer. The combination of calorie restriction and omega-3 fatty acids may be a more potent antiinflammatory diet than either regimen alone. The type of fiber that is most protective against colon cancer may be dependent on the type of dietary fat consumed simultaneously. Vitamin E derivatives that possess no antioxidant activity may be potent inhibitors of cancer, but not normal, cell growth. SUMMARY: Dietary modification has shown its greatest beneficial effect when started prior to or immediately after the onset of disease. Also, understanding how the subtypes or isoforms of nutrients function is important since their physiological effects may be drastically different. It is important to understand the entire dietary profile of an individual when making dietary recommendations because one nutrient, or dietary ingredient, may enhance or cancel out the beneficial effects of another dietary ingredient.

Aged↗

PubMed2004

CD28 activation does not down-regulate Cbl-b expression in aged rat T-lymphocytes.

It is well known that T-lymphocyte proliferation declines ex vivo with age, and is associated with decreased expression and/or activity of stimulatory intracellular signaling proteins. However, the role of inhibitory intracellular signaling molecules like the ubiquitin ligase Cbl-b in regulating T-lymphocyte function in aging is largely unknown. Therefore, we tested the hypothesis that T-lymphocyte proliferation declines with age, in part, due to increased expression of Cbl-b. We show that young splenic T-lymphocytes reduced Cbl-b expression when stimulated with anti-CD3 and anti-CD28 antibodies, while in aged T-lymphocytes the CD28-dependent Cbl-b down-regulation did not occur. This effect did not appear to be due to reduced CD28 receptor expression on aged T-lymphocytes. The mechanism for lack of Cbl-b down-regulation may involve the proteasome since blocking proteasomal activity in young T-lymphocytes prevented Cbl-b down regulation while there was no effect in aged T-lymphocytes on Cbl-b expression. These data provide evidence for a novel mechanism by which aging reduces T-lymphocyte function.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Dietary restriction and immune function.

Dietary restriction is beneficial in preventing a multitude of diseases, many of which may involve the immune system in their etiology. Recent reports examining dietary restriction focused on T lymphocytes and macrophages. Dietary restriction delays the onset of T-lymphocyte-dependent autoimmune disease; this may be attributed to improved antioxidant defense mechanisms, blunting shifts in T-lymphocyte subset proportions and preventing DNA mutation frequencies. The beneficial effects of dietary restriction were shown in both the CD4 and CD8 T-lymphocyte subsets as well as in various immune compartments such as the spleen, mesenteric lymph nodes, peripheral blood, thymus, and salivary glands. In contrast, dietary restriction may have negative effects on macrophage function because recent evidence showed that dietary restriction rendered mice more susceptible to peritonitis and stimulated macrophages produced lower amounts of cytokines. The application of dietary restriction regimens to humans would be difficult; however, understanding the biochemical and molecular targets of dietary restriction in the immune system may lead to the development of new dietary strategies to delay or prevent the onset of aging, cancer, and autoimmune disease.

Aging↗

PubMed2003

Aging and acyl-CoA binding protein alter mitochondrial glycerol-3-phosphate acyltransferase activity.

It is well known that cellular function declines with age. Since phosphatidic acid (PtdOH) biosynthesis is central to the generation of membrane phospholipids, the hypothesis that aging decreases PtdOH biosynthesis was tested. Glycerol-3-phosphate acyltransferase (GPAT) and lysophosphatidic acid acyltransferase (LAT) activities were examined in isolated mitochondria and microsomes from young and old rat liver. The results show that mitochondrial GPAT preference for palmitoyl-CoA over oleoyl-CoA was only observed if albumin or acyl-CoA binding protein (ACBP) were present in the assay in the young rats. Furthermore, mitochondrial GPAT activity was significantly reduced in the presence of albumin and ACBP in aged mitochondria using palmitoyl-CoA as the substrate. These data show, for the first time, that mitochondrial GPAT acyl-CoA preference is due to the presence of a protein that binds acyl-CoAs, not the enzyme itself, and that aging significantly reduces mitochondrial GPAT activity.

Acylation↗

PubMed2002

Albumin stimulates lysophosphatidic acid acyltransferase activity in T-lymphocyte membranes.

Phosphatidic acid (PtdOH) and lysophosphatidic acid (lysoPtdOH) have been shown to enhance T-lymphocyte function. However, the FA preference and influence of acyl-CoA binding proteins on lysoPtdOH and PtdOH biosynthesis are not known. Therefore, we determined glycerol-3-phosphate acyltransferase (GPAT) and lysophosphatidic acid acyltransferase (LAT) activity in rat T-lymphocyte and liver membrane preparations in the presence of palmitoyl-CoA and oleoyl-CoA with or without BSA. We found two different properties of GPAT and LAT in whole T-lymphocyte membrane preparations relative to liver. First, T-lymphocyte basal GPAT and LAT activities were similar, whereas in liver membranes LAT activity was 10-fold higher than GPAT. Second, T-lymphocyte LAT, but not GPAT, activity was inducible (fivefold) by the addition of albumin in the presence of palmitoyl-CoA but not oleoyl-CoA. In contrast, albumin stimulated GPAT, but not LAT, activity in liver membranes in the presence of palmitoyl-CoA. These results show, for the first time, that T-lymphocyte LAT activity can be increased by the presence of an acyl-CoA binding protein, which may indicate a new important control mechanism for regulating intracellular lysoPtdOH and PtdOH levels in T-lymphocytes.

Acyltransferases↗