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1.  Analysis of 27 vascular-related proteins reveals that NT-proBNP is a potential biomarker for Alzheimer’s disease and mild cognitive impairment: A pilot-study 
Experimental gerontology  2013;50:114-121.
Alzheimer’s disease (AD) is a severe neurodegenerative disease. Cerebrovascular changes often accompany AD-related pathology. Despite a considerable progress in the diagnostic accuracy of AD, no blood biomarkers have been established so far. The aim of the present study was to search for changes in plasma levels of 27 vascular-related proteins of healthy controls, patients with mild cognitive impairment (MCI) and AD. In a sample of 80 participants we showed that out of these 27 proteins, six proteins were slightly changed (up to 1.5×) in AD (alpha2-macroglobulin, apolipoprotein-A1, plasminogen activator inhibitor, RAGE, Tissue Inhibitors of Metalloproteinases-1 and Trombospondin-2) and one marker (serum amyloid A) was enhanced up to 6× but with a very high variance. However, N-terminal pro-brain natriuretic peptide (NT-proBNP) was significantly enhanced both in MCI and AD patients (1.9×). In a second analysis of a sample of 110 subjects including younger healthy controls, we confirmed that NT-proBNP has the potential to be a stable candidate protein for both diagnosis and AD disease progression.
PMCID: PMC4312837  PMID: 24333505
Diagnosis; Plasma; Biomarker; Alzheimer; Mild cognitive impairment; Multiplex ELISA; NT-proBNP
2.  [No title available] 
PMCID: PMC3914538  PMID: 24316039
3.  [No title available] 
PMCID: PMC4072042  PMID: 24316035
4.  [No title available] 
PMCID: PMC4096533  PMID: 24316036
5.  Glycogen-synthase kinase-3β is decreased in peripheral blood mononuclear cells of patients with mild cognitive impairment 
Experimental gerontology  2009;44(0):370-371.
Glycogen-synthase kinase-3 (GSK-3) plays a central role in Alzheimer’s disease (AD). It is involved in the hyper-phosphorylation of Tau and the increased production of β-amyloid. Despite its eminent role, only one study has been published so far in AD blood samples, reporting an increase of GSK-3α and −3β levels in white blood cells. In this study, we measured GSK-3α and −3β by quantitative ELISA in peripheral blood mononuclear cells of patients with mild cognitive impairment (MCI), AD and depression in comparison to healthy subjects. In contrast to the previous study, we observed a significant reduction of GSK-3β levels in MCI patients and less pronounced in AD but not in depression. The data indicate that high GSK-3 brain activity is not reflected in peripheral blood mononuclear cells. Therefore, we conclude that more longitudinal studies have to be performed to clarify whether GSK-3 blood levels may qualify as disease specific biological markers.
PMCID: PMC4311052  PMID: 19249342
Alzheimer; GSK-3; Monocytes; Tau-protein
6.  Soluble cell adhesion molecules in monocytes of Alzheimer’s disease and mild cognitive impairment 
Experimental gerontology  2009;45(1):70-74.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with characteristic neuropathological features that are accompanied by inflammatory processes and release of pro-inflammatory cytokines. There is evidence that microglial cells are a key mediator of damage in AD. The microglial compartment may arise to a greater part from activation and transmigration of circulating monocytes. The aim of the present pilot study was to explore, if different cell adhesion molecules (ICAM-1 and -3, PECAM-1, VCAM-1, P-, L- and E-selectins, E-cadherin), RAGE and CD14 are affected in monocytes of healthy subjects compared to patients suffering from AD or mild cognitive impairment (MCI). Monocytes were isolated by negative magnetic selection (MACS) from EDTA blood samples, and extracts were analyzed by Searchlight Multiplex ELISAs. When compared to healthy subjects, the ratio of monocytic ICAM-3/CD14 was significantly decreased in MCI and AD patients and the ratio of the monocytic P-selectin/CD14 was specifically decreased in AD patients. In conclusion, our data show that monocytic cell adhesion molecules are decreased in AD and MCI patients. Further larger longitudinal studies should then clarify whether any of these parameters may be useful as a diagnostic biomarker.
PMCID: PMC4311053  PMID: 19836440
CAMs; ICAM; VCAM; Selectins; CSF; Cerebrospinal fluid; Blood; Diagnosis; Alzheimer
7.  Prospective associations between inflammatory and hemostatic markers and physical functioning limitations in mid-life women: Longitudinal Results of the Study of Women's Health Across the Nation (SWAN) 
Experimental gerontology  2013;49:10.1016/j.exger.2013.10.016.
Due to the public health burden of age-related declines in physical functioning, it is important to identify targets for intervention for the prevention of functional decline. We prospectively examined whether higher levels of inflammatory and hemostatic markers (high-sensitivity C-reactive protein (hs-CRP), plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator antigen (tPA-ag), fibrinogen, and Factor VIIc (FVIIc)) were prospectively associated with reporting greater limitations in perceived physical functioning, and explored potential racial differences in the associations, in a multi-ethnic sample of mid-life women.
Women (45 – 56 years) in the Study of Women's Health Across the Nation who completed the physical functioning scale of the Medical Outcome Short Form (SF-36) at follow-up visits 4, 6, or 8 and had inflammatory/hemostatic measures in the preceeding year were included (n=2296). The continuous SF-36 physical function score was categorized as: no limitation (86–100 points), some limitation (51–85 points), and substantial limitation (0–50 points). Physical function category at time t was modeled a function of each biomarker, separately, at time t-1 using ordinal generalized estimating equations.
After adjusting for age, race/ethnicity, body size, sociodemographic, medical and lifestyle factors, higher levels of tPA-ag and hs-CRP were associated with subsequently reporting greater limitations in physical functioning, although the latter was only marginally significant (p=0.13). For each standard deviation (SD) increase in logtPA-ag, the odds of some or substantial limitations was 1.18 (95%CI 1.09,1.27); for each SD increase in loghs-CRP, the odds of some or substantial limitation was (1.08, 95%CI 0.98,1.19). In African American women only, higher fibrinogen levels were associated with subsequently reporting greater limitations (OR=1.30, 95%CI 1.13,1.50, for each one SD increase in fibrinogen).
Higher levels of inflammatory and hemostatic markers were prospectively associated with greater limitations in perceived physical functioning in mid-life women.
PMCID: PMC3878447  PMID: 24212137
Inflammation; Hemostasis; Physical Functioning; Women
8.  Ventromedial PFC, Parahippocampal, and Cerebellar Connectivity Are Associated with Temporal Discounting in Old Age 
Experimental gerontology  2013;48(12):10.1016/j.exger.2013.10.003.
Temporal discounting occurs when a greater delayed reward is forsaken for a smaller immediate reward, and has been associated with a number of financial and health care outcomes important for older adults. Using resting-state fMRI and seed regions of interest in the left and right fronto-insular (FI) cortex, we explored the neurobiological substrate of temporal discounting in 123 non-demented older adults from the Rush Memory and Aging Project. For the left FI, temporal discounting was positively associated with functional connectivity to the right ventromedial prefrontal cortex and middle temporal regions, and negatively associated with parahippocampal and right cerebellar regions. For the right FI, temporal discounting was negatively associated with functional connectivity to a right cerebellar region. Connectivity maps of both left and right seed regions of interest overlapped in the right cerebellum. Results support the notion of different brain functional connectivity patterns associated with the dynamic range of temporal discounting in old age.
PMCID: PMC3855854  PMID: 24135750
Temporal discounting; aging; functional connectivity; fronto-insular cortex; ventromedial prefrontal cortex
9.  Lifespan extension of rotifers by treatment with red algal extracts 
Experimental gerontology  2013;48(12):10.1016/j.exger.2013.09.007.
Aging results from an accumulation of damage to macromolecules inhibiting cellular replication, repair, and other necessary functions. Damage may be due to environmental stressors such as metal toxicity, oxidative stress caused by imperfections in electron transfer reactions, or other metabolic processes. In an effort to discover medical treatments that counteract this damage, we initiated a search for small molecule drugs from natural sources using life table experiments which, through their unbiased approach, present the opportunity to discover first-in-class molecules. We have identified marine red algae as a source of natural products that slow aging of the invertebrate rotifer Brachionus manjavacas. Rotifers are a promising model organism for life extension studies as they maintain a short, measurable lifespan while also having an extensive literature related to aging. Rotifer lifespan was increased 9–14% by exposure to three of a total of 200 screened red algal extracts. Bioassay guided fractionation led to semi-purified extracts composed primarily of lipids responsible for rotifer life extension. The life extending mixture from the red alga Acanthophora spicifera contained eicosanoic, octadecanoic, and hexadecanoic acids as well as several unidentified unsaturated fatty acids. The life extending effects of these small molecule mixtures are not a result of their direct antioxidant capacity; other unknown mechanisms of action are likely involved. An understanding of how these natural products interact with their molecular targets could lead to selective and effective treatments for slowing aging and reducing age related diseases.
PMCID: PMC3856191  PMID: 24120568
Aging; Antioxidant; Fatty Acid; Lifespan; Lipid; Rotifer; Invertebrate
10.  Morbidity risks among older adults with pre-existing age-related diseases 
Experimental gerontology  2013;48(12):1395-1401.
Multi-morbidity is common among older adults; however, for many aging-related diseases there is no information for U.S. elderly population on how earlier-manifested disease affects the risk of another disease manifested later during patient’s lifetime. Quantitative evaluation of risks of cancer and non-cancer diseases for older adults with pre-existing conditions is performed using the Surveillance, Epidemiology, and End Results (SEER) Registry data linked to the Medicare Files of Service Use (MFSU). Using the SEER-Medicare data containing individual records for 2,154,598 individuals, we empirically evaluated age patterns of incidence of age-associated diseases diagnosed after the onset of earlier manifested disease and compared these patterns with those in general population. Individual medical histories were reconstructed using information on diagnoses coded in MFSU, dates of medical services/procedures, and Medicare enrollment/disenrollment. More than threefold increase of subsequent diseases risk was observed for 15 disease pairs, majority of them were i) diseases of the same organ and/or system (e.g., Parkinson disease for patients with Alzheimer disease, HR=3.77, kidney cancer for patients with renal failure, HR=3.28) or ii) disease pairs with primary diseases being fast-progressive cancers (i.e., lung, kidney, and pancreas), e.g., ulcer (HR=4.68) and melanoma (HR=4.15) for patients with pancreatic cancer. Lower risk of subsequent disease was registered for 20 disease pairs, mostly among patients with Alzheimer’s or Parkinson’s disease, e.g., decreased lung cancer risk among patients with Alzheimer’s (HR=0.64) and Parkinson’s (HR=0.60) disease. Synergistic and antagonistic dependences in geriatric disease risks were observed among US elderly confirming known and detecting new associations of wide spectrum of age-associated diseases. The results can be used in optimization of screening, prevention and treatment strategies of chronic diseases among U.S. elderly population.
PMCID: PMC3895485  PMID: 24064264
Medicare; chronic disease onset; dependent risks; comorbidity; aging; geriatric disease
11.  The effect of an advanced glycation end-product crosslink breaker and exercise training on vascular function in older individuals: a randomized factorial design trial 
Experimental gerontology  2013;48(12):1509-1517.
Aging leads to accumulation of irreversible advanced glycation end-products (AGEs), contributing to vascular stiffening and endothelial dysfunction. When combined with the AGE-crosslink breaker Alagebrium, exercise training reverses cardiovascular aging in experimental animals. This study is the first to examine the effect of Alagebrium, with and without exercise training, on endothelial function, arterial stiffness and cardiovascular risk in older individuals. Forty-eight non-exercising individuals (mean age 70±4 years) without manifest diseases or use of medication were allocated into 4 groups for a 1-year intervention: Exercise training & Alagebrium (200mg/day); Exercise training & placebo; No exercise training & Alagebrium (200mg/day); No exercise training & placebo. We performed a maximal exercise test (VO2max) and measured endothelial function using venous occlusion plethysmography and intra-arterial infusion of acetylcholine, sodium nitroprusside and NG-monomethyl-L-arginine. Arterial stiffness was measured using pulse wave velocity. Cardiovascular risk was calculated using the Lifetime Risk Score (LRS). In the exercise training groups, LRS and VO2max improved significantly (23.9±4.5 to 27.2±4.6mlO2/min/kg, p<0.001). Endothelial response to the vasoactive substances did not change, nor did arterial stiffness in any of the four groups. In conclusion, one year of exercise training significantly improved physical fitness and lifetime risk for cardiovascular disease without affecting endothelial function or arterial stiffness. The use of the AGE-crosslink breaker Alagebrium had no independent effect on vascular function, nor did it potentiate the effect of exercise training. Despite the clinical benefits of exercise training for older individuals, neither exercise training nor Alagebrium (alone or in combination) was able to reverse the vascular effects of decades of sedentary aging.
PMCID: PMC3934851  PMID: 24400341
Advanced Glycation End-products; Aging; Alagebrium; Arterial stiffness; Endothelial function; Exercise training
12.  Possible protective role of the 489C>T P2X7R polymorphism in Alzheimer's disease 
Experimental Gerontology  2014;60:117-119.
Inflammation is a key factor in the onset and progression of Alzheimer's disease (AD). The P2X7 receptor (P2X7R) is increasingly recognized as key pro-inflammatory receptor. A recent study has shown that activation of microglia by amyloid β (Aβ) and associated release of IL-1β, requires P2X7R expression. In this study we assessed by RT-PCR in genomic DNA samples, the frequency of two single-nucleotide polymorphisms (SNP) of P2X7R in AD patients compared to age-matched non demented elderly. Our data show that the 489C>T SNP was significantly less frequent in AD patients than in controls (p = 0.01), whereas there was no statistical difference in 1513A>C frequency in either groups. In addition, presence of the 1513C allele and absence of the 489C allele decreased the probability of having AD by about four fold. In conclusion, our data show a strong negative association between the P2X7R 489C>T polymorphism and AD, especially in the presence of the 1513C allele.
PMCID: PMC4266448  PMID: 25456845
Aβ, amyloid β; AD, Alzheimer's disease; CHD, coronary heart disease; CI, confidence interval; CTR, non-demented control subjects; OR, odds ratio; P2X7R, P2X7 receptor; SNP, single-nucleotide polymorphisms; Alzheimer's disease; P2X7R; Polymorphism; rs3751143; rs208294
13.  Dramatic fertility decline in aging C. elegans males is associated with mating execution deficits rather than diminished sperm quality 
Experimental gerontology  2013;48(11):1156-1166.
Although much is known about female reproductive aging, fairly little is known about the causes of male reproductive senescence. We developed a method that facilitates culture maintenance of Caenorhabditis elegans adult males, which enabled us to measure male fertility as populations age, without profound loss of males from the growth plate. We find that the ability of males to sire progeny declines rapidly in the first half of adult lifespan and we examined potential factors that contribute towards reproductive success, including physical vigor, sperm quality, mating apparatus morphology, and mating ability. Of these, we find little evidence of general physical decline in males or changes in sperm number, morphology, or capacity for activation, at time points when reproductive senescence is markedly evident. Rather, it is the loss of efficient mating ability that correlates most strongly with reproductive senescence. Low insulin signaling can extend male ability to sire progeny later in life, although insulin impact on individual facets of mating behavior is complex. Overall, we suggest that combined modest deficits, predominantly affecting the complex mating behavior rather than sperm quality, sum up to block effective C. elegans male reproduction in middle adult life.
PMCID: PMC4169024  PMID: 23916839
Aging Sperm; C. elegans; Males Fertility
14.  Aging-related Changes in the Iron Status of Skeletal Muscle 
Experimental gerontology  2013;48(11):10.1016/j.exger.2013.08.011.
The rise in non-heme iron (NHI) concentration observed in skeletal muscle of aging rodents is thought to contribute to the development of sarcopenia. The source of the NHI has not been identified, nor have the physiological ramifications of elevated iron status in aged muscle been directly examined. Therefore, we assessed plantaris NHI and heme iron (HI) levels in addition to expression of proteins involved in iron uptake (transferrin receptor-1; TfR1), storage (ferritin), export (ferroportin; FPN), and regulation (iron regulatory protein-1 (IRP1) and -2 (IRP2)) of male F344xBN F1 rats (n=10/group) of various ages (8, 18, 28, 32, and 36 months) to further understand iron regulation in aging muscle. In a separate experiment, iron chelator (pyridoxal isonicotinoyl hydrazone; PIH) or vehicle was administered to male F344xBN F1 rats (n=8/group) beginning at 30 months of age to assess the impact on plantaris muscle mass and function at ~36 months of age. Principle findings revealed the increased NHI concentration in old age was consistent with concentrating effects of muscle atrophy and reduction in HI levels, with no change in the total iron content of the muscle. The greatest increase in muscle iron content occurred during the period of animal growth and was associated with downregulation of TfR1 and IRP2 expression. Ferritin upregulation did not occur until senescence and the protein remained undetectable during the period of muscle iron content elevation. Lastly, administration of PIH did not significantly (p>0.05) impact NHI or measures of muscle atrophy or contractile function. In summary, this study confirms that the elevated NHI concentration in old age is largely due to the loss in muscle mass. The increased muscle iron content during aging does not appear to associate with cytosolic ferritin storage, but the functional consequences of elevated iron status in old age remains to be determined.
PMCID: PMC3812819  PMID: 23994517
Sarcopenia; muscle aging; pyridoxal isonicotinoyl hydrazone; muscle function; skeletal muscle iron regulation
15.  Role of PGC-1α in exercise training- and resveratrol-induced prevention of age-associated inflammation 
Experimental gerontology  2013;48(11):1274-1284.
Age-related metabolic diseases are often associated with low-grade inflammation. The aim of the present study was to investigate the role of the transcriptional co-activator PGC-1α in the potential beneficial effects of exercise training and/or resveratrol in the prevention of age-associated low-grade inflammation. To address this, a long-term voluntary exercise training and resveratrol supplementation study was conducted.
Experimental setup
Three month old whole body PGC-1α KO and WT mice were randomly assigned to four groups: untrained chow-fed, untrained chow-fed supplemented with resveratrol, chow-fed voluntarily exercise trained and chow-fed supplemented with resveratrol and voluntarily exercise trained. The intervention lasted 12 months and three month old untrained chow-fed mice served as young controls.
Voluntary exercise training prevented an age-associated increase (p<0.05) in systemic IL-6 and adiposity in WT mice. PGC-1α expression was required for a training-induced prevention of an age-associated increase (p<0.05) in skeletal muscle TNFα protein. Independently of PGC-1α, both exercise training and resveratrol prevented an age-associated increase (p<0.05) in skeletal muscle protein carbonylation.
The present findings highlight that exercise training is a more effective intervention than resveratrol supplementation in reducing age-associated inflammation and that PGC-1α in part is required for the exercise training-induced anti-inflammatory effects.
PMCID: PMC4045249  PMID: 23916840
Aging; low-grade inflammation; exercise training; resveratrol; PGC-1α
16.  Aging Compounds Western Diet-Associated Large Artery Endothelial Dysfunction in Mice: Prevention by Voluntary Aerobic Exercise 
Experimental gerontology  2013;48(11):10.1016/j.exger.2013.08.001.
We tested the hypothesis that aging will exacerbate the negative vascular consequences of exposure to a common physiological stressor, i.e., consumption of a “western” (high fat/high sucrose) diet (WD) by inducing superoxide-associated reductions in nitric oxide (NO) bioavailability, and that this would be prevented by voluntary aerobic exercise. Incremental stiffness and endothelium-dependent dilation (EDD) were measured in the carotid arteries of young (5.4±0.3 mo, N=20) and old (30.4±0.2 mo, N=19) male B6D2F1 mice fed normal chow (NC: 17% fat, 0% sucrose) or a western diet (40% fat, 19% sucrose) diet and housed in either standard cages or cages equipped with running wheels for 10–14 weeks. Incremental stiffness was higher in old NC (P<0.05) and both young (P<0.01) and old (P<0.01) WD fed mice compared with young NC mice, but WD did not further increase stiffness in the old mice. In cage control mice, EDD was 17% lower in both NC fed old mice and young WD fed mice (P<0.05). Consumption of WD by old mice led to a further 20% reduction in EDD (P<0.05). Incremental stiffness was 28% lower and EDD was 38% greater in old WD fed mice with access to running wheels vs. old WD fed control mice (P<0.05) and not different from young NC fed controls. Wheel running also tended to improve EDD (+9%, P=0.11), but not incremental stiffness in young WD fed mice. Ex vivo treatment with the superoxide scavenger TEMPOL and NO inhibitor L-NAME abolished these respective effects of age, WD and voluntary running on EDD. Ingestion of a WD induces similar degrees of endothelial dysfunction in old and young adult B6D2F1 mice, and these effects are mediated by a superoxide-dependent impairment of NO bioavailability. However, the combination of old age and WD, a common occurrence in our aging society, results in a marked, additive reduction in endothelial function. Importantly, regular voluntary aerobic exercise reduces arterial stiffness and protects against the adverse influence of WD on endothelial function in old animals by preventing superoxide suppression of NO. These findings may have important implications for arterial aging and the prevention of age-associated cardiovascular diseases.
PMCID: PMC3840721  PMID: 23954368
vasodilation; aging; western diet; obesity; exercise
17.  Longer leukocyte telomere length in Costa Rica's Nicoyan Peninsula: A population-based study 
Experimental gerontology  2013;48(11):10.1016/j.exger.2013.08.005.
Studies in humans suggest that leukocyte telomere length may act as a marker of biological aging. We investigated whether individuals in the Nicoya region of Costa Rica, known for exceptional longevity, had longer telomere length than those in other parts of the country. After controlling for age, age squared, rurality, rainy season and gender, mean leukocyte telomere length in Nicoya was substantially longer (81 base pairs, p<0.05) than in other areas of Costa Rica, providing evidence of a biological pathway to which this notable longevity may be related. This relationship remains unchanged (79 base pairs, p<0.05) after statistically controlling for nineteen potential biological, dietary and social and demographic mediators. Thus the difference in mean leukocyte telomere length that characterizes this unique region does not appear to be explainable by traditional behavioral and biological risk factors. More detailed examination of mean leukocyte telomere length by age shows that the regional telomere length difference declines at older ages.
PMCID: PMC3819141  PMID: 23988653
telomere length; Costa Rica; aging; biomarkers; socioeconomic; longevity
18.  Long-term calorie restriction decreases metabolic cost of movement and prevents decrease of physical activity during aging in the rhesus monkeys 
Experimental gerontology  2013;48(11):10.1016/j.exger.2013.08.002.
Short-term (<1 year) calorie restriction (CR) has been reported to decrease physical activity and metabolic rate in humans and non-human primate models; however, studies examining the very long-term (>10 year) effect of CR on these parameters are lacking.
The objective of this study was to examine metabolic and behavioral adaptations to long-term CR longitudinally in rhesus macaques.
Eighteen (10 male, 8 female) control (C) and 24 (14 male, 10 female) age matched CR rhesus monkeys between 19.6 and 31.9 years old were examined after 13 and 18 years of moderate adult-onset CR. Energy expenditure (EE) was examined by doubly labeled water (DLW; TEE) and respiratory chamber (24hrEE). Physical activity was assessed both by metabolic equivalent (MET) in a respiratory chamber and by an accelerometer. Metabolic cost of movements during 24h were also calculated. Age and fat-free mass were included as covariates.
Adjusted total and 24hr EE were not different between C and CR. Sleeping metabolic rate was significantly lower, and physical activity level was higher in CR than in C independent from the CR-induced changes in body composition. The duration of physical activity above 1.6 METs was significantly higher in CR than in C, and CR had significantly higher accelerometer activity counts than C. Metabolic cost of movements during 24h were significantly lower in CR than in C. The accelerometer activity counts were significantly decreased after seven years in C animals, but not in CR animals.
The results suggest that long-term CR decreases basal metabolic rate, but maintains higher physical activity with lower metabolic cost of movements compared with C.
PMCID: PMC3882119  PMID: 23954367
caloric restriction; energy expenditure; physical activity; energy cost of movement; rhesus monkey; adaptation
19.  The somatotropic axis and aging: Mechanisms and persistent questions about practical implications 
Experimental gerontology  2009;44(0):372-374.
Reduced somatotropic (GH/IGF-1) signaling delays aging and extends longevity in laboratory mice. However, it is unclear whether the physiological decrease of GH and IGF-1 levels with age represents a symptom of declining neuroendocrine function, a cause of age-related alterations in body composition and functionality or a protective mechanism against age-associated disease. Although available clinical evidence does not support the use of recombinant GH as an anti-aging therapy, many studies suggest the potential utility of GH and GH secretagogues in the treatment of sarcopenia and frailty.
PMCID: PMC4207209  PMID: 19371777
20.  Calorie restriction in mice overexpressing UCP3: evidence that prior mitochondrial uncoupling alters response 
Experimental gerontology  2012;47(5):361-371.
Calorie restriction (CR) without malnutrition is the only intervention to consistently increase lifespan in all species tested, and lower age-related pathologies in mammals including humans. It has been suggested that uncoupling of mitochondrial oxidative phosphorylation, using chemical uncouplers, mimics CR, and that overlapping mechanisms underlie the phenotypic changes induced by uncoupling and CR. We aimed to critically assess this using a unique mouse model of skeletal muscle-targeted UCP3-induced uncoupling (UCP3Tg), and focused our studies mainly on skeletal muscle mitochondria. Compared to ad libitum fed Wt mice, skeletal muscle mitochondria from ad libitum fed UCP3Tg mice showed higher basal uncoupling and lower H2O2 emission, with unchanged maximal oxidative phosphorylation, and mitochondrial content. UCP3Tg CR mice showed some tendency for differential adaptation to CR, with lowered H+ leak conductance and evidence for higher H2O2 emission from skeletal muscle mitochondria following 2 weeks CR, and failure to lower H2O2 emission after 1 month CR. Differential adaptation was also apparent at the whole body level: while UCP3Tg CR mice lost as much weight as Wt CR mice, the proportion of muscle lost was higher in UCP3Tg mice. However, a striking outcome of our studies was the absence of change with CR in many of the parameters of mitochondrial function and content that we measured in mice of either genotype. Overall, our study raises the question of whether CR can consistently modify skeletal muscle mitochondria; alterations with CR may only be apparent under certain conditions such as during the 2 wk CR intervention in the UCP3Tg mice.
PMCID: PMC4203376  PMID: 22406134
uncoupling proteins; oxidative phosphorylation; oxidative stress; mitochondrial biogenesis; indirect calorimetry
21.  The Effect of Fasting on Indicators of Muscle Damage 
Experimental gerontology  2012;48(10):1101-1106.
Many studies have tested the consumption of foods and supplements to reduce exercise-induced muscle damage, but fasting itself is also worthy of investigation due to reports of beneficial effects of caloric restriction and/or intermittent fasting on inflammation and oxidative stress. This preliminary investigation compared indicators of exercise-induced muscle damage between upper-body untrained participants (N = 29, 22 yrs old (SD = 3.34), 12 women) who completed 8 hour water-only fasts or ate a controlled diet in the eight hours prior to five consecutive laboratory sessions. All sessions were conducted in the afternoon hours (i.e., post meridiem) and the women completed the first session while in the follicular phase of their menstrual cycles. Measures of muscle pain, resting elbow extension, upper arm girth, isometric strength, myoglobin (Mb), total nitric oxide (NO), interleukin 1beta (IL1b), and tumor necrosis factor alpha (TNFa) were collected before and after eccentric contractions of the non-dominant elbow flexors were completed. The fasting group’s loss of elbow extension was less than the post-prandial group (p < .05, eta2 = .10), but the groups did not change differently across time for any other outcome measures. However, significantly higher NO (p < .05, eta2 = .22) and lower TNFa (p < .001, eta2 = .53) were detected in the fasting group than the post-prandial group regardless of time. These results suggest intermittent fasting does not robustly inhibit the signs and symptoms of exercise-induced muscle damage, but such fasting may generally affect common indirect markers of muscle damage.
PMCID: PMC3622193  PMID: 23266375
delayed-onset muscle soreness; stretch injury
22.  Dehydroepiandrosterone sulfate (DHEAS) as an endocrine marker of aging in calorie restriction studies 
Experimental gerontology  2013;48(10):1136-1139.
The adrenal steroid, dehydroepiandrosterone sulfate (DHEAS), is generally regarded as being a reliable endocrine marker of aging, because in humans and nonhuman primates its circulating concentrations are very high during young adulthood, and the concentrations then decline markedly during aging. Despite promising results from early studies, we were recently surprised to find that caloric restriction (CR) did little to prevent or delay the decline of DHEAS concentrations in old rhesus macaques. Here we summarize the use of circulating DHEAS concentrations as a biomarker of aging in CR studies and suggest reasons for its limited value. Although DHEAS can reliably predict aging in animals maintained on a standard diet, dietary manipulations may affect liver enzymes involved in the metabolism of steroid hormones. Consequently, in CR studies the reliability of using DHEAS as a biomarker of aging may be compromised.
PMCID: PMC3641169  PMID: 23318475
Adrenal gland; Biomarker; Cortisol; DHEAS; Rhesus macaque
23.  Dietary restriction supports peripheral nerve health by enhancing endogenous protein quality control mechanisms 
Experimental gerontology  2012;48(10):1085-1090.
The peripheral nervous system (PNS) comprises of an extensive network of connections that convey information between the central nervous system (CNS) and peripheral organs. Long myelinated nerve fibers are particularly susceptible to age-related changes, as maintenance of the insulating glial membrane requires extensive synthesis and processing of many proteins. In rodent models, peripheral demyelination caused by genetic risk factors or by normal aging are attenuated by intermittent fasting (IF) or calorie restriction (CR) supporting a role for dietary intervention in preserving neural function. This review will summarize recent studies examining mechanisms by which life-long CR or extended IF supports peripheral nerve health.
PMCID: PMC3652890  PMID: 23267845
24.  High carbohydrate-low protein consumption maximizes Drosophila lifespan 
Experimental gerontology  2013;48(10):1129-1135.
Dietary restriction extends lifespan in a variety of organisms, but the key nutritional components driving this process and how they interact remain uncertain. In Drosophila, while a substantial body of research suggests that protein is the major dietary component affecting longevity, recent studies claim that carbohydrates also play a central role. To clarify how nutritional factors influence longevity, nutrient consumption and lifespan were measured on a series of diets with varying yeast and sugar content. We show that optimal lifespan requires both high carbohydrate and low protein consumption, but neither nutrient by itself entirely predicts lifespan. Increased dietary carbohydrate or protein concentration does not always result in reduced feeding—the regulation of food consumption is best described by a constant daily caloric intake target. Moreover, due to differences in food intake, increased concentration of a nutrient within the diet does not necessarily result in increased consumption of that particular nutrient. Our results shed light on the issue of dietary effects on lifespan and highlight the need for accurate measures of nutrient intake in dietary manipulation studies.
PMCID: PMC3687007  PMID: 23403040
Aging; Dietary restriction; Drosophila; Feeding; Longevity; Nutrition
25.  Weight loss in obese adults 65 years and older: A review of the controversy 
Experimental gerontology  2013;48(10):1054-1061.
Obesity in older adults is ubiquitous in many developed countries and is related to various negative health outcomes, making it an important public health target for intervention. However, treatment approaches for obesity in older adults remain controversial due to concerns surrounding the difficulty of behavior change with advancing age, exacerbating the age-related loss of skeletal muscle and bone, and the feasibility of long-term weight maintenance and related health consequences. This review serves to systematically examine the evidence regarding weight loss interventions with a focus on obese (body mass index 30 kg/m2 and above) older adults (aged 65 years and older) and some proposed mechanisms associated with exercise and caloric restriction (lifestyle intervention). Our findings indicate that healthy weight loss in this age group can be achieved through lifestyle interventions of up to a one-year period. Most interventions reviewed reported a loss of lean body mass and bone mineral density with weight loss. Paradoxically muscle quality and physical function improved. Inflammatory molecules and metabolic markers also improved, although the independent and additive effects of exercise and weight loss on these pathways are poorly understood. Using our review inclusion criteria, only one small pilot study investigating long-term weight maintenance and associated health implications was found in the literature. Future research on lifestyle interventions for obese older adults should address the loss of bone and lean body mass, inflammatory mechanisms, and include sufficient follow up to assess long-term weight maintenance and health outcomes.
PMCID: PMC3714333  PMID: 23403042
older adults; obesity; weight loss; lifestyle intervention; weight maintenance

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