Potential biomarkers of ageing

Life span in individual humans is very heterogeneous.Thus, the ageing rate, measured as the decline of functional capacity and stress resistance, is different in every individual. There have been attempts made to analyse this individual age, the so-called biological age, in comparison to chronological age. Biomarkers of ageing should help to characterise this biological age and, as age is a major risk factor in many degenerative diseases,could be subsequently used to identify individuals at high risk of developing age-associated diseases or disabilities.Markers based on oxidative stress, protein glycation,inflammation, cellular senescence and hormonal deregulation are discussed.     

NF-κB pathway activators as potential ageing biomarkers: targets for new therapeutic strategies

Chronic inflammation is a major biological mechanism underpinning biological ageing process and age-related diseases. Inflammation is also the key response of host defense against pathogens and tissue injury. Current opinion sustains that during evolution the host defense and ageing process have become linked together. Thus, the large array of defense factors and mechanisms linked to the NF-κB system seem to be involved in ageing process. This concept leads us in proposing inductors of NF-κB signaling pathway as potential ageing biomarkers. On the other hand, ageing biomarkers, represented by biological indicators and selected through apposite criteria, should help to characterize biological age and, since age is a major risk factor in many degenerative diseases, could be subsequently used to identify individuals at high risk of developing age-associated diseases or disabilities. In this report, some inflammatory biomarkers will be discussed for a better understanding of the concept of biological ageing, providing ideas on eventual working hypothesis about potential targets for the development of new therapeutic strategies and improving, as consequence, the quality of life of elderly population.     

Liver mitochondrial respiratory functions decline with age

Human liver mitochondrial respiration rates in Chinese populations of various ages were assayed with an oxygraph. In this study, State 3 and State 4 respiration rates, respiratory control ratio (RCR), and ADP/O ratio were measured for 35 Chinese subjects of 31 to 76 years old. We found a significant negative correlation between age and respiratory control and ADP/O ratios tested. Moreover, the respiratory control and ADP/O ratios decreased with the increase of age. These findings suggest that a substantial fall in mitochondrial oxidative capacity in ageing liver may be an important contributor to the ageing process.     

Epigenetic age prediction

Advanced age is the main common risk factor for cancer, cardiovascular disease and neurodegeneration. Yet, more is known about the molecular basis of any of these groups of diseases than the changes that accompany ageing itself. Progress in molecular ageing research was slow because the tools predicting whether someone aged slowly or fast (biological age) were unreliable. To understand ageing as a risk factor for disease and to develop interventions, the molecular ageing field needed a quantitative measure; a clock for biological age. Over the past decade, a number of age predictors utilising DNA methylation have been developed, referred to as epigenetic clocks. While they appear to estimate biological age, it remains unclear whether the methylation changes used to train the clocks are a reflection of other underlying cellular or molecular processes, or whether methylation itself is involved in the ageing process. The precise aspects of ageing that the epigenetic clocks capture remain hidden and seem to vary between predictors. Nonetheless, the use of epigenetic clocks has opened the door towards studying biological ageing quantitatively, and new clocks and applications, such as forensics, appear frequently. In this review, we will discuss the range of epigenetic clocks available, their strengths and weaknesses, and their applicability to various scientific queries.     

Is the parasitization capacity of Trichogramma cordubensis influenced by the age of the females?

We investigated the parasitization capacity of Trichogramma cordubensis Vargas & Cabello (Hymenoptera: Trichogrammatidae) females aged 24 h, 48 h, 72 h, 96 h, 120 h, and 144 h, using Ephestia kuehniella Zeller (Lepidoptera: Pyralidae) eggs as hosts. Wasps were held without hosts during the period of ageing, therefore being increasingly time-limited with respect to parasitization as they got older. The total number of parasitized hosts decreased as the age of the parasitoid increased. However, the proportion of lifetime parasitism carried out on the first day increased with wasp age, up to 120-h old females. These results show that the parasitization capacity of ageing T. cordubensis females changes as they become time-limited. The consequences of such changes for biological control programs are discussed.     

DNA damage, cellular senescence and organismal ageing: causal or correlative?

Cellular senescence has long been used as a cellular model for understanding mechanisms underlying the ageing process. Compelling evidence obtained in recent years demonstrate that DNA damage is a common mediator for both replicative senescence, which is triggered by telomere shortening, and premature cellular senescence induced by various stressors such as oncogenic stress and oxidative stress. Extensive observations suggest that DNA damage accumulates with age and that this may be due to an increase in production of reactive oxygen species (ROS) and a decline in DNA repair capacity with age. Mutation or disrupted expression of genes that increase DNA damage often result in premature ageing. In contrast, interventions that enhance resistance to oxidative stress and attenuate DNA damage contribute towards longevity. This evidence suggests that genomic instability plays a causative role in the ageing process. However, conflicting findings exist which indicate that ROS production and oxidative damage levels of macromolecules including DNA do not always correlate with lifespan in model animals. Here we review the recent advances in addressing the role of DNA damage in cellular senescence and organismal ageing.     

综述: 造血干细胞衰老的研究进展

成体干细胞衰老是组织器官老化的重要原因之一.越来越多的证据显示,免疫系统的衰老起始于造血干细胞(HSC)功能的下降,即造血干细胞的衰老直接影响免疫系统的功能.然而,有关HSC衰老的机理和分子机制仍旧不清楚.在这篇综述中,我们总结了造血干细胞衰老的表型,同时从细胞内在及外在两个方面探讨论了HSC衰老的分子机制.     

Reactive oxygen species target specific tryptophan site in the mitochondrial ATP synthase

The release of reactive oxygen species (ROS) as side products of aerobic metabolism in the mitochondria is an unavoidable consequence. As the capacity of organisms to deal with this exposure declines with age, accumulation of molecular damage caused by ROS has been defined as one of the central events during the ageing process in biological systems as well as in numerous diseases such as Alzheimer's and Parkinson's Dementia. In the filamentous fungus Podospora anserina, an ageing model with a clear defined mitochondrial etiology of ageing, in addition to the mitochondrial aconitase the ATP synthase alpha subunit was defined recently as a hot spot for oxidative modifications induced by ROS. In this report we show, that this reactivity is not randomly distributed over the ATP Synthase, but is channeled to a single tryptophan residue 503. This residue serves as an intra-molecular quencher for oxidative species and might also be involved in the metabolic perception of oxidative stress or regulation of enzyme activity. A putative metal binding site in the proximity of this tryptophan residue appears to be crucial for the molecular mechanism for the selective targeting of oxidative damage.     

Physiological ageing of potato tubers: A Review

Numerous theories have been proposed to describe the complex process of ageing in biological systems. Two general groups of ageing theories currently exist: 1) stochastic where the accumulation of random molecular damage leads to loss of information vital to the cell; and, 2) systemic where an organised, genetically based sequence of metabolic activities leads to programmed ageing. Whether these are acceptable models of ageing in potato tubers is unknown although the tuber could provide a useful experimental system for studying ageing. An initial requirement for advancing the concept of ageing in potato tubers must centre on the development of a suitable ageing index. A review of the literature suggests that a modified approach to ‘sprouting capacity’ and ‘incubation period’ may allow tuber ageing to be described in mathematical terms that would, in turn, facilitate the development of a physiological ageing index as well as temperature sensitive predictive models. Although a number of biochemical studies of ageing have been pursued, the development of adequate biomarkers has yet to achieve a coordinated level of development as found in a range of organisms. For example, ageing in other biological systems may be viewed as an outcome of an accumulation of random molecular damage and may be primarily caused by a changing balance between reactive oxygen species and diminishing levels of protective agents such as superoxide dismutase, alpha‐tocopherol or vitamin C. The exploration of these and similar problems in the context of appropriate modelling approaches should allow a better understanding of physiological ageing in potato tubers.     

Changes in the level of sister chromatid exchanges in cultured Chinese hamster cells undergoing limited proliferation

"Stationary phase ageing" of cultured Chinese hamster cells (when proliferation rate decreases and in the stationary growth phase) produces an increase in the frequency of spontaneous sister chromatid exchanges (SCE). Thiophosphamide-induced (24 h) frequency of SCE increases from 2-day to 5-day "age" and later (in the stationary phase) is practically the same. The "stationary ageing" cultured cells are suggested to be used as a model system for studying molecular-genetic age changes.     

Fragile DNA repair mechanism reduces ageing in multicellular model

DNA damages, as well as mutations, increase with age. It is believed that these result from increased genotoxic stress and decreased capacity for DNA repair. The two causes are not independent, DNA damage can, for example, through mutations, compromise the capacity for DNA repair, which in turn increases the amount of unrepaired DNA damage. Despite this vicious circle, we ask, can cells maintain a high DNA repair capacity for some time or is repair capacity bound to continuously decline with age? We here present a simple mathematical model for ageing in multicellular systems where cells subjected to DNA damage can undergo full repair, go apoptotic, or accumulate mutations thus reducing DNA repair capacity. Our model predicts that at the tissue level repair rate does not continuously decline with age, but instead has a characteristic extended period of high and non-declining DNA repair capacity, followed by a rapid decline. Furthermore, the time of high functionality increases, and consequently slows down the ageing process, if the DNA repair mechanism itself is vulnerable to DNA damages. Although counterintuitive at first glance, a fragile repair mechanism allows for a faster removal of compromised cells, thus freeing the space for healthy peers. This finding might be a first step toward understanding why a mutation in single DNA repair protein (e.g. Wrn or Blm) is not buffered by other repair proteins and therefore, leads to severe ageing disorders.     

A mathematical model of ageing in yeast

Budding yeast, Saccharomyces cerevisiae, is commonly used as a system to study cellular ageing. Yeast mother cells are capable of only a limited number of divisions before they undergo senescence, whereas newly formed daughters usually have their replicative age "reset" to zero. Accumulation of extrachromosomal ribosomal DNA circles (ERCs) appears to be an important contributor to ageing in yeast, and we describe a mathematical model that we developed to examine this process. We show that an age-related accumulation of ERCs readily explains the observed features of yeast ageing but that in order to match the experimental survival curves quantitatively, it is necessary that the probability of ERC formation increases with the age of the cell. This implies that some other mechanism(s), in addition to ERC accumulation, must underlie yeast ageing. We also demonstrate that the model can be used to gain insight into how an extra copy of the Sir2 gene might extend lifespan and we show how the model makes novel, testable predictions about patterns of age-specific mortality in yeast populations.     

Phenotype correlations reveal the relationships of physiological systems underlying human ageing

Ageing is characterized by degeneration and loss of function across multiple physiological systems. To study the mechanisms and consequences of ageing, several metrics have been proposed in a hierarchical model, including biological, phenotypic and functional ageing. In particular, phenotypic ageing and interconnected changes in multiple physiological systems occur in all ageing individuals over time. Recently, phenotypic age, a new ageing measure, was proposed to capture morbidity and mortality risk across diverse subpopulations in US cohort studies. Although phenotypic age has been widely used, it may overlook the complex relationships among phenotypic biomarkers. Considering the correlation structure of these phenotypic biomarkers, we proposed a composite phenotype analysis (CPA) strategy to analyse 71 biomarkers from 2074 individuals in the Rugao Longitudinal Ageing Study. CPA grouped these biomarkers into 18 composite phenotypes according to their internal correlation, and these composite phenotypes were mostly consistent with prior findings. In addition, compared with prior findings, this strategy exhibited some different yet important implications. For example, the indicators of kidney and cardiovascular functions were tightly connected, implying internal interactions. The composite phenotypes were further verified through associations with functional metrics of ageing, including disability, depression, cognitive function and frailty. Compared to age alone, these composite phenotypes had better predictive performances for functional metrics of ageing. In summary, CPA could reveal the hidden relationships of physiological systems and identify the links between physiological systems and functional ageing metrics, thereby providing novel insights into potential mechanisms underlying human ageing.     

Disposable Soma Theory and the Evolution of Maternal Effects on Ageing

Maternal effects are ubiquitous in nature and affect a wide range of offspring phenotypes. Recent research suggests that maternal effects also contribute to ageing, but the theoretical basis for these observations is poorly understood. Here we develop a simple model to derive expectations for (i) if maternal effects on ageing evolve; (ii) the strength of maternal effects on ageing relative to direct environmental effects; and (iii) the predicted relationships between environmental quality, maternal age and offspring lifespan. Our model is based on the disposable soma theory of ageing, and the key assumption is thus that mothers trade off their own somatic maintenance against investment in offspring. This trade-off affects the biological age of offspring at birth in terms of accumulated damage, as indicated by biomarkers such as oxidative stress or telomere length. We find that the optimal allocation between investment in maternal somatic investment and investment in offspring results in old mothers and mothers with low resource availability producing offspring with reduced life span. Furthermore, the effects are interactive, such that the strongest maternal age effects on offspring lifespan are found under low resource availability. These findings are broadly consistent with results from laboratory studies investigating the onset and rate of ageing and field studies examining maternal effects on ageing in the wild.     

Mitochondrial respiration in blood platelets of depressive patients

Recent evidences include mitochondrial dysfunctions in pathophysiology of mood disorders. We examined association between depressive disorders and mitochondrial respiration using both intact and permeabilized blood platelets. In intact platelets, physiological respiration, maximal capacity of electron transport system and respiratory rate after complex I inhibition were decreased in depressive patients, who reached partial remission, compared to healthy controls. Respiratory rates were unchanged in several respiratory states in permeabilized platelets. Results indicate that changes in respiratory rate in intact platelets can be used as biological marker of depressive disorder. The hypothesis that decreased mitochondrial respiratory rate participate in pathophysiology of depression was supported.     

Mitochondrial involvement in the ageing process. Facts and controversies

Mitochondria are believed to be involved in human ageing. Whilst it is clear that various mitochondrial DNA mutations do accumulate in human tissues with age, whether or not they interfere with respiratory chain function is uncertain. We question the results of previous studies which have measured respiratory chain function in human skeletal muscle with age. Whilst cytochrome c oxidase deficient fibres are a real finding in skeletal muscle, the contribution of mitochondrial DNA mutations to human ageing is still controversial. Our results show for mitochondria to be involved in ageing then it must be through a more subtle mechanism than a global decline in respiratory chain function. (Mol Cell Biochem 174: 325–328, 1997)     

Age-dependent characteristics of the skin peripheral blood flow oscillations by nonlinear dynamics methods in humans

Study of peripheral microhaemodynamics was carried out with laser Doppler flowmetry in healthy volunteers of different age groups. The ageing changes in the state of the skin peripheral blood flow, in the functioning of separate links and regulatory systems ofmicrovascular bed have been estimated in terms of relative entropy and fractal dimension values. The revealed significant age-dependent decrease of relative entropy values in the respiratory rhythm ranges, the neurogenic and myogenic activities yielded some evidence concerning the reduction of the microcirculation system chaotic changes within these frequency ranges during the ageing. The significant increase of fractal dimension values in the ranges of cardio-rhythm and the endothelial activity in the oldest group with the mean age of 77 years indicated that the structural complexity of the oscillations in these frequency ranges increased during ageing.     

Analysis of age-associated changes in mitochondrial free radical generation by rat testis

Throughout spermatogenesis, mitochondria undergo a morphological and functional differentiation. Mitochondria are involved in the production of reactive oxygen species (ROS), considered one of the mediators of ageing. Particularly, lipid peroxidation is regarded as a major phenomenon by which ROS can impair cellular function. In the present study, we examined the production of superoxide anion, superoxide dismutase activity and the effect of Fe²⁺/ascorbate induced-lipid peroxidation on the respiratory chain activities of testis mitochondria throughout the process of spermatogenesis and ageing. Mitochondria from rat testes generated superoxide anion, mainly using NADH as substrate, which increased according to age. The activity of SOD is age-dependent and greatly stimulated during the first wave of spermatogenesis, but decreases in adulthood and old age. TBARS concentration was also markedly increased by ageing. The activity of mitochondrial respiratory chain complexes is differentially affected by oxidative stress induced by iron/ascorbate, succinate-dehydrogenase activity being less vulnerable than that of NADH-dehydrogenase and cytochrome c oxidase. The data suggest that ageing is accompanied by reduced activity of SOD, leading to excessive oxidative stress and enhanced lipid peroxidation that compromises the functionality of the electron transport chain. The data support the concept that mitochondrial function is an important determinant in ageing.     

Accounting for Age Uncertainty in Growth Modeling,the Case Study of Yellowfin Tuna (Thunnus albacares) of the Indian Ocean

Age estimates, typically determined by counting periodic growth increments in calcified structures of vertebrates, are the basis of population dynamics models used for managing exploited or threatened species. In fisheries research, the use of otolith growth rings as an indicator of fish age has increased considerably in recent decades. However, otolith readings include various sources of uncertainty. Current ageing methods, which converts an average count of rings into age, only provide periodic age estimates in which the range of uncertainty is fully ignored. In this study, we describe a hierarchical model for estimating individual ages from repeated otolith readings. The model was developed within a Bayesian framework to explicitly represent the sources of uncertainty associated with age estimation, to allow for individual variations and to include knowledge on parameters from expertise. The performance of the proposed model was examined through simulations, and then it was coupled to a two-stanza somatic growth model to evaluate the impact of the age estimation method on the age composition of commercial fisheries catches. We illustrate our approach using the saggital otoliths of yellowfin tuna of the Indian Ocean collected through large-scale mark-recapture experiments. The simulation performance suggested that the ageing error model was able to estimate the ageing biases and provide accurate age estimates, regardless of the age of the fish. Coupled with the growth model, this approach appeared suitable for modeling the growth of Indian Ocean yellowfin and is consistent with findings of previous studies. The simulations showed that the choice of the ageing method can strongly affect growth estimates with subsequent implications for age-structured data used as inputs for population models. Finally, our modeling approach revealed particularly useful to reflect uncertainty around age estimates into the process of growth estimation and it can be applied to any study relying on age estimation.     

Development of DNA methylation-based epigenetic age predictors in loblolly pine (Pinus taeda)

Biological ageing is connected to life history variation across ecological scales and informs a basic understanding of age-related declines in organismal function. Altered DNA methylation dynamics are a conserved aspect of biological ageing and have recently been modelled to predict chronological age among vertebrate species. In addition to their utility in estimating individual age, differences between chronological and predicted ages arise due to acceleration or deceleration of epigenetic ageing, and these discrepancies are linked to disease risk and multiple life history traits. Although evidence suggests that patterns of DNA methylation can describe ageing in plants, predictions with epigenetic clocks have yet to be performed. Here, we resolve the DNA methylome across CpG, CHG, and CHH-methylation contexts in the loblolly pine tree (Pinus taeda) and construct epigenetic clocks capable of predicting ages in this species within 6% of its maximum lifespan. Although patterns of CHH-methylation showed little association with age, both CpG and CHG-methylation contexts were strongly associated with ageing, largely becoming hypomethylated with age. Among age-associated loci were those in close proximity to malate dehydrogenase, NADH dehydrogenase, and 18S and 26S ribosomal RNA genes. This study reports one of the first epigenetic clocks in plants and demonstrates the universality of age-associated DNA methylation dynamics which can inform conservation and management practices, as well as our ecological and evolutionary understanding of biological ageing in plants.