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1.  Remodelling of biological parameters during human ageing: evidence for complex regulation in longevity and in type 2 diabetes 
Age  2011;35(2):419-429.
Factor structure analyses have revealed the presence of specific biological system markers in healthy humans and diseases. However, this type of approach in very old persons and in type 2 diabetes (T2DM) is lacking. A total sample of 2,137 Italians consisted of two groups: 1,604 healthy and 533 with T2DM. Age (years) was categorized as adults (≤65), old (66–85), oldest old (>85–98) and centenarians (≥99). Specific biomarkers of routine haematological and biochemical testing were tested across each age group. Exploratory factorial analysis (EFA) by principal component method with Varimax rotation was used to identify factors including related variables. Structural equation modelling (SEM) was applied to confirm factor solutions for each age group. EFA and SEM identified specific factor structures according to age in both groups. An age-associated reduction of factor structure was observed from adults to oldest old in the healthy group (explained variance 60.4% vs 50.3%) and from adults to old in the T2DM group (explained variance 57.4% vs 44.2%). Centenarians showed three-factor structure similar to those of adults (explained variance 58.4%). The inflammatory component became the major factor in old group and was the first one in T2DM. SEM analysis in healthy subjects suggested that the glucose levels had an important role in the oldest old. Factorial structure change during healthy ageing was associated with a decrease in complexity but showed an increase in variability and inflammation. Structural relationship changes observed in healthy subjects appeared earlier in diabetic patients and later in centenarians.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9348-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-011-9348-8
PMCID: PMC3592946  PMID: 22174010
Ageing; Exploratory factor analysis; Structural equation modelling; Centenarians; Diabetic patients
2.  JAG1 and COL1A1 polymorphisms and haplotypes in relation to bone mineral density variations in postmenopausal Mexican-Mestizo Women 
Age  2011;35(2):471-478.
Osteoporosis is characterized by low bone mineral density (BMD). One of the most important factors that influence BMD is the genetic contribution. The collagen type 1 alpha 1 (COL1A1) and the JAGGED (JAG1) have been investigated in relation to BMD. The aim of this study was to investigate the possible association between two single-nucleotide polymorphisms (SNPs) of COL1A1, their haplotypes, and one SNP of JAG1 with BMD in postmenopausal Mexican-Mestizo women. Seven hundred and fifty unrelated postmenopausal women were included. Risk factors were recorded and BMD was measured in lumbar spine, total hip, and femoral neck by dual-energy X-ray absorptiometry. DNA was obtained from blood leukocytes. Two SNPs in COL1A1 (rs1800012 and rs1107946) and one in JAG1 (rs2273061) were studied. Real-time PCR allelic discrimination was used for genotyping. The differences between the means of the BMDs according to genotype were analyzed with covariance. Deviations from Hardy–Weinberg equilibrium were tested. Pairwise linkage disequilibrium between single nucleotide polymorphisms was calculated by direct correlation r2, and haplotype analysis of COL1A1 was conducted. Under a dominant model, the rs1800012 polymorphism of the COL1A1 showed an association with BMD of the lumbar spine (P = 0.021). In addition, analysis of the haplotype of COL1A1 showed that the G–G haplotype presented a higher BMD in lumbar spine. We did not find an association between the s1107946 and rs2273061 polymorphisms of the COL1A1 and JAG1, respectively. Our results suggest that the rs1800012 polymorphism of the COL1A1, in addition to one haplotype, were significantly associated with BMD variation in Mexican-Mestizo postmenopausal women.
doi:10.1007/s11357-011-9363-9
PMCID: PMC3592947  PMID: 22174012
Bone mineral density; Polymorphisms; COL1A1; JAG1; Haplotypes; Postmenopausal Mexican-Mestizo women
3.  Genomics of human health and aging 
Age  2011;35(2):455-469.
Despite notable progress of the candidate-gene and genome-wide association studies (GWAS), understanding the role of genes contributing to human health and lifespan is still very limited. We use the Framingham Heart Study to elucidate if recognizing the role of evolution and systemic processes in an aging organism could advance such studies. We combine throughput methods of GWAS with more detail methods typical for candidate-gene analyses and show that both lifespan and ages at onset of CVD and cancer can be controlled by the same allelic variants. The risk allele carriers are at highly significant risk of premature death (e.g., RR = 2.9, p = 5.0 × 10−66), onset of CVD (e.g., RR = 1.6, p = 4.6 × 10−17), and onset of cancer (e.g., RR = 1.6, p = 1.5 × 10−6). The mechanism mediating the revealed genetic associations is likely associated with biological aging. These aging-related phenotypes are associated with a complex network which includes, in this study, 62 correlated SNPs even so these SNPs can be on non-homologous chromosomes. A striking result is three-fold, highly significant (p = 3.6 × 10−10) enrichment of non-synonymous SNPs (N = 27) in this network compared to the entire qualified set of the studied SNPs. Functional significance of this network is strengthened by involvement of genes for these SNPs in fundamental biological processes related to aging (e.g., response to stimuli, protein degradation, apoptosis) and by connections of these genes with neurological (20 genes) and cardio-vascular (nine genes) processes and tumorigenesis (10 genes). These results document challenging role of gene networks in regulating human health and aging and call for broadening focus on genomics of such phenotypes.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9362-x) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-011-9362-x
PMCID: PMC3592948  PMID: 22174011
Aging; Lifespan; Survival; Healthy aging; Gene networks
4.  Accelerated protein evolution analysis reveals genes and pathways associated with the evolution of mammalian longevity 
Age  2011;35(2):301-314.
The genetic basis of the large species differences in longevity and aging remains a mystery. Thanks to recent large-scale genome sequencing efforts, the genomes of multiple species have been sequenced and can be used for cross-species comparisons to study species divergence in longevity. By analyzing proteins under accelerated evolution in several mammalian lineages where maximum lifespan increased, we identified genes and processes that are candidate targets of selection when longevity evolves. We identified several proteins with longevity-specific selection patterns, including COL3A1 that has previously been related to aging and proteins related to DNA damage repair and response such as DDB1 and CAPNS1. Moreover, we found that processes such as lipid metabolism and cholesterol catabolism show such patterns of selection and suggest a link between the evolution of lipid metabolism, cholesterol catabolism, and the evolution of longevity. Lastly, we found evidence that the proteasome–ubiquitin system is under selection specific to lineages where longevity increased and suggest that its selection had a role in the evolution of longevity. These results provide evidence that natural selection acts on species when longevity evolves, give insights into adaptive genetic changes associated with the evolution of longevity in mammals, and provide evidence that at least some repair systems are selected for when longevity increases.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9361-y) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-011-9361-y
PMCID: PMC3592953  PMID: 22205409
Aging; Evolutionary genomics; Protein evolution; Mammals; Proteasome
5.  Troponin T nuclear localization and its role in aging skeletal muscle 
Age  2011;35(2):353-370.
Troponin T (TnT) is known to mediate the interaction between Tn complex and tropomyosin (Tm), which is essential for calcium-activated striated muscle contraction. This regulatory function takes place in the myoplasm, where TnT binds Tm. However, recent findings of troponin I and Tm nuclear translocation in Drosophila and mammalian cells imply other roles for the Tn–Tm complex. We hypothesized that TnT plays a nonclassical role through nuclear translocation. Immunoblotting with different antibodies targeting the NH2- or COOH-terminal region uncovered a pool of fast skeletal muscle TnT3 localized in the nuclear fraction of mouse skeletal muscle as either an intact or fragmented protein. Construction of TnT3–DsRed fusion proteins led to the further observation that TnT3 fragments are closely related to nucleolus and RNA polymerase activity, suggesting a role for TnT3 in regulating transcription. Functionally, overexpression of TnT3 fragments produced significant defects in nuclear shape and caused high levels of apoptosis. Interestingly, nuclear TnT3 and its fragments were highly regulated by aging, thus creating a possible link between the deleterious effects of TnT3 and sarcopenia. We propose that changes in nuclear TnT3 and its fragments cause the number of myonuclei to decrease with age, contributing to muscle damage and wasting.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9368-4) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-011-9368-4
PMCID: PMC3592954  PMID: 22189912
Troponin T; Nuclear localization; Skeletal muscle; Aging; Apoptosis; Nucleolus; RNA polymerase
6.  Angiotensin-converting enzyme inhibitors and incidence of mild cognitive impairment. The Italian Longitudinal Study on Aging 
Age  2011;35(2):441-453.
Midlife elevated blood pressure and hypertension contribute to the development of Alzheimer's disease (AD) and overall dementia. We sought to estimate whether angiotensin-converting enzyme inhibitors (ACE-Is) reduced the risk of developing mild cognitive impairment (MCI) in cognitively normal individuals. In the Italian Longitudinal Study on Aging, we evaluated 1,445 cognitively normal individuals treated for hypertension but without congestive heart failure from a population-based sample from eight Italian municipalities with a 3.5-year follow-up. MCI was diagnosed with current clinical criteria. Dementia, AD, and vascular dementia were diagnosed based on DSM-IIIR criteria, NINCDS–ADRDA criteria, and ICD-10 codes. Among 873 hypertension-treated cognitively normal subjects, there was no significant association between continuous exposure to all ACE-Is and risk of incident MCI compared with other antihypertensive drugs [hazard ratio (HR), 0.45, 95% confidence interval (CI), 0.16–1.28]. Captopril exposure alone did not significantly modify the risk of incident MCI (HR, 1.80, 95% CI, 0.39–8.37). However, the enalapril sub-group alone (HR, 0.17, 95% CI, 0.04 –0.84) or combined with the lisinopril sub-group (HR, 0.27, 95% CI, 0.08–0.96), another ACE-I structurally related to enalapril and with similar potency, were associated with a reduced risk of incident MCI. Study duration exposure to ACE-Is as a “class” was not associated with incident MCI in older hypertensive adults. However, within-class differences linked to different chemical structures and/or drug potencies may exist, with a possible effect of the enalapril and lisinopril sub-groups in reducing the risk of incident MCI.
doi:10.1007/s11357-011-9360-z
PMCID: PMC3592955  PMID: 22203459
Angiotensin-converting enzyme inhibitors; Mild cognitive impairment; Dementia; Antihypertensive drugs
7.  DHEA, DHEA-S and cortisol responses to acute exercise in older adults in relation to exercise training status and sex 
Age  2011;35(2):395-405.
The aim of the present study was to investigate resting measures of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEA-S) and cortisol, and the response and recovery of these hormones to acute exercise, in male and female older adults of different exercise training status. Participants were 49 community-dwelling older adults (23 females) aged between 60 and 77 years who were either sedentary (n = 14), moderately active (n = 14) or endurance trained (n = 21). Participants undertook an acute bout of exercise in the form of an incremental submaximal treadmill test. The exercise lasted on average 23 min 49 s (SD = 2 min 8 s) and participants reached 76.5% (SD = 5.44) of the predicted maximal heart rate. Blood samples were collected prior to exercise, immediately, and 1 h post-exercise. DHEA levels significantly increased immediately post-exercise; however, DHEA-S levels only significantly increased in females. Cortisol significantly decreased immediately post-exercise and 1 h post-exercise compared to pre-exercise. There were no significant differences in resting hormone levels or hormonal responses to exercise between training status groups. The findings suggest that exercise can stimulate DHEA production in older adults and that hormonal responses to exercise differ between male and female older adults.
doi:10.1007/s11357-011-9345-y
PMCID: PMC3592957  PMID: 22105939
DHEA; DHEA-S; Cortisol; Acute exercise; Training status; Sex; Older adults
8.  Effect of Bcl-2 rs956572 SNP on regional gray matter volumes and cognitive function in elderly males without dementia 
Age  2011;35(2):343-352.
The Bcl-2 gene is a major regulator of neural plasticity and cellular resilience. A single-nucleotide polymorphism (SNP) in the Bcl-2 gene, Bcl-2 rs956572, significantly modulates the expression of Bcl-2 protein and cellular vulnerability to apoptosis. This study investigated the association between the Bcl-2 rs956572 SNP and brain structural abnormalities in non-demented elders, and to test the relationship between neuropsychological performance and regional gray matter (GM) volumes. Our sample comprised 97 non-demented elderly men with a mean age of 80.6 ± 5.6 years (range, 65 to 92 years). Cognitive test results, magnetic resonance imaging, and genotyping of Bcl-2 rs956572 were examined for each subject. The differences in regional GM volumes between G homozygotes and A-allele carriers were tested using optimized voxel-based morphometry. Subjects with G homozygotes exhibited significantly worse performance in the language domain of the Cognitive Abilities Screening Instrument (CASI; p = 0.009). They also showed significantly smaller GM volumes in the right middle temporal gyrus (MTG) (BA 21), but larger GM volumes in the left precuneus (BA 31), right lingual gyrus (BA 18), and left superior occipital gyrus (BA 19) relative to A-allele carriers (p < 0.001). A trend toward a positive correlation between right MTG GM volumes and the language domain of CASI was also evident (r = 0.181; p = 0.081). The findings suggest that Bcl-2 rs956572 SNP may modulate cognitive function and regional GM volume in non-demented elderly men, and that this polymorphism may affect language performance through its effect on the right MTG.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9367-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-011-9367-5
PMCID: PMC3592959  PMID: 22198673
Bcl-2; MRI; Volumetry; Cognition; Aged; Polymorphism
9.  The use of honeybees reared in a thermostatic chamber for aging studies 
Age  2011;35(1):149-158.
Honeybees (Apis mellifera) are an attractive model system for studying aging. However, the aging level of worker honeybees from the field hive is in dispute. To eliminate the influence of task performance and confirm the relationship between chronological age and aging, we reared newly emerged workers in a thermostat at 34°C throughout their lives. A survivorship curve was obtained, indicating that workers can be reared away from the field hive, and the only difference between these workers is age. To confirm that these workers can be used for aging studies, we assayed age-related molecules in the trophocytes and fat cells of young and old workers. Old workers expressed more senescence-associated β-galactosidase, lipofuscin granules, lipid peroxidation, and protein oxidation than young workers. Furthermore, cellular energy metabolism molecules were also assayed. Old workers exhibited less ATP concentration, β-oxidation, and microtubule-associated protein light chain 3 (LC3) than young workers. These results demonstrate that honeybees reared in a thermostatic chamber can be used for aging studies and cellular energy metabolism in the trophocytes and fat cells of workers changes with advancing age.
doi:10.1007/s11357-011-9344-z
PMCID: PMC3543731  PMID: 22124884
Trophocyte; Fat cell; Aging; Age-related molecules; Cellular energy metabolism; Honeybee
10.  Fatigability as a function of physical activity energy expenditure in older adults 
Age  2011;35(1):179-187.
Increased fatigue is a predictor of morbidity and mortality in older adults. Fatigability defines a change in performance or self-reported fatigue in response to physical activity (PA). However, the relationship of fatigability to PA-related energy expenditure (PAEE) is unknown. Changes in performance, fatigue, and energy expenditure were measured simultaneously in 17 adults (11 females, 74–94 years old) performing eight standardized PA tasks with various energy expenditure requirements in a whole-room indirect calorimeter. Change in performance was objectively measured using a PA movement monitor and change in fatigue was self-reported on a seven-point scale for each task. Performance and perceived fatigability severity scores were calculated as a ratio of change in performance and fatigue, respectively, and PAEE. We found that change in both objective performance and self-reported fatigue were associated with energy expenditure (Spearman rho = −0.72 and −0.68, respectively, p < 0.001) on a task requiring relatively high level of energy expenditure. The performance and perceived fatigability severity scores were significantly correlated (rho = 0.77, p < 0.001) on this task. In summary, results of this proof of concept pilot study show that both perceived and performance fatigability severity scores are related to PAEE-induced fatigue on a task requiring relatively high level of energy expenditure. We conclude that fatigability severity is a valid measure of PAEE-induced fatigue in older adults.
doi:10.1007/s11357-011-9338-x
PMCID: PMC3543733  PMID: 22113348
Aging; Fatigue; Tiredness; Resting energy expenditure; Physical activity
11.  Genetic diversity contributes to abnormalities in pain behaviors between young and old rats 
Age  2011;35(1):1-10.
Aging has profound yet unpredictable effects on pain perception and incidence of anxiety disorders. However, the mechanisms underlying age-related pathologies are confounded by contradictory observations in rodent models. Therefore, the goal of our study was to test the hypothesis that genetic variability contributes to age-related pain behaviors and susceptibility to anxiety. To address this hypothesis, we examined pain and anxiety-like behavior in young or old Brown Norway (BN), Fisher 344, and BN/F344 (F1), three rat strains used in studies to evaluate the effect of aging. Mechanosensitive thresholds were assessed using the Von Frey assay, and visceral pain sensitivity was measured via the visceromotor response to colorectal distension. Anxiety-like behavior and exploration was quantified in the elevated plus maze. In the BN strain, old rats exhibited increased mechanosensitive thresholds compared to young rats; however, age did not affect visceral sensitivity in this strain. In F344-BN rats, the number of abdominal contractions induced by the highest colonic distension pressure was significantly lower in old rats. However, following colonic sensitization, a difference was no longer apparent. In the F-344 strain, visceral hypersensitivity following afferent sensitization was evident in young rats at all distension pressures but was not observed in older animals at 20 mmHg. Aging significantly reduced maze exploration across all strains. Our data demonstrate that age- and strain-related alterations exist in pain behavior and highlight the effects of aging on exploratory behavior. These findings suggest that strain differences contribute to the controversial data on the effects of aging on pain perception.
doi:10.1007/s11357-011-9323-4
PMCID: PMC3543734  PMID: 22095259
Genetic diversity; Strain differences; Visceral pain; Mechanosensitive thresholds; Anxiety; Aging
12.  Glial molecular alterations with mouse brain development and aging: up-regulation of the Kir4.1 and aquaporin-4 
Age  2011;35(1):59-67.
Glial cells, besides participating as passive supporting matrix, are also proposed to be involved in the optimization of the interstitial space for synaptic transmission by tight control of ionic and water homeostasis. In adult mouse brain, inwardly rectifying K+ (Kir4.1) and aquaporin-4 (AQP4) channels localize to astroglial endfeets in contact with brain microvessels and glutamate synapses, optimizing clearance of extracellular K+ and water from the synaptic layers. However, it is still unclear whether there is an age-dependent difference in the expressions of Kir4.1 and AQP4 channels specifically during postnatal development and aging when various marked changes occur in brain and if these changes region specific. RT-PCR and immunoblotting was conducted to compare the relative expression of Kir4.1 and AQP4 mRNA and protein in the early and mature postnatal (0-, 15-, 45-day), adult (20-week), and old age (70-week) mice cerebral and cerebellar cortices. Expressions of Kir4.1 and AQP4 mRNA and protein are very low at 0-day. A pronounced and continuous increase was observed by mature postnatal ages (15-, 45-days). However, in the 70-week-old mice, expressions are significantly up-regulated as compared to 20-week-old mice. Both genes follow the same age-related pattern in both cerebral and cerebellar cortices. The time course and expression pattern suggests that Kir4.1 and AQP4 channels may play an important role in brain K+ and water homeostasis in early postnatal weeks after birth and during aging.
doi:10.1007/s11357-011-9330-5
PMCID: PMC3543735  PMID: 22057895
Kir4.1; AQP4; Glia; Postnatal development; Aging; K+ and water homeostasis
13.  Androgen depletion in humans leads to cavernous tissue reorganization and upregulation of Sirt1–eNOS axis 
Age  2011;35(1):35-47.
Aging and physiological androgen decay leads to structural changes in corpus cavernosum (CC) that associate with erectile function impairment. There is evidence that such changes relate to nitric oxide (NO) bioavailability, an endothelial compound produced by the action of endothelial NO synthase (eNOS), and is regulated by sirtuin-1 (Sirt1), a NAD+-dependent protein deacetylase. Taking into account the reduced NO synthesis observed in aging and erectile dysfunction, we aimed to characterize human CC of androgen-deprived, young, and aged individuals postulating that androgen deprivation induces modifications similar to those observed in aging. Human penile fragments were collected from young individuals submitted to male-to-female sex reassignment procedure, who undergone an androgen deprivation chemical regimen, from young organ donors and from aged patients submitted to penile deviation surgery. They were processed for histomorphometric analysis of smooth muscle (SM) and connective tissues (CT), and dual-immunofluorescence of alpha-actin/vWf or Sirt1, and endothelin-1/eNOS. Estrogen receptors were analyzed by immunohistochemistry and semiquantification of Sirt1, eNOS, and phospho-Akt was assayed by Western blotting. Androgen withdrawal, similarly to aging, leads to a noteworthy reduction of SM-to-CT ratio in CC. However, in contrast to young and aged, a significant increase in penile Sirt1 expression accompanied by an increase in total eNOS expression was observed in androgen-depleted individuals. No changes were evidenced in phospho-Akt system and estrogen receptors were undetectable. These findings indicate that Sirt1 regulates the expression of eNOS in human CC employing mechanisms influenced by androgen depletion.
doi:10.1007/s11357-011-9328-z
PMCID: PMC3543737  PMID: 22052036
Hypogonadism; Human cavernous tissue; Endothelial dysfunction; Sirtuin-1; Endothelial nitric oxide synthase (eNOS)
14.  MiR-34 modulates Caenorhabditis elegans lifespan via repressing the autophagy gene atg9 
Age  2011;35(1):11-22.
Evidence for a regulatory role of the miR-34 family in senescence is growing. However, the exact role of miR-34 in aging in vivo remains unclear. Here, we report that a mir-34 loss-of-function mutation in Caenorhabditis elegans markedly delays the age-related physiological decline, extends lifespan, and increases resistance to heat and oxidative stress. We also found that RNAi against autophagy-related genes, atg4, bec-1, or atg9, significantly reversed the lifespan-extending effect of the mir-34 mutants. Furthermore, miR-34a inhibits Atg9A expression at the post-transcriptional level in vitro, and the miR-34a binding sequences in the 3'-UTR of Atg9A contributes to the modulation of Atg9A expression by miR-34a. Our results demonstrate that the C. elegans mir-34 mutation extends lifespan by enhancing autophagic flux in C. elegans, and that miR-34 represses autophagy by directly inhibiting the expression of the autophagy-related proteins Atg9 in mammalian cells.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9324-3) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-011-9324-3
PMCID: PMC3543738  PMID: 22081425
C. elegans; Mir-34; Autophagy; Aging; Lifespan
15.  A complex dietary supplement augments spatial learning, brain mass, and mitochondrial electron transport chain activity in aging mice 
Age  2011;35(1):23-33.
We developed a complex dietary supplement designed to offset five key mechanisms of aging and tested its effectiveness in ameliorating age-related cognitive decline using a visually cued Morris water maze test. All younger mice (<1 year old) learned the task well. However, older untreated mice (>1 year) were unable to learn the maze even after 5 days, indicative of strong cognitive decline at older ages. In contrast, no cognitive decline was evident in older supplemented mice, even when ∼2 years old. Supplemented older mice were nearly 50% better at locating the platform than age-matched controls. Brain weights of supplemented mice were significantly greater than controls, even at younger ages. Reversal of cognitive decline in activity of complexes III and IV by supplementation was significantly associated with cognitive improvement, implicating energy supply as one possible mechanism. These results represent proof of principle that complex dietary supplements can provide powerful benefits for cognitive function and brain aging.
doi:10.1007/s11357-011-9325-2
PMCID: PMC3543739  PMID: 22120182
Cognitive aging; Learning; Aging; Dietary supplements; Mitochondria; Brain mass
16.  Changes of cortico-muscular coherence: an early marker of healthy aging? 
Age  2011;35(1):49-58.
Cortico-muscular coherence (CMC) at beta frequency (13–30 Hz) occurs particularly during weak to moderate isometric contraction. It is a well-established measure of communication between the primary motor cortex (M1) and corresponding muscles revealing information about the integrity of the pyramidal system. Although the slowing of brain and muscle dynamics during healthy aging has been evidenced, functional communication as determined by CMC has not been investigated so far. Since decline of motor functions at higher age is likely to be associated with CMC changes, the present study aims at shedding light on the functionality of the motor system from a functional interaction perspective. To this end, CMC was investigated in 27 healthy subjects aging between 22 and 77 years during isometric contraction of their right forearm. Neuromagnetic activity was measured using whole-head magnetoencephalography (MEG). Muscle activity was measured by means of surface electromyography (EMG) of the right extensor digitorum communis (EDC) muscle. Additionally, MEG-EMG phase lags were calculated in order to estimate conducting time. The analysis revealed CMC and M1 power amplitudes to be increased with age accompanied by slowing of M1, EMG, and CMC. Frequency changes were particularly found in subjects aged above 40 years suggesting that at this middle age, neurophysiological changes occur, possibly reflecting an early neurophysiological marker of seniority. Since MEG–EMG phase lags did not vary with age, changes cannot be explained by alterations of nerve conduction. We argue that the M1 power amplitude increase and the shift towards lower frequencies might represent a neurophysiological marker of healthy aging which is possibly compensated by increased CMC amplitude.
doi:10.1007/s11357-011-9329-y
PMCID: PMC3543740  PMID: 22037920
Aging; Oscillations; Cortico-muscular coherence; Motor control; Magnetoencephalography
17.  Aging enhances contraction to thromboxane A2 in aorta from female senescence-accelerated mice 
Age  2011;35(1):117-128.
The time-course for aging-associated effects on vascular reactivity to U46619, a stable analogue of thromboxane A2 (TXA2), was studied in aorta from female senescence-accelerated mice-prone (SAMP8), a murine model of accelerated senescence. SAMP8 and senescence-accelerated mice-resistant (SAMR1) were divided into three groups: 3-, 6- and 10-month-old. Contractile curves to U46619 (10−9 to 10−6 M) were performed in aortic rings in the absence or in the presence of nitric oxide synthase (NOS) inhibitor NG-nitro-l-arginine methyl ester (l-NAME; 10−4 M) and/or cyclooxygenase (COX) inhibitor indomethacin (10−5 M). Protein and gene expression for COX-1 and COX-2 were determined by immunofluorescence and real-time PCR, respectively. Maximal contraction to U46619 was markedly higher in SAMP8 at all ages. In SAMR1, increases were seen at 10 months, while SAMP8 displays augmented contraction at 6 months, which was further increased at 10 months. l-NAME enhanced U46619 contractions in both 6-month-old groups, although the increase was higher on vessels from SAMR1 at this age. Indomethacin equally increased U46619 contractions in both 3-month-old groups, suggesting the production of vasodilator prostaglandin in young animals. In contrast, at 6 and 10 months indomethacin decreased U46619 contractions in both groups, indicating an aging-associated swap to a release of contractile prostanoids in aorta. In conclusion, aging enhances contractile responses to TXA2 in aorta from female mice by a mechanism involving a decrease of NO production and increased action of contractile prostanoids. This process occurs earlier in SAMP8 mice, establishing these mice as good model to study cardiovascular aging in a convenient and standard time-course.
doi:10.1007/s11357-011-9337-y
PMCID: PMC3543741  PMID: 22102320
U46619; NO bioavailability; Contractile prostanoids; Vascular reactivity
18.  The effect of resveratrol on lifespan depends on both gender and dietary nutrient composition in Drosophila melanogaster 
Age  2011;35(1):69-81.
Resveratrol, a polyphenolic compound, has been shown to extend lifespan in different organisms. Emerging evidence suggests that the prolongevity effect of resveratrol depends on dietary composition. However, the mechanisms underlying the interaction of resveratrol and dietary nutrients in modulating lifespan remain elusive. Here, we investigated the effect of resveratrol on lifespan of Drosophila melanogaster fed diets differing in the concentrations of sugar, yeast extract, and palmitic acid representing carbohydrate, protein, and fat, respectively. Resveratrol at up to 200 μM in diets did not affect lifespan of wild-type female flies fed a standard, restricted or high sugar–low protein diet, but extended lifespan of females fed a low sugar–high protein diet. Resveratrol at 400 μM extended lifespan of females fed a high-fat diet. Lifespan extension by resveratrol was associated with downregulation of genes in aging-related pathways, including antioxidant peroxiredoxins, insulin-like peptides involved in insulin-like signaling and several downstream genes in Jun-kinase signaling involved in oxidative stress response. Furthermore, resveratrol increased lifespan of superoxide dismutase 1 (sod1) knockdown mutant females fed a standard or high-fat diet. No lifespan extension by resveratrol was observed in wild-type and sod1 knockdown males under the culture conditions in this study. Our results suggest that the gender-specific prolongevity effect of resveratrol is influenced by dietary composition and resveratrol promotes the survival of flies by modulating genetic pathways that can reduce cellular damage. This study reveals the context-dependent effect of resveratrol on lifespan and suggests the importance of dietary nutrients in implementation of effective aging interventions using dietary supplements.
doi:10.1007/s11357-011-9332-3
PMCID: PMC3543742  PMID: 22083438
Resveratrol; Lifespan; Dietary composition; Aging intervention; Superoxide dismutase 1; Oxidative stress
19.  Insulin receptor signaling mediates APP processing and β-amyloid accumulation without altering survival in a transgenic mouse model of Alzheimer’s disease 
Age  2011;35(1):83-101.
In brains from patients with Alzheimer’s disease (AD), expression of insulin receptor (IR), insulin-like growth factor-1 receptor (IGF-1R), and insulin receptor substrate proteins is downregulated. A key step in the pathogenesis of AD is the accumulation of amyloid precursor protein (APP) cleavage products, β-amyloid (Aβ)1-42 and Aβ1–40. Recently, we and others have shown that central IGF-1 resistance reduces Aβ accumulation as well as Aβ toxicity and promotes survival. To define the role of IR in this context, we crossed neuron-specific IR knockout mice (nIR−/−) with Tg2576 mice, a well-established mouse model of an AD-like pathology. Here, we show that neuronal IR deficiency in Tg2576 (nIR−/−Tg2576) mice leads to markedly decreased Aβ burden but does not rescue premature mortality of Tg2576 mice. Analyzing APP C-terminal fragments (CTF) revealed decreased α-/β-CTFs in the brains of nIR−/−Tg2576 mice suggesting decreased APP processing. Cell based experiments showed that inhibition of the PI3-kinase pathway suppresses endosomal APP cleavage and decreases α- as well as β-secretase activity. Deletion of only one copy of the neuronal IGF-1R partially rescues the premature mortality of Tg2576 mice without altering total amyloid load. Analysis of Tg2576 mice expressing either a dominant negative or constitutively active form of forkhead box-O (FoxO)1 did not reveal any alteration of amyloid burden, APP processing and did not rescue premature mortality in these mice. Thus, our findings identified IR signaling as a potent regulator of Aβ accumulation in vivo. But exclusively decreased IGF-1R expression reduces AD-associated mortality independent of β-amyloid accumulation and FoxO1-mediated transcription.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9333-2) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-011-9333-2
PMCID: PMC3543743  PMID: 22057897
Insulin receptor; Insulin-like growth factor-1 receptor; β-Amyloid; Alzheimer’s disease; Tg2576 mice
20.  Aging and vascular dysfunction: beneficial melatonin effects 
Age  2011;35(1):103-115.
Aging is characterized by a progressive deterioration of physiological functions and metabolic processes. In aging and in diseases associated with the elderly, the loss of cells in vital structures or organs may be related to several factors. Sirtuin1 (SIRT1) is a member of the sirtuin family of protein deacetylases involved in life span extension; however, its involvement in the aging is not yet completely defined. Recently, melatonin, a pleiotropic molecule, shown to activate SIRT1 in primary neurons of young animals, as well as in aged neurons of a murine model of senescence. Melatonin is known to modulate oxidative stress-induced senescence and pro-survival pathways. We treated 6- and 15-week-old apolipoprotein E (APOE)-deficient mice (APOE 6w and 15w) with two melatonin formulations (FAST and RETARD) to evaluate their anti-aging effect. Morphological changes in vessels (aortic arch) of APOE mice were evaluated SIRT1, p53, endothelial nitric oxide synthase (eNOS), and endothelin-1 (ET-1) markers. We demonstrate that SIRT1 and eNOS decresed in APOE mice between 6 and 15 weeks and that aging induced an elevated expression of p53 and ET-1 in APOE animals. Melatonin improved the impairment of endothelial damage and reduced loss of SIRT1 and eNOS decreasing p53 and ET-1 expression. The RETARD melatonin preparation caused a greater improvement of vessel cytoarchitecture. In summary, we indicate that SIRT1-p53-eNOS axis as one of the important marker of advanced vascular dysfunctions linked to aging. Finally, we suggest that extended-release melatonin (RETARD) provides a more appropriate option for contrasting these dysfunctions compared with rapid release melatonin (FAST) administration.
doi:10.1007/s11357-011-9336-z
PMCID: PMC3543744  PMID: 22109832
Melatonin; Atherosclerosis; Aging; Endothelial cells
21.  Thymic function failure and C-reactive protein levels are independent predictors of all-cause mortality in healthy elderly humans 
Age  2011;35(1):251-259.
Relationship between thymic function and elderly survival has been suspected, despite the fact that formal proof is elusive due to technical limitations of thymic function-related markers. The newly described sj/β-TREC ratio allows now, by overcoming these limitations, an accurate measurement of thymic output in elderly humans. Thus, the aim of this study was to determine the impact of thymic function and inflammatory markers on healthy elderly human survival. Healthy volunteers (n = 151), aged over 65, were asked to participate (CARRERITAS cohort). Subjects were excluded if diagnosed of dementia or, during the last 6 months, had clinical data of infection, hospital admission, antitumor therapy, or any treatment that could influence the immune status. Thymic function (sj/β-TREC ratio), CD4:CD8 T cell ratio, C-reactive protein, interleukin-6, and neutrophilia were determined from basal samples. All basal variables and age were associated with 2-year all-cause mortality. Multivariate analysis showed that only thymic function and C-reactive protein were independently associated with time to death. In conclusion, we show, for the first time, the direct role of thymic function in human survival. C-reactive protein raise is also a marker of mortality in the healthy elderly, in a thymic-independent way.
doi:10.1007/s11357-011-9341-2
PMCID: PMC3543745  PMID: 22095260
Thymic function; sj/beta-TREC ratio; Immunosenescence; Aging; Elderly; CRP; Elderly survival; Human mortality; Inflamm-aging
22.  Postprandial antioxidant gene expression is modified by Mediterranean diet supplemented with coenzyme Q10 in elderly men and women 
Age  2011;35(1):159-170.
Postprandial oxidative stress is characterized by an increased susceptibility of the organism towards oxidative damage after consumption of a meal rich in lipids and/or carbohydrates. We have investigated whether the quality of dietary fat alters postprandial gene expression and protein levels involved in oxidative stress and whether the supplementation with coenzyme Q10 (CoQ) improves this situation in an elderly population. Twenty participants were randomized to receive three isocaloric diets each for 4 weeks: Mediterranean diet supplemented with CoQ (Med + CoQ diet), Mediterranean diet (Med diet), saturated fatty acid-rich diet (SFA diet). After 12-h fast, volunteers consumed a breakfast with a fat composition similar to that consumed in each of the diets. Nrf2, p22phox and p47phox, superoxide dismutase 1 and 2 (SOD1 and SOD2), glutathione peroxidase 1 (GPx1), thiorredoxin reductase (TrxR) gene expression and Kelch-like ECH associating protein 1 (Keap-1) and citoplasmic and nuclear Nrf2 protein levels were determined. Med and Med + CoQ diets induced lower Nrf2, p22phox, p47phox, SOD1, SOD2 and TrxR gene expression and higher cytoplasmic Nrf2 and Keap-1 protein levels compared to the SFA diet. Moreover, Med + CoQ diet produced lower postprandial Nrf2 gene expression and lower nuclear Nrf2 protein levels compared to the other diets and lower GPx1 gene expression than the SFA diet. Our results support the antioxidant effect of a Med diet and that exogenous CoQ supplementation has a protective effects against free radical overgeneration through the lowering of postprandial oxidative stress modifying the postprandial antioxidant protein levels and reducing the postprandial expression of antioxidant genes in peripheral blood mononuclear cells.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9331-4) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-011-9331-4
PMCID: PMC3543746  PMID: 22057896
CoQ10; Mediterranean diet; Oxidative stress; Gene expression
23.  Age-related loss of noradrenergic neurons in the brains of triple transgenic mice 
Age  2011;35(1):139-147.
Microscopic findings in Alzheimer’s disease (AD) at autopsy include a wide cortical distribution of beta amyloid (Aβ)-containing plaques and diminished numbers of pyramidal neurons in CA1 of hippocampus and tyrosine hydroxylase-positive (TH+) neurons in the locus coeruleus (LC). To better understand the neuropathology underlying cognitive decline in AD, we analyzed the AD-type neuropathology in brains of triple transgenic (3×Tg) mice harboring mutations for APPswe, PS1M146V, and tauP301L. Histochemical and immunohistochemical staining and computerized stereology were carried out in age-matched young, early middle age, and late middle age 3×Tg mice. The 3×Tg mice showed an intracellular Aβ deposition in subiculum and CA1 pyramidal neurons and an extracellular distribution of amyloid plaques specifically in the subiculum of hippocampal formation and in neocortical layer V. The 3×Tg mice also showed an age-related loss of TH+ neurons in LC, with a loss of 37% of these neurons at 15 months of age. There was no loss of CA1 neurons at any age examined. Reduced AD-type neuropathology in CA1 of 3×Tg mice suggests a possible neuroprotective role for high intracellular-to-extracellular ratios of insoluble Aβ deposits. Understanding the neurobiology of this apparent neuroprotection could lead to an improved understanding of age-related cognitive function in general, and the development of novel strategies for the therapeutic management of AD patients.
doi:10.1007/s11357-011-9343-0
PMCID: PMC3543748  PMID: 22127507
Locus coeruleus; Hippocampus; Alzheimer’s disease; Triple transgenic mice; Double transgenic mice
24.  Genes and the ageing muscle: a review on genetic association studies 
Age  2011;35(1):207-233.
Western populations are living longer. Ageing decline in muscle mass and strength (i.e. sarcopenia) is becoming a growing public health problem, as it contributes to the decreased capacity for independent living. It is thus important to determine those genetic factors that interact with ageing and thus modulate functional capacity and skeletal muscle phenotypes in older people. It would be also clinically relevant to identify ‘unfavourable’ genotypes associated with accelerated sarcopenia. In this review, we summarized published information on the potential associations between some genetic polymorphisms and muscle phenotypes in older people. A special emphasis was placed on those candidate polymorphisms that have been more extensively studied, i.e. angiotensin-converting enzyme (ACE) gene I/D, α-actinin-3 (ACTN3) R577X, and myostatin (MSTN) K153R, among others. Although previous heritability studies have indicated that there is an important genetic contribution to individual variability in muscle phenotypes among old people, published data on specific gene variants are controversial. The ACTN3 R577X polymorphism could influence muscle function in old women, yet there is controversy with regards to which allele (R or X) might play a ‘favourable’ role. Though more research is needed, up-to-date MSTN genotype is possibly the strongest candidate to explain variance among muscle phenotypes in the elderly. Future studies should take into account the association between muscle phenotypes in this population and complex gene–gene and gene–environment interactions.
doi:10.1007/s11357-011-9327-0
PMCID: PMC3543750  PMID: 22037866
Sarcopenia; Ageing; Genetic variation; Muscle phenotypes

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