Cockayne Syndrome is a segmental premature aging syndrome, which can be caused by loss of function of the CSB protein. CSB is essential for genome maintenance and has numerous interaction partners with established roles in different DNA repair pathways including transcription coupled nucleotide excision repair and base excision repair. Here, we describe a new interaction partner for CSB, the DNA glycosylase NEIL2. Using both cell extracts and recombinant proteins, CSB and NEIL2 was found to physically interact independently of DNA. We further found that CSB is able to stimulate NEIL2 glycosylase activity on a 5-hydroxyl uracil lesion in a DNA bubble structure substrate in vitro. A novel 4,6-diamino-5-formamidopyrimidine (FapyA) specific incision activity of NEIL2 was also stimulated by CSB. To further elucidate the biological role of the interaction, immunofluorescence studies were performed, showing an increase in cytoplasmic CSB and NEIL2 co-localization after oxidative stress. Additionally, stalling of the progression of the transcription bubble with α-amanitin resulted in increased co-localization of CSB and NEIL2. Finally, CSB knockdown resulted in reduced incision of 8-hydroxyguanine in a DNA bubble structure using whole cell extracts. Taken together, our data supports a biological role for CSB and NEIL2 in transcription associated base excision repair.
Cockayne Syndrome; CSB; NEIL2; base excision repair; oxidative damage
Mitochondrial DNA (mtDNA) exists in multiple copies per cell and is essential for oxidative phosphorylation. Depleted or mutated mtDNA promotes numerous human diseases and may contribute to aging. Reduced TORC1 signaling in the budding yeast, Saccharomyces cerevisiae, extends chronological lifespan (CLS) in part by generating a mitochondrial ROS (mtROS) signal that epigenetically alters nuclear gene expression. To address the potential requirement for mtDNA maintenance in this response, we analyzed strains lacking the mitochondrial base-excision repair enzyme Ntg1p. Extension of CLS by mtROS signaling and reduced TORC1 activity, but not caloric restriction, was abrogated in ntg1Δ strains that exhibited mtDNA depletion without defects in respiration. The DNA damage response (DDR) kinase Rad53p, which transduces pro-longevity mtROS signals, is also activated in ntg1Δ strains. Restoring mtDNA copy number alleviated Rad53p activation and re-established CLS extension mtROS-mediated longevity signaling, indicating that Rad53p senses mtDNA depletion directly. Finally, DDR kinases regulate nucleus-mitochondria localization dynamics of Ntg1p. From these results, we conclude that the DDR pathway senses mtDNA instability and regulates Ntg1p in response. Furthermore, Rad53p senses multiple mitochondrial stresses in a hierarchical manner to elicit specific physiological outcomes, exemplified by mtDNA depletion overriding the ability of Rad53p to transduce an adaptive mtROS longevity signal.
chronological lifespan; DNA damage response; mtDNA; Rad53p; reactive oxygen species
The effect of aging on natural killer cell homeostasis is not well studied in humans or in animal models. We compared natural killer (NK) cells from young and aged mice to investigate age-related defects in NK cell distribution, and development. Our findings indicate aged mice have reduced NK cells in most peripheral tissues, but not in bone marrow. Reduction of NK cells in periphery was attributed to a reduction of the most mature CD11b+ CD27− NK cells. Apoptosis was not found to explain this specific reduction of mature NK cells. Analysis of NK cell development in bone marrow revealed that aged NK cells progress normally through early stages of development, but a smaller percentage of aged NK cells achieved terminal maturation. Less mature NK cells in aged bone marrow correlated with reduced proliferation of immature NK cells. We propose advanced age impairs bone marrow maturation of NK cells, possibly affecting homeostasis of NK cells in peripheral tissues. These alterations in NK cell maturational status have critical consequences for NK cell function in advanced age: reduction of the mature circulating NK cells in peripheral tissues of aged mice affects their overall capacity to patrol and eliminate cancerous and viral infected cells.
Ataxia-telangiectasia (A-T) is a neurodegenerative syndrome caused by the mutation of the ATM gene. The ATM protein is a PI3kinase family member best known for its role in the DNA damage response. While repair of DNA damage is a critical function that every CNS neuron must perform, a growing body of evidence indicates that the full range of ATM functions includes some that are unrelated to DNA damage yet are essential to neuronal survival and normal function. For example, ATM participates in the regulation of synaptic vesicle trafficking and is essential for the maintenance of normal LTP. In addition ATM helps to ensure the cytoplasmic localization of HDAC4 and thus maintains the histone ‘code’ of the neuronal genome by suppressing genome-wide histone deacetylation, which alters the message and protein levels of many genes that are important for neuronal survival and function. The growing list of ATM functions that go beyond its role in the DNA damage response offers a new perspective on why individuals with A-T express such a wide range of neurological symptoms, and suggests that not all A-T symptoms need to be understood in the context of the DNA repair process.
Histone deacetylase; cell cycle; neurodegeneration; synaptic vesicle; LTP
The repair of damaged DNA is essential to maintain longevity of an organism. The brain is a matrix of different neural cell types including proliferative astrocytes and post-mitotic neurons. Post-mitotic DNA repair is a version of proliferative DNA repair, with a reduced number of available pathways and most of these attenuated. Base Excision Repair (BER) is one pathway that remains robust in neurons; it is this pathway that resolves the damage due to oxidative stress. This oxidative damage is an unavoidable byproduct of respiration, and considering the high metabolic activity of neurons this type of damage is particularly pertinent in the brain. The accumulation of oxidative DNA damage over time is a central aspect of the theory of aging and repair of such chronic damage is of the highest importance. We review research conducted in BER mouse models to clarify the role of this pathway in the neural system. The requirement for BER in proliferating cells also correlates with high levels of many of the BER enzymes in neurogenesis after DNA damage. However, the pathway is also necessary for normal neural maintenance as larger infarct volumes after ischemic stroke are seen in some glycosylase deficient animals. Further, the requirement for DNA polymerase β in post-mitotic BER is potentially more important than in proliferating cells due to reduced levels of replicative polymerases. The BER response may have particular relevance for the onset and progression of many neurodegenerative diseases associated with an increase in oxidative stress including Alzheimer’s.
BER; Neurodegeneration; DNA repair; Aging
Despite evidence of a substantial genetic component, the genetic factors that underlie longevity in humans remain to be identified. Previous genome-wide linkage and association studies have not found strong evidence for the contribution of common variants besides the APOE gene, suggesting the role of rare variants in human longevity. To discover rare variants that might contribute to longevity, we selected 988 candidate genes and performed a pilot study to identify novel non-synonymous variants in 6 Ashkenazi Jewish centenarians older than 105. Our candidate genes act in pathways implicated in aging and longevity, including neurodegeneration, cognitive function, lipid metabolism, DNA repair, and genome maintenance. By implementing custom-designed Agilent SureSelect target capture and next-generation sequencing, we discovered a total of 89 novel non-synonymous SNPs (nsSNPs) and validated 51 nsSNPs by iPLEX MassArray assays. Genotyping analysis of these novel SNPs in 410 Ashkenazi Jewish controls and 390 centenarians showed significant enrichment (5.3 fold, p=0.02) of the p.Y318C variant in PMS2 and significant depletion (7.5 fold, p=0.04) of the p.V465A variant in GABRR3 in centenarians compared to controls. Our study presents the potential of targeted next-generation sequencing for discovery of rare but functional genetic variation which may lead to exceptional longevity in humans.
Centenarian; Human longevity; Functional variant; Candidate genes; Target capture and next-generation sequencing
Ageing is the main risk factor for the development of dementing neurodegenerative diseases (NDs) and it is accompanied by the accumulation of variations in mitochondrial DNA. The resulting tissue-specific alterations in ATP production and availability cause deteriorations of cerebral clearance mechanisms that are important for the removal of toxic peptides and its aggregates. ABC transporters were shown to be the most important exporter superfamily for toxic peptides, e.g. β-amyloid and α-synuclein. Their activity is highly dependent on the availability of ATP and forms a directed energy-exporter network, linking decreased mitochondrial function with highly impaired ABC transporter activity and disease progression. In this paper, we describe a network based on interactions between ageing, energy metabolism, regeneration, accumulation of toxic peptides and the development of proteopathies of the brain with a focus on Alzheimer’s disease (AD). Additionally, we provide new experimental evidence for interactions within this network in regenerative processes in AD.
ageing; ABC transporters; mitochondria; Alzheimer’s disease; Parkinson’s disease; energy metabolism; dementia; neurodegeneration; ABCB1; ABCC1; ABCA7; ABCA1; Aqp4
The formation of 5-hydroxymethylcytosine (5hmC), a key intermediate of DNA demethylation, is driven by the ten eleven translocation (TET) family of proteins that oxidize 5-methylcytosine (5mC) to 5hmC. To determine whether methylation/demethylation status is altered during the progression of Alzheimer’s disease (AD), levels of TET1, 5mC and subsequent intermediates, including 5hmC, 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) were quantified in nuclear DNA from the hippocampus/parahippocampal gyrus (HPG) and the cerebellum of 5 age-matched normal controls, 5 subjects with preclinical AD (PCAD) and 7 late-stage AD (LAD) subjects by immunochemistry. The results showed significantly (p < 0.05) increased levels of TET1, 5mC, and 5hmC in the HPG of PCAD and LAD subjects. In contrast, levels of 5fC and 5caC were significantly (p < 0.05) decreased in the HPG of PCAD and LAD subjects. Overall, the data suggest altered methylation/demethylation patterns in vulnerable brain regions prior to the onset of clinical symptoms in AD suggesting a role in the pathogenesis of the disease.
Alzheimer’s disease; preclinical Alzheimer’s disease; 5-hydroxymethylcytosine; 5-methylcytosine
Activation of xenobiotic metabolism pathways has been linked to lifespan extension in different models of aging. However, the mechanisms underlying activation of xenobiotic genes remain largely unknown. Here we showed that although FXR mRNA levels do not change significantly, FXR (farnesoid X receptor, Nr1h4) protein levels are elevated in the livers of the long-lived Little mice, leading to increased DNA binding activity of FXR. Hepatic FXR expression is sex-dependent in wild-type mice but not in Little mice, implying that up-regulation of FXR might be dependent on the reduction of growth hormone in Little mice. Growth hormone treatment decreased hepatic expression of FXR and xenobiotic genes Abcb1a, Fmo3 and Gsta2 in both wild-type and Little mice, suggesting an association between FXR and xenobiotic gene expression. We found that Abcb1a is transactivated by FXR via direct binding of FXR/retinoid X receptor α (RXRα) heterodimer to a response element at the proximal promoter. FXR also positively controls Fmo3 and Gsta2 expression through direct interaction with the response elements in these genes. Our study demonstrates that xenobiotic genes are direct transcriptional targets of FXR and suggests that FXR signaling may play a critical role in the lifespan extension observed in Little mice.
FXR; xenobiotic detoxification gene; Little mice; growth hormone
The aging heart displays a loss of bioenergetic reserve capacity partially mediated through lower fatty acid utilization. We investigated whether the age-related impairment of cardiac fatty acid catabolism occurs, at least partially, through diminished levels of L-carnitine, which would adversely affect carnitine palmitoyltransferase 1 (CPT1), the rate-limiting enzyme for fatty acyl-CoA uptake into mitochondria for β-oxidation. Old (24–28 mos) Fischer 344 rats were fed ± acetyl-L-carnitine (ALCAR; 1.5% [w/v]) for up to four weeks prior to sacrifice and isolation of cardiac interfibrillar (IFM) and subsarcolemmal (SSM) mitochondria. IFM displayed a 28% (p < 0.05) age-related loss of CPT1 activity, which correlated with a decline (41%, p < 0.05) in palmitoyl-CoA-driven state 3 respiration. Interestingly, SSM had preserved enzyme function and efficiently utilized palmitate. Analysis of IFM CPT1 kinetics showed both diminished Vmax and Km (60% and 49% respectively, p < 0.05) when palmitoyl-CoA was the substrate. However, no age-related changes in enzyme kinetics were evident with respect to L-carnitine. ALCAR supplementation restored CPT1 activity in heart IFM, but not apparently through remediation of L-carnitine levels. Rather, ALCAR influenced enzyme activity over time, potentially by modulating conditions in the aging heart that ultimately affect palmitoyl-CoA binding and CPT1 kinetics.
Carnitine palmitoyltransferase 1; kinetics; aging; interfibrillar mitochondria; acetyl-L-carnitine
The longevity of an organism is directly related to its ability to effectively cope with cellular stress. Heat shock response (HSR) protects the cells against accumulation of damaged proteins after exposure to elevated temperatures and also in ageing cells. To understand the role of Hsp70 in regulating life span of Daphnia, we examined the expression of Hsp70 in two ecotypes that exhibit strikingly different life spans. D. pulicaria, the long lived ecotype, showed a robust Hsp70 induction as compared to the shorter lived D. pulex. Interestingly, the short-lived D. pulex isolates showed no induction of Hsp70 at the mid point in their life span. In contrast to this, the long-lived D. pulicaria continued to induce Hsp70 expression at an equivalent age. We further show that the Hsp70 expression was induced at transcriptional level in response to heat shock. The transcription factor responsible for Hsp70 induction, heat shock factor-1 (HSF-1), although present in aged organisms did not exhibit DNA-binding capability. Thus, the decline of Hsp70 induction in old organisms could be attributed to a decline in HSF-1’s DNA-binding activity. These results for the first time, present a molecular analysis of the relationship between HSR and life span in Daphnia.
Daphnia; heat shock; Hsp70; HSF-1; longevity; ageing
Age associated cognitive impairment is associated with low levels of IGF-1, oxidative stress, and neuronal loss in the hippocampus. Ames dwarf mice are long-lived animals that exhibit peripheral IGF-1 deficiency. Hippocampal-based spatial memory (a homolog of cognitive function) has not been evaluated in these long-living mice.
Materials and methods
We evaluated the hippocampal-based spatial memory in 3-, 12- and 24-month-old Ames dwarf and wild type mice using the Barnes maze and the T-maze. We also examined the effect of a hippocampal-specific toxin, kainic acid (KA), on spatial memory to determine whether Ames mice were resistant to the cognitive impairment induced by this compound.
We found that Ames dwarf mice exhibit enhanced learning, making fewer errors and using less time to solve both the Barnes and T-mazes. Dwarf mice also have significantly better short-term memory as compared to wild type mice. Both genotypes exhibited neuronal loss in the CA1 and CA3 areas of the hippocampus following KA, but Ames dwarf mice retained their spatial memory.
Our results show that Ames dwarf mice retained their spatial memory despite neurodegeneration when compared to wild type mice at an “equiseizure” dose of KA.
Ames dwarf; Hippocampus; Spatial memory; Barnes maze; Kainic acid
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.
Aging; Age-related hearing loss; Mitochondria; Oxidative stress; Antioxidants; Apoptosis; Bak; Cochlea; Alpha-lipoic acid; Coenzyme Q10
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.
arterial stiffness; endothelial dysfunction; nitric oxide; oxidative stress
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.
Snell dwarf mice; sulfur metabolism; redox; sexual dimorphism; global DNA methylation; mathematical model
•Colonic crypts with mitochondrial dysfunction accumulate with age in PolgA+/mut mice.•Mitochondrial dysfunction is caused by clonally expanded mtDNA point mutations.•The mutations are random and their expansion is not subject to selective constraints.•Colonic crypts of aged humans have a similar mtDNA mutation spectrum and phenotype.•PolgA+/mut mice are a good model to study mitochondrial dysfunction in ageing colon.
Clonally expanded mitochondrial DNA (mtDNA) mutations resulting in focal respiratory chain deficiency in individual cells are proposed to contribute to the ageing of human tissues that depend on adult stem cells for self-renewal; however, the consequences of these mutations remain unclear. A good animal model is required to investigate this further; but it is unknown whether mechanisms for clonal expansion of mtDNA mutations, and the mutational spectra, are similar between species. Here we show that mice, heterozygous for a mutation disrupting the proof-reading activity of mtDNA polymerase (PolgA+/mut) resulting in an increased mtDNA mutation rate, accumulate clonally expanded mtDNA point mutations in their colonic crypts with age. This results in focal respiratory chain deficiency, and by 81 weeks of age these animals exhibit a similar level and pattern of respiratory chain deficiency to 70-year-old human subjects. Furthermore, like in humans, the mtDNA mutation spectrum appears random and there is an absence of selective constraints. Computer simulations show that a random genetic drift model of mtDNA clonal expansion can accurately model the data from the colonic crypts of wild-type, PolgA+/mut animals, and humans, providing evidence for a similar mechanism for clonal expansion of mtDNA point mutations between these mice and humans.
Mitochondria; Ageing; Colon; MtDNA; Mouse
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.
PMID: 21893079 CAMSID: cams4494
Lifespan; Caenorhabditis elegans; FUdR; gas-1; genetics of aging
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.
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.
interferon (IFN); piggyBac-derived element 3 (PGBD3); fusion protein; AP-1 family transcription factor (c-Jun); CCCTC-binding factor (CTCF)
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.
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.
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.
Aging; aging mechanisms; mTOR; human population
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.
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.
Dysregulation; biomarker; multivariate; aging; physiology
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.
DNA oxidation; RNA oxidation; Protein oxidation; Single Strand Breaks; CRP