Biomedical subjects

Tracey Phillips

Publications and source records attributed to Tracey Phillips.

9 recordsLinked to original sources

PubMed2005

Exercise by lifelong voluntary wheel running reduces subsarcolemmal and interfibrillar mitochondrial hydrogen peroxide production in the heart.

Evidence suggests that mitochondrial dysfunction and oxidant production, in association with an accumulation of oxidative damage, contribute to the aging process. Regular physical activity can delay the onset of morbidity, increase mean lifespan, and reduce the risk of developing several pathological states. No studies have examined age-related changes in oxidant production and oxidative stress in both subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria in combination with lifelong exercise. Therefore, we investigated whether long-term voluntary wheel running in Fischer 344 rats altered hydrogen peroxide (H2O2) production, antioxidant defenses, and oxidative damage in cardiac SSM and IFM. At 10-11 wk of age, rats were randomly assigned to one of two groups: sedentary and 8% food restriction (sedentary; n = 20) or wheel running and 8% food restriction (runners; n = 20); rats were killed at 24 mo of age. After the age of 6 mo, running activity was maintained at an average of 1,145 +/- 248 m/day. Daily energy expenditure determined by doubly labeled water technique showed that runners expended on average approximately 70% more energy per day than the sedentary rats. Long-term voluntary wheel running significantly reduced H2O2 production from both SSM (-10.0%) and IFM (-9.6%) and increased daily energy expenditure (kJ/day) significantly in runners compared with sedentary controls. Additionally, MnSOD activity was significantly lowered in SSM and IFM from wheel runners, which may reflect a reduction in mitochondrial superoxide production. Activities of the other major antioxidant enzymes (glutathione peroxidase and catalase) and glutathione levels were not altered by wheel running. Despite the reduction in mitochondrial oxidant production, no significant differences in oxidative stress levels (4-hydroxy-2-nonenal-modified proteins, protein carbonyls, and malondialdehyde) were detected between the two groups. The health benefits of chronic exercise may be, at least partially, due to a reduction in mitochondrial oxidant production; however, we could not detect a significant reduction in several selected parameters of oxidative stress.

Adaptation, Physiological↗

PubMed2005

Energy expenditure of calorically restricted rats is higher than predicted from their altered body composition.

Debate exists over the impact of caloric restriction (CR) on the level of energy expenditure. At the whole animal level, CR decreases metabolic rates but in parallel body mass also declines. The question arises whether the reduction in metabolism is greater, smaller or not different from the expectation based on body mass change alone. Answers to this question depend on how metabolic rate is normalized and it has recently been suggested that this issue can only be resolved through detailed morphological investigation. Added to this issue is the problem of how appropriate the resting energy expenditure is to characterize metabolic events relating to aging phenomena. We measured the daily energy demands of young and old rats under ad libitum (AD) food intake or 40% CR, using the doubly labeled water (DLW) method and made detailed morphological examination of individuals, including 21 different body components. Whole body energy demands of CR rats were lower than AD rats, but the extent of this difference was much less than expected from the degree of caloric restriction, consistent with other studies using the DLW method on CR animals. Using multiple regression and multivariate data reduction methods we built two empirical predictive models of the association between daily energy demands and body composition using the ad lib animals. We then predicted the expected energy expenditures of the CR animals based on their altered morphology and compared these predictions to the observed daily energy demands. Independent of how we constructed the prediction, young and old rats under CR expended 30 and 50% more energy, respectively, than the prediction from their altered body composition. This effect is consistent with recent intra-specific observations of positive associations between energy metabolism and lifespan and theoretical ideas about mechanisms underpinning the relationship between oxygen consumption and reactive oxygen species production in mitochondria.

Animals↗

PubMed2005

Muscle fiber specific apoptosis and TNF-alpha signaling in sarcopenia are attenuated by life-long calorie restriction.

Increased tumor necrosis factor-alpha (TNF-alpha) levels have been found with age and are connected to muscle atrophy and cell loss, yet the signaling events that occur in vivo are unknown. Calorie restriction (CR), a robust intervention shown to repeatedly evade the physiological declines associated with aging, has been reported to reduce TNF-alpha and may assist in understanding the mechanisms of muscle sarcopenia. The effects of age and CR on muscle mass, myocyte area, fiber number, myocyte TNF-alpha expression, plasma TNF-alpha levels, and specific elements linked with the TNF-alpha signaling cascade (TNF-R1, IKKgamma, IkappaBalpha, p65, NF-kappaB binding activity, FADD, caspase-8, and DNA fragmentation) were investigated in soleus (predominately Type I fiber), and superficial vastus lateralis (SVL, predominately Type II fiber), of 6-month-old ad libitum fed (6AL), 26-month-old ad libitum fed (26AL), and 26-month-old calorie-restricted (26CR) male Fischer 344 rats (CR = 40% restriction compared with ad libitum). Plasma TNF-alpha was increased with age, and the age-associated rise was attenuated with life-long CR. In soleus muscle, we reported a greater capacity to cultivate inflammatory signaling through the transcription factor NF-kappaB compared with that detected in SVL with age. In contrast, in the SVL TNF-alpha stimulated apoptotic signaling with age to a much higher extent than was observed in the soleus. Moreover, a reduction in muscle mass, cross-sectional area, and fiber number in the SVL coincided with this age-linked elevation in apoptosis. In agreement with CR's ability, TNF-alpha stimulation of both inflammatory and apoptotic pathways were abrogated. Our results suggest that TNF-alpha signals transmitted to specific fiber types determine the decision of selecting life or death signaling pathways and are linked to the extent of fiber loss experienced in the aging muscle. Such a specific potential may constitute a major proponent in the pathogenesis of sarcopenia.

Aging↗

PubMed2004

Doxorubicin treatment in vivo activates caspase-12 mediated cardiac apoptosis in both male and female rats.

We investigated in vivo the chemotherapeutic anthracycline agents doxorubicin and its ability to activate mitochondrial-mediated, receptor-mediated and endoplasmic/sarcoplasmic reticulum-mediated apoptosis transduction pathways in cardiac tissue from male and female rats. We administered a single low dose of doxorubicin (10 mg/kg of body weight, i.p.) and then isolated mitochondrial and cytosolic proteins one and four days later from the heart. Caspase-3 protein content and caspase-3 activity were significantly increased after day four of doxorubicin treatment in both male and female rats. However, while males had DNA fragmentation at day one but not day four following doxorubicin administration, females showed no significant increase in DNA fragmentation at either time. Caspase-12, localized in the SR, is considered a central caspase, and its activation by cleavage via calpain indicates activation of the SR-mediated pathway of apoptosis. Cleaved caspase-12 content and calpain activity significantly increased after day four of doxorubicin treatment in both sexes. In the mitochondrial-mediated pathway, there were no significant treatment effects observed in cytosolic cytochrome c and cleaved (active) caspase-9 in either sex. In control rats (saline injection), glutathione peroxidase (GPX) activity and hydrogen peroxide (H2O2) production were lower in females compared to males. Doxorubicin treatment did not significantly affect H2O2, GPX activity or ATP production in isolated mitochondria in either sex. Female rats produced significantly lower levels of H2O2 production one day after doxorubicin treatment, whereas male rats produced significantly less mitochondrial H2O2 four days after doxorubicin treatment. The receptor-mediated pathway (caspase-8 and c-FLIP) showed no evidence of being significantly activated by doxorubicin treatment. Hence, doxorubicin-induced apoptosis in vivo is mediated by the SR to a greater extent than other apoptotic pathways and should therefore be considered for targeted therapeutic interventions. Moreover, no major sex differences exist in apoptosis signaling transduction cascade due to doxorubicin treatment.

Animals↗

PubMed2004

C-reactive protein genotypes affect baseline, but not exercise training-induced changes, in C-reactive protein levels.

OBJECTIVE: The goal of this study is to determine whether C-reactive protein (CRP) gene variants affect baseline and training-induced changes in plasma CRP levels. METHODS AND RESULTS: Sixty-three sedentary men and women aged 50 to 75 years old underwent baseline testing (Vomax, body composition, CRP levels). They repeated these tests after 24 weeks of exercise training while on a low-fat diet. The CRP +219G/A variant significantly associated with CRP levels before and after training after accounting for the effects of demographic and biological variables. CRP -732A/G genotype was significantly related on a univariate basis to CRP levels after training. The CRP +29T/A variant did not affect CRP levels before or after training. In regression analyses, the +219 and -732 variants each had significant effects on CRP levels before and after training. Subjects homozygous for the common A/G -732/+219 haplotype exhibited the highest CRP levels, and having the rare allele at either site was associated with significantly lower CRP levels. CRP levels decreased significantly with training (-0.38+/-0.18 mg/L; P=0.03). However, none of the CRP variants was associated with the training-induced CRP changes. CONCLUSIONS: CRP +219G/A and -732A/G genotypes and haplotypes and exercise training appear to modulate CRP levels. However, training-induced CRP reductions appear to be independent of genotype at these loci.

Adenine↗

PubMed2004

Lifelong aspirin supplementation as a means to extending life span.

Arising from an initiative by the National Institute of Aging (NIA) requesting novel proposals challenged with increasing lifespan and longevity, our laboratory has generated a hypothesis to test the efficacy of lifelong, low-dosage aspirin administration as a means to achieving this goal. The intervention testing program (currently underway) proposing aspirin as an anti-aging agent evolved from the multitude of properties encompassed in aspirin and the potential of these attributes to prevent the cellular and functional declines, particularly from inflammatory and oxidative sources, evidenced to contribute to aging. Aspirin is a widely administered, cheap, anti-inflammatory, and antioxidant compound that has a variety of positive effects on the immune system and cardiovascular health. Notably, aspirin may affect oxidant production, cytokine responses, and block glycooxidation reactions, thus posing it as a triple threat against the symptoms of aging. Whether aging is molded by interplay between oxidative stress and inflammatory mediators has received little attention; however, we and other laboratories have explored this notion and have observed an elevated inflammatory status with age. Stemming from these observations and in view of the limited success of antioxidant therapies in improving lifespan in long-lived species, in this article we propose a protocol to examine life-long use of a very low dose anti-inflammatory compound such as aspirin to engage the inflammatory and endogenous oxidative insults accompanying aging and, in so doing, attempt to increase maximum and mean life span.

Animals↗

PubMed2003

Exercise, antioxidants, and HSP72: protection against myocardial ischemia/reperfusion.

Endurance exercise is associated with protection against myocardial ischemia/reperfusion (I/R) injury and has been shown to increase heat shock protein 72 (HSP72). Dietary antioxidants have also been reported to decrease I/R-induced injury. Because exercise and antioxidants may provide cardioprotection via different mechanisms, combining these countermeasures could provide additive protection. Alternatively, because exercise-induced oxidant production may promote expression of HSP72, antioxidants could attenuate exercise-induced HSP72 expression and decrease exercise-related cardioprotection. These experiments examined the individual and combined effects of exercise and antioxidants on myocardial I/R injury (in vivo). Rats receiving a mixed antioxidant diet or control diet were assigned to exercise or sedentary groups and randomized to receive: (i) short I/R (myocardial stunning), (ii) long I/R (myocardial infarction), or (iii) sham surgery. Antioxidants significantly increased total antioxidant capacity and attenuated exercise-related HSP72 accumulation. Nonetheless, during short I/R, exercise-trained animals demonstrated improved left ventricular developed pressure (LVDP), independent of diet. Further, antioxidants alone resulted in improved LVDP. Finally, compared to control diet/sedentary animals, both exercise groups (control and antioxidant diets) and the antioxidant diet/sedentary group sustained smaller infarctions. We conclude that exercise and antioxidants can independently provide protection against myocardial contractile dysfunction and infarction, and the combination of these two strategies does not enhance or inhibit the protection observed with each individual countermeasure.

Animals↗

PubMed2003

A dietary supplement attenuates IL-6 and CRP after eccentric exercise in untrained males.

PURPOSE: This study investigated the effects of a dietary supplement on exercise-induced markers of cell damage and the inflammatory mediators C-reactive protein (CRP) and interleukin-6 (IL-6). METHODS: The supplement contained mixed tocopherols, flavonoids, and docosahexaenoate. Forty healthy, nonsmoking, untrained males (aged 18-35 yr) were randomly assigned to receive either the supplement (N = 20) or placebo (N = 20) during the 14-d experimental protocol. Blood samples were collected on day 0 (baseline), day 7 (eccentric exercise-induced injury), day 10, and day 14. OBJECTIVE: Markers of cell damage (creatine kinase (CK) and lactate dehydrogenase (LDH)) and inflammation IL-6 and CRP were assessed at these time points in conjunction with subjective range of motion (ROM) and perceived pain measurements. Statistical analyses were conducted using nonparametric methods (P < 0.05). RESULTS: Eccentric arm curl exercise was used to induce an acute phase injury response as evidenced by significant (P < 0.0001) increases in CK, LDH, and pain, as well as a decreased range of motion 3 d after the exercise. There were no significant differences between groups in CK and LDH responses. In contrast, there were significant group differences for IL-6 (P = 0.008) and CRP (P = 0.003). At day 10, by Mann-Whitney U test of changes, the placebo group had significantly greater increases in IL-6 and CRP than the treatment group (P = 0.05 and P < 0.01), respectively. CONCLUSION: This study suggested that exercise-induced inflammation, evaluated by changes in IL-6 and CRP, was significantly reduced by the dietary supplement.

Adult↗

PubMed2002

Doxorubicin treatment in vivo causes cytochrome C release and cardiomyocyte apoptosis, as well as increased mitochondrial efficiency, superoxide dismutase activity, and Bcl-2:Bax ratio.

There have been very few investigations as to whether mitochondrial-mediated apoptosis in vivo is the underlying mechanism of doxorubicin cardiotoxicity. Moreover, no investigations have been conducted to determine whether there are adaptive responses after doxorubicin treatment. We administered a single dose of doxorubicin (20 mg/kg) to male rats and isolated intact mitochondria from their hearts 4 days later. Apoptosis, as determined by the amount of cytosolic mononucleosomal and oligonucleosomal DNA fragments (180 bp or multiples), was significantly increased after doxorubicin treatment. In contrast, Troponin-T, a cardiac-specific marker for necrotic damage, was unaltered 4 days after doxorubicin treatment. Cytosolic cytochrome c increased 2-fold in the doxorubicin-treated rats and was significantly correlated (r = 0.88; P < 0.01) with the increase in caspase-3 activity observed. Moreover, the level of bleomyocin-detectable iron in serum was significantly increased and may have contributed to the increase in oxidative stress, which was indicated by an increase in cytosolic 8-iso prostaglandin F(2alpha). Cytosolic copper zinc superoxide dismutase activity also increased significantly further supporting the notion that doxorubicin increases superoxide radical production. In addition to adaptations to antioxidant defenses, other adaptive mechanisms occurred in the mitochondria such as an increase in the respiratory P/O ratio and an increase in the Bcl-2:Bax ratio. These findings demonstrate that doxorubicin induces oxidative stress and mitochondrial-mediated apoptosis, as well as adaptive responses by the mitochondria to protect cardiac myocytes in vivo.

Amino Acid Sequence↗