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26.  Evidence from case–control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity 
Age  2012;35(2):487-500.
In this study, we investigated 102 single-nucleotide polymorphisms (SNPs) covering the common genetic variation in 16 genes recurrently regarded as candidates for human longevity: APOE; ACE; CETP; HFE; IL6; IL6R; MTHFR; TGFB1; APOA4; APOC3; SIRTs 1, 3, 6; and HSPAs 1A, 1L, 14. In a case–control study of 1,089 oldest-old (ages 92–93) and 736 middle-aged Danes, the minor allele frequency (MAF) of rs769449 (APOE) was significantly decreased in the oldest-old, while the MAF of rs9923854 (CETP) was significantly enriched. These effects were supported when investigating 1,613 oldest-old (ages 95–110) and 1,104 middle-aged Germans. rs769449 was in modest linkage equilibrium (R2 = 0.55) with rs429358 of the APOE-ε4 haplotype and adjusting for rs429358 eliminated the association of rs769449, indicating that the association likely reflects the well-known effect of rs429358. Gene-based analysis confirmed the effects of variation in APOE and CETP and furthermore pointed to HSPA14 as a longevity gene. In a longitudinal study with 11 years of follow-up on survival in the oldest-old Danes, only one SNP, rs2069827 (IL6), was borderline significantly associated with survival from age 92 (P-corrected = 0.064). This advantageous effect of the minor allele was supported when investigating a Dutch longitudinal cohort (N = 563) of oldest-old (age 85+). Since rs2069827 was located in a putative transcription factor binding site, quantitative RNA expression studies were conducted. However, no difference in IL6 expression was observed between rs2069827 genotype groups. In conclusion, we here support and expand the evidence suggesting that genetic variation in APOE, CETP, and IL6, and possible HSPA14, is associated with human longevity.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9373-7) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-011-9373-7
PMCID: PMC3592963  PMID: 22234866
Human longevity; Candidate gene association study; Case–control data; Longitudinal data
27.  Characterization of skeletal alterations in a model of prematurely aging mice 
Age  2012;35(2):383-393.
An age-related bone loss occurs, apparently associated with the concomitant increase in an oxidative stress situation. However, the underlying mechanisms of age-related osteopenia are ill defined since these studies are time consuming and require the use of many animals (mainly rodents). Here, we aimed to characterize for the first time the bone status of prematurely aging mice (PAM), which exhibit an increased oxidative stress. Tibiae from adult (6 months) PAM show an increase in bone mineral density (BMD) and bone mineral content (assessed by bone densitometry) versus those in their normal counterparts (non-prematurely aging mice, NPAM) and similarly decreased in both kinds of mouse with age. However, at this bone site, trabecular BMD (determined by μ-computerized tomography) was similar in both adult PAM and old (18 months) NPAM. Femurs from these groups of mice present an increase in oxidative stress, inflammation, osteoclastogenic, and adipogenic markers, but a decrease in the gene expression of osteoblastic differentiation markers and of the Wnt/β-catenin pathway. Our findings show that adult PAM recapitulate various age-related bone features, and thus are a suitable model for premature bone senescence studies.
doi:10.1007/s11357-011-9372-8
PMCID: PMC3592965  PMID: 22234865
Aging; Osteoporosis; Oxidative stress; Mouse
28.  Mechanistic insights into the impairment of memory B cells and antibody production in the elderly 
Age  2012;35(2):371-381.
It is well established that immunologic memory generated early in life can be maintained into old age and mediate robust anamnestic antibody responses. Little is known, however, about the initiation of memory B cells in the elderly. We have conducted a prospective analysis of the quantities and functionalities of antigen-specific B cell responses and its association with the functional helper CD4+T cell responses. The ability of naïve B cells from old (60–80 years) and young (20–31 years) humans to establish functional memory was examined following primary and booster vaccination with an inactivated-virus vaccine against tick-borne encephalitis. Our data show that the number of antigen-specific memory B cells generated during primary vaccination was ∼3-fold lower in old than in young individuals. The maintenance and booster responsiveness of these memory B cells were not compromised, as evidenced by similar increases in specific memory B cell frequencies upon revaccination in old and young adults. In contrast, the Ab response mediated per memory B cell after revaccination was dramatically diminished in the elderly. Also, antigen-specific IL-2-positive CD4+T cell responses were strongly reduced in the elderly and displayed an excellent correlation with Ab titres. The data suggest that the dramatically lower antibody response in the elderly could only partially be accounted for by the reduced B cell numbers and was strongly correlated with profound functional defects in CD4 help.
doi:10.1007/s11357-011-9371-9
PMCID: PMC3592966  PMID: 22282053
Immunosenescence; B memory cells; Aging; TBE vaccination; CD4+T cells; CD154
29.  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
30.  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
31.  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
32.  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
33.  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)
34.  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
35.  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
36.  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
37.  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
38.  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
39.  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
40.  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
41.  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
42.  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
43.  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
44.  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
46.  Psychological stress and aging: role of glucocorticoids (GCs) 
Age  2011;34(6):1421-1433.
Psychological stress has extreme adverse consequences on health. However, the molecular mechanisms that mediate and accelerate the process of aging due to stress hormone are not well defined. This review has focused on diverse molecular paths that come out in response to chronic psychological stress via releasing of excessive glucocorticoids (GCs), involved in the aging process. GCs suppress transcription of nuclear cell adhesion molecules which impair synaptic plasticity, memory formation, and cognitive ability. Again, GCs promote muscle atrophy by means of motivating ubiquitin proteasome system and can repress muscle protein synthesis by inhibition of PI3-kinase/Akt pathway. GCs also inhibit interleukin-2 synthesis through suppressing T cell receptor signal that leads to loss of T cell activation, proliferation, and B-cell activation. Moreover, GCs increase the expression of collagenase-3, RANK ligand, and colony stimulating factor-1 that induce bone resorption. In general, stress-induced GCs can play causal role for aging and age-related disorders.
doi:10.1007/s11357-011-9319-0
PMCID: PMC3528378  PMID: 21971999
Chronic psychological stress; Glucocorticoid; Glucocorticoid receptor; Aging
47.  Effect of calorie restriction and refeeding on skin wound healing in the rat 
Age  2011;34(6):1453-1458.
Calorie restriction (CR) is a reliable anti-aging intervention that attenuates the onset of a number of age-related diseases, reduces oxidative damage, and maintains function during aging. In the current study, we assessed the effects of CR and other feeding regimens on wound healing in 7-month-old Fischer-344 rats from a larger cohort of rats that had been fed either ad libitum (AL) or 40% calorie restricted based on AL consumption. Rats were assigned to one of three diet groups that received three skin punch wounds along the dorsal interscapular region (12-mm diameter near the front limbs) of the back as follows: (1) CR (n = 8) were wounded and maintained on CR until they healed, (2) AL (n = 5) were wounded and maintained on AL until wound closure was completed, and (3) CR rats were refed (RF, n = 9) AL for 48 h prior to wounding and maintained on AL until they healed. We observed that young rats on CR healed more slowly while CR rats refed for 48 h prior to wounding healed as fast as AL fed rats, similar to a study reported in aged CR and RF mice (Reed et al. 1996). Our data suggest that CR subjects, regardless of age, fail to heal well and that provision of increased nutrition to CR subjects prior to wounding enhances the healing process.
doi:10.1007/s11357-011-9321-6
PMCID: PMC3528375  PMID: 22037865
Aging; Calorie restriction; Refeeding; Wound healing
48.  The role of DNA exonucleases in protecting genome stability and their impact on ageing 
Age  2011;34(6):1317-1340.
Exonucleases are key enzymes involved in many aspects of cellular metabolism and maintenance and are essential to genome stability, acting to cleave DNA from free ends. Exonucleases can act as proofreaders during DNA polymerisation in DNA replication, to remove unusual DNA structures that arise from problems with DNA replication fork progression, and they can be directly involved in repairing damaged DNA. Several exonucleases have been recently discovered, with potentially critical roles in genome stability and ageing. Here we discuss how both intrinsic and extrinsic exonuclease activities contribute to the fidelity of DNA polymerases in DNA replication. The action of exonucleases in processing DNA intermediates during normal and aberrant DNA replication is then assessed, as is the importance of exonucleases in repair of double-strand breaks and interstrand crosslinks. Finally we examine how exonucleases are involved in maintenance of mitochondrial genome stability. Throughout the review, we assess how nuclease mutation or loss predisposes to a range of clinical diseases and particularly ageing.
doi:10.1007/s11357-011-9306-5
PMCID: PMC3528374  PMID: 21948156
Exonuclease; Aging; Ageing; WRN; FAN1; FEN1; EXOG; EXDL2; Mitochondria; Proofreading; DNA repair; DNA replication
49.  Protein:carbohydrate ratios explain life span patterns found in Queensland fruit fly on diets varying in yeast:sugar ratios 
Age  2011;34(6):1361-1368.
Dietary restriction extends life span across a vast diversity of taxa, but significant challenges remain in elucidating the underlying mechanisms. Distinguishing between caloric and nutrient effects is an essential step. Recent studies with Drosophila and tephritid fruit flies have reported increased life span as dietary yeast-to-sugar ratios decreased and these effects have been attributed to changes in protein-to-carbohydrate (P:C) ratios of the diets rather than calories. However, yeast is a complex mix of macronutrients and micronutrients, and hence changes in yeast content of the diet necessarily alters other nutrients in lockstep. To explicitly test whether studies using yeast are justified in attributing results to diet protein content rather than correlated nutrients, we developed a chemically defined diet allowing manipulation of just the ratio of protein (free amino acids) to carbohydrate (sucrose) levels of diets while holding other nutrients constant. Mated, female Queensland fruit flies (Q-flies) were fed 1 of 18 diets varying in P:C ratios and diet concentration. Diet consumption, egg production, and life span were recorded for each fly. In close concordance with recent studies using yeast diets, flies had increased life span as P:C ratios decreased, and caloric restriction did not extend life span. Similarly, egg production was maximized on high P:C ratios, but lifetime egg production was maximized on intermediate P:C ratios, indicating a life history trade-off between life span and egg production rate. Finally, Q-flies adjusted their diet intake in response to P:C ratios and diet concentration. Our results substantiate recent claims that P:C ratios significantly modulate life span in flies.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9308-3) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-011-9308-3
PMCID: PMC3528373  PMID: 21904823
Bactrocera tryoni; Dietary restriction; Geometric framework; Holidic diet; Lifespan; Life history trade-off; Nutrition
50.  Changes in behaviors of male C57BL/6J mice across adult life span and effects of dietary restriction 
Age  2011;34(6):1435-1452.
Behavioral analysis is a high-end read-out of aging impact on an organism, and here, we have analyzed behaviors in 4-, 22-, and 28-month-old male C57BL/6J with a broad range of tests. For comparison, a group of 28-month-old males maintained on dietary restriction (DR) was included. The most conspicuous alteration was the decline in exploration activity with advancing age. Aging also affected other behaviors such as motor skill acquisition and grip strength, in contrast to latency to thermal stimuli and visual placement which were unchanged. Object recognition tests revealed intact working memory at 28 months while memory recollection was impaired already at 22 months. Comparison with female C57BL/6J (Fahlström et al., Neurobiol Aging 32:1868–1880, 2011) revealed that alterations in aged males and females are similar and that several of the behavioral indices correlate with age in both sexes. Moreover, we examined if behavioral indices in 22-month-old males could predict remaining life span as suggested in the study by Ingram and Reynolds (Exp Aging Res 12(3):155–162, 1986) and found that exploratory activity and motor skills accounted for up to 65% of the variance. Consistent with that a high level of exploratory activity and preserved motor capacity indicated a long post-test survival, 28-month-old males maintained on DR were more successful in such tests than ad libitum fed age-matched males. In summary, aged C57BL/6J males are marked by a reduced exploratory activity, an alteration that DR impedes. In light of recently published data, we discuss if a diminishing drive to explore may associate with aging-related impairment of central aminergic pathways.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9320-7) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-011-9320-7
PMCID: PMC3528371  PMID: 21989972
Sensorimotor; Memory; Cognition; Gender; Calorie restriction

Results 26-50 (445)