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3.  The impact of obesity on balance control in community-dwelling older women 
Age  2012;35(3):883-890.
Older individuals have impaired balance control, particularly those that are frail and/or have sensory deprivations. Obese individuals show faster body sway during upright stance than normal weight individuals, suggesting that they also have difficulty controlling balance even if they do not have the same sensory issues as the older people. Therefore, the objective of this study was to examine if obesity is associated to a decreased balance control in older women. Postural sway of normal weight (n = 15, age = 70.8 ± 5.5 years; BMI = 22.2 ± 1.9 kg/m2), overweight (n = 15, age = 71.7 ± 4.3 years; BMI = 27.3 ± 1.3 kg/m2), and obese (n = 15, age = 71.1 ± 4.3 years; BMI = 33.1 ± 3.4 kg/m2) women was measured with a force platform for normal quiet stance lasting for 30 s in opened and closed eyes conditions. The obese group oscillated at a faster speed than the normal weight group (vision 0.99 ± 0.29 cm/s vs. 0.70 ± 0.16 cm/s, p < 0.01; no vision 1.43 ± 0.50 cm/s vs. 0.87 ± 0.23 cm/s, p < 0.01). The obese group exhibited greater range in both axes without vision compared to the normal weight group (p < 0.05). When observing sway density parameters, the obese group also spent less time in stability zones (2 mm radius area in which the center of pressure is relatively stable), and the distance between these stability zones are greater than the normal weight group in both visual conditions (p < 0.01 and p < 0.05, respectively). Obesity clearly affects postural control in older women. Our results suggest that obesity has a negative impact on the capacity of older woman to adequately use proprioceptive information for posture control. As postural instability or balance control deficits are identified as a risk factor for falling, our results also suggest that obesity in older women could be considered as another potential contributing factor for falling.
doi:10.1007/s11357-012-9386-x
PMCID: PMC3636380  PMID: 22318311
Posture; Balance control; Postural stability; Elderly; Older women; Obesity
4.  Aging and substitutive hormonal therapy influence in regional and subcellular distribution of ERα in female rat brain 
Age  2012;35(3):821-837.
Estrogens are not only critical for sexual differentiation it is well-known for the role of 17β-estradiol (E2) in the adult brain modulating memory, learning, mood and acts as a neuroprotector. E2 exerts its actions through two classical receptors: estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). The distribution of both receptors changes from one brain area to another, E2 being able to modulate their expression. Among the classical features of aging in humans, we find cognitive impairment, dementia, memory loss, etc. As estrogen levels change with age, especially in females, it is important to know the effects of low E2 levels on ERα distribution; results from previous studies are controversial regarding this issue. In the present work, we have studied the effects of long-term E2 depletion as well as the ones of E2 treatment on ERα brain distribution of ovariectomized rats along aging in the diencephalon and in the telencephalon. We have found that ovariectomy causes downregulation and affects subcellular localization of ERα expression during aging, meanwhile prolonged estrogen treatment produces upregulation and overexpression of the receptor levels. Our results support the idea of the region-specific neuroprotection mechanisms mediated by estradiol.
doi:10.1007/s11357-012-9415-9
PMCID: PMC3636381  PMID: 22648398
Hormonal therapy; Aging; Estrogen receptor alpha; Brain; Estradiol; Telencephalon; Diencephalon
5.  Reversing T cell immunosenescence: why, who, and how 
Age  2012;35(3):609-620.
Immunosenescence is the term commonly used to describe the multifaceted phenomenon encompassing all changes occurring in the immune system during aging. It contributes to render older adults more prone to develop infectious disease and main age-related diseases. While age clearly imposes drastic changes in immune physiology, older adults have heterogeneous health and immune phenotypes. This confronts scientists and researcher to develop more age-specific interventions rather than simply adopting intervention regimes used in younger people and this in order to maintain immune protection in older adults. Thus, this review provides evidences of the central role played by cell-mediated immunity in the immunosenescence process and explores the means by which senescent state of the cell-mediated immune function could be identified and predicted using biomarkers. Furthermore considerations are given to recent advances made in the field of age-specific immune interventions that could contribute to maintain immune protection, to improve quality of life, and/or to promote healthy aging of the growing part of the population.
doi:10.1007/s11357-012-9393-y
PMCID: PMC3636382  PMID: 22367580
Cell-mediated immunity; Healthy aging; Immunosenescence; TREC ratio; Thymus TREC
6.  Diet mediates the relationship between longevity and reproduction in mammals 
Age  2012;35(3):921-927.
The disposable soma hypothesis posits a negative correlation between longevity and reproduction, presumably because these aspects of fitness compete for a limited pool of nutrients. However, diet, which varies widely among animals, could affect the availability of key nutrients required for both reproduction and longevity, especially protein. We used a comparative database of mammal life history data to test the hypothesis that carnivores experience less of a negative relationship between reproduction and longevity than herbivores. Annual reproduction and adult mass were significant predictors of longevity among all mammals; although, the relative importance of reproduction and mass for explaining longevity varied among trophic levels. In herbivores, reproduction was a stronger predictor of longevity than mass. Carnivores showed the opposite pattern with reproduction explaining much less of the variation in longevity. Omnivores showed an intermediate pattern with mass and reproduction explaining similar amounts of variation in longevity. In addition, longevity and reproduction were significantly higher in omnivores than herbivores and carnivores, which were not different from each other. Higher dietary protein at higher trophic levels may allow mammals to avoid potential conflicts between reproduction and longevity. However, there may be potential costs of carnivorous diets that limit the overall performance of carnivores and explain the peak in reproduction and longevity for omnivores.
doi:10.1007/s11357-011-9380-8
PMCID: PMC3636383  PMID: 22237559
Mammal; Disposable soma theory; Trophic level; Diet
7.  Reversible epigenetic histone modifications and Bdnf expression in neurons with aging and from a mouse model of Alzheimer’s disease 
Age  2012;35(3):519-531.
With aging and Alzheimer’s disease (AD), there is an increased sensitivity to stress along with declines in the memory-associated neurotrophin brain-derived neurotrophic factor in AD. We have replicated this aging phenotype in cultured neurons from aged mice despite being grown in the same environmental conditions as young neurons. This led us to hypothesize that age-related differences in epigenetic acetylation and methylation of histones are associated with age-related gene regulation. We cultured hippocampal/cortical neurons from the 3xTg-AD mouse model and from non-transgenic mice to quantify single cell acetylation and methylation levels across the life span. In non-transgenic neurons, H3 acetylation was unchanged with age, while H4 acetylation decreased with age of the donor. Compared to non-transgenic neurons, 3xTg-AD neurons had higher levels of H3 and H4 acetylation beginning at 4 months of age. In contrast to non-transgenic neurons, 3xTg-AD neurons increased acetylation with age; 3xTg-AD neurons also responded differently to inhibition of histone deacetylases at an early age. Importantly, treatment of non-transgenic neurons with the AD peptide Aβ also elevated levels of acetylation. We also examined the repressive function of histone H3 lysine 9 (H3K9) methylation. H3K9 methylation increased with age in non-transgenic neurons, which was amplified further in 3xTg-AD neurons. The dominant effect of higher H3K9 methylation was supported by lower Bdnf gene expression in non-transgenic and 3xTg-AD mice. These data show that the epigenetic states of non-transgenic and 3xTg-AD brain neurons are profoundly different and reversible, beginning at 4 months of age when the first memory deficits are reported.
doi:10.1007/s11357-011-9375-5
PMCID: PMC3636384  PMID: 22237558
3xTg-AD; Histone methylation; Histone acetylation; Epigenetics
8.  Biological aging alters circadian mechanisms in murine adipose tissue depots 
Age  2012;35(3):533-547.
Biological aging alters the metabolism and volume of adipose tissue depots. Recent evidence suggests that circadian mechanisms play a role in promoting adipogenesis, obesity, and lipodystrophy. The current study compared cohorts of younger (5–9 months) and older (24–28 months) C57BL/6 mice as a function of biological age and circadian time. Advanced age significantly reduced the weight of the brown, epididymal, inguinal, and retroperitoneal adipose depots but not total body weight. The older mice reduced their physical activity by >50% and delayed their activity initiation after light offset. The expressed transcriptome in brown and white adipose depots and liver of both cohorts displayed evidence of circadian rhythmicity; however, the oscillating mRNAs differed significantly between age groups and across tissues. The amplitude of Cry1, a component of the negative arm of the circadian apparatus, and downstream regulators such as Rev-erbα were elevated in the older relative to the younger cohorts as a function of circadian time. Overall, transcript levels differed significantly for 557 (inguinal adipose), 1,016 (liver), and 1,021 (brown adipose) expressed sequences between the cohorts as a function of age. These included transcripts encoding proteins within the canonical and non-canonical Wnt pathways. Since the Wnt pathway regulates adipose stem cell differentiation and shares a critical enzyme, glycogen synthase kinase 3β, with the circadian mechanism, the intersection between these two fundamental regulatory mechanisms merits further investigation with respect to biological aging of adipose tissues.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-012-9389-7) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-012-9389-7
PMCID: PMC3636385  PMID: 22411258
Brown adipose; Circadian; Liver; Oscillation; Transcriptomics; White adipose
9.  Immune-endocrine biomarkers as predictors of frailty and mortality: a 10-year longitudinal study in community-dwelling older people 
Age  2012;35(3):963-971.
Frailty is a multidimensional geriatric syndrome characterised by a state of increased vulnerability to disease. Its causes are unclear, limiting opportunities for intervention. Age-related changes to the immune-endocrine axis are implicated. This study investigated the associations between the immune-endocrine axis and frailty as well as mortality 10 years later among men and women aged 65 to 70 years. We studied 254 participants of the Hertfordshire Ageing Study at baseline and 10-year follow-up. At baseline, they completed a health questionnaire and had collection of blood samples for immune-endocrine analysis. At follow-up, Fried frailty was characterised and mortality ascertained. Higher baseline levels of differential white cell counts (WCC), lower levels of dehydroepiandosterone sulphate (DHEAS) and higher cortisol:DHEAS ratio were all significantly associated with increased odds of frailty at 10-year follow-up. Baseline WCC and cortisol:DHEAS clearly discriminated between individuals who went on to be frail at follow-up. We present the first evidence that immune-endocrine biomarkers are associated with the likelihood of frailty as well as mortality over a 10-year period. This augments our understanding of the aetiology of frailty, and suggests that a screening programme at ages 60–70 years could help to identify individuals who are at high risk of becoming frail and who would benefit from early, targeted intervention, for example with DHEA supplementation or anti-inflammatory strategies. Progress towards the prevention of frailty would bring major health and socio-economic benefits at the individual and the population level.
doi:10.1007/s11357-012-9396-8
PMCID: PMC3636387  PMID: 22388931
Frailty; Aging; Immunosenescence; Inflam-aging; White Blood Cells; DHEAS; Screening
10.  Blueberry consumption prevents loss of collagen in bone matrix and inhibits senescence pathways in osteoblastic cells 
Age  2012;35(3):807-820.
Ovariectomy (OVX)-induced bone loss has been linked to increased bone turnover and higher bone matrix collagen degradation as the result of osteoclast activation. However, the role of degraded collagen matrix in the fate of resident bone-forming cells is unclear. In this report, we show that OVX-induced bone loss is associated with profound decreases in collagen 1 and Sirt1. This was accompanied by increases in expression and activity of the senescence marker collagenase and expression of p16/p21 in bone. Feeding a diet supplemented with blueberries (BB) to pre-pubertal rats throughout development or only prior to puberty [postnatal day 21 (PND21) to PND34] prevents OVX-induced effects on expression of these molecules at PND68. In order to provide more evidence and gain a better understanding on the association between bone collagen matrix and resident bone cell fate, in vitro studies on the cellular senescence pathway using primary calvarial cells and three cell lines (ST2 cells, OB6, and MLO-Y4) were conducted. We found that senescence was inhibited by collagen in a dose–response manner. Treatment of cells with serum from OVX rats accelerated osteoblastic cell senescence pathways, but serum from BB-fed OVX rats had no effect. In the presence of low collagen or treatment with OVX rat serum, ST2 cells exhibited higher potential to differentiate into adipocytes. Finally, we demonstrated that bone cell senescence is associated with decreased Sirt1 expression and activated p53, p16, and p21. These results suggest that (1) a significant prevention of OVX-induced bone cell senescence from adult rats can occur after only 14 days consumption of a BB-containing diet immediately prior to puberty, and (2) the molecular mechanisms underlying this effect involves, at least in part, prevention of collagen degradation.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-012-9412-z) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-012-9412-z
PMCID: PMC3636388  PMID: 22555620
Blueberry; Diet; Bone loss; Osteoblast; Senescence
11.  Rejuvenating activity of salidroside (SDS): dietary intake of SDS enhances the immune response of aged rats 
Age  2012;35(3):637-646.
It is well known that immune response decreases with aging. Salidroside (SDS), an antioxidant component isolated from the traditional Chinese medicine roseroot Rhodiola rosea, has been demonstrated to possess potent anti-aging and health-promoting activities. However, the mechanism underlying these activities is poorly understood. In this study, we clearly demonstrated that (1) dietary intake of SDS induced a considerable increase in total T cells (CD3+) and T helper cells (CD4+) in aged (21 months old) Wistar male rats; (2) SDS supplementation significantly increased the DTH response, a T cell-mediated immune response, in aged rats; and (3) SDS supplementation remarkably promoted the production of total anti-KLH IgG, anti-KLH IgG1, and anti-KLH IgG2α in aged rats without disturbing immune homeostasis. These indicate that SDS is able to counteract immunosenescence, thereby resulting in rejuvenation. Practically, SDS may be used to help the elderly to generate an improved response to vaccine with stronger humoral and cell-mediated immune responses.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-012-9394-x) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-012-9394-x
PMCID: PMC3636390  PMID: 22367581
Rats; Salidroside; Ageing; Anti-ageing; Immune response
12.  Exceptionally old mice are highly resistant to lipoxidation-derived molecular damage 
Age  2012;35(3):621-635.
Membrane unsaturation plays an important role in the aging process and the determination of inter-species animal longevity. Furthermore, the accumulation of oxidation-derived molecular damage to cellular components particularly in the nervous and immune systems over time leads to homeostasis loss, which highly influences age-related morbidity and mortality. In this context, it is of great interest to know and discern the degree of membrane unsaturation and the steady-state levels of oxidative damage in both physiological systems from long-lived subjects. In the present work, adult (28 ± 4 weeks), old (76 ± 4 weeks) and exceptionally old (128 ± 4 weeks) BALB/c female mice were used. Brain and spleen were analysed for membrane fatty acid composition and specific markers of protein oxidation, glycoxidation and lipoxidation damage, i.e. glutamic semialdehyde, aminoadipic semialdehyde, carboxyethyl-lysine, carboxymethyl-lysine and malondialdehyde-lysine, by gas chromatography–mass spectrometry. The results showed significantly lower peroxidizability index in brain and spleen from exceptionally old animals when compared to old specimens. The higher membrane resistance to lipid peroxidation and lower lipoxidation-derived molecular damage found in exceptionally old animals was associated with a significantly lower desaturase activity and peroxisomal β-oxidation. Protein oxidation markers in brain and spleen from adult and exceptionally old animals showed similar levels, which were higher in old mice. In addition, the higher levels of the glycoxidation-derived marker observed in exceptionally old animals, as well as in adult mice, could be considered as a good indicator of a better bioenergetic state of these animals when compared to the old group. In conclusion, low lipid oxidation susceptibility and maintenance of adult-like protein lipoxidative damage could be key mechanisms for longevity achievement.
doi:10.1007/s11357-012-9391-0
PMCID: PMC3636393  PMID: 22367548
Aging; Brain; Longevity; Peroxidizability index; Protein oxidation; Spleen
13.  Accumulated hippocampal formaldehyde induces age-dependent memory decline 
Age  2012;35(3):583-596.
Aging is an important factor in memory decline in aged animals and humans and in Alzheimer’s disease and is associated with the impairment of hippocampal long-term potentiation (LTP) and down-regulation of NR1/NR2B expression. Gaseous formaldehyde exposure is known to induce animal memory loss and human cognitive decline; however, it is unclear whether the concentrations of endogenous formaldehyde are elevated in the hippocampus and how excess formaldehyde affects LTP and memory formation during the aging process. In the present study, we report that hippocampal formaldehyde accumulated in memory-deteriorating diseases such as age-related dementia. Spatial memory performance was gradually impaired in normal Sprague–Dawley rats by persistent intraperitoneal injection with formaldehyde. Furthermore, excess formaldehyde treatment suppressed the hippocampal LTP formation by blocking N-methyl-d-aspartate (NMDA) receptor. Chronic excess formaldehyde treatment over a period of 30 days markedly decreased the viability of the hippocampus and down-regulated the expression of the NR1 and NR2B subunits of the NMDA receptor. Our results indicate that excess endogenous formaldehyde is a critical factor in memory loss in age-related memory-deteriorating diseases.
doi:10.1007/s11357-012-9388-8
PMCID: PMC3636394  PMID: 22382760
Alzheimer’s disease (AD); Aging; Endogenous formaldehyde; Long-term potentiation (LTP); Long-term memory (LTM); NMDA receptor
14.  RETRACTED ARTICLE: Aging decreases rate of docosahexaenoic acid synthesis-secretion from circulating unesterified α-linolenic acid by rat liver 
Age  2012;35(3):597-608.
Docosahexaenoic acid (DHA, 22:6n-3), an n-3 polyunsaturated fatty acid (PUFA) found at high concentrations in brain and retina and critical to their function, can be obtained from fish products or be synthesized from circulating α-linolenic acid (α-LNA, 18:3n-3) mainly in the liver. With aging, liver synthetic enzymes are reported reduced or unchanged in the rat. To test whether liver synthesis-secretion of DHA from α-LNA changes with age, we measured whole-body DHA conversion coefficients and rates in unanesthetized adult male Fischer-344 rats aged 10, 20, or 30 months, fed an eicosapentaenoic acid (EPA, 20:5n-3)- and DHA-containing diet. Unesterified [U- 13 C]α-LNA bound to albumin was infused intravenously for 2 h, while [13 C]-esterified n-3 PUFAs were measured in arterial plasma, as were unlabeled unesterified and esterified PUFA concentrations. Plasma unesterified n-3 PUFA concentrations declined with age, but esterified n-3 PUFA concentrations did not change significantly. Calculated conversion coefficients were not changed significantly with age, whereas synthesis-secretion rates (product of conversion coefficient and unesterified plasma α-LNA concentration) of esterified DHA and n-3 DPA were reduced. Turnovers of esterified n-3 PUFAs in plasma decreased with age, whereas half-lives increased. The results suggest that hepatic capacity to synthesize DHA and other n-3 PUFAs from circulating α-LNA is maintained with age in the rat, but that reduced plasma α-LNA availability reduces net synthesis-secretion. As unesterified plasma DHA is the form that is incorporated preferentially into brain phospholipid, its reduced synthesis may be deleterious to brain function in aged rats.
doi:10.1007/s11357-012-9390-1
PMCID: PMC3636395  PMID: 22388930
Liver; Synthesis-secretion rate; Conversion; Aging; Age; Metabolism; Alpha-linolenic acid; n-3 Polyunsaturated fatty acids (n-3 PUFAs); Docosahexaenoic acid (DHA); Lipid
15.  Melatonin can improve insulin resistance and aging-induced pancreas alterations in senescence-accelerated prone male mice (SAMP8) 
Age  2012;35(3):659-671.
The aim of the present study was to investigate the effect of aging on several parameters related to glucose homeostasis and insulin resistance in pancreas and how melatonin administration could affect these parameters. Pancreas samples were obtained from two types of male mice models: senescence-accelerated prone (SAMP8) and senescence-accelerated-resistant mice (SAMR1). Insulin levels in plasma were increased with aging in both SAMP8 and SAMR1 mice, whereas insulin content in pancreas was decreased with aging in SAMP8 and increased in SAMR1 mice. Expressions of glucagon and GLUT2 messenger RNAs (mRNAs) were increased with aging in SAMP8 mice, and no differences were observed in somatostatin and insulin mRNA expressions. Furthermore, aging decreased also the expressions of Pdx-1, FoxO 1, FoxO 3A and Sirt1 in pancreatic SAMP8 samples. Pdx-1 was decreased in SAMR1 mice, but no differences were observed in the rest of parameters on these mice strains. Treatment with melatonin was able to decrease plasma insulin levels and to increase its pancreatic content in SAMP8 mice. In SAMR1, insulin pancreatic content and plasma levels were decreased. HOMA-IR was decreased with melatonin treatment in both strains of animals. On the other hand, in SAMP8 mice, treatment decreased the expression of glucagon, GLUT2, somatostatin and insulin mRNA. Furthermore, it was also able to increase the expression of Sirt1, Pdx-1 and FoxO 3A. According to these results, aging is associated with significant alterations in the relative expression of pancreatic genes associated to glucose metabolism. This has been especially observed in SAMP8 mice. Melatonin administration was able to improve pancreatic function in old SAMP8 mice and to reduce HOMA-IR improving their insulin physiology and glucose metabolism.
doi:10.1007/s11357-012-9397-7
PMCID: PMC3636397  PMID: 22411259
Pancreas; Aging; Melatonin; Senescence-accelerated mouse
16.  Neuromuscular adaptations to concurrent training in the elderly: effects of intrasession exercise sequence 
Age  2012;35(3):891-903.
The aim of this study was investigate the effects of different intrasession exercise orders in the neuromuscular adaptations induced by concurrent training in elderly. Twenty-six healthy elderly men (64.7 ± 4.1 years), were placed into two concurrent training groups: strength prior to (SE, n = 13) or after (ES, n = 13) endurance training. Subjects trained strength and endurance training during 12 weeks, three times per week performing both exercise types in the same training session. Upper and lower body one maximum repetition test (1RM) and lower-body isometric peak torque (PTiso) and rate of force development were evaluated as strength parameters. Upper and lower body muscle thickness (MT) was determined by ultrasonography. Lower-body maximal surface electromyographic activity of vastus lateralis and rectus femoris muscles (maximal electromyographic (EMG) amplitude) and neuromuscular economy (normalized EMG at 50 % of pretraining PTiso) were determined. Both SE and ES groups increased the upper- and lower-body 1RM, but the lower-body 1RM increases observed in the SE was higher than ES (35.1 ± 12.8 vs. 21.9 ± 10.6 %, respectively; P < 0.01). Both SE and ES showed MT increases in all muscles evaluated, with no differences between groups. In addition, there were increases in the maximal EMG and neuromuscular economy of vastus lateralis in both SE and ES, but the neuromuscular economy of rectus femoris was improved only in SE (P < 0.001). Performing strength prior to endurance exercise during concurrent training resulted in greater lower-body strength gains as well as greater changes in the neuromuscular economy (rectus femoris) in elderly.
doi:10.1007/s11357-012-9405-y
PMCID: PMC3636398  PMID: 22453934
Combined training; Electromiography; Muscle thickness; Aerobic exercise; Resistance exercise
17.  The role of the T cell in age-related inflammation 
Age  2012;35(3):563-572.
Ageing is accompanied by alterations to T-cell immunity and also by a low-grade chronic inflammatory state termed inflammaging. The significance of these phenomena is highlighted by their being predictors of earlier mortality. We have recently published that the proinflammatory cytokine TNFα is a strong inducer of CD4+ T-cell senescence and T-cell differentiation, adding to the growing body of literature implicating proinflammatory molecules in mediating these critical age-related T-cell alterations. Moreover, the inflammatory process is also being increasingly implicated in the pathogenesis of many common and severe age-related diseases, including cancer, cardiovascular diseases and type 2 diabetes. Furthermore, major age-related risk factors for poor health, such as obesity, stress and smoking, are also associated with an upregulation in systemic inflammatory markers. We propose the idea that the ensuing inflammatory response to influenza infection propagates cardiovascular diseases and constitutes a major cause of influenza-related mortality. While inflammation is not a negative phenomenon per se, this age-related dysregulation of inflammatory responses may play crucial roles driving age-related pathologies, T-cell immunosenescence and CMV reactivation, thereby underpinning key features of the ageing process.
doi:10.1007/s11357-012-9381-2
PMCID: PMC3636399  PMID: 22252437
Immunosenescence; Inflammaging; Influenza; Inflammation; TNFα; p38
18.  Molecular characterization of the transition to mid-life in Caenorhabditis elegans 
Age  2012;35(3):689-703.
We present an initial molecular characterization of a morphological transition between two early aging states. In previous work, an age score reflecting physiological age was developed using a machine classifier trained on images of worm populations at fixed chronological ages throughout their lifespan. The distribution of age scores identified three stable post-developmental states and transitions. The first transition occurs at day 5 post-hatching, where a significant percentage of the population exists in both state I and state II. The temperature dependence of the timing of this transition (Q10 ~ 1.17) is too low to be explained by a stepwise process with an enzymatic or chemical rate-limiting step, potentially implicating a more complex mechanism. Individual animals at day 5 were sorted into state I and state II groups using the machine classifier and analyzed by microarray expression profiling. Despite being isogenic, grown for the same amount of time, and indistinguishable by eye, these two morphological states were confirmed to be molecularly distinct by hierarchical clustering and principal component analysis of the microarray results. These molecular differences suggest that pharynx morphology reflects the aging state of the whole organism. Our expression profiling yielded a gene set that showed significant overlap with those from three previous age-related studies and identified several genes not previously implicated in aging. A highly represented group of genes unique to this study is involved in targeted ubiquitin-mediated proteolysis, including Skp1-related (SKR), F-box-containing, and BTB motif adaptors.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-012-9401-2) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-012-9401-2
PMCID: PMC3636400  PMID: 22610697
Machine classifier; Biomarker of aging; Metastable aging state; Microarray analysis
19.  Relationship between ventilatory function and age in master athletes and a sedentary reference population 
Age  2012;35(3):1007-1015.
Ageing is accompanied with a decline in respiratory function. It is hypothesised that this may be attenuated by high physical activity levels. We performed spirometry in master athletes (71 women; 84 men; 35–86 years) and sedentary people (39 women; 45 men; 24–82 years), and calculated the predicted lung age (PLA). The negative associations of age with forced expiratory volume in 1 s (FEV1; 34 mL·year−1) and other ventilatory parameters were similar in controls and master athletes. FEV1pred was 9 % higher (P < 0.005) and PLA 15 % lower (P = 0.013) in athletes than controls. There were no significant differences between endurance and power athletes and sedentary people in maximal inspiratory and expiratory pressure. Neither age-graded performance nor weekly training hours were significantly related to lung age. Life-long exercise does not appear to attenuate the age-related decrease in ventilatory function. The better respiratory function in master athletes than age-matched sedentary people might be due to self-selection and attrition bias.
doi:10.1007/s11357-012-9409-7
PMCID: PMC3636401  PMID: 22544616
FEV1; Lung age; Mouth pressure; Physical activity; Peak expiratory flow; Physical exercise
20.  Fitness, fatness and survival in elderly populations 
Age  2012;35(3):973-984.
This study examines the relative importance of fitness versus fatness in predicting mortality in elderly populations aged 70 years and over, and whether fitness may account for the ‘paradoxical’ relationship between better survival and increasing weight. Four thousand community-living Chinese men and women aged 65 years or over were recruited and stratified so that approximately 33% were in each of the age groups: 65–69, 70–74, and 75 or above. Medical history, height, weight, waist–hip ratio, body composition using DEXA, and walking speed were obtained. They were followed up for a mean of 7.0 years to ascertain death. Compared with the high fitness category, those in the moderate and low categories have a 43% and 68% increased risk of mortality at 7 years adjusting for multiple confounders. When mortality risk according to various fatness indicators was examined, only the lowest quartile of BMI, BFI, and FLMR conferred statistically significant increased risk. Fitness categories were significantly associated with all fatness indicators. The finding of fewer people in the high fitness category among the highest quartiles of other fatness indicators suggests that fitness is not the underlying mechanism for the obesity paradox. Within each quartile of fatness indicator, there was a significant trend towards reduced mortality with increasing fitness. In conclusion, the study confirms the beneficial effects of cardiorespiratory fitness on mortality but does not explain the ‘obesity paradox’. The findings underscore the importance of maintaining physical fitness through exercise and re-confirm the importance of weight maintenance in reducing mortality risk.
doi:10.1007/s11357-012-9398-6
PMCID: PMC3636403  PMID: 22391688
Body mass index; Body fat; Waist–hip ratio; Fitness; Mortality
21.  The interactions of oxidative stress and inflammation with vascular dysfunction in ageing: the vascular health triad 
Age  2012;35(3):705-718.
Oxidative stress and inflammation are increased with advancing age. Evidence suggests that oxidative stress and inflammation both lead to impaired vascular function. There is also evidence to suggest that inflammation may cause an increase in radical production leading to enhanced oxidative stress. In addition, oxidative stress may cause an increase in inflammation; however, the interactions between these factors are not fully understood. In this review, we propose the vascular health triad, which draws associations and interactions between oxidative stress and inflammation seen in ageing, and the consequences for vascular function. We review evidence suggesting that exercise may ameliorate the age-related decline in vascular function, through reductions in both oxidative stress and inflammation.
doi:10.1007/s11357-012-9402-1
PMCID: PMC3636404  PMID: 22453933
Reactive oxygen and nitrogen species; Nitric oxide; Free radical; Inflammatory response; Older age; Endothelium
22.  Cerebral blood flow and cerebrovascular reactivity at rest and during sub-maximal exercise: Effect of age and 12-week exercise training 
Age  2012;35(3):905-920.
Chronic reductions in cerebral blood flow (CBF) and cerebrovascular reactivity to CO2 are risk factors for cerebrovascular disease. Higher aerobic fitness is associated with higher CBF at any age; however, whether CBF or reactivity can be elevated following an exercise training intervention in healthy individuals is unknown. The aim of this study was to assess the effect of exercise training on CBF and cerebrovascular reactivity at rest and during exercise in young and older individuals. Ten young (23 ± 5 years; body mass index (BMI), 26 ± 3 kg m−2; \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ {\mathop{V}\limits^{ \cdot }{_{\text{O2}}}}\max $$\end{document}, 35 ± 5 ml kg−1 min−1) and 10 older (63 ± 5 years; BMI, 25 ± 3.0 kg m−2; \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ {\mathop{V}\limits^{ \cdot }{_{\text{O2}}}}\max $$\end{document}, 26 ± 4 ml kg-1 min−1) previously sedentary individuals breathed 5 % CO2 for 3 min at rest and during steady-state cycling exercise (30 and 70 % heart rate range (HRR)) prior to and following a 12-week aerobic exercise intervention. Effects of training on middle cerebral artery blood velocity (MCAv) at rest were unclear in both age groups. The absolute MCAv response to exercise was greater in the young (9 and 9 cm s−1 (30 and 70 % HRR, respectively) vs. 5 and 4 cm s−1 (older), P < 0.05) and was similar following training. Cerebrovascular reactivity was elevated following the 12-week training at rest (2.87 ± 0.76 vs. 2.54 ± 1.12 cm s−1 mm Hg−1, P = 0.01) and during exercise, irrespective of age. The finding of a training-induced elevation in cerebrovascular reactivity provides further support for exercise as a preventative tool in cerebrovascular and neurological disease with ageing.
doi:10.1007/s11357-012-9414-x
PMCID: PMC3636405  PMID: 22669592
Ageing; Exercise training; Fitness; Cerebral blood flow; CO2 reactivity
23.  Survivin expression increases during aging and enhances the resistance of aged human fibroblasts to genotoxic stress 
Age  2012;35(3):549-562.
Survivin, an important anti-apoptotic protein, is highly expressed in most cancers, which generally arise in cells of older individuals. We have shown here accumulation of survivin and phospho-survivin in aged normal human skin fibroblasts and mice organs. This age-related accumulation of survivin was due to protein stabilization through association with the molecular chaperone Hsp90 protein, which was also up-regulated during aging. Interestingly, Hsp90 binds preferentially to phospho-survivin, which explains its higher stability. In addition, we provide clear evidence that aged cells exhibit apoptosis resistance when challenged with UV light, cisplatin, γ-rays or H2O2 as compared to their younger counterparts. In response to γ-rays and H2O2, the levels of Bcl-2 and both forms of survivin were up-regulated in old cells, but not in their corresponding young ones. This repression of survivin and phospho-survivin in young cells is p53 dependent. Importantly, survivin inhibition/down-regulation with flavopiridol or specific shRNAs increased the apoptotic response of old fibroblasts to various genotoxic agents, and restored the pro-apoptotic Bax/Bcl2 ratio and the increase in the levels of cleaved caspase-3 and PARP in old cells. These results show the role of survivin in the age-dependent resistance of human fibroblasts, and provide new insights into the molecular mechanisms that underlie the complex relationship between aging, apoptosis, and cancer.
doi:10.1007/s11357-011-9378-2
PMCID: PMC3636406  PMID: 22252435
Aging; Apoptosis; Cancer; DNA damage; Survivin
24.  Cardiovascular risk in cognitively preserved elderlies is associated with glucose hypometabolism in the posterior cingulate cortex and precuneus regardless of brain atrophy and apolipoprotein gene variations 
Age  2012;35(3):777-792.
Cardiovascular risk factors (CVRF) possibly contribute to the emergence of Alzheimer's disease (AD). Fluorodeoxyglucose-positron emission tomography (FDG-PET) has been widely used to demonstrate specific patterns of reduced cerebral metabolic rates of glucose (CMRgl) in subjects with AD and in non-demented carriers of the apolipoprotein ε4 (APOE ε4) allele, the major genetic risk factor for AD. However, functional neuroimaging studies investigating the impact of CVRF on cerebral metabolism have been scarce to date. The present FDG-PET study investigated 59 cognitively preserved elderlies divided into three groups according to their cardiovascular risk based on the Framingham 10-year risk Coronary Heart Disease Risk Profile (low-, medium-, and high-risk) to examine whether different levels of CVRF would be associated with reduced CMRgl, involving the same brain regions affected in early stages of AD. Functional imaging data were corrected for partial volume effects to avoid confounding effects due to regional brain atrophy, and all analyses included the presence of the APOE ε4 allele as a confounding covariate. Significant cerebral metabolism reductions were detected in the high-risk group when compared to the low-risk group in the left precuneus and posterior cingulate gyrus. This suggests that findings of brain hypometabolism similar to those seen in subjects with AD can be detected in association with the severity of cardiovascular risk in cognitively preserved individuals. Thus, a greater knowledge about how such factors influence brain functioning in healthy subjects over time may provide important insigths for the future development of strategies aimed at delaying or preventing the vascular-related triggering of pathologic brain changes in the AD.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-012-9413-y) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-012-9413-y
PMCID: PMC3636408  PMID: 22544617
Aging; Alzheimer's disease; Positron emission tomography; Framingham Heart Study Risk Score; Apolipoprotein E
25.  Zinc: dietary intake and impact of supplementation on immune function in elderly 
Age  2012;35(3):839-860.
The diet in the elderly does not provide a sufficient level of nutrients needed to maintain an adequate healthy status leading to micronutrient deficiencies and impaired immune response with subsequent development of degenerative diseases. Nutrient “zinc” is a relevant micronutrient involved in maintaining a good integrity of many body homeostatic mechanisms, including immune efficiency, owing to its requirement for the biological activity of many enzymes, proteins and for cellular proliferation and genomic stability. Old people aged 60–65 years and older have zinc intakes below 50% of the recommended daily allowance on a given day. Many causes can be involved: among them, altered intestinal absorption, inadequate mastication, psychosocial factors, drugs interactions, altered subcellular processes (zinc transporters (Zip and ZnT family), metallothioneins, divalent metal transporter-1). Zinc supplementation may remodel the immune alterations in elderly leading to healthy ageing. Several zinc trials have been carried out with contradictory data, perhaps due to incorrect choice of an effective zinc supplementation in old subjects showing subsequent zinc toxic effects on immunity. Old subjects with specific IL-6 polymorphism (GG allele carriers; named C−) are more prone for zinc supplementation than the entire old population, in whom correct dietary habits with foods containing zinc (Mediterranean diet) may be sufficient in restoring zinc deficiency and impaired immune response. We summarise the main causes of low zinc dietary intake in elderly reporting an update on the impact of zinc supplementation upon the immune response also on the basis of individual IL-6 polymorphism.
doi:10.1007/s11357-011-9377-3
PMCID: PMC3636409  PMID: 22222917
Dietary zinc intake; Zinc intestinal absorption; Zinc supplementation; IL-6 polymorphism; Ageing; Immunosenescence

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