Purpose-The purpose of this study was to examine the relationship of exercise energy expenditure (EEE) with both telomere length and telomerase activity in addition to accounting for hTERT C-1327T promoter genotype.Methods-Sixty-nine (n = 34 males; n = 35 females) participants 50-70 yr were assessed for weekly EEE level using the Yale Physical Activity Survey. Lifetime consistency of EEE was also determined. Subjects were recruited across a large range of EEE levels and separated into quartiles: 0-990, 991-2340, 2341-3540, and 93541 kcalIwk j1 . Relative telomere length and telomerase activity were measured in peripheral blood mononuclear cells (PBMC).Results-The second EEE quartile exhibited significantly longer telomere lengths [1.12 T 0.03 relative units (RU)] than both the first and fourth EEE quartiles (0.94 T 0.03 and 0.96 T 0.03 RU, respectively; P G 0.05) but was not different from the third quartile. Telomerase activity was not different among the EEE quartiles. An association was observed between telomerase enzyme activity and hTERT genotype with the TT genotype (1.0 • 10 j2 T 4.0 • 10 j3 attomoles (amol) per 10,000 cells; n = 19) having significantly greater telomerase enzyme activity than both the CT (1.3 • 10 j3 T 3.2 • 10 j3 ; n = 30) and CC groups (5.0 • 10 j4 T 3.9 • 10 j3 ; n = 20; P = 0.01).Conclusion-These results indicate that moderate physical activity levels may provide a protective effect on PBMC telomere length compared with both low and high EEE levels. Keywords TELOMERE BIOLOGY; EXERCISE ENERGY EXPENDITURE; hTERT GENOTYPE; GENETICS; DNAPhysical activity (PA) and increased physical fitness are known to decrease the likelihood of morbidity and mortality from a variety of causes (e.g., reduced cardiovascular disease (CVD), insulin resistance, and hypertension) (6), with concomitant increases in longevity (21). Whereas the reduction of disease end points will necessarily increase longevity, whether PA also directly affects cellular aging remains unclear for either rodents or humans (7). Telomere length is a primary biomarker of cellular aging that has recently been associated with CVD (1), insulin resistance and hypertension (14), and morbidity and mortality (9). In the present study, we explored the correlation of PA levels with telomere length and telomerase enzyme activity.Address for correspondence: Stephen M. Roth, Ph.D., 2134 SPH Bldg, Department of Kinesiology, University of Maryland, College Park, MD 20742-2611; E-mail: sroth1@umd.edu.. Telomeres are found on the ends of linear chromosomes and act as a mitotic clock (18), which shortens with every cell division until cellular senescence. Thus, telomeres are considered an important aging biomarker (2,4). Telomeres and their length are not, however, static entities but rather are a dynamic system (4). In certain cells, the ribonucleoprotein, telomerase, maintains and lengthens telomeres, allowing continued mitotic activity without progression to senescence (5). In cells with telomerase activity, telomere length can be maintain...

The amyloid 13-protein is deposited in senile plaques and the cerebrovasculature in Alzheimer disease (AD). Since it is derived from proteolytic processing of its parent protein, the amyloid 13-protein precursor (APP), we investigated whether levels of the secreted forms of APP are altered in cerebrospinal fluid (CSF) of AD patients. Quantitative immunoblotting studies with the anti-APP monoclonal antibody P2-1 revealed that probable AD patients had markedly lower CSF APP levels than did demented non-Alzheimer-type patients and healthy control subjects. Using antibody P2-1 in an enzyme-linked immunosorbent assay, we measured CSF levels of APP in a larger population consisting of 13 patients diagnosed with probable AD, 18 patients diagnosed with dementia (non-Alzheimer type), and 16 nondemented, healthy controls.Mean CSF levels of APP were =3.5-fold lower in the live patients diagnosed with probable AD compared to the demented non-Alzheimer-type controls or the nondemented, healthy individuals. These findings suggest that abnormal metabolism of APP is reflected in the extracellular fluids of the central nervous system and that CSF levels of soluble APP provide a useful biochemical marker to assist in the clinical diagnosis of AD.Alzheimer disease (AD) leads to a progressive and irreversible loss of memory and cognitive function in afflicted elderly individuals. One study has suggested that the disease afflicts as many as 4 million people in the United States alone (1). The hallmark event of AD is deposition of the amyloid }3-protein in senile plaques within brain parenchyma and in cerebral vessel walls of afflicted individuals (2-6). The amyloid (3-protein is a 4.2-kDa peptide proteolytically derived from a large precursor protein designated the amyloid 13-protein precursor (APP) (7-10). APPs can be translated from at least three alternatively spliced mRNAs, two of which contain an additional insert that encodes a domain homologous to Kunitztype serine protease inhibitors (11-13). The secreted form of APP that contains the Kunitz inhibitor domain is identical to the previously described protease inhibitor protease nexin 2 (PN-2) (14, 15). Soluble derivatives of APP are present in brain and cerebrospinal fluid (CSF), suggesting a normal function in the central nervous system (14,(16)(17)(18)(19)(20). Recent studies have suggested that abnormal proteolytic processing of APP leads to formation of the amyloid (3-protein (21-23), which in turn may contribute to the pathology of AD. Abnormal proteolysis associated with AD may, therefore, lead to altered levels of APP in the central nervous system.Previous studies suggested that CSF levels of secreted forms of APP were higher in AD patients than in control subjects (16,19,20). On the other hand, more recent reports indicated that the amounts of secreted APP in CSF were slightly decreased in AD patients (24-26). However, the measurements in those studies employed various antibodies prepared against synthetic peptides or expression products corresponding to variou...

Performance on the Sternberg working memory task, and MEG cortical response on a variation of the Sternberg task were examined in middle-aged carriers and non-carriers of the APOE epsilon4 allele. Physical activity was also assessed to examine whether exercise level modifies the relationship between APOE genotype and neurocognitive function. Regression revealed that high physical activity was associated with faster RT in the six- and eight-letter conditions of the Sternberg in epsilon4 carriers, but not in the non-carriers after controlling for age, gender, and education (N=54). Furthermore, the MEG analysis revealed that sedentary epsilon4 carriers exhibited lower right temporal lobe activation on matching probe trials relative to high-active epsilon4 carriers, while physical activity did not distinguish non-carriers (N=23). The M170 peak was identified as a potential marker for pre-clinical decline as epsilon4 carriers exhibited longer M170 latency, and highly physically active participants exhibited greater M170 amplitude to matching probe trials.

The results support specificity of the physical activity/cognition relationship in older individuals. The results may be explained by additive benefit from participation in physical activity to the frontal lobe (i.e., beyond any benefits from cognitive stimulation), a region that mediates executive function and experiences accelerated age-related decline. In summary, habitual physical activity is positively related to executive performance in older men and women into the 10th decade.

This study tested the hypothesis that interactions of endogenous angiotensin H (All) with the noradrenergic neuroeffector junction are important in renin-dependent hypertension. In the in situ blood-perfused rat mesentery, in normal rats exogenous All potentiated mesenteric vascular responses to periarterial (sympathetic) nerve stimulation (PNS) more than vascular responses to exogenous norepinephrine (NE). In 2-kidney-i-clip (2K-1C) rats with renovascular hypertension mesenteric vascular responses to PNS and NE were greater than in sham-operated rats, and renovascular hypertension mimicked the effects of exogenous All with respect to enhancing responses to PNS more than responses to NE. In 2K-iC rats, but not in sham-operated rats, i-Sar-8-Ile-AII markedly suppressed vascular responses to PNS, without influencing responses to NE. Finally, l-Sar-8-Ile-All attenuated sympathetic nerve stimulation-induced neuronal spillover of NE in 2K-iC rats, but not in sham-operated rats. These data indicate that renovascular hypertension enhances noradrenergic neurotransmission, and that this enhancement is mediated in part by AII-induced facilitation of NE release.