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1.  Cytomegalovirus is associated with reduced telomerase activity in the Whitehall II cohort 
Experimental gerontology  2013;48(4):385-390.
Telomere length and telomerase activity have received increased attention as markers of cellular aging, but the determinants of inter-individual variation in these markers are incompletely understood. Cytomegalovirus (CMV) infection may be particularly important for telomere and telomerase dynamics due to its dramatic impact on peripheral blood lymphocyte composition, i.e., increasing the number and proportions of highly differentiated T cells that are characterized by shorter telomere length (TL) and lowered telomerase activity (TA). However, the possible relationship between CMV infection and leukocyte TL and TA has not been well-examined in vivo. This study examined the associations of CMV seropositivity and CMV IgG antibodies with leukocyte (TL) and (TA) in a sample of 434 healthy individuals (ages 53–76) from the Whitehall II cohort. Positive CMV serostatus was significantly associated with lower TA among women, and higher CMV IgG antibody levels were associated with lower TA in the overall sample. However, neither CMV seropositivity nor CMV IgG antibody levels (reflecting subclinical reactivation) among the seropositive were significantly associated with TL. These associations were robust to adjustment for age, employment grade, BMI, and smoking status. The results demonstrate that CMV seropositivity and subclinical reactivation predict lower TA. Future longitudinal studies should test whether the association of CMV with lower TA contributes to accelerated telomere shortening over time.
doi:10.1016/j.exger.2013.01.016
PMCID: PMC3626117  PMID: 23403382
telomeres; telomerase; cytomegalovirus; infections; Whitehall II
2.  Neuromuscular determinants of maximum walking speed in well-functioning older adults 
Experimental gerontology  2013;48(3):358-363.
Maximum walking speed may offer an advantage over usual walking speed for clinical assessment of age-related declines in mobility function that are due to neuromuscular impairment. The objective of this study was to determine the extent to which maximum walking speed is affected by neuromuscular function of the lower extremities in older adults. We recruited two groups of healthy, well functioning older adults who differed primarily on maximum walking speed. We hypothesized that individuals with slower maximum walking speed would exhibit reduced lower extremity muscle size and impaired plantarflexion force production and neuromuscular activation during a rapid contraction of the triceps surae muscle group (soleus (SO) and gastrocnemius (MG)).
All participants were required to have usual 10-meter walking speed >1.0 m/s. If the difference between usual and maximum 10m walking speed was < 0.6 m/s, the individual was assigned to the “Slower” group (n=8). If the difference between usual and maximum 10-meter walking speed was > 0.6 m/s, the individual was assigned to the “Faster” group (n=12). Peak rate of force development (RFD) and rate of neuromuscular activation (rate of EMG rise) of the triceps surae muscle group were assessed during a rapid plantarflexion movement. Muscle cross sectional area of the right triceps surae, quadriceps and hamstrings muscle groups was determined by magnetic resonance imaging.
Across participants, the difference between usual and maximal walking speed was predominantly dictated by maximum walking speed (r=.85). We therefore report maximum walking speed (1.76 and 2.17 m/s in Slower and Faster, p<.001) rather than the difference between usual and maximal. Plantarflexion RFD was 38% lower (p=.002) in Slower compared to Faster. MG rate of EMG rise was 34% lower (p=.01) in Slower than Faster, but SO rate of EMG rise did not differ between groups (p=.73). Contrary to our hypothesis, muscle CSA was not lower in Slower than Faster for the muscle groups tested, which included triceps surae (p=.44), quadriceps (p=.76) and hamstrings (p=.98). MG rate of EMG rise was positively associated with RFD and maximum 10m walking speed, but not usual 10m walking speed.
These findings support the conclusion that maximum walking speed is limited by impaired neuromuscular force and activation of the triceps surae muscle group. Future research should further evaluate the utility of maximum walking speed for use in clinical assessment to detect and monitor age-related functional decline.
doi:10.1016/j.exger.2013.01.010
PMCID: PMC3594593  PMID: 23376102
aging; walking; mobility; muscle; electromyography
3.  A Myostatin Inhibitor (Propeptide-Fc) Increases Muscle Mass and Muscle Fiber Size in Aged Mice but Does not Increase Bone Density or Bone Strength 
Experimental gerontology  2013;48(9):898-904.
Loss of muscle and bone mass with age are significant contributors to falls and fractures among the elderly. Myostatin deficiency is associated with increased muscle mass in mice, dogs, cows, sheep and humans, and mice lacking myostatin have been observed to show increased bone density in the limb, spine, and jaw. Transgenic overexpression of myostatin propeptide, which binds to and inhibits the active myostatin ligand, also increases muscle mass and bone density in mice. We therefore sought to test the hypothesis that in vivo inhibition of myostatin using an injectable myostatin propeptide (GDF8 propeptide-Fc) would increase both muscle mass and bone density in aged (24 mo) mice. Mice were injected weekly (20 mg/kg body weight) with recombinant myostatin propeptide-Fc (PRO) or vehicle (VEH; saline) for four weeks. There was no difference in body weight between the two groups at the end of the treatment period, but PRO treatment significantly increased mass of the tibialis anterior muscle (+7%) and increased muscle fiber diameter of the extensor digitorum longus (+16%) and soleus (+6%) muscles compared to VEH treatment. Bone volume relative to total volume (BV/TV) of the femur calculated by microCT did not differ significantly between PRO- and VEH-treated mice, and ultimate force (Fu), stiffness (S), toughness (U) measured from three-point bending tests also did not differ significantly between groups. Histomorphometric assays also revealed no differences in bone formation or resorption in response to PRO treatment. These data suggest that while developmental perturbation of myostatin signaling through either gene knockout or transgenic inhibition may alter both muscle and bone mass in mice, pharmacological inhibition of myostatin in aged mice has a more pronounced effect on skeletal muscle than on bone.
doi:10.1016/j.exger.2013.06.004
PMCID: PMC3930487  PMID: 23832079
sarcopenia; osteoporosis; fractures; anabolic therapy
4.  High serum Cu and Cu/Zn ratios correlate with impairments in bone density, physical performance and overall health in a population of elderly men with frailty characteristics 
Experimental gerontology  2012;47(7):491-496.
Serum Cu levels rise with age and high Cu/Zn ratios are linked with multiple-cause mortality in the elderly. The relationships of these parameters to measures of musculoskeletal health and frailty have not yet been analyzed. We used inductively coupled mass spectrometry to assess serum levels of Cu and Zn and probed for relationships between serum Cu levels and the Cu/Zn ratio with specific measures of bone, physical and overall health in a cohort of 144 frail elderly men. Subjects were divided into quintiles based on serum metal levels and comparisons for functional measures were made between the reference (middle) group and the low and high groups. Subjects’ serum metal values were normally distributed. We found significant correlations between high Cu/Zn ratios and deficits in femoral bone mineral density, measures of speed and strength, muscle mass and hematocrit. High Cu/Zn ratios were also correlated with decreased triglycerides and increased reliance on ADL assistance. This study identifies specific deficits associated with high Cu/Zn ratios that span multiple organ systems and supports earlier studies indicating that serum Cu levels and the Cu/Zn ratio may serve as useful predictive biomarkers for poor health in the elderly.
doi:10.1016/j.exger.2012.03.014
PMCID: PMC3928553  PMID: 22484083
Copper; Zinc; Bone Mineral Density; Muscle Strength; ADL; Hematocrit
5.  Fasting or caloric restriction for Healthy Aging 
Experimental gerontology  2013;48(10):1003-1005.
Aging is associated with a host of biological changes that contribute to a progressive decline in cognitive and physical function, ultimately leading to a loss of independence, and increased risk of mortality. To date, prolonged caloric restriction (i.e., a reduction in caloric intake without malnutrition) is the only non-genetic intervention that has consistently been found to extend both mean and maximal life span across a variety of species. Most individuals have difficulty sustaining prolonged caloric restriction, which has led to a search for alternative approaches that can produce similar to benefits as caloric restriction. A growing body of evidence indicates that fasting periods and intermittent fasting regimens in particular can trigger similar biological pathways as caloric restriction. For this reason, there is increasing scientific interest in further exploring the biological and metabolic effects of intermittent fasting periods, as well as whether long-term compliance may be improved by this type of dietary approach. This special will highlight the latest scientific findings related to the effects of both caloric restriction and intermittent fasting across various species including yeast, fruit flies, worms, rodents, primates, and humans. A specific emphasis is placed on translational research with findings from basic bench to bedside reviewed and practical clinical implications discussed.
doi:10.1016/j.exger.2013.04.011
PMCID: PMC3919445  PMID: 23639403
6.  EPINEPHRINE AND GLUCOSE MODULATE TRAINING-RELATED CREB PHOSPHORYLATION IN OLD RATS: RELATIONSHIPS TO AGE-RELATED MEMORY IMPAIRMENTS 
Experimental gerontology  2012;48(2):115-127.
Epinephrine enhances memory in young adult rats, in part, by increasing blood glucose levels needed to modulate memory. In old rats, epinephrine is deficient at raising blood glucose levels and thus is only moderately effective at enhancing memory. In contrast, systemic glucose injections improve memory in old rats, with resulting memory performance equal to that of young rats. The diminished response of glucose to training in old rats may blunt downstream neurochemical and molecular mechanisms needed to upregulate memory processes. In the first experiment, young adult and old rats were trained on an inhibitory avoidance task with immediate post-training injections of aCSF or glucose into the dorsal hippocampus. Old rats had significant memory impairments compared to young rats 7 days after training. Intrahippocampal injections of glucose reversed age-related deficits, improving memory scores in old rats to values seen in young rats. A second experiment examined age-related changes in activation of the transcription factor CREB, which is widely implicated in memory formation and may act downstream of hormonal and metabolic signals. Activation was assessed in response to training with systemic injections of epinephrine and glucose at doses known to enhance memory. Young adult and old rats were trained on inhibitory avoidance with immediate post-training systemic injections of saline, epinephrine, or glucose. After training, old rats had significant impairments in CREB phosphorylation in area CA1 and the dentate gyrus region of the hippocampus, and in the basolateral and lateral amygdala. Epinephrine and glucose attenuated age-related deficits in CREB phosphorylation, but were more effective in the amygdala and hippocampus, respectively. Together, these results support the view that age-related changes in blood glucose responses to epinephrine contribute to memory impairments, which may be related to alterations in regional patterns of CREB phosphorylation.
doi:10.1016/j.exger.2012.11.010
PMCID: PMC3557608  PMID: 23201424
Epinephrine; glucose; CREB; memory; aging; hippocampus
7.  Fatigability and Recovery of Arm Muscles with Advanced Age for Dynamic and Isometric Contractions 
Experimental gerontology  2012;48(2):259-268.
This study determined whether age-related mechanisms can increase fatigue of arm muscles during maximal velocity dynamic contractions, as occurs in the lower limb. We compared elbow flexor fatigue of young (n=10, 20.8 ± 2.7 years) and old men (n=16, 73.8 ± 6.1 years) during and in recovery from a dynamic and an isometric postural fatiguing task. Each task was maintained until failure while supporting a load equivalent to 20% of maximal voluntary isometric contraction (MVIC) torque. Transcranial magnetic stimulation (TMS) was used to assess supraspinal fatigue (superimposed twitch, SIT) and muscle relaxation. Time to failure was longer for old men than young for the isometric task (9.5±3.1 vs. 17.2±7.0 min, P=0.01) but similar for the dynamic task (6.3±2.4 min vs. 6.0±2.0 min, P = 0.73). Initial peak rate of relaxation was slower for the old men than young, and associated with a longer time to failure for both tasks (P<0.05). Low initial power during elbow flexion was associated with the greatest difference (reduction) in time to failure between the isometric task and dynamic task (r =−0.54, P=0.015). SIT declined after both fatigue tasks similarly with age, although recovery of SIT was associated with MVIC recovery for the old (both sessions) but not the young. Biceps brachii and brachioradialis EMG activity (%MVIC) of old men were greater than young during the dynamic fatiguing task (P<0.05), but similar during the isometric task. Muscular mechanisms and greater relative muscle activity (EMG activity) explain the greater fatigue during dynamic task for the old men compared with young in elbow flexor muscles. Recovery of MVC torque however relies more on recovery of supraspinal fatigue among older men than the young men.
doi:10.1016/j.exger.2012.10.006
PMCID: PMC3557758  PMID: 23103238
time to task failure; muscle fatigue; peripheral fatigue; supraspinal fatigue; aging
8.  Curcumin Ameliorates Arterial Dysfunction and Oxidative Stress with Aging 
Experimental gerontology  2012;48(2):269-276.
We tested the hypothesis that curcumin supplementation would reverse arterial dysfunction and vascular oxidative stress with aging. Young (Y, 4–6 mo) and old (O, 26–28 mo) male C57BL6/N mice were given normal or curcumin supplemented (0.2%) chow for 4 weeks (n = 5–10/group/measure). Large elastic artery stiffness, assessed by aortic pulse wave velocity (aPWV), was greater in O (448 ± 15 vs. 349 ± 15 cm/s) and associated with greater collagen I and advanced glycation end-products and less elastin (all P < 0.05). In O, curcumin restored aPWV (386 ± 15 cm/s), collagen I and AGEs to levels not different vs. Y. Ex vivo carotid artery acetylcholine (ACh)-induced endothelial-dependent dilation (EDD, 79 ± 3 vs. 94 ± 2%), nitric oxide (NO) bioavailability and protein expression of endothelial NO synthase (eNOS) were lower in O (all P < 0.05). In O, curcumin restored NO-mediated EDD (92 ± 2%) to levels of Y. Acute ex vivo administration of the superoxide dismutase (SOD) mimetic TEMPOL normalized EDD in O control mice (93 ± 3%), but had no effect in Y control or O curcumin treated animals. O had greater arterial nitrotyrosine abundance, superoxide production and NADPH oxidase p67 subunit expression, and lower manganese SOD (all P < 0.05), all of which were reversed with curcumin. Curcumin had no effects on Y. Curcumin supplementation ameliorates age-associated large elastic artery stiffening, NO-mediated vascular endothelial dysfunction, oxidative stress and increases in collagen and AGEs in mice. Curcumin may be a novel therapy for treating arterial aging in humans.
doi:10.1016/j.exger.2012.10.008
PMCID: PMC3557759  PMID: 23142245
AGEs; arterial stiffness; endothelial function; collagen
9.  Effects of the activin A-myostatin-follistatin system on aging bone and muscle progenitor cells 
Experimental gerontology  2012;48(2):290-297.
The activin A-myostatin-follistatin system is thought to play an important role in the regulation of muscle and bone mass throughout growth, development, and aging; however, the effects of these ligands on progenitor cell proliferation and differentiation in muscle and bone are not well understood. In addition, age-associated changes in the relative expression of these factors in musculoskeletal tissues have not been described. We therefore examined changes in protein levels of activin A, follistatin, and myostatin (GDF-8) in both muscle and bone with age in C57BL6 mice using ELISA. We then investigated the effects of activin A, myostatin and follistatin on the proliferation and differentiation of primary myoblasts and mouse bone marrow stromal cells (BMSCs) in vitro. Myostatin levels and the myostatin:follistatin ratio increased with age in the primarily slow-twitch mouse soleus muscle, whereas the pattern was reversed with age in the fast-twitch extensor digitorum longus muscle. Myostatin levels and the myostatin: follistatin ratio increased significantly (+75%) in mouse bone marrow with age, as did activin A levels (+17%). Follistatin increased the proliferation of primary myoblasts from both young and aged mice, whereas myostatin increased proliferation of younger myoblasts but decreased proliferation of older myoblasts. Myostatin reduced proliferation of both young and aged BMSCs in a dose-dependent fashion, and activin A increased mineralization in both young and aged BMSCs. Together these data suggest that aging in mice is accompanied by changes in the expression of activin A and myostatin, as well as changes in the response of bone and muscle progenitor cells to these factors. Myostatin appears to play a particularly important role in the impaired proliferative capacity of muscle and bone progenitor cells from aged mice.
doi:10.1016/j.exger.2012.11.004
PMCID: PMC3678732  PMID: 23178301
sarcopenia; myoblasts; bone marrow stromal cells; proliferation; differentiation
10.  Chemical regulation of mid- and late-life longevities inDrosophila 
Experimental gerontology  2012;48(2):240-249.
We tested the effects of a Class I histone deacetylase inhibitor (HDAcI), sodium butyrate (NaBu), on the longevity of normal- and long-lived strains of Drosophila melanogaster. This HDAcI has mixed effects in the normal-lived Ra strain as it decreases mortality rates and increases longevity when administered in the transition or senescent spans, but decreases longevity when administered over the health span only or over the entire adult lifespan. Mostly deleterious effects are noted when administered by either method to the long-lived La strain. Thus “mid- to late-life” drugs may have different stage-specific effects on different genomes of a model organism. A different HDAcI (suberoylanilide hydroxamic acid, SAHA) administered to the normal-lived strain showed similar late-life extending effects, suggesting that this is not an isolated effect of one drug. These data also show that the use of an HDAcI can significantly alter the mortality rate of the senescent span by decreasing its vulnerability, or short-term risk of death, in a manner similar to that of dietary restriction. These studies may help to shed light on the frailty syndrome affecting some aging organisms.
doi:10.1016/j.exger.2012.09.006
PMCID: PMC3899347  PMID: 23044027
Sodium butyrate; SAHA; HDAc inhibitors; Longevity regulation; Drosophila; Stage-specific drug sensitivity; Healthy senescence
11.  Translating Advances from the Basic Biology of Aging into Clinical Application 
Experimental gerontology  2012;48(1):1-5.
Recently, lifespan and healthspan have been extended in experimental animals using interventions that are potentially translatable into humans. A great deal of thought and work are needed beyond the usual steps in drug development to advance these findings into clinical application. Realistic pre-clinical and clinical trials paradigms need to be devised. Focusing on subjects with symptoms of age-related diseases or frailty or who are at imminent risk of developing these problems, measuring effects on short-term, clinically relevant outcomes, as opposed to long-term outcomes such as healthspan or lifespan, and developing biomarkers and outcome measures acceptable to regulatory agencies will be important. Research funding is a major roadblock, as is lack of investigators with combined expertise in the basic biology of aging, clinical geriatrics, and conducting investigational new drug clinical trials. Options are reviewed for developing a path from the bench to the bedside for interventions that target fundamental aging processes.
doi:10.1016/j.exger.2012.11.014
PMCID: PMC3543864  PMID: 23237984
Aging; Cellular Senescence; Translation
12.  Enteric-delivered rapamycin enhances resistance of aged mice to pneumococcal pneumonia through reduced cellular senescence 
Experimental gerontology  2012;47(12):958-965.
Rapamycin, a potent immunomodulatory drug, has shown promise in the amelioration of numerous age-associated diseases including cancer, Alzheimer’s disease and cardiac hypertrophy. Yet the elderly, the population most likely to receive therapeutic rapamycin, are already at increased risk for infectious disease; thus concern exists that rapamycin may exacerbate age-associated immune dysfunctions and worsen infection outcomes. Herein, we examined the impact of enteric delivered rapamycin monotherapy (eRapa) on susceptibility of aged (22–24 month) C57BL/6 mice to Streptococcus pneumoniae, the leading bacterial cause of community-acquired pneumonia. Following challenge with S. pneumoniae, administration of eRapa conferred modest protection against mortality. Reduced mortality was the result of diminished lung damage rather than reduced bacterial burden. eRapa had no effect on basal levels of Interleukin (IL)-1α, IL-6, IL-10, IL-12p70, KC, Interferon-γ, Tumor necrosis factor α and Monocyte chemotactic protein-1 in whole lung homogenates or during pneumococcal pneumonia. Previously we have demonstrated that cellular senescence enhances permissiveness for bacterial pneumonia through increased expression of the bacterial ligands Laminin receptor (LR), Platelet-activating factor receptor (PAFr) and Cytokeratin 10 (K10). These proteins are co-opted by S. pneumoniae and other respiratory tract pathogens for host cell attachment during lung infection. UM-HET3 mice on eRapa had reduced lung cellular senescence as determined by levels of the senescence markers p21 and pRB, but not mH2A.1. Mice on eRapa also had marked reductions in PAFr, LR, and K10. We conclude that eRapa protected aged mice against pneumonia through reduced lung cellular senescence, which in turn, lowered bacterial ligand expression.
doi:10.1016/j.exger.2012.08.013
PMCID: PMC3490008  PMID: 22981852
aging; rapamycin; pneumonia; cellular senescence; Streptococcus pneumoniae
13.  The pervasiveness of interleukin-1 in Alzheimer pathogenesis: a role for specific polymorphisms in disease risk 
Experimental gerontology  2000;35(4):481-487.
Interleukin-1 (IL-1) has been implicated as a key molecule in Alzheimer pathogenesis based on findings of an IL-1 overexpression in Alzheimer brain that is directly related to plaque progression and tangle formation, and on findings that IL-1 induces excessive synthesis, translation, and processing of neuronal β-amyloid precursor protein (βAPP) as well as synthesis of most known plaque-associated proteins. In addition, IL-1 activates astrocytes, with the important consequence of over-expression of the neuritogenic cytokine S100β and overgrowth of dystrophic neurites in neuritic plaques. As further evidence of the importance of IL-1 in Alzheimer pathogenesis, two new genetic studies of inheritance of specific polymorphisms in IL-1 genes in Alzheimer and control patients show that homozygosity for a specific IL-1A gene polymorphism at least triples risk for development of Alzheimer’s disease. This increase is associated with earlier age of onset. Homozygosity for this polymorphism plus another in the IL-1B gene further increases risk.
PMCID: PMC3833595  PMID: 10959036
Alzheimer’s disease; Interleukin-1; Genetic risk; Immunogenetics
14.  Vascular dementia: different forms of vessel disorders contribute to the development of dementia in the elderly brain 
Experimental gerontology  2012;47(11):816-824.
The diagnosis of vascular dementia (VaD) describes a group of various vessel disorders with different types of vascular lesions that finally contribute to the development of dementia. Most common forms of VaD in the elderly brain are subcortical vascular encephalopathy, strategic infarct dementia, and the multi infarct encephalopathy. Hereditary forms of VaD are rare. Most common is the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Sporadic forms of VaD are caused by degenerative vessel disorders such as atherosclerosis, small vessel disease (SVD) including small vessel arteriosclerosis, arteriolosclerosis, and lipohyalinosis, and cerebral amyloid angiopathy (CAA). Less frequently inflammatory vessel disorders and tumor-associated vessel lesions (e.g. angiocentric T-cell or angiotropic large cell lymphoma) can cause symptoms of dementia. Here, we review and discuss the impact of vessel disorders to distinct vascular brain tissue lesions and to the development of dementia in elderly individuals. The impact of coexisting neurodegenerative pathology in the elderly brain to VaD as well as the correlation between SVD and CAA expansion in the brain parenchyma with that of Alzheimer’s disease (AD)-related pathology is highlighted. We conclude that “pure” VaD is rare and most frequently caused by infarctions. However, there is a significant contribution of vascular lesions and vessel pathology to the development of dementia that may go beyond tissue damage due to vascular lesions. Insufficient blood blow and alterations of the perivascular drainage mechanisms of the brain may also lead to a reduced protein clearance from extracellular space and subsequent increase of proteins in the brain parenchyma, such as the amyloid β-protein, and foster, thereby, the development of AD-related neurodegeneration. As such, it seems to be important for clinical practice to consider treatment of potentially coexisting AD pathology in cognitively impaired patients with vascular lesions.
doi:10.1016/j.exger.2012.05.023
PMCID: PMC3470831  PMID: 22705146
Atherosclerosis; small vessel disease; cerebral amyloid angiopathy; dementia; neurodegeneration; perivascular drainage
15.  Cerebral amyloid angiopathy impact on endothelium 
Experimental gerontology  2012;47(11):838-842.
Cerebral amyloid angiopathy (CAA) is an age-associated disease characterized by amyloid deposition in cerebral and meningeal vessel walls. CAA is detected in the majority of the individuals with dementia and also in a large number of non-demented elderly individuals. In addition, CAA is strongly associated with Alzheimer’s disease (AD) pathology. Mechanical consequences including intra-cerebral or subarachnoid hemorrhage remains CAA most feared complication, but only a small fraction of CAA results in severe bleeding. On the hand the non-mechanical consequences in cerebrovascular regulation are prevalent and may be even more deleterious. Studies of animal models have provided strong evidence linking the vasoactive Aβ 1–40, the main species found in CAA, to disturbances in endothelial-dependent factors, disrupting cerebrovascular regulation Here, we aimed to review experimental findings regarding the non-mechanical consequences of CAA for cerebrovascular regulation and discuss the implications of these results to clinical practice.
doi:10.1016/j.exger.2012.08.005
PMCID: PMC3500138  PMID: 22944481
amyloid; angiopathy; dementia; Alzheimer’s disease; animal models; endothelium; cerebrovascular dysfunction; blood brain barrier
16.  Effects of exercise on circadian rhythms and mobility in aging Drosophila melanogaster 
Experimental gerontology  2013;48(11):1260-1265.
Daily life functions such as sleep and feeding oscillate with circa 24 h period due to endogenous circadian rhythms generated by circadian clocks. Genetic or environmental disruption of circadian rhythms is associated with various aging-related phenotypes. Circadian rhythms decay during normal aging, and there is a need to explore strategies that could avert age-related changes in the circadian system. Exercise was reported to delay aging in mammals. Here, we investigated whether daily exercise via stimulation of upward climbing movement could improve circadian rest/activity rhythms in aging Drosophila melanogaster. We found that repeated exercise regimen did not strengthen circadian locomotor activity rhythms in aging flies and had no effect on their lifespan. We also tested the effects of exercise on mobility and determined that regular exercise lowered age-specific climbing ability in both wild type and clock mutant flies. Interestingly, the climbing ability was most significantly reduced in flies carrying a null mutation in the core clock gene period, while rescue of this gene significantly improved climbing to wild type levels. Our work highlights the importance of period in sustaining endurance in aging flies exposed to physical challenge.
doi:10.1016/j.exger.2013.07.013
PMCID: PMC3798010  PMID: 23916842
Circadian clock; exercise; endurance; aging
17.  The nurse’s load: early-life exposure to brood-rearing affects behavior and lifespan in honey bees (Apis mellifera) 
Experimental gerontology  2009;44(0):467-471.
Long-lived honey bees (Apis mellifera) develop in fall. This pattern may be explained by reduced nurse loads. When the amount of brood in colonies declines as a function of adverse foraging conditions, adult bees build up surplus nutrient stores that include vitellogenin, a behavioral affector protein that also can increase lifespan. Although the seasonal reduction in exposure to nursing tasks predictably results in vitellogenin accumulation, the assumption that long-lived adults thereby develop is confounded by a concomitant decline in foraging effort. Foraging activity reduces lifespan, and is influenced by colony resource consumption, brood pheromones, availability of nectar and pollen, and weather. Here, we perform the first controlled experiment where the nursing environment of pre-foraging sister bees was set to vary, while their foraging environment later was set to be the same. We measure vitellogenin, age at foraging onset and lifespan. We establish that reduced brood-rearing increases vitellogenin levels, and delays foraging onset and death. Longevity is largely explained by the effect of nursing on the onset of foraging behavior, but is also influenced by the level of brood-rearing independent of behavioral change. Our findings are consistent with the roles of vitellogenin in regulation of honey bee behavior and lifespan.
doi:10.1016/j.exger.2009.02.013
PMCID: PMC3798062  PMID: 19264121
18.  The Evolution of Transfers and Life Histories 
Experimental gerontology  2012;47(10):803-806.
Much of life history theory analyzes life histories of independent, isolated individuals, who grow, forage, reproduce, and die. However, in many species social interactions such as food sharing are a key part of the life history strategy, altering the energetic budget constraint. Transfers and sharing raise reproductive success and also alter the fitness impact of other aspects of the life history. We discuss a variety of traits and behaviors for which transfers are important, synthesizing results from a number of earlier papers. Topics include the U-shaped mortality curve, post reproductive survival, causes of early life mortality decline, why intergenerational transfers evolve and co-evolve with longevity, time preference, sexual dimorphism and sexual differences in transfers, menopause, demographic advantages of social sharing, and consequences of social sharing for life history evolution.
doi:10.1016/j.exger.2012.06.004
PMCID: PMC3436974  PMID: 22750486
transfers; intergenerational; menopause; mortality; sexual dimorphism; life history
19.  Age, growth and size interact with stress to determine life span and mortality 
Experimental gerontology  2012;47(10):782-786.
Individuals in a large experimental field population, of the short-lived perennial species Plantago lanceolata, were followed to determine the sources of variation that influence mortality and life span. The design included multiple age groups with initially similar genetic structure, which made it possible to separate age effects from period effects and to identify the genetic component to variation in life span. During a period of stress, individuals of all ages showed parallel increases in mortality but different cohorts experienced this period of high mortality at different ages. This then influenced the distribution of life spans across cohorts. Age and size-age interactions influenced mortality during the period of stress. Smaller individuals died but only if they were old. Additionally, growth and age interacted with stress such that older individuals had negative growth and high mortality whereas younger individuals had positive growth and relatively lower mortality during stress. The results of this study show that it is not simply the environment that can have a major impact on demography in natural populations, rather, age, size and growth can interact with the environment to influence mortality and life span when the environment is stressful.
doi:10.1016/j.exger.2012.05.020
PMCID: PMC3436992  PMID: 22664575
Demography; natural population; life history; condition-dependent aging; plant senescence
20.  From the womb to the tomb: the role of transfers in shaping the evolved human life history 
Experimental gerontology  2012;47(10):807-813.
Humans are the longest living and slowest growing of all primates. Although most primates are social, humans are highly cooperative and social in ways that likely co-evolved with the slow human life history. In this paper we highlight the role of resource transfers and non-material assistance within and across generations in shaping low human mortality rates. The use of complex cooperative strategies to minimize risk is a necessary precursor for selecting further reductions in mortality rate in late adulthood. In conjunction with changes in the age-profile of production, the impacts of resource transfers and other forms of cooperation on reducing mortality likely played an important role in selection on post-reproductive lifespan throughout human evolution. Using medical data and ethnographic interviews, we explore several types of common risks experienced by Tsimane forager-horticulturalists, and quantify the types and targets of aid. Our results illustrate the importance of transfers in several key domains and suggest that the absence of transfers would greatly increase human mortality rates throughout the life course.
doi:10.1016/j.exger.2012.05.006
PMCID: PMC3437008  PMID: 22595699
intergenerational transfers; sharing; life history evolution; longevity; Tsimane
21.  Fertility/longevity trade offs under limiting-male conditions in mating populations of Caenorhabditis elegans 
Experimental gerontology  2012;47(10):759-763.
Evolutionary theories of aging suggest that trade-offs between longevity and fitness should be found under certain conditions. In C. elegans, there is little evidence for the existence of such tradeoffs. We asked if fertility/longevity trade-offs exist in populations of randomly mating males and hermaphrodites. We set up a large population of young males and 5-day-old hermaphrodites that were no longer self-fertile. We then allowed them to mate for one day with an equal number young males and then separated hermaphrodites to individual plates and determined daily fertility of individual hermaphrodites. There was a significant negative relationship between late-life fertility and individual longevity.
doi:10.1016/j.exger.2012.06.010
PMCID: PMC3437009  PMID: 22771817
Genetics; Nematodes; Fertility; Demography; Longevity; Evolutionary Theory; Antagonistic Pleiotropy
22.  Trading Stages: Life Expectancies in Structured Populations 
Experimental gerontology  2012;47(10):773-781.
Interest in stage-and age structured models has recently increased because they can describe quantitative traits such as size that are left out of age-only demography. Available methods for the analysis of effects of vital rates on lifespan in stage-structured models have not been widely applied because they are hard to use and interpret, and tools for age and stage structured populations are missing. We present easily interpretable expressions for the sensitivities and elasticities of life expectancy to vital rates in age-stage models, and illustrate their application with two biological examples. Much of our approach relies on trading of time and mortality risk in one stage for time and risk in others. Our approach contributes to the new framework of the study of age- and stage-structured biodemography.
doi:10.1016/j.exger.2012.05.015
PMCID: PMC3437015  PMID: 22664576
Mulit-state models; age-stage structure; survival; markov chain process; life history evolution; perturbation analysis
23.  The specific contributions of force and velocity to muscle power in older adults 
Experimental gerontology  2012;47(8):608-613.
The purpose of this study is to examine the relative importance of the force-based and velocity-based measures of muscle performance to explain inter-individual differences in power production capability and functional task performance. Participants included seventy-nine men and women: middle-aged healthy adults (MH: 40–55 years), older healthy adults (OH: 70–85 years), and older adults with mobility limitations (OML: 70–85 years). Muscle power at 180°/s, isometric maximal torque, and maximal contraction velocity at 40% 1RM were measured during unilateral leg extension. The Short Physical Performance Battery (SPPB) was used to differentiate between healthy and mobility limited older adults. Functional task performance was assessed using multiple chair rise and stair climb tests. Leg extensor force (torque), but not maximal contraction velocity, was significantly associated with muscle power in MH. Both torque and velocity were significantly associated with muscle power in OH. Maximal velocity, but not torque, was associated with power in OML. Maximal velocity demonstrated an association with multiple chair rise time and stair climb time in OML, but not MH or OH. It is concluded that movement velocity is an increasingly important determinant of maximal power output with advancing age. Furthermore, movement velocity is also a critical component of functional task performance with aging and may contribute to functional deficits. These findings help to explain why the rate-dependent variable power has emerged as a critical component of both assessment and rehabilitation of muscular performance and physical function in older adults.
doi:10.1016/j.exger.2012.05.010
PMCID: PMC3778449  PMID: 22626972
Power; Velocity; Strength; Aging; Function
24.  Aging increases mitochondrial DNA damage and oxidative stress in liver of rhesus monkeys 
Experimental gerontology  2011;47(1):29-37.
While the mechanisms of cellular aging remain controversial, a leading hypothesis is that mitochondrial oxidative stress and mitochondrial dysfunction play a critical role in this process. Here, we provide data in aging rhesus macaques supporting the hypothesis that increased oxidative stress is a major characteristic of aging and may be responsible for the age-associated increase in mitochondrial dysfunction. We measured mitochondrial DNA (mtDNA) damage by quantitative PCR in liver and peripheral blood mononuclear cells of young, middle age, and old monkeys and show that older monkeys have increases in the number of mtDNA lesions. There was a direct correlation between the amount of mtDNA lesions and age, supporting the role of mtDNA damage in the process of aging. Liver from older monkeys showed significant increases in lipid peroxidation, protein carbonylations and reduced antioxidant enzyme activity. Similarly, peripheral blood mononuclear cells from the middle age group showed increased levels in carbonylated proteins, indicative of high levels of oxidative stress. Together, these results suggest that the aging process is associated with defective mitochondria, where increased production of reactive oxygen species results in extensive damage at the mtDNA and protein levels. This study provides valuable data based on the rhesus macaque model further validating age-related mitochondrial functional decline with increasing age and suggesting that mtDNA damage might be a good biomarker of aging.
doi:10.1016/j.exger.2011.10.002
PMCID: PMC3770191  PMID: 22027539
mitochondrial DNA; aging; mitochondria; antioxidant enzymes; rhesus monkey; liver
25.  The Effects of Pre-habilitative Conditioning on Unloading-induced Adaptations in Young and Aged Neuromuscular Systems 
Experimental gerontology  2012;47(9):687-694.
The capacity of pre-habilitative conditioning – exercise performed a priori – to mitigate neuromuscular maladaptations to disuse is unclear. This study evaluated pre-habilitation by examining neuromuscular junctions (NMJs) and the myofibers they innervate in young adult and aged muscles. Within each age category, 40 rats were divided into four treatment groups: 1) Control, 2) hindlimb suspended (unloaded), 3) prehabilitative conditioning preceding hindlimb suspension, and 4) pre-habilitative conditioning alone. Cytofluorsecent staining was used to visualize NMJs, and histochemical staining to assess myofiber profiles (size and type). Statistical analysis featured 2-way ANOVA with main effects for age and treatment, along with interaction. NMJs consistently revealed significant (P ≤ 0.05) main effects for age, but not treatment, or interaction. Typically, aged NMJs showed elongated nerve terminal branching, and more dispersed post-synaptic clusters of ACh receptors, resulting in reduced post-synaptic area per given length of pre-synaptic branching. Analysis of myofiber profiles showed significant main effects for age, treatment, and their interaction. Aged myofibers were smaller than young ones and a higher percentage of them were Type I. Aged fibers experienced significantly greater unloading-induced atrophy than young ones. Pre-habilitative conditioning significantly attenuated unloading-induced atrophy among aged, but not young myofibers. It was also observed that pre-habilitative conditioning alone increased myofiber size among aged, but not young adult muscles. In summary, myofibers were more sensitive than NMJs to the treatment interventions implemented. Although more sensitive to the negative effects of muscle unloading, aged myofibers were also more responsive to the hypertrophic effects of pre-habilitative conditioning.
doi:10.1016/j.exger.2012.06.005
PMCID: PMC3418459  PMID: 22750484
myofiber; synapse; atrophy; disuse; old; unweighting

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