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1.  Mitochondrial oxidative damage and apoptosis in age-related hearing loss 
Age-related hearing loss (AHL) is a universal feature of mammalian aging and is the most common sensory disorder in the elderly population. Experimental evidence suggests that mitochondrial dysfunction associated with reactive oxygen species (ROS) plays a central role in the aging process of cochlear cells. Although it is well established that mitochondria are the major source of ROS in the cell, specific molecular mechanisms of aging induced by ROS remain poorly characterized. Here we review the evidence that supports a central role for Bak-mediated mitochondrial apoptosis in AHL. We also propose that this mechanism may be of general relevance to age-related cell death in long-lived post-mitotic cells of multiple tissues, providing an opportunity for a targeted therapeutic intervention in human aging.
PMCID: PMC4086639  PMID: 20434479
Aging; Age-related hearing loss; Mitochondria; Oxidative stress; Antioxidants; Apoptosis; Bak; Cochlea; Alpha-lipoic acid; Coenzyme Q10
2.  The Autophagy Enhancer Spermidine Reverses Arterial Aging 
Arterial aging, characterized by stiffening of large elastic arteries and the development of arterial endothelial dysfunction, increases cardiovascular disease (CVD) risk. We tested the hypothesis that spermidine, a nutrient associated with the anti-aging process autophagy, would improve arterial aging. Aortic pulse wave velocity (aPWV), a measure of arterial stiffness, was ~20% greater in old (O, 28 months) compared with young C57BL6 mice (Y, 4 months, P < 0.05). Arterial endothelium-dependent dilation (EDD), a measure of endothelial function, was ~25% lower in O (P < 0.05 vs. Y) due to reduced nitric oxide (NO) bioavailability. These impairments were associated with greater arterial oxidative stress (nitrotyrosine), superoxide production, and protein cross-linking (advanced glycation end-products, AGEs) in O (all P < 0.05). Spermidine supplementation normalized aPWV, restored NO-mediated EDD and reduced nitrotyrosine, superoxide, AGEs and collagen in O. These effects of spermidine were associated with enhanced arterial expression of autophagy markers, and in vitro experiments demonstrated that vascular protection by spermidine was autophagy-dependent. Our results indicate that spermidine exerts a potent anti-aging influence on arteries by increasing NO bioavailability, reducing oxidative stress, modifying structural factors and enhancing autophagy. Spermidine may be a promising nutraceutical treatment for arterial aging and prevention of age-associated CVD.
PMCID: PMC3700669  PMID: 23612189
arterial stiffness; endothelial dysfunction; nitric oxide; oxidative stress
3.  Sulfur-based Redox Alterations in Long-lived Snell Dwarf Mice 
Changes in sulfur-based redox metabolite profiles in multiple tissues of long-lived Snell dwarf mice were compared with age- and sex-matched controls. Plasma methionine and its oxidation products, hypotaurine and taurine, were increased in Snell dwarfs while cystine and glutathione levels were decreased, leading to an oxidative shift in the redox potential. Sexual dimorphism in renal cystathionine β-synthase (CBS) activity was observed in control mice but not in Snell dwarfs. Instead, female Snell mice exhibited ~2-fold higher CBS activity, comparable to levels seen in male Snell dwarf and in control mice. Taurine levels were significantly higher in kidney and brain of Snell dwarf versus control mice. Methionine adenosyltransferase (MAT) was higher in liver of Snell dwarfs, and the higher concentration of its product, S-adenosylmethionine, was correlated with elevated global DNA methylation status. Application of a mathematical model for methionine metabolism revealed that the metabolite perturbations in Snell dwarfs could be explained by decreased methionine transport, increased MAT and increased methyltransferase activity. Our study provides a comprehensive map of systemic differences in the sulfur network between Snell dwarfs and controls, providing the necessary foundation for assessment of nutrition-linked metabolic status in long-lived versus control animals.
PMCID: PMC3962791  PMID: 23707637
Snell dwarf mice; sulfur metabolism; redox; sexual dimorphism; global DNA methylation; mathematical model
4.  FUdR causes a twofold increase in the lifespan of the mitochondrial mutant gas-1 
Mechanisms of ageing and development  2011;132(10):519-521.
The nematode worm Caenorhabditis elegans has been used to identify hundreds of genes that influence longevity and thereby demonstrate the strong influence of genetics on lifespan determination. In order to simplify lifespan studies in worms, many researchers have employed 5-fluoro-2′-deoxyuridine (FUdR) to inhibit the development of progeny. While FUdR has little impact on the lifespan of wild-type worms, we demonstrate that FUdR causes a dramatic, dose-dependent, two-fold increase in the lifespan of the mitochondrial mutant gas-1. Thus, the concentration of FUdR employed in a lifespan study can determine whether a particular strain is long-lived or short-lived compared to wild-type.
PMCID: PMC4074524  PMID: 21893079 CAMSID: cams4494
Lifespan; Caenorhabditis elegans; FUdR; gas-1; genetics of aging
5.  Mitochondrial deficiency in Cockayne syndrome 
Cockayne syndrome is a rare inherited disorder characterized by accelerated aging, cachectic dwarfism and many other features. Recent work has implicated mitochondrial dysfunction in the pathogenesis of this disease. This is particularly interesting since mitochondrial deficiencies are believed to be important in the aging process. In this review, we will discuss recent findings of mitochondrial pathology in Cockayne syndrome and suggest possible mechanisms for the mitochondrial dysfunction.
PMCID: PMC3663877  PMID: 23435289
6.  What role (if any) does the highly conserved CSB-PGBD3 fusion protein play in Cockayne syndrome? 
The PGBD3 piggyBac transposon inserted into CSB intron 5 early in the primate lineage. As a result of alternative splicing, the human CSB gene now encodes three proteins: CSB, a CSB-PGBD3 fusion protein that joins the N-terminal CSB domain to the C-terminal PGBD3 transposase domain, and PGBD3 transposase. The fusion protein is as highly conserved as CSB, suggesting that it is advantageous in health; however, expression of the fusion protein in CSB-null cells induces a constitutive interferon (IFN) response. The fusion protein binds in vivo to PGBD3-related MER85 elements, but is also tethered to c-Jun, TEAD1, and CTCF motifs by interactions with the cognate transcription factors. The fusion protein regulates nearby genes from the c-Jun (and to a lesser extent TEAD1 and CTCF) motifs, but not from MER85 elements. We speculate that the fusion protein interferes with CSB-dependent chromatin remodeling, generating double-stranded RNA (dsRNA) that induces an IFN response through endosomal TLR or cytoplasmic RIG-I and/or MDA5 RNA sensors. We suggest that the fusion protein was fixed in primates because an elevated IFN response may help to fight viral infection. We also speculate that an inappropriate IFN response may contribute to the clinical presentation of CS.
PMCID: PMC3654029  PMID: 23369858
interferon (IFN); piggyBac-derived element 3 (PGBD3); fusion protein; AP-1 family transcription factor (c-Jun); CCCTC-binding factor (CTCF)
7.  Multiple interaction partners for Cockayne syndrome proteins: implications for genome and transcriptome maintenance 
Cockayne syndrome (CS) is characterized by progressive multisystem degeneration and is classified as a segmental premature aging syndrome. The majority of CS cases are caused by defects in the CS complementation group B (CSB) protein and the rest are mainly caused by defects in the CS complementation group A (CSA) protein. Cells from CS patients are sensitive to UV light and a number of other DNA damaging agents including various types of oxidative stress. The cells also display transcription deficiencies, abnormal apoptotic response to DNA damage, and DNA repair deficiencies. Herein we have critically reviewed the current knowledge about known protein interactions of the CS proteins. The review focuses on the participation of the CSB and CSA proteins in many different protein interactions and complexes, and how these interactions inform us about pathways that are defective in the disease.
PMCID: PMC3695466  PMID: 23583689
Cockayne syndrome; protein interactions; DNA repair deficiency; transcription deficiency; mitochondria
The Cockayne syndrome complementation group B protein, CSB, plays pivotal roles in transcription regulation and DNA repair. CSB belongs to the SNF2/SWI2 ATP-dependent chromatin remodeling protein family, and studies from many laboratories have revealed that CSB has multiple activities and modes of regulation. To understand the underlying mechanisms of Cockayne syndrome, it is necessary to understand how the biochemical activities of CSB are used to carry out its biological functions. In this review, we summarize our current knowledge of the structure, function and regulation of CSB, and discuss how these properties can impact the biological functions of this chromatin remodeler.
PMCID: PMC3750219  PMID: 23422418
Interventions which inhibit TOR activity (including rapamycin and caloric restriction) lead to downstream gene expression changes and increased lifespan in laboratory models. However, the role of mTOR signaling in human aging is unclear.
We tested the expression of mTOR-related transcripts in two independent study cohorts; the InCHIANTI population study of aging and the San Antonio Family Heart Study (SAFHS). Expression of 27/56 (InCHIANTI) and 19/44 (SAFHS) genes were associated with age after correction for multiple testing. 8 genes were robustly associated with age in both cohorts. Genes involved in insulin signaling (PTEN, PI3K, PDK1), ribosomal biogenesis (S6K), lipid metabolism (SREBF1), cellular apoptosis (SGK1), angiogenesis (VEGFB), insulin production and sensitivity (FOXO), cellular stress response (HIF1A) and cytoskeletal remodeling (PKC) were inversely correlated with age, whereas genes relating to inhibition of ribosomal components (4EBP1) and inflammatory mediators (STAT3) were positively associated with age in one or both datasets.
We conclude that the expression of mTOR-related transcripts is associated with advancing age in humans. Changes seen are broadly similar to mTOR inhibition interventions associated with increased lifespan in animals. Work is needed to establish whether these changes are predictive of human longevity and whether further mTOR inhibition would be beneficial in older people.
PMCID: PMC3998676  PMID: 22813852
Aging; aging mechanisms; mTOR; human population
10.  Stem Cells and Aging in the Hematopoietic System 
The effector cells of the blood have limited lifetimes and must be replenished continuously throughout life from a small reserve of hematopoietic stem cells (HSCs) in the bone marrow. Although serial bone marrow transplantation experiments in mice suggest that the replicative potential of HSCs is finite, there is little evidence that replicative senescence causes depletion of the stem cell pool during the normal lifespan of either mouse or man. Studies conducted in murine genetic models defective in DNA repair, intracellular ROS management, and telomere maintenance indicate that all these pathways are critical to the longevity and stress response of the stem cell pool. With age, HSCs show an increased propensity to differentiate towards myeloid rather than lymphoid lineages, which may contribute to the decline in lymphopoiesis that attends aging. Challenges for the future include assessing the significance of ‘lineage skewing’ to immune dysfunction, and investigating the role of epigenetic dysregulation in HSC aging.
PMCID: PMC3992834  PMID: 18479735
11.  A novel statistical approach shows evidence for multi-system physiological dysregulation during aging 
Previous studies have identified many biomarkers that are associated with aging and related outcomes, but the relevance of these markers for underlying processes and their relationship to hypothesized systemic dysregulation is not clear. We address this gap by presenting a novel method for measuring dysregulation via the joint distribution of multiple biomarkers and assessing associations of dysregulation with age and mortality. Using longitudinal data from the Women's Health and Aging Study, we selected a 14-marker subset from 63 blood measures: those that diverged from the baseline population mean with age. For the 14 markers and all combinatorial sub-subsets we calculated a multivariate distance called the Mahalanobis distance (MHBD)2 for all observations, indicating how “strange” each individual's biomarker profile was relative to the baseline population mean. In most models, MHBD correlated positively with age, MHBD increased within individuals over time, and higher MHBD predicted higher risk of subsequent mortality. Predictive power increased as more variables were incorporated into the calculation of MHBD. Biomarkers from multiple systems were implicated. These results support hypotheses of simultaneous dysregulation in multiple systems and confirm the need for longitudinal, multivariate approaches to understanding biomarkers in aging.
PMCID: PMC3971434  PMID: 23376244
Dysregulation; biomarker; multivariate; aging; physiology
12.  Markers of Oxidant Stress that are Clinically Relevant in Aging and Age-related Disease 
Despite the long held hypothesis that oxidant stress results in accumulated oxidative damage to cellular macromolecules and subsequently to aging and age-related chronic disease, it has been difficult to consistently define and specifically identify markers of oxidant stress that are consistently and directly linked to age and disease status. Inflammation because it is also linked to oxidant stress, aging, and chronic disease also plays an important role in understanding the clinical implications of oxidant stress and relevant markers. Much attention has focused on identifying specific markers of oxidative stress and inflammation that could be measured in easily accessible tissues and fluids (lymphocytes, plasma, serum). The purpose of this review is to discuss markers of oxidant stress used in the field as biomarkers of aging and age-related diseases, highlighting differences observed by race when data is available. We highlight DNA, RNA, protein, and lipid oxidation as measures of oxidative stress, as well as other well-characterized markers of oxidative damage and inflammation and discuss their strengths and limitations. We present the current state of the literature reporting use of these markers in studies of human cohorts in relation to age and age-related disease and also with a special emphasis on differences observed by race when relevant.
PMCID: PMC3664937  PMID: 23428415
DNA oxidation; RNA oxidation; Protein oxidation; Single Strand Breaks; CRP
13.  Genomic Response to Selection for Postponed Senescence in Drosophila 
Limited lifespan and senescence are quantitative traits, controlled by many interacting genes with individually small and environmentally plastic effects, complicating genetic analysis. We performed genome wide analysis of gene expression for two Drosophila melanogaster lines selected for postponed senescence and one control, unselected line to identify candidate genes affecting lifespan as well as variation in lifespan. We obtained gene expression profiles for young flies of all lines, all lines at the time only 10% of the control lines survived, and the time at which 10% of the selected lines survived. Transcriptional responses to aging involved 19% of the genome. The transcriptional signature of aging involved the down-regulation of genes affecting proteolysis, metabolism, oxidative phosphorylation, and mitochrondrial function; and the up-regulation of genes affecting protein synthesis, immunity, defense responses, and the detoxification of xenobiotic substances. The transcriptional signature of postponed senescence involved the up-regulation of proteases and phosphatases and genes affecting detoxification of xenobiotics; and the down-regulation of genes affecting immunity, defense responses, metabolism and muscle function. Functional tests of 17 mutations confirmed 12 novel genes affecting Drosophila lifespan. Identification of genes affecting longevity by analysis of gene expression changes in lines selected for postponed senescence thus complements alternative genetic approaches.
PMCID: PMC3918434  PMID: 23262286
aging; postponed senescence; gene expression; candidate genes; artificial selection
14.  Compensatory increase in USP14 activity accompanies impaired proteasomal proteolysis during aging. 
The deubiquitinating enzyme, USP14, found in association with the proteasome is essential in mediating ubiquitin trimming and in ensuring ubiquitin-homeostasis. As aging is accompanied by a significant decline in proteasomal proteolysis in primary human T lymphocytes, we evaluated the contributory role of USP14 in this decline. Our studies for the first time demonstrate that enzymatic activity of proteasome-associated USP14 is significantly higher in T cells obtained from elderly donors. Additionally, such an increase in USP14 activity could be mimicked by chemically inhibiting the proteasome, using Lactacystin. Thus, USP14 activity appears to be reciprocally regulated by the catalytic function of the 26S proteasome. To determine whether the inhibition of USP14 activity counter regulates proteasomal proteolysis, T cells pretreated with a small molecule inhibitor of USP14, IU1, were activated and assessed for IκBα degradation as a measure of proteasomal proteolysis. While T cells obtained from young donors demonstrated increased degradation of IκBα, those from the elderly remained unaffected by IU1 pretreatment. Taken together, these results demonstrate that the decrease in proteolysis of proteasomal substrates during aging is independent of the increased USP14 activity and that the reciprocal regulation of USP14 and proteasomal catalytic activity may be necessary to maintain cellular ubiquitin homeostasis.
PMCID: PMC3558606  PMID: 23291607
Aging; T Lymphocytes; Proteasome; Deubiquitinating enzyme; USP14; Ubiquitin
15.  Genotoxic stress accelerates age-associated degenerative changes in intervertebral discs 
Intervertebral disc degeneration (IDD) is the leading cause of debilitating spinal disorders such as chronic lower back pain. Aging is the greatest risk factor for IDD. Previously, we demonstrated IDD in a murine model of a progeroid syndrome caused by reduced expression of a key DNA repair enzyme. This led us to hypothesize that DNA damage promotes IDD. To test our hypothesis, we chronically exposed adult wild-type (Wt) and DNA repair-deficient Ercc1−/Δ mice to the cancer therapeutic agent mechlorethamine (MEC) or ionization radiation (IR) to induce DNA damage and measured the impact on disc structure. Proteoglycan, a major structural matrix constituent of the disc, was reduced 3-5x in the discs of MEC- and IR-exposed animals compared to untreated controls. Expression of the protease ADAMTS4 and aggrecan proteolytic fragments were significantly increased. Additionally, new PG synthesis was reduced 2-3x in MEC- and IR-treated discs compared to untreated controls. Both cellular senescence and apoptosis were increased in discs of treated animals. The effects were more severe in the DNA repair-deficient Ercc1−/Δ mice than in Wt littermates. Local irradiation of the vertebra in Wt mice elicited a similar reduction in PG. These data demonstrate that genotoxic stress drives degenerative changes associated with IDD.
PMCID: PMC3558562  PMID: 23262094
Intervertebral disc; aging; DNA damage; genotoxic stress; matrix proteoglycan
16.  Greater filamin C, GSK3α, and GSK3β serine phosphorylation in insulin-stimulated isolated skeletal muscles of calorie restricted 24 month-old rats 
Moderate calorie restriction (CR) can improve insulin-stimulated Akt phosphorylation and glucose uptake in muscles from 24 month-old rats, but the specific Akt substrates linking CR-effects on Akt to glucose uptake and other cellular processes are uncertain. We probed CR’s influence on site-specific phosphorylation of five Akt substrates (AS160Ser588, TBC1D1Thr596, FLNcSer2213, GSK3αSer21, and GSK3βSer9) in predominantly fast-twitch (epitrochlearis) and predominantly slow-twitch (soleus) muscles. We observed no CR-effect on phosphorylation of AS160Ser588 or TBC1D1Thr596, but there was a CR-induced increase in insulin-stimulated FLNcSer2213, GSK3αSer21, and GSK3βSer9 phosphorylation for both muscles. These results indicate that CR does not uniformly affect insulin-mediated phosphorylation of Akt substrates in fast- or slow-twitch muscles from 24 month-old rats.
PMCID: PMC3558636  PMID: 23246341
17.  DNA Strand Breaks, Neurodegeneration and Aging in the Brain 
Mechanisms of ageing and development  2008;129(0):10.1016/j.mad.2008.03.008.
Defective responses to DNA single- or double-strand breaks can result in neurological disease, underscoring the critical importance of DNA repair for neural homeostasis. Human DNA repair-deficient syndromes are generally congenital, in which brain pathology reflects the consequences of developmentally incurred DNA damage. Although, it is unclear to what degree DNA strand-break repair defects in mature neural cells contributes to disease pathology. However, DNA single-strand breaks are a relatively common lesion which if not repaired can impact cells via interference with transcription. Thus, this lesion, and probably to a lesser extent DNA double strand breaks, may be particularly relevant to aging in the neural cell population. In this review we will examine the consequences of defective DNA strand break repair towards homeostasis in the brain. Further, we also consider the utility of mouse models as reagents to understand the connection between DNA strand breaks and aging in the brain.
PMCID: PMC3831510  PMID: 18455751
DNA damage; DNA repair; nervous system; aging; ATM; AOA1; SCAN1
18.  Ocular parameters of biological ageing in HIV-infected individuals in South Africa: relationship with chronological age and systemic biomarkers of ageing 
Mechanisms of ageing and development  2013;134(9):10.1016/j.mad.2013.08.002.
HIV-infected individuals have an increased risk of age-related morbidity despite antiretroviral treatment (ART). Several anatomic and functional ophthalmological parameters are associated with increasing chronological age. These may, therefore, potentially serve as biomarkers of ageing. We investigated associations between ocular parameters (lens density, retinal vessel calibre, corneal endothelium and retinal nerve fibre layer thickness) and two ‘cellular’ biomarkers of ageing (leukocyte telomere length and CDKN2A expression) and with frailty in a cross-sectional study of 216 HIV-infected individuals. All ocular parameters, telomere length and frailty were associated with chronological age, whereas CDKN2A expression was not. Retinal venular calibre and lens density were associated with shorter telomere length (p-trend=0.04, and 0.08, respectively), whereas CDKN2A expression and frailty status were not associated with ocular parameters. Longitudinal studies are warranted to assess the integration of retinal vascular calibre and lens density with systemic markers to develop an overall index of biological ageing in HIV infection.
PMCID: PMC3818088  PMID: 23994067
Telomeres; CDKN2A; lens density; retinal vessel calibre; HIV
19.  takeout-dependent longevity is associated with altered Juvenile Hormone signaling 
Mechanisms of ageing and development  2012;133(11-12):637-646.
In order to understand the molecular mechanisms of longevity regulation, we recently performed a screen designed to enrich for genes common to several longevity interventions. Using this approach, we identified the Drosophila melanogaster gene takeout. takeout is upregulated in a variety of long-lived flies, and extends life span when overexpressed. Here, we investigate the mechanisms of takeout-dependent longevity.
takeout overexpression specifically in the fat body is sufficient to increase fly longevity and is additive to the longevity effects of dietary restriction. takeout long-lived flies do not show phenotypes often associated with increased longevity, such as enhanced stress resistance or major metabolic abnormalities. However, males exhibit greatly diminished courtship behavior, leading to a reduction in fertility. Interestingly, takeout contains a binding domain for Juvenile Hormone, a fly hormone that plays a role in the regulation of developmental transitions. Importantly, the longevity and courtship phenotypes of takeout overexpressing flies are reversed by treatment with the Juvenile Hormone analog methoprene.
These data suggest that takeout is a key player in the tradeoff-switch between fertility and longevity. takeout may control fertility via modulation of courtship behavior. This regulation may occur through Juvenile Hormone binding to takeout and a subsequent reduction in Juvenile Hormone signaling activity.
PMCID: PMC3518612  PMID: 22940452
Drosophila melanogaster; Juvenile Hormone; longevity; fertility; aging
20.  Reduced AMPK-ACC and mTOR signaling in muscle from older men, and effect of resistance exercise 
AMP-activated protein kinase (AMPK) is a key energy-sensitive enzyme that controls numerous metabolic and cellular processes. Mammalian target of rapamycin (mTOR) is another energy/nutrient-sensitive kinase that controls protein synthesis and cell growth. In this study we determined whether older versus younger men have alterations in the AMPK and mTOR pathways in skeletal muscle, and examined the effect of a long term resistance type exercise training program on these signaling intermediaries. Older men had decreased AMPKα2 activity and lower phosphorylation of AMPK and its downstream signaling substrate acetyl-CoA carboxylase (ACC). mTOR phosphylation also was reduced in muscle from older men. Exercise training increased AMPKα1 activity in older men, however, AMPKα2 activity, and the phosphorylation of AMPK, ACC and mTOR, were not affected. In conclusion, older men have alterations in the AMPK-ACC and mTOR pathways in muscle. In addition, prolonged resistance type exercise training induces an isoform-selective up regulation of AMPK activity.
PMCID: PMC3631591  PMID: 23000302
Aging; Skeletal muscle; AMPK; mTOR; Resistance exercise
21.  Siphon Regeneration Capacity is Compromised During Aging in the Ascidian Ciona intestinalis 
Mechanisms of ageing and development  2012;133(9-10):629-636.
The ascidian Ciona intestinalis has a short life span and powerful regeneration capacities. The regeneration of the oral siphon (OS) involves wound healing, blastema formation, cell proliferation, and replacement of eight oral pigment organs (OPO), the latter via differentiation and migration of stem/precursor cells from localized siphon niches in the siphon. The restoration of OPO pattern during OS regeneration occurs with a high degree of accuracy through three successive cycles of amputation. It is shown here that oral siphons of the largest and oldest members of a wild Ciona population do not completely regenerate their siphons after amputation. The loss of regeneration capacity was accompanied by reduced cell proliferation. In contrast to arrested OS outgrowth, the stem/precursor cells responsible for OPO replacement “over-differentiate” after OS amputation in the oldest animals, the typical number of OPO is increased from eight to twelve-sixteen, and malformed OPO are produced. Also in contrast to younger animals, the oldest animals of the population show arrested OPO development after two consecutive cycles of amputation and regeneration. We conclude that there is a size and age threshold in Ciona after which the regenerative capacity of the OS is compromised due to effects of aging on cell proliferation.
PMCID: PMC3455139  PMID: 22935550
Ascidian; Ciona intestinalis; siphon regeneration; oral pigment organs; cell proliferation
22.  Impaired Adaptability of in Vivo Mitochondrial Energetics to Acute Oxidative Insult in Aged Skeletal Muscle 
Mechanisms of ageing and development  2012;133(9-10):620-628.
Periods of elevated reactive oxygen species (ROS) production are a normal part of mitochondrial physiology. However, little is known about age-related changes in the mitochondrial response to elevated ROS in vivo. Significantly, ROS-induced uncoupling of oxidative phosphorylation has received attention as a negative feedback mechanism to reduce mitochondrial superoxide production. Here we use a novel in vivo spectroscopy system to test the hypothesis that ROS-induced uncoupling is diminished in aged mitochondria. This system simultaneously acquires 31P magnetic resonance and near-infrared optical spectra to non-invasively measure phosphometabolite and O2 concentrations in mouse skeletal muscle. Using low dose paraquat to elevate intracellular ROS we assess in vivo mitochondrial function in young, middle aged, and old mice. Oxidative phosphorylation was uncoupled to the same degree in response to ROS at each age, but this uncoupling was associated with loss of phosphorylation capacity and total ATP in old mice only. Using mice lacking UCP3 we demonstrate that this in vivo uncoupling is independent of this putative uncoupler of skeletal muscle mitochondria. These data indicate that ROS-induced uncoupling persists throughout life, but that oxidative stress leads to mitochondrial deficits and loss of ATP in aged organisms that may contribute to impaired function and degeneration.
PMCID: PMC3456966  PMID: 22935551
Mitochondria; Uncoupling; Oxidative Stress; Skeletal Muscle; UCP3
23.  Genotype × age interaction in human transcriptional ageing 
Mechanisms of ageing and development  2012;133(9-10):581-590.
Individual differences in biological ageing (i.e., the rate of physiological response to the passage of time) may be due in part to genotype-specific variation in gene action. However, the sources of heritable variation in human age-related gene expression profiles are largely unknown. We have profiled genome-wide expression in peripheral blood mononuclear cells from 1,240 individuals in large families and found 4,472 human autosomal transcripts, representing ~4,349 genes, significantly correlated with age. We identified 623 transcripts that show genotype by age interaction in addition to a main effect of age, defining a large set of novel candidates for characterization of the mechanisms of differential biological ageing. We applied a novel SNP genotype×age interaction test to one of these candidates, the ubiquilin-like gene UBQLNL, and found evidence of joint cis-association and genotype by age interaction as well as trans-genotype by age interaction for UBQLNL expression. Both UBQLNL expression levels at recruitment and cis genotype are associated with longitudinal cancer risk in our study cohort.
PMCID: PMC3541784  PMID: 22871458
Transcriptional ageing; genotype by age interaction; ubiquitins; UBQLNL; cancer risk gene
24.  Ocular parameters of biological ageing in HIV-infected individuals in South Africa: Relationship with chronological age and systemic biomarkers of ageing☆ 
•HIV is associated with age-related morbidity despite antiretroviral treatment.•Ocular age-related parameters may serve as biomarkers of ageing.•Lens density may have a role in the determination of biological age in HIV infection.
HIV-infected individuals have an increased risk of age-related morbidity despite antiretroviral treatment (ART). Several anatomic and functional ophthalmological parameters are associated with increasing chronological age. These may, therefore, potentially serve as biomarkers of ageing. We investigated associations between ocular parameters (lens density, retinal vessel calibre, corneal endothelium and retinal nerve fibre layer thickness) and two ‘cellular’ biomarkers of ageing (leukocyte telomere length and CDKN2A expression) and with frailty in a cross-sectional study of 216 HIV-infected individuals. All ocular parameters, telomere length and frailty were associated with chronological age, whereas CDKN2A expression was not. Retinal venular calibre and lens density were associated with shorter telomere length (p-trend = 0.04, and 0.08, respectively), whereas CDKN2A expression and frailty status were not associated with ocular parameters. Longitudinal studies are warranted to assess the integration of retinal vascular calibre and lens density with systemic markers to develop an overall index of biological ageing in HIV infection.
PMCID: PMC3818088  PMID: 23994067
Telomeres; CDKN2A; Lens density; Retinal vessel calibre; HIV
25.  Coevolution of telomerase activity and body mass in mammals: From mice to beavers 
Telomerase is repressed in the majority of human somatic tissues. As a result human somatic cells undergo replicative senescence, which plays an important role in suppressing tumorigenesis, and at the same time contributes to the process of aging. Repression of somatic telomerase activity is not a universal phenomenon among mammals. Mice, for example, express telomerase in somatic tissues, and mouse cells are immortal when cultured at physiological oxygen concentration. What is the status of telomerase in other animals, beyond human and laboratory mouse, and why do some species evolve repression of telomerase activity while others do not? Here we discuss the data on telomere biology in various mammalian species, and a recent study of telomerase activity in a large collection of wild rodent species, which showed that telomerase activity coevolves with body mass, but not lifespan. Large rodents repress telomerase activity, while small rodents maintain high levels of telomerase activity in somatic cells. We discuss a model that large body mass presents an increased cancer risk, which drives the evolution of telomerase suppression and replicative senescence.
PMCID: PMC3733351  PMID: 18387652
Telomerase; Aging; Cancer; Evolution

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