Onset Of Age-related Diseases Research Articles

Growth hormone in adipose dysfunction and senescence

Growth hormone (GH) is an important modulator of maturation, adiposity, and metabolism in mammals. It also has profound effects on age-related disease onset and healthspan [1]. GH-deficient and -resistant mice have up to a 78% increase in maximum lifespan and are protected from age-related metabolic dysfunction and cancer [2]. Although lifespan does not appear to be extended in humans with GH resistance, these individuals are protected from a variety of age-related pathologies, particularly diabetes and cancer [3]. Several mechanisms have been proposed and likely contribute to the pro-survival effects of curtailed GH action, including enhanced stress resistance, xenobiotic metabolism, and insulin sensitivity in combination with reduced inflammation [1]. In contrast, both mice and humans with excess GH develop phenotypes indicative of premature aging and have greater disease burden and mortality risk [1, 2]. Furthermore, mice and humans with altered GH action also display profound changes in adipose tissue homeostasis and lipid distribution. GH-deficient and -resistant mice preferentially deposit lipid in subcutaneous adipose depots, whereas humans with Laron Syndrome exhibit markedly increased subcutaneous and visceral adiposity [1, 2]. Despite the development of obesity, the overwhelming majority of these mice and human subjects are safeguarded from metabolic dysfunction. Conversely, transgenic GH-overexpressing mice and human acromegaly patients remain lean throughout life, yet often develop insulin resistance and an elevated pro-inflammatory status [1]. These observations suggest GH may accelerate declines in adipose tissue homeostasis, which has previously been linked with age-related perturbations in systemic inflammation and metabolism [4]. Adipose tissue functional capacity declines with advancing age [4]. This deterioration is particularly evident in subcutaneous depots, which promotes increased visceral adiposity, ectopic lipid deposition, and concomitant metabolic disturbances. Preadipocyte proliferation and differentiation potential are curtailed with aging and result in reduced lipid deposition in subcutaneous adipose tissue [4]. Pro-inflammatory cytokines, chemokines, and extracellular matrix proteases are believed to play a central role in preadipocyte dysfunction and adipose tissue remodeling with aging. Senescent cells, which possess a highly pro-inflammatory secretome, accumulate in adipose tissue with advancing age, and thus, have emerged as a potential contributor to adipose tissue dysfunction [4]. Interestingly, the elimination of senescent cells preserves adipose tissue mass and enhances healthspan in mice with an accelerated aging phenotype [5]. Given that GHdeficient and -resistant mice appear to be protected from age-related lipid redistribution and metabolic dysfunction, we hypothesized that GH action would be predictive of subcutaneous adipose tissue lipid storage capacity and senescent cell burden. To test our hypothesis, we evaluated adipose tissue functional capacity and senescent cell accumulation in several models with altered GH action. Our study, now published in Aging, establishes a relationship between GH action, lipid deposition, and adipose tissue senescent cell accumulation [6]. To start, we confirmed that both GH-deficient and -resistant models are protected from age-related lipid redistribution as evidenced by greater subcutaneous to visceral adipose tissue ratios than their respective control littermates at 18 months of age. These findings were supported by the observation that GH-resistant mice also accumulated less hepatic triglycerides during this time. We subsequently determined that primary subcutaneous preadipocytes from 20-month old GH-resistant mice possess greater differentiation capacity than those from age-matched controls; providing a potential explanation for enhanced lipid storage capacity of subcutaneous adipose tissue in mice with curtailed GH action. Considering the close connection between inflammatory status, adipose tissue homeostasis, and GH action, we sought to determine if our previous findings were associated with adipose tissue senescent cell accumulation. We found that GH-deficient and -resistant mice exhibited far less senescent cell burden in several adipose tissue depots compared to control littermates at 18 months of age. Conversely, GHoverexpressing (10 months of age) and GH-injected (19 months of age) mice accumulated more senescent cells within adipose tissue than their controls, which we later determined was similar to 24-month old chronologically aged mice. We conclude that senescent cell accumulation in adipose tissue is linked with GH activity and may play a key role in age-related adipose tissue dysfunction. It is currently unclear if GH directly promotes cellular senescence in adipose tissue through geroconversion [7], or if GH-mediated effects on insulin-like growth factor-1 (IGF-1) and insulin signaling pathways play a more dominant role [1, 2]. Future investigation of the role these distinct, yet related, signaling pathways play in the emergence of cellular senescence will provide insights into links among aging, cellular senescence, and adipose tissue dysfunction. Studies using a new class of drugs that selectively clear senescent cells, senolytic agents [8], in experimental animals and eventually humans with obesity and excess or diminished GH and IGF-1 action will be a path towards testing if these links are causal.

The role of 17β-estradiol in the regulation of antioxidant enzymes via the Nrf2-Keap1 pathway in the livers of CBA/H mice.

We aimed to explore the impact of surgical 17β-estradiol (E2) deprivation/administration on the expression of antioxidant enzymes with an emphasis on the alteration of the NF-E2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2/Keap1) pathway under physiological conditions in the livers of CBA/H mice of both sexes. Hepatic oxidative stress markers were determined by measuring lipid peroxidation and DNA damage using the comet assay. The expression and activities of two isoforms of superoxide dismutase (Sod-1, Sod-2) and catalase (Cat) were studied using real-time PCR, Western blot and spectrophotometrical analyses. The effect of E2 on Nrf2/Keap1 protein levels and localization was assessed using cytosolic and nuclear fractions. We demonstrate the E2-mediated repression of the antioxidant enzymes Sod-1, Sod-2 and Cat in the livers of ovariectomized mice treated with E2 and its association with a decreased level of Nrf2/Keap1 proteins in the nucleus. We observed beneficial effects of long-term E2 administration on lipid peroxidation but not on DNA damage in the livers of ovariectomized mice. The results of this study may additionally confirm the protective ability of E2 in prolonging the onset of age-related disease in females that ultimately contributes to their longer lifespan.

Molecular mechanisms of dietary restriction in aging-insights from Caenorhabditis elegans research.

Dietary restriction (DR) is one of the most robust environmental manipulations that not only extend life span but also delay the onset of age-related diseases in almost every species examined. Caenorhabditis elegans plays an important role in aging studies due to its simple life cycle, easy genetic manipulations and highly conserved genome. Recent studies have demonstrated that the beneficial effects of DR are mediated by the highly conserved transcription factors and signaling pathways in C. elegans. Here we review recent progress in the methodology and molecular mechanisms of DR using C. elegans as a model, as well as prospects for future research.

Development of a novel postnatal neurobehavioral scale for evaluation of common marmoset monkeys.

Common marmoset (Callithrix jacchus) monkeys when compared to rhesus macaques (Macaca mullatta) present several advantages for disease modeling, especially transgenic initiatives, as they commonly give birth to twins, which increases sample size, have accelerated development and a shorter life span that facilitates the analysis of the onset of age-related diseases. Yet, no tools are currently available to assess marmoset neurodevelopment during the initial first month of life. Here we report the creation of a novel Primate Postnatal Neurobehavioral Assessment Scale for marmoset monkeys (PPNAS-M) that was based on currently available scales for human and rhesus monkeys. Twenty-four healthy marmoset infants (12 females, 12 males) from 12 families were evaluated. The infant assessments involved 10-minute testing administered at 15 and 30 days after birth. The PPNAS-M consists of 41 noninvasive tests grouped into 5 testing categories: visual orienting, auditory and spatial orienting, motor responses, righting and body strength, and temperament tests. Testing at these two ages did not affect the overall health of the infants, suggesting that the PPNAS-M is a non-invasive testing tool. Significant maturation was demonstrated by increased scores in each of the five testing categories from postnatal day 15 to 30, with developmental patterns unique to marmosets. Principal component analysis defined 4 item groups (Orientation, State Control, Motor Maturity and Sensory Sensitivity) with 5 variables each. Orientation and State Control factors were highly similar to each other at both ages and correlated highly with previous item groupings used with rhesus macaques. Our results indicate that the PPNAS-M is a useful assessment tool for detecting neuromotor, attention, and temperament status of infant marmosets and that it is sensitive to developmental effects. Further studies to validate the PPNAS-M for the assessment of normal development versus early effects of developmental perturbations associated to prenatal exposures and transgenesis are warranted.

Microrna Mediated Regulation of Hematopoietic Stem Cell Aging

Aging hematopoietic stem cells (HSCs) exhibit numerous functional alterations including reduced capacity for self-renewal, myeloid-biased differentiation, and reduced production of mature lymphocytes and red blood cells. Interventions such as calorie restriction (CR) and rapamycin (Rapa) treatment have been shown to increase lifespan and to delay the onset of age-related diseases, and some studies have demonstrated that they may improve HSC function through poorly defined mechanisms. We and others have shown that microRNAs (miRNAs) are potent cell-intrinsic regulators of HSC self-renewal and lineage specification and also contribute to age-related disorders such as acute myeloid leukemia (AML) and the myelodysplastic syndromes (MDS). We hypothesized that miRNAs may underlie the recovery of HSC function observed in anti-aging mouse models, and thus we characterized miRNA expression profiles from HSCs (Lin-c-Kit+Sca-1+CD34-CD150+) from young mice (12-16 weeks old), old mice (20-22 months), and old mice that had been treated with anti-aging interventions. Evaluation of HSCs from CR and Rapa treated old mice revealed numerous changes consistent with inhibition/reversal of age-related HSC changes including a 5-fold reduction in HSC frequency (p=0.04), 2-fold increase in erythroid progenitors (pro-erythroblasts, p=0.04), 2.5 fold increase in common lymphoid progenitors (CLP; Lin-c-Kit+Sca-1+CD127+FLK2+, p=0.05), as well as 3.5-fold increase in peripheral blood B cells (p=0.002), 2.2 fold decrease in platelets (p=0.01), and increased red blood cells (p=0.04). These changes were associated with statistically significant increases in the percentage of HSCs in S/M/G2 (p=0.045), and undergoing apoptosis (p=0.05). Using a TaqMan-based qPCR expression profiling method evaluating 750 miRNAs, we found that old HSCs exhibited altered expression of 91 miRNAs compared to young (FDR <0.1, P <0.05). Moreover, HSCs from both CR and Rapa treated old mice exhibited expression of 60 miRNAs at levels similar to young, normal HSCs. miR-125b, a miRNA we and others previously showed to positively regulate HSC self-renewal, was reduced 2.2-fold in old mice, and its expression was restored in CR and Rapa treated HSCs. Lentivirally mediated expression of miR-125b in old HSCs increased their long-term reconstitution capacity 8.1-fold compared to control old HSCs based on donor chimerism levels at 16 weeks post-transplantation, resulting in chimerism levels similar to mice transplanted with young HSCs expressing miR-125b. The improved HSC engraftment capacity of old HSCs transduced with miR-125b was accompanied by statistically significant increases in the frequencies of lymphoid biased HSCs (Lin-c-Kit+Sca-1+CD34-CD150neg-low), megakaryocyte-erythroid progenitors (MEPs), CLPs, and peripheral blood B- and T-cells, compared to old HSCs transduced with control lentivirus (p<0.05 for all indicated cell types). While enforced expression of high levels of miR-125b in mouse HSPCs has been reported to induce myeloid leukemias, there was no evidence of a hematologic malignancy in mice transplanted with miR-125b transduced old HSCs up to 6 months post-transplantation. Overall, these results demonstrate that functional HSC aging phenotypes can be that inhibited/reversed by anti-aging interventions, that miR-125b regulates HSC aging, and that anti-aging interventions may exert their positive effects on HSC function by regulating miR-125b expression. DisclosuresNo relevant conflicts of interest to declare.

SnapShot: Mammalian Sirtuins

The mammalian sirtuins have emerged as critical regulators of cellular stress resistance, energy metabolism, and tumorigenesis. In some contexts, they delay the onset of age-related diseases and promote a healthy lifespan. The seven mammalian sirtuins, SIRT1-7, share a highly conserved NAD+-binding catalytic core domain although they exhibit distinct expression patterns, catalytic activities, and biological functions. This SnapShot provides an overview of these properties, with an emphasis on their relevance to aging.

PHA-4/FOXA-regulated microRNA feed forward loops during Caenorhabditis elegans dietary restriction.

Dietary restriction (DR) increases life span and delays the onset of age-related diseases across species. However, the molecular mechanisms have remained relatively unexplored in terms of gene regulation. InC. elegans, a popular model for aging studies, the FOXA transcription factor PHA-4 is a robust genetic regulator of DR, although little is known about how it regulates gene expression. We profiled the transcriptome and miRNAome of an eat-2 mutant, a genetic surrogate of DR, by Next Generation sequencing and find that most of the miRNAs are upregulated in the young-adult worms, none significantly downregulated. Interestingly, PHA-4 can potentially regulate the expression of most of these miRNA genes. Remarkably, many of the PHA-4-regulated genes that are induced during DR are also targets of the PHA-4-upregulated miRNAs, forming a large feed-forward gene regulatory network. The genes targeted by the feed-forward loops (FFLs) are enriched for functions related to ubiquitin-mediated decay, lysosomal autophagy, cellular signalling, protein folding etc., processes that play critical roles in DR and longevity. Together our data provides a framework for understanding the complex and unique regulatory network employed during DR, suggesting that PHA-4 employs such FFLs to fine-tune gene expression and instil robustness in the system during energy crisis.

A05 Session 1: Translational Hibernation : Lessons from mammalian hibernators: Surviving the adverse effects of hypothermia and ischemia–reperfusion

The ability to induce a hypometabolic state holds immense clinical promise since it serves as a means of lowering tissue energy needs and reducing ischemia damage; however, is also associated with many adverse effects in humans and most mammals. Nonetheless, hypometabolic states produced by drug administration or chilling have been applied for treatment of stroke, heart attack, multiple organ failure, as well as brain and spinal cord injury. Moreover, the ability to induce and maintain a dormant state could improve chances of survival for injured patients during transport to medical facilities, delay the onset of age-related diseases, or extend the viability of donor organs removed for transplantation. Naturally occurring hypometabolic states occur in species from seven orders of mammals, suggesting that the torpor phenotype arises from a genotype present in all mammals, including humans. Consequently, mammalian hibernators are of particular interest because they endure hypothermia, ischemia–reperfusion, restricted nutritional resources and yet transition seamlessly to and from the torpid state. To investigate the mechanisms that promote cycles of torpor-arousal without injurious effects, we surveyed targets across a range of cellular processes including metabolism, signal transduction and cellular survival, and epigenetics in 13-lined ground squirrels (Ictidomys tridecemlineatus). As a result, we identified key targets that showed differential expression during torpor with involvement in: (1) fuel utilization and balancing cellular energetics, (2) mitogen-activated protein kinase (MAPK) signal transduction and MAPK-responsive transcription factors and downstream genes, and (3) epigenetic changes including histone modifications and methylation. The data show that central to achieving a hypometabolic state are global molecular controls to inhibit ATP-expensive cellular processes as well as selective implementation of cytoprotective strategies. Furthermore, these data collectively isolate a set of molecular signatures or “fingerprints” in the areas of metabolic rate depression, stress resistance, and epigenetics which define suspended animation. Ultimately, scientific exploration of all forms of hibernation/torpor which differ in length, depth, and body temperature will enable the possibility of exploiting the properties of hypometabolism for the benefit of disease research and human health.

Growth hormone action predicts age-related white adipose tissue dysfunction and senescent cell burden in mice.

The aging process is associated with the development of several chronic diseases. White adipose tissue (WAT) may play a central role in age-related disease onset and progression due to declines in adipogenesis with advancing age. Recent reports indicate that the accumulation of senescent progenitor cells may be involved in age-related WAT dysfunction. Growth hormone (GH) action has profound effects on adiposity and metabolism and is known to influence lifespan. In the present study we tested the hypothesis that GH activity would predict age-related WAT dysfunction and accumulation of senescent cells. We found that long-lived GH-deficient and -resistant mice have reduced age-related lipid redistribution. Primary preadipocytes from GH-resistant mice also were found to have greater differentiation capacity at 20 months of age when compared to controls. GH activity was also found to be positively associated with senescent cell accumulation in WAT. Our results demonstrate an association between GH activity, age-related WAT dysfunction, and WAT senescent cell accumulation in mice. Further studies are needed to determine if GH is directly inducing cellular senescence in WAT or if GH actions on other target organs or alternative downstream alterations in insulin-like growth factor-1, insulin or glucose levels are responsible.

SRT2104 extends survival of male mice on a standard diet and preserves bone and muscle mass.

Increased expression of SIRT1 extends the lifespan of lower organisms and delays the onset of age-related diseases in mammals. Here, we show that SRT2104, a synthetic small molecule activator of SIRT1, extends both mean and maximal lifespan of mice fed a standard diet. This is accompanied by improvements in health, including enhanced motor coordination, performance, bone mineral density, and insulin sensitivity associated with higher mitochondrial content and decreased inflammation. Short-term SRT2104 treatment preserves bone and muscle mass in an experimental model of atrophy. These results demonstrate it is possible to design a small molecule that can slow aging and delay multiple age-related diseases in mammals, supporting the therapeutic potential of SIRT1 activators in humans.

Molecular Gerontology: From Homeodynamics to Hormesis

The science and study of the biological basis of aging, biogerontology, is now a well-established field with solid scientific base. A paradigm-shift in gerontology has occurred by realising the fact that biological aging occurs in spite of the presence of complex homeodynamic pathways of maintenance, repair and defence, and there is no "enemy within". This viewpoint separates the modulation of aging from the treatment of one or more age-related diseases. A promising strategy in biogerontology is to slow down aging and to extend healthspan by hormetin-mediated hormesis. Physical, nutritional and mental hormetins, which initiate stress responses and strengthen the homeodynamics, are potentially effective aging modulators. As a biomedical issue, the biological process of aging underlies all major diseases, and while the optimal treatment of every disease is a social and moral necessity, preventing the onset of agerelated diseases by intervening in the basic process of aging is the best approach for designing novel pharmaceutical interventions.

The SIRT1 Activator SRT1720 Extends Lifespan and Improves Health of Mice Fed a Standard Diet

The prevention or delay of the onset of age-related diseases prolongs survival and improves quality of life while reducing the burden on the health care system. Activation of sirtuin 1 (SIRT1), an NAD(+)-dependent deacetylase, improves metabolism and confers protection against physiological and cognitive disturbances in old age. SRT1720 is a specific SIRT1 activator that has health and lifespan benefits in adult mice fed a high-fat diet. We found extension in lifespan, delayed onset of age-related metabolic diseases, and improved general health in mice fed a standard diet after SRT1720 supplementation. Inhibition of proinflammatory gene expression in both liver and muscle of SRT1720-treated animals was noted. SRT1720 lowered the phosphorylation of NF-κB pathway regulators in vitro only when SIRT1 was functionally present. Combined with our previous work, the current study further supports the beneficial effects of SRT1720 on health across the lifespan in mice.

Funkcjonalne polimorfizmy genów leptyny i receptora leptyny korelują z długowiecznością oraz z ryzykiem zawału mięśnia serca i cukrzycy 2 typu

Longevity is commonly associated with good health and with delayed onset of age-related diseases with usually benign course. Leptin (LEP) significantly affects metabolism and numerous functions of the organism. To find out if extreme longevity and its phenotype are associated with genetic variants of leptin and leptin receptor (LEPR) genes, we analysed the frequencies of the -2548 G/A and +19 G/A LEP, as well as the K109R, Q223R, and K656N LEPR polymorphisms in centenarians and in control groups. The frequencies of the LEP and LEPR polymorphisms were tested by restriction fragment length polymorphism in 128 centenarians, 414 young controls (Y), 226 myocardial infarction (MI) patients, and 190 type 2 diabetes mellitus (DM2) patients. The GG genotype of the -2548 G/A LEP polymorphism was significantly more common in centenarians than in the Y, MI and DM2 groups (p = 0.048, p = 0.003, p = 0.049, respectively). In addition, the AA genotype of the K109R LEPR polymorphism was significantly less frequent in centenarians than in the Y, MI, and DM2 groups (p = 0.026, p = 0.013, and p = 0.001, respectively). We suggest that the leptin pathway plays a role in the regulation of longevity, possibly by modulating the risk of development of MI and of DM2.

Poor oral health, a potential new geriatric syndrome

This article presents a brief introduction to the medical aspects of ageing and age-related diseases, and to some geriatric syndromes, followed by a discussion on their impact on general and oral healthcare provision to community-dwelling older people. Recent investigations suggest that inflammation constitutes a biological foundation of ageing and the onset of age-related diseases. Multimorbidity and polypharmacy, together with alterations in pharmacokinetics and pharmacodynamics, make older people at risk of adverse medication reactions. A side effect of several medications is causing xerostomia and hyposalivation, and both the type and number of medications used are relevant. New options of general healthcare provision to community-dwelling older people are the use of mobility aids and assistive technology devices, domiciliary health care, respite care and telecare. Their oral health status may be jeopardised by frailty, disability, care dependency and limited access to professional oral health care. Recommendations for improvement are the following: better integrating oral health care into general health care, developing and implementing an oral healthcare guideline, providing customised oral hygiene care aids, domiciliary oral healthcare provision, visiting dental hygienists and/or nurses, oral hygiene telecare, easily and safely accessible dental offices, transforming dentistry into medical oral health care and upgrading dentists to oral physicians. In case oral healthcare providers do not take the responsibility of persuading society of the importance of adequate oral health, weakened oral health of community-dwelling older people will become a potential new geriatric syndrome.

Present and future of anti-ageing epigenetic diets

The rapid technological advancements achieved in the last years have boosted the progressive identification of age-associated epigenetic changes. These studies not only contribute to shed light on the molecular basis of ageing and age-related diseases but, given the plasticity of epigenetic modifications, also provide the basis for anti-ageing interventions to counteract the onset of age-related diseases. In this review we will discuss nutritional interventions as a promising approach that can positively counteract epigenetic changes associated with ageing and promote the health for the elderly. First, we will give an overview of age-associated epigenetic signatures, focusing on DNA methylation. Then, we will report recent evidences regarding the epigenetic changes induced by nutritional interventions in the adulthood (referred as “epigenetic diets”), such as (i) caloric/dietary restriction, (ii) diet supplementation with nutrients involved in one-carbon metabolism and (iii) diet supplementation with bioactive food components. Attention will be drawn on the limits of current studies and the need of proper human models, such as those provided by the ongoing European project NU-AGE. Finally, we will discuss the potential impact of epigenetic diets on inflammaging and age-related diseases, focusing on cardiovascular disease, highlighting the involvement of epigenetic modifications other than DNA methylation, such as microRNA.

New insights into the chemical and biochemical basis of the "yang-invigorating" action of chinese yang-tonic herbs.

In the practice of traditional Chinese medicine, many Yang-tonic herbs have been used for retarding the decline in bodily function and delaying the onset of age-related diseases. Our earlier studies have demonstrated that Yang-invigorating herbs/formulations protect against oxidative injury in various organs and also extend the median lifespan in mice. This lifespan extension was associated with an upregulation of cellular antioxidant status including that of mitochondria whose functional capacity is also increased by “Yang-invigorating” herbs/formulations. In this paper, we propose that triterpenes and phytosterols, which are ubiquitously found in Yang-tonic herbs, may be the chemical entities responsible for enhancing mitochondrial functional and antioxidant capacity and thus the “Yang-invigorating” action. The biochemical mechanism underlying this “Yang-invigorating” action may involve a sustained production of low levels of mitochondrial reactive oxygen species (ROS) secondary to an increased activity of the electron transport chain, with the possible involvement of mitochondrial uncoupling. The increase in mitochondrial functional capacity can retard the decline in bodily function during aging, whereas the mitochondrial ROS production is instrumental in eliciting a glutathione antioxidant response via redox-sensitive signaling pathways, which can delay the onset of age-related diseases.

Downregulation of the Werner syndrome protein induces a metabolic shift that compromises redox homeostasis and limits proliferation of cancer cells.

The Werner syndrome protein (WRN) is a nuclear protein required for cell growth and proliferation. Loss-of-function mutations in the Werner syndrome gene are associated with the premature onset of age-related diseases. How loss of WRN limits cell proliferation and induces replicative senescence is poorly understood. Here, we show that WRN depletion leads to a striking metabolic shift that coordinately weakens the pathways that generate reducing equivalents for detoxification of reactive oxygen species and increases mitochondrial respiration. In cancer cells, this metabolic shift counteracts the Warburg effect, a defining characteristic of many malignant cells, resulting in altered redox balance and accumulation of oxidative DNA damage that inhibits cell proliferation and induces a senescence-like phenotype. Consistent with these findings, supplementation with antioxidant rescues at least in part cell proliferation and decreases senescence in WRN-knockdown cancer cells. These results demonstrate that WRN plays a critical role in cancer cell proliferation by contributing to the Warburg effect and preventing metabolic stress.

Evidence of changes to skeletal muscle contractile properties during the initiation of disease in the ageing guinea pig model of osteoarthritis

BackgroundOsteoarthritis (OA) is the most common joint disorder in the world and represents the leading cause of pain and disability in the elderly population. Advancing age remains the single greatest risk factor for OA. Several studies have characterised disease development in the guinea pig ageing model of OA in terms of its joint histopathology and inflammatory cytokine profile. However, the quadriceps muscle has yet to be studied in relation to age-related disease onset or early disease progression. Therefore, we examined whether the initiation of OA in the Dunkin Hartley guinea pig is associated with changes in the quadriceps skeletal muscle. Male Dunkin Hartley guinea pigs (N = 24) were group housed with free access to standard guinea pig chow and water. At 2, 3, 5 and 7 months of age, six animals were selected based on their proximity to the median weight of the cohort. OA severity was graded at each time point by the assessment of toluidine blue stained step coronal sections of the total knee joint. Serum CTX II was measured as a potential biomarker of OA severity. Myosin Heavy Chain (MHC) isoforms were determined by a validated real-time PCR assay. Oxidative and glycolytic potential was determined in quadriceps homogenates via the measurement of ICDH and LDH activity.ResultsInitiation of OA in the DH strain guinea pig occurred between 2 and 3 months of age and progressed until 7 months when the final analyses were conducted. Serum CTX II significantly decreased during this early period of OA initiation and levels were unrelated to the histopathological severity of knee OA at any of the time points assessed. MHC mRNA measurements revealed a significant elevation in MHC IIX mRNA (associated with fast-twitch skeletal muscle fibres) coincident with the initiation of OA at 3 months of age, with preliminary findings suggestive of a positive correlation to OA severity at this time point.ConclusionsThese preliminary findings suggest that disease initiation in the ageing guinea pig model of OA is not associated with overt quadriceps muscle atrophy but instead is coincident with altered expression of mRNAs associated with quadriceps skeletal muscle contractile properties (specifically fast-twitch MHC IIX).

Hydrogen Sulfide Is an Endogenous Regulator of Aging in Caenorhabditis elegans

To investigate the role of endogenous hydrogen sulfide (H2S) in the control of aging and healthspan of Caenorhabditis elegans. We show that the model organism, C. elegans, synthesizes H2S. Three H2S-synthesizing enzymes are present in C. elegans, namely cystathionine γ lyase (CSE), cystathionine β synthetase, and 3-mercaptopyruvate transferase (MPST or 3-MST). Genetic deficiency of mpst-1 (3-MST orthologue 1), but not cth-2 (CSE orthologue), reduced the lifespan of C. elegans. This effect was reversed by a pharmacological H2S donor (GYY4137). GYY4137 also reduced detrimental age-dependent changes in a range of physiological indices, including pharyngeal contraction and defecation. Treatment of C. elegans with GYY4137 increased the expression of several age-related, stress response, and antioxidant genes, whereas MitoSOX Red fluorescence, indicative of reactive oxygen species generation, was increased in mpst-1 knockouts and decreased by GYY4137 treatment. GYY4137 additionally increased the lifespan in short-lived mev-1 mutants with elevated oxidative stress and protected wild-type C. elegans against paraquat poisoning. The lifespan-prolonging and health-promoting effects of H2S in C. elegans are likely due to the antioxidant action of this highly cell-permeable gas. The possibility that novel pharmacological agents based on the principle of H2S donation may be able to retard the onset of age-related disease by slowing the aging process warrants further study. Our results show that H2S is an endogenous regulator of oxidative damage, metabolism, and aging in C. elegans and provide new insight into the mechanisms, which control aging in this model organism.

Telomere length: a marker of disease susceptibility?

Telomeres, the caps found at the ends of chromosomes, have clinical significance for health: a growing literature links shorter telomeres with depression, poor health behaviors, age-related diseases, and mortality (Epel et al., 2010; Lin et al., 2012). Elegant prior work by Cohen and his colleagues clearly demonstrated that psychological stress and socioeconomic status (SES) alter infectious disease risk (Cohen et al., 2013). In their newest paper, Cohen and colleagues show that adults with lower SES during childhood had shorter telomeres on CD8+CD28− T-cells and were more likely to develop the common cold than adults with a higher childhood SES (Cohen et al., in press). The authors argue that lower childhood SES speeds the progression to replicative senescence in CD8+CD28− T-cells, an important T-cell subset because of its role in cancer and viral illnesses; shorter CD8+CD28− telomeres reflect greater senescence (Cohen et al., in press). Accordingly, childhood SES could have a far-reaching impact on disease susceptibility. Inflammation may be one mechanism linking lower childhood SES to shortened telomeres; inflammation triggers T-cell proliferation, one known cause of telomere shortening (Kiecolt-Glaser et al., 2013). Indeed, converging evidence suggests that other forms of childhood adversity, such as abuse or neglect, are linked to elevated levels of inflammation and shortened telomeres. For example, adults who experienced more early life adversity had higher inflammation and shorter telomeres than adults who experienced less early life adversity (Kiecolt-Glaser et al., 2011). Importantly, Cohen’s paper suggests that early childhood stressors may affect immune function throughout the lifespan (Cohen et al., in press); related work has demonstrated that adult SES also has immune consequences, potentially because low SES adults report high levels of stress and depression (Jaremka et al., 2013). For instance, adults with lower subjective SES had stronger inflammatory responses to a laboratory speech task than those with higher subjective SES, and tended to rate the task as more threatening and less manageable (Derry et al., 2013). Taken together, previous research and the new Cohen paper suggest that low SES and early life stress elevate inflammation, thereby shortening telomeres and increasing infectious disease susceptibility during adulthood. Prior work investigating the links among SES, early life adversity, inflammation, and disease susceptibility often utilized relatively healthy adult samples. Indeed, Cohen and colleagues tested their hypotheses with a unique sample of extremely healthy adults (Cohen et al., in press); their volunteers were free from major medical comorbidities and were not taking medication other than birth control. Furthermore, their average age was 29.8, with a range from 18 to 55. The odds of needing prescription medication for one or more chronic conditions rise steeply during middle age, and thus their sample represents the very best case scenario in terms of physical and mental health. Although telomere attrition is an important correlate of aging, health status affects this relationship. For example, healthy centenarians had longer telomeres than centenarians who had two or more chronic health conditions (Terry et al., 2008). Accordingly, chronic illness may further accelerate age-related telomere shortening. Indeed, many chronic diseases, including cancer, have inflammatory correlates or consequences (Jaremka et al., 2013). In this context, elevated inflammation among cancer survivors carries clear risks for accelerated aging. The tissue damage resulting from surgery, chemotherapy, and radiation may evoke inflammatory responses and thus shorten telomeres. Furthermore, many people reduce physical activity and gain weight during cancer treatment; low physical activity and adiposity are risk factors for higher inflammation and shorter telomeres, placing cancer survivors at further risk of accelerated aging. Depression, which affects a subset of cancer survivors, promotes inflammation and the premature aging of immune cells (Hewitt et al., 2003; Jaremka et al., 2013). Accordingly, the combination of depression and inflammatory-related chronic diseases may be a particularly potent challenge to cell aging. The findings by Cohen and colleagues suggest that this accelerated cell aging may affect disease susceptibility among cancer survivors; shortened telomeres enhance risk of infectious (Cohen et al., in press) and age-related diseases (Epel et al., 2010). Indeed, cancer survivors experience higher rates of other comorbid illnesses, such as cardiovascular disease, than those who have not had cancer (Hewitt et al., 2003); infectious disease risk may also be higher. In sum, inflammation and accelerated cell aging represent important pre-disease mechanisms that may be improved or worsened through multiple behavioral and biomedical pathways (Kiecolt-Glaser et al., 2013). Because short telomeres predict early disease, slowing immune cell aging could have broad effects by slowing the onset of age-related diseases.