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1.  Dehydroepiandrosterone and age-related cognitive decline 
Age  2009;32(1):61-67.
In humans the circulating concentrations of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) decrease markedly during aging, and have been implicated in age-associated cognitive decline. This has led to the hypothesis that DHEA supplementation during aging may improve memory. In rodents, a cognitive anti-aging effect of DHEA and DHEAS has been observed but it is unclear whether this effect is mediated indirectly through conversion of these steroids to estradiol. Moreover, despite the demonstration of correlations between endogenous DHEA concentrations and cognitive ability in certain human patient populations, such correlations have yet to be convincingly demonstrated during normal human aging. This review highlights important differences between rodents and primates in terms of their circulating DHEA and DHEAS concentrations, and suggests that age-related changes within the human DHEA metabolic pathway may contribute to the relative inefficacy of DHEA replacement therapies in humans. The review also highlights the value of using nonhuman primates as a pragmatic animal model for testing the therapeutic potential of DHEA for age-associate cognitive decline in humans.
doi:10.1007/s11357-009-9113-4
PMCID: PMC2829637  PMID: 19711196
Dehydroepiandrosterone; Cognitive decline; Intracrinology; Neurosteroidogenesis
2.  Dehydroepiandrosterone and age-related cognitive decline 
Age (Dordrecht, Netherlands)  2009;32(1):61-67.
In humans the circulating concentrations of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) decrease markedly during aging, and have been implicated in age-associated cognitive decline. This has led to the hypothesis that DHEA supplementation during aging may improve memory. In rodents, a cognitive anti-aging effect of DHEA and DHEAS has been observed but it is unclear whether this effect is mediated indirectly through conversion of these steroids to estradiol. Moreover, despite the demonstration of correlations between endogenous DHEA concentrations and cognitive ability in certain human patient populations, such correlations have yet to be convincingly demonstrated during normal human aging. This review highlights important differences between rodents and primates in terms of their circulating DHEA and DHEAS concentrations, and suggests that age-related changes within the human DHEA metabolic pathway may contribute to the relative inefficacy of DHEA replacement therapies in humans. The review also highlights the value of using nonhuman primates as a pragmatic animal model for testing the therapeutic potential of DHEA for age-associate cognitive decline in humans.
doi:10.1007/s11357-009-9113-4
PMCID: PMC2829637  PMID: 19711196
Dehydroepiandrosterone; Cognitive decline; Intracrinology; Neurosteroidogenesis
3.  The effect of n-3 fatty acids on bone biomarkers in Iranian postmenopausal osteoporotic women: a randomized clinical trial 
Age  2009;32(2):179-186.
Recently, n-3 fatty acids are in the center of attention for their potent anti-inflammatory effects. Osteoporosis as a chronic senile disease is associated with inflammation, and the role of inflammatory mediators has been demonstrated in recent years. The beneficial effects of n-3 fatty acids on bone were proven in many animal studies, while to date, no conclusive data is available in human. The aim of this study was to evaluate the impact of n-3 fatty acids on bone biomarkers in osteoporotic postmenopausal women. Twenty-five osteoporotic postmenopausal women were recruited in the study and randomized in treatment and control groups. The patients received 900 mg n-3 fatty acid capsules or placebo per day for 6 months. Serum levels of osteocalcin, bone alkaline phosphatase (BALP), calcium, vitamin D, and parathormone and urine concentration of pyridinoline (Pyd) were measured at baseline, second month, and sixth month in both groups. In the treatment group, compared with baseline, at the second month, osteocalcin increased slightly; thereafter, it showed decrement trend until the end of the study. In the control group, it decreased all over the study. None of these changes was significant. BALP showed nonsignificant decrease from baseline over the time in both groups. Urine level of Pyd decreased significantly (P < 0.05) in the treatment group, while no significant change was seen in the control group. Serum calcium and vitamin D increased in both groups; however, changes were not significant. No significant changes were seen in calcium clearance and parathormone. In conclusion, n-3 fatty acids can decrease bone resorption; however, it could not affect bone formation significantly after 6 months treatment. Further investigations are recommended.
doi:10.1007/s11357-009-9122-3
PMCID: PMC2861748  PMID: 19967563
Osteoporosis; n-3 fatty acids; Osteocalcin; Bone alkaline phosphatase; Pyridinoline
4.  What determines age-related disease: do we know all the right questions? 
Age  2009;32(2):155-160.
The average human lifespan has increased throughout the last century due to the mitigation of many infectious diseases. More people now die of age-related diseases than ever before, but these diseases have been resistant to elimination. Progress has been made in treatments and preventative measures to delay the onsets of these diseases, but most cancers and vascular diseases are still with us and they kill about the same fraction of the population year after year. For example, US Caucasian female deaths from breast plus genital cancers have remained a fairly constant ~7% of the age-related disease deaths from 1938 to 1998 and have been consistently ~2-fold greater than female colon plus rectal cancer deaths over that span. This type of stability pattern pervades the age-related diseases and suggests that intrinsic properties within populations determine these fractions. Recognizing this pattern and deciphering its origin will be necessary for the complete understanding of these major causes of death. It would appear that more than the random processes of aging drive this effect. The question is how to meaningfully approach this problem. This commentary discusses the epidemiological and aging perspectives and their current limitations in providing an explanation. The age of bioinformatics offers hope, but only if creative systems approaches are forthcoming.
doi:10.1007/s11357-009-9120-5
PMCID: PMC2861754  PMID: 19904627
Disease; Aging; Epidemiology; Bioinformatics; Genetics; Failure mechanisms
5.  Both endoplasmic reticulum and mitochondria are involved in disc cell apoptosis and intervertebral disc degeneration in rats 
Age  2009;32(2):161-177.
Intervertebral disc cell apoptosis occurs through either death receptor or mitochondrial pathway, but whether disc cell apoptosis is also mediated by the endoplasmic reticulum (ER) pathway remains unclear. The objective of this study was to investigate whether ER and mitochondria are co-involved in disc cell apoptosis and intervertebral disc degeneration (IVDD) in rats. Forty-eight rats were used for in vivo experiments. IVDD was characterized by X-ray and histomorphology examination, disc cell apoptosis was detected by TUNEL staining, and the co-involvement of ER and mitochondria in apoptosis was determined by immunohistochemical staining for GRP78, GADD153, caspase-12, and cytochrome C. Additional eight rats were used for annular cell isolation and culture. After sodium nitroprusside treatment, annular cell apoptosis was observed morphologically and quantified by flow cytometry; the expression of biomarkers of ER stress and mitochondrial dysfunction were analyzed by reverse transcriptase PCR (RT-PCR), fluorescence double labeling, and Western blot; and mitochondrial membrane potential was detected by 5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolcarbo cyanine iodide (JC-1) staining. Finally, NS3694 and Z-ATAD-FMK were employed to inhibit the formation of apoptosome complex and the activation of caspase-12, respectively, and apoptotic incidence and caspase-9 activity were assayed. We found that IVDD, induced by unbalanced dynamic and static forces in the rats, was accompanied by increased disc cell apoptosis and enhanced expression of GRP78, GADD153, caspase-12, and cytochrome C. Annular cell apoptosis induced by sodium nitroprusside was confirmed by morphologic observation and flow cytometry. With increased apoptosis, the expression of GRP78, GADD153, and caspase-12 upregulated, mitochondrial membrane potential decreased, and accumulation of cytochrome C in the cytosol manifested. Furthermore, NS3694 and Z-ATAD-FMK dramatically suppress annular cell apoptosis and caspase-9 activity. In conclusion, disc cell apoptosis mediated simultaneously by ER and mitochondria plays a potent role in IVDD.
doi:10.1007/s11357-009-9121-4
PMCID: PMC2861755  PMID: 19960285
Intervertebral disc degeneration; Apoptosis; Endplasmic reticulum; Mitochondria
6.  Female fertility and longevity 
Age  2009;32(1):79-84.
Does bearing children shorten a woman’s life expectancy? Pleiotropic theories of aging predict that it should, and in particular, the Disposable Soma theory predicts unequivocally that this effect should be inescapable. But many demographic studies, historic and current, have found no such effect. In this context, the Caerphilly cohort study stands apart as the sole test that corroborates the theory. Why has this study found an effect that others fail to see? Their analysis is based on Poisson regression, a statistical technique that is accurate only if the underlying data are Poisson-distributed. But the distribution of the number of children born to women in the Caerphilly database departs strongly from Poisson at the high end. This makes the result overly sensitive to a handful of women with 15 children or more who lived before 1700. When these five women are removed from a database of more than 2,900, the Poisson regression no longer shows a significant result. Bilinear regression relating life span to fertility and date of birth results in a small positive coefficient for fertility, in agreement with the main trend of reported results.
doi:10.1007/s11357-009-9116-1
PMCID: PMC2829636  PMID: 19731082
Disposable soma; Pleiotropy; Senescence; Aging; Fertility; Life history; Tradeoff
7.  Thermoregulation in mice exhibits genetic variability early in senescence 
Age  2009;32(1):31-37.
Aging leads to a loss of thermoregulation that can be readily monitored in laboratory mice. However, it is unclear from previous studies—we provide a tabular summary of 15 articles—whether significant loss occurs by midlife (∼15 months of age). In this study, we examined 34 females from 22 LSXSS strains starting at 4 and 8 months of age (17 mice per age group). We used transponders inserted just under the loose skin of the pelt and calibrated against rectal body temperature to measure temperatures quickly without restraint. We found that the mean body temperatures measured 5 months later (9 and 13 months of age) had dropped significantly below normal in both groups: 0.6ºC lower in the younger cohort and 1.0ºC lower in the older cohort. These drops were not associated with weight loss or signs of pathology. Notably, the loss of thermoregulation between 8 and 13 months of age also exhibited genetic variation that was highly significant (P = 0.004). Such variation is potentially a powerful tool for determining the cause of thermoregulatory loss with age and whether this loss predicts senescence changes later in life, including the force of mortality.
doi:10.1007/s11357-009-9109-0
PMCID: PMC2829639  PMID: 19669936
Aging; Body temperature; Genetics; LSXSS; Mice; Thermoregulation
8.  Revealing system-level correlations between aging and calorie restriction using a mouse transcriptome 
Age  2009;32(1):15-30.
Although systems biology is a perfect framework for investigating system-level declines during aging, only a few reports have focused on a comprehensive understanding of system-level changes in the context of aging systems. The present study aimed to understand the most sensitive biological systems affected during aging and to reveal the systems underlying the crosstalk between aging and the ability of calorie restriction (CR) to effectively slow-down aging. We collected and analyzed 478 aging- and 586 CR-related mouse genes. For the given genes, the biological systems that are significantly related to aging and CR were examined according to three aspects. First, a global characterization by Gene Ontology (GO) was performed, where we found that the transcriptome (a set of genes) for both aging and CR were strongly related in the immune response, lipid metabolism, and cell adhesion functions. Second, the transcriptional modularity found in aging and CR was evaluated by identifying possible functional modules, sets of genes that show consistent expression patterns. Our analyses using the given functional modules, revealed systemic interactions among various biological processes, as exemplified by the negative relation shown between lipid metabolism and the immune response at the system level. Third, transcriptional regulatory systems were predicted for both the aging and CR transcriptomes. Here, we suggest a systems biology framework to further understand the most important systems as they age.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-009-9106-3) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-009-9106-3
PMCID: PMC2829640  PMID: 19590981
Aging; Calorie restriction; Systems biology; Transcriptome analysis
9.  Chronic 17β-estradiol treatment improves skeletal muscle insulin signaling pathway components in insulin resistance associated with aging 
Age  2009;32(1):1-13.
Insulin resistance is a common feature of aging in both humans and rats. In the case of females, it seems to be related to loss of gonadal function, due mainly due to a decrease in plasma estrogen levels. Several causes have been postulated for this insulin resistance, among them changes in several steps of the insulin pathway. In view of these findings, the purpose of the present study was to examine the role of chronic 17β-estradiol treatment on insulin sensitivity during the aging process, and its effects on levels of the insulin-sensitive glucose transporter Glut4 (both total and plasma membrane localized), the interaction between p85α subunit of PI3-k and IRS-1, Tyr- and Ser-612 phosphorylation of IRS-1 levels, and Ser-473 phosphorylation of Akt. The present findings indicate that 17β-estradiol treatment is able to minimize the deleterious effect of aging on insulin sensitivity, at least at the level of plasma membrane localized Glut4. Nevertheless further research is needed to determine this conclusively.
doi:10.1007/s11357-009-9095-2
PMCID: PMC2829641  PMID: 19462258
Aging; Insulin resistance; 17β-estradiol; Glut4; Akt, p85α; IRS-1
10.  The effect of old age on apolipoprotein E and its receptors in rat liver 
Age  2009;32(1):69-77.
Apolipoprotein E (apoE) is associated with aging and some age-related diseases. The majority of apoE is produced by hepatocytes for the receptor-mediated uptake of lipoproteins. Here, the effects of age on the hepatic expression and distribution of apoE and its receptors were determined using immunofluorescence, Western blots, and quantitative PCR in rat liver tissue and isolated hepatocytes. The expression of apoE mRNA and protein was not influenced significantly by aging. Immunofluorescence studies in isolated hepatocytes showed that apoE was more likely to be co-localized with early endosomes, golgi, and microtubules in isolated old hepatocytes. The mRNA expression of the receptor involved in sequestration of apoE, heparan sulfate proteoglycan was reduced in old age, without any significant effect on the expression of either the low-density lipoprotein receptor or low density-lipoprotein receptor-related protein. Old age is associated with changes in hepatic apoE intracellular trafficking and heparan sulfate proteoglycan expression that might contribute to age-related disease.
doi:10.1007/s11357-009-9115-2
PMCID: PMC2829642  PMID: 19809892
Apolipoprotein E; Liver; Hepatocyte; Ageing; Aging; Low-density lipoprotein receptor; Low density-lipoprotein receptor-related protein; Heparan sulfate proteoglycan
11.  Effects of long-term calorie restriction and endurance exercise on glucose tolerance, insulin action, and adipokine production 
Age  2009;32(1):97-108.
Calorie restriction (CR) slows aging and is thought to improve insulin sensitivity in laboratory animals. In contrast, decreased insulin signaling and/or mild insulin resistance paradoxically extends maximal lifespan in various genetic animal models of longevity. Nothing is known regarding the long-term effects of CR on glucose tolerance and insulin action in lean healthy humans. In this study we evaluated body composition, glucose, and insulin responses to an oral glucose tolerance test and serum adipokines levels in 28 volunteers, who had been eating a CR diet for an average of 6.9 ± 5.5 years, (mean age 53.0 ± 11 years), in 28 age-, sex-, and body fat-matched endurance runners (EX), and 28 age- and sex-matched sedentary controls eating Western diets (WD). We found that the CR and EX volunteers were significantly leaner than the WD volunteers. Insulin sensitivity, determined according to the HOMA-IR and the Matsuda and DeFronzo insulin sensitivity indexes, was significantly higher in the CR and EX groups than in the WD group (P = 0.001). Nonetheless, despite high serum adiponectin and low inflammation, ∼40% of CR individuals exhibited an exaggerated hyperglycemic response to a glucose load. This impaired glucose tolerance is associated with lower circulating levels of IGF-1, total testosterone, and triiodothyronine, which are typical adaptations to life-extending CR in rodents.
doi:10.1007/s11357-009-9118-z
PMCID: PMC2829643  PMID: 19904628
Calorie restriction; Endurance exercise; Glucose tolerance; Insulin action; Adipokines; Glycation
12.  Ageing of the postural vertical 
Age  2009;32(1):51-60.
A postural vertical (PV) tilted backward has been put forward as a reason explaining the backward disequilibrium often observed in elderly fallers. This raises the question of a possible ageing process of the PV involving a backward tilt of verticality perception increasing with age. We have explored this hypothesis by measuring PV in pitch using the wheel paradigm in 87 healthy subjects aged from 20 to 97 years. The possibility that this physiological ageing accelerated in the second part of life was also analysed. Two indices were calculated: the mean orientation (PV-orient) and the dispersion (PV-uncert). The correlation between age and PV-orient was r = −0.2 (p < 0.05). Added to the fact that PV was twice as shifted backward in the 38 seniors over 50 years (−1.15° ± 1.40°) as in the 49 young adults under 50 years (−0.45° ± 0.97°; t = 2.75, p < 0.01), this indicates the existence of a physiological ageing process on the direction perceived as vertical by the whole body, with a slight backward shift of PV throughout the life span. The correlation between age and PV-uncert was r = 0.35 (p < 0.001) in all subjects and r = 0.59 (p < 0.001) in seniors. This indicates that subjects get less and less accurate in their perception of the postural vertical with age, especially very old subjects who show great uncertainty in determining with their body the direction of the vertical. Taken together, these findings indicate that the internal model of verticality is less robust in elderly people. This may play a part in their postural decline.
doi:10.1007/s11357-009-9112-5
PMCID: PMC2829644  PMID: 19711197
Verticality; Postural control; Subjective vertical; Postural vertical; Ageing
13.  Apolipoprotein D synthesis progressively increases in frontal cortex during human lifespan 
Age  2009;32(1):85-96.
Apolipoprotein D (apo D) is a lipocalin present in the nervous system that may be related to processes of reinnervation, regeneration and neuronal cell protection. On the other hand, apo D expression has been correlated, in some brain regions, with normal ageing and neurodegenerative diseases. To elucidate the regional and cellular expression of apo D in normal human brain during ageing, we performed a detailed and extensive study in samples of post-mortem human cerebral cortices. To achieve this study, slot-blot techniques, for protein and mRNA, as well as immunohistochemistry and hybridohistochemistry methods, were used. A positive correlation for apo D expression with ageing was found; furthermore, mRNA levels, as well as the protein ones, were higher in the white than in the grey matter. Immunohistochemistry and non-isotopic in situ hybridization showed that apo D is synthesised in both neurons and glial cells. Apo D expression is notorious in oligodendrocytes, but with ageing, the number of neurons that synthesise apo D is increased. Our results indicate that apo D could play a fundamental role in central nervous system ageing and in the reduction of products derived from lipid peroxidation. The increment in the expression of apo D with ageing can be included in a global mechanism of cellular protection to prevent the deleterious effects caused by ageing.
doi:10.1007/s11357-009-9117-0
PMCID: PMC2829646  PMID: 19936966
Apolipoprotein D; Ageing; Human; Frontal cortex; In situ hybridization; Immunohistochemistry
14.  Evidence for only two independent pathways for decreasing senescence in Caenorhabditis elegans 
Age  2009;32(1):39-49.
Cold temperature, dietary restriction, reduced insulin/insulin-like growth factor signaling, and mutations in mitochondrial genes have all been shown to extend the lifespan of Caenorhabditis elegans (Kenyon et al., Nature 366:461–464, 1993; Klass, Mech Ageing Dev 6:413–429, 1977; Lakowski and Hekimi, Science 272:1010–1013, 1996). Additionally, all of them extend the lifespan of mice (Bluher et al., Science 299:572–574, 2003; Conti et al., Science 314:825–828, 2006; Holzenberger et al., Nature 421:182–187, 2003; Liu et al., Genes Dev 19:2424–2434, 2005; Weindruch and Walford, Science 215:1415–1418, 1982). The mechanism by which these treatments extend lifespan is currently unknown, but our study uses an epistatic approach to show that these four manipulations are mainly additive in terms of lifespan. Classical interpretation of this data suggests that these manipulations are independent of each other. However, using a Gompertz mortality rate analysis, the maximum mortality rate doubling time can be achieved through the use of only dietary restriction and cold temperature, suggesting that the mechanisms by which cold temperature and caloric restriction extend lifespan are the only independent mechanisms.
doi:10.1007/s11357-009-9110-7
PMCID: PMC2829647  PMID: 19662517
Caenorhabditis elegans; Aging; Lifespan; Gompertz analysis
15.  Alteration of Aβ metabolism-related molecules in predementia induced by AlCl3 and d-galactose 
Age  2009;31(4):277-284.
The purpose of this study was to look for alterations in β-amyloid peptide (Aβ) metabolism-related molecules in predementia, the early stage of Alzheimer’s disease (AD). AlCl3 (Al) and d-galactose (D-gal) were used to induce the mouse model for predementia and AD. Protein expression of β-amyloid (Aβ), β-secretase (BACE1), neprilysin (NEP), insulin degrading enzyme (IDE) and receptor for advanced glycation end products (RAGE) in the brain was measured. The results indicated that Al + D-gal induced an AD-like behavioral deficit at 90 days. The period from 45 to 75 days showed no significant behavioral deficit, and we tentatively define this as predementia in this model. A significant increase in BACE1 and decreasing NEP characterized days 45–90 in the cortex and hippocampus. However, high Aβ occurred at day 60. IDE increased from day 60 to day 75. There was no change in RAGE. The results suggest that the observed changes in BACE1, NEP and Aβ in predementia might relate to a different stage of the AD-like pathology, which may be developed into useful biomarkers for the diagnosis of very early AD.
doi:10.1007/s11357-009-9099-y
PMCID: PMC2813045  PMID: 19468866
Predementia; β-Amyloid; β-Secretase; Neprilysin
16.  Cellular senescence: unravelling complexity 
Age  2009;31(4):353-363.
Cellular senescence might be a tumour suppressing mechanism as well as a contributor to age-related loss of tissue function. It has been characterised classically as the result of the loss of DNA sequences called telomeres at the end of chromosomes. However, recent studies have revealed that senescence is in fact an intricate process, involving the sequential activation of multiple cellular processes, which have proven necessary for the establishment and maintenance of the phenotype. Here, we review some of these processes, namely, the role of mitochondrial function and reactive oxygen species, senescence-associated secreted proteins and chromatin remodelling. Finally, we illustrate the use of systems biology to address the mechanistic, functional and biochemical complexity of senescence.
doi:10.1007/s11357-009-9108-1
PMCID: PMC2813046  PMID: 19618294
Senescence; Oxidative stress; Mitochondria; Secretory phenotype; Systems biology; Interactomes
17.  Could Sirt1-mediated epigenetic effects contribute to the longevity response to dietary restriction and be mimicked by other dietary interventions? 
Age  2009;31(4):327-341.
Dietary restriction (DR) increases lifespan in a range of evolutionarily distinct species. The polyphenol resveratrol may be a dietary mimetic of some effects of DR. The pivotal role of the mammalian histone deacetylase (HDAC) Sirt1, and its homologue in other organisms, in mediating the effects of both DR and resveratrol on lifespan/ageing suggests it may be the common conduit through which these dietary interventions influence ageing. We propose the novel hypothesis that effects of DR relevant to lifespan extension include maintenance of DNA methylation patterns through Sirt1-mediated epigenetic effects, and proffer the view that dietary components, including resveratrol, may mimic these actions.
doi:10.1007/s11357-009-9104-5
PMCID: PMC2813047  PMID: 19568959
Dietary restriction; Sirt1; Resveratrol; Epigenetics; DNA methylation; Histone acetylation
18.  Liver X receptor β: maintenance of epidermal expression in intrinsic and extrinsic skin aging 
Age  2009;31(4):365-372.
Aging in human skin is the composite of time-dependent intrinsic aging plus photoaging induced by chronic exposure to ultraviolet radiation. Nuclear hormone receptors coordinate diverse processes including metabolic homeostasis. Liver X receptor β (LXRβ) is a close human homologue of daf-12, a regulator of nematode longevity. LXRβ is positively regulated by sirtuin-1 and resveratrol, while LXRβ-null mice show transcriptional profiles similar to those seen in aged human skin. In these studies, we examined LXRβ expression in aged and photoaged human skin. Volunteers were recruited to assess intrinsic aging and photoaging. Epidermal LXRβ mRNA was examined by in situ hybridization while protein was identified by immunofluorescence. No significant changes were observed in either LXRβ mRNA or protein expression between young and aged volunteers (mRNA p = 0.90; protein p = 0.26). Similarly, LXRβ protein expression was unaltered in photoaged skin (p = 0.75). Our data therefore suggest that, while not playing a major role in skin aging, robust cutaneous expression implies a fundamental role for LXRβ in epidermal biology.
doi:10.1007/s11357-009-9111-6
PMCID: PMC2813049  PMID: 19697157
Nuclear hormone receptors; Skin; Aging; Liver X receptor
19.  Nitrones for understanding and ameliorating the oxidative stress associated with aging 
Age  2009;31(4):269-276.
Oxidative damage from reactive oxygen species (ROS) and the carbon-centred radicals arising from them is important to the process of aging, and age-related diseases are generally caused, exacerbated or mediated by oxidative stress. Nitrones can act as spin traps to detect, identify, quantify and locate the radicals responsible using electron paramagnetic resonance (EPR or ESR) spectroscopy, and a new carnitine-derived nitrone, CarnDOD-7C, designed to accumulate in mitochondria is reported. Nitrones also have potential as therapeutic antioxidants, e.g. for slowing cellular aging, and as tools for chemical biology. Two low-molecular weight nitrones, DIPEGN-2 and DIPEGN-3, are reported, which combine high water-solubility with high lipophilicity and obey Lipinski's rule of five.
doi:10.1007/s11357-009-9098-z
PMCID: PMC2813050  PMID: 19479343
Aging; Oxidative stress; Reactive oxygen species; Radicals; Electron paramagnetic resonance spectroscopy; Nitrones; Antioxidants
20.  Chemical changes in aging Drosophila melanogaster 
Age  2009;31(4):343-351.
The “Green Theory” of aging proposes that organismal lifespan is limited by the failure to repair molecular damage generated by a broad range of metabolic processes. Two specific predictions arise from this: (1) that these processes will produce a wide variety of stable but dysfunctional compounds that increase in concentration with age, and (2) that organisms maintained under conditions that extend lifespan will display a reduced rate of accumulation of such “molecular rubbish”. To test these predictions, novel analytical techniques were developed to investigate the accumulation of damaged compounds in Drosophila melanogaster. Simple preparative techniques were developed to produce digests of whole D. melanogaster for use in three-dimensional (3D) fluorimetry and 1H NMR spectrometry. Cohorts of Drosophila maintained under normal conditions showed an age-related increase in signals consistent with damage whereas those maintained under conditions of low temperature and dietary restriction did not. 1H NMR revealed distinct age-associated spectral changes that will facilitate the identification of novel compounds that both increase and decrease during aging in this species. These findings are consistent with the predictions of the “Green Theory”.
doi:10.1007/s11357-009-9105-4
PMCID: PMC2813051  PMID: 19585275
Drosophila melanogaster; Aging; Green theory; Oxidative damage; Glycation; Spectroscopy
21.  Tissue elasticity and the ageing elastic fibre 
Age  2009;31(4):305-325.
The ability of elastic tissues to deform under physiological forces and to subsequently release stored energy to drive passive recoil is vital to the function of many dynamic tissues. Within vertebrates, elastic fibres allow arteries and lungs to expand and contract, thus controlling variations in blood pressure and returning the pulmonary system to a resting state. Elastic fibres are composite structures composed of a cross-linked elastin core and an outer layer of fibrillin microfibrils. These two components perform distinct roles; elastin stores energy and drives passive recoil, whilst fibrillin microfibrils direct elastogenesis, mediate cell signalling, maintain tissue homeostasis via TGFβ sequestration and potentially act to reinforce the elastic fibre. In many tissues reduced elasticity, as a result of compromised elastic fibre function, becomes increasingly prevalent with age and contributes significantly to the burden of human morbidity and mortality. This review considers how the unique molecular structure, tissue distribution and longevity of elastic fibres pre-disposes these abundant extracellular matrix structures to the accumulation of damage in ageing dermal, pulmonary and vascular tissues. As compromised elasticity is a common feature of ageing dynamic tissues, the development of strategies to prevent, limit or reverse this loss of function will play a key role in reducing age-related morbidity and mortality.
doi:10.1007/s11357-009-9103-6
PMCID: PMC2813052  PMID: 19588272
Elastic fibres; Elastin; Fibrillin microfibrils; Biomechanics; Ageing
22.  Circadian clock resetting in the mouse changes with age 
Age  2009;31(4):293-303.
The most widely recognised consequence of normal age-related changes in biological timing is the sleep disruption that appears in old age and diminishes the quality of life. These sleep disorders are part of the normal ageing process and consist primarily of increased amounts of wakefulness and reduced amounts of deep sleep. Changes in the amplitude and timing of the sleep-wake cycle appear to represent, at least in part, a loss of effective circadian regulation of sleep. Understanding alterations in the characteristics of stimuli that help to consolidate internal rhythms will lead to recommendations to improve synchronisation in old age. Converging evidence from both human and animal studies indicate that senescence is associated with alterations in the neural structure thought to be primarily responsible for the generation of the circadian oscillation, the suprachiasmatic nuclei (SCN). Work has shown that there are changes in the anatomy, physiology and ability of the clock to reset in response to stimuli with age. Therefore it is possible that at least some of the observed age-related changes in sleep and circadian timing could be mediated at the level of the SCN. The SCN contain a circadian clock whose activity can be recorded in vitro for several days. We have tested the response of the circadian clock to a number of neurochemicals that reset the clock in a manner similar to light, including glutamate, N-methyl-D-aspartate (NMDA), gastrin-releasing peptide (GRP) and histamine (HA). In addition, we have also tested agents which phase shift in a pattern similar to behavioural ‘non-photic’ signals, including neuropeptide Y (NPY), serotonin (5HT) and gamma-aminobutyric acid (GABA). These were tested on the circadian clock in young and older mice (approximately 4 and 15 months old). We found deficits in the response to specific neurochemicals but not to others in our older mice. These results indicate that some changes seen in the responsiveness of the circadian clock to light with age may be mediated at the level of the SCN. Further, the responsiveness of the circadian clock with age is attenuated to some, but not all stimuli. This suggests that not all clock stimuli loose their effectiveness with age, and that it may be possible to compensate for deficits in clock performance by enhancing the strength of those stimulus pathways which are intact.
doi:10.1007/s11357-009-9102-7
PMCID: PMC2813053  PMID: 19557547
Circadian; Brain slice; Suprachiasmatic
23.  KLRG1—more than a marker for T cell senescence 
Age  2009;31(4):285-291.
The co-inhibitory receptor killer-cell lectin like receptor G1 (KLRG1) is expressed on NK cells and antigen-experienced T cells and has been postulated to be a marker of senescence. Whilst KLRG1 has frequently been used as a marker of cellular differentiation, data are emerging indicating that KLRG1 plays an inhibitory role. In this review we examine evidence highlighting this view of KLRG1 with emphasis on the functional defects that arise during T cell differentiation with age that may, in part, be actively maintained by inhibitory receptor signalling.
doi:10.1007/s11357-009-9100-9
PMCID: PMC2813054  PMID: 19479342
KLRG1; Inhibitory; ITIM; Highly differentiated T cell
24.  Frontiers proposal. National Institute on Aging “bench to bedside: estrogen as a case study” 
Age  2009;31(3):199-210.
On 28–29 September 2004, the National Institute on Aging (NIA) convened scientists for a workshop on the aging female brain focused on translating into clinical practice discoveries concerning estrogens and progestogens. Workshop objectives were to examine effects of estrogen and progestogen on brain and cognitive function in relation to aging, to examine consistencies and apparent discrepancies between Women’s Health Initiative Memory Study findings and other research on cognitive function, to determine whether additional hormone interventions could be developed in this area, and to offer advice on design of clinical trials for other interventions that might ameliorate cognitive aging. Following the workshop, participants joined by other interested scientists organized into regional work groups to continue the dialogue begun in Bethesda and to propose recommendations for NIA. The resulting recommendations, referred to as the “Frontiers Proposal for Estrogen and Cognitive Aging”, acknowledge the persistence of critical gaps in our understanding of how decline in ovarian steroid secretion during reproductive aging and use of ovarian steroid hormone therapy affect normal brain function and risk for late-life neurodegenerative disorders such as Alzheimer’s disease. There is a pressing need for preclinical, human, and integrated studies on the relationship between the menopausal transition and midlife exposures to estrogens, progestogens and related compounds, and risks for age-associated cognitive disorders. Research is also needed on better predictors of adverse cognitive outcomes, valid biomarkers for risks associated with hormone therapy use, enhanced tools for monitoring brain function and disease progression, and novel forms of therapy for improving long-term cognitive outcomes.
doi:10.1007/s11357-009-9087-2
PMCID: PMC2734241  PMID: 19277902
Aging; Alzheimer’s disease; Cognition; Dementia; Estrogen; Menopause; Progestogen
25.  Women’s cognitive health special edition 
Age  2009;31(3):189-190.
doi:10.1007/s11357-009-9090-7
PMCID: PMC2734242  PMID: 19277900

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