Vascular dementia: From pathobiology to emerging perspectives.

Vascular dementia (VaD) is the second most common type of dementia. VaD is synonymous with ageing, and its symptoms place a significant burden on the health and wellbeing of older people. Despite the identification of a substantial number of risk factors for VaD, the pathological mechanisms underpinning this disease remain to be fully elucidated. Consequently, a biogerontological imperative exists to highlight the modifiable lifestyle factors which can mitigate against the risk of developing VaD. This review will critically examine some of the factors which have been revealed to modulate VaD risk. The survey commences by providing an overview of the putative mechanisms which are associated with the pathobiology of VaD. Next, the factors which influence the risk of developing VaD are examined. Finally, emerging treatment avenues including epigenetics, the gut microbiome, and pro-longevity pharmaceuticals are discussed. By drawing this key evidence together, it is our hope that it can be used to inform future experimental investigations in this field.

A new mathematical model of folate homeostasis in E. coli highlights the potential importance of the folinic acid futile cycle in cell growth.

Folate (vitamin B9) plays a central role in one-carbon metabolism in prokaryotes and eukaryotes. This pathway mediates the transfer of one-carbon units, playing a crucial role in nucleotide synthesis, methylation, and amino acid homeostasis. The folinic acid futile cycle adds a layer of intrigue to this pathway, due to its associations with metabolism, cell growth, and dormancy. It also introduces additional complexity to folate metabolism. A logical way to deal with such complexity is to examine it by using mathematical modelling. This work describes the construction and analysis of a model of folate metabolism, which includes the folinic acid futile cycle. This model was tested under three in silico growth conditions. Model simulations revealed: 1) the folate cycle behaved as a stable biochemical system in three growth states (slow, standard, and rapid); 2) the initial concentration of serine had the greatest impact on metabolite concentrations; 3) 5-formyltetrahydrofolate cyclo-ligase (5-FCL) activity had a significant impact on the levels of the 7 products that carry the one-carbon donated from folates, and the redox couple NADP/NADPH; this was particularly evident in the rapid growth state; 4) 5-FCL may be vital to the survival of the cells by maintaining low levels of homocysteine, as high levels can induce toxicity; and 5) the antifolate therapeutic trimethoprim had a greater impact on folate metabolism with higher nutrient availability. These results highlight the important role of 5-FCL in intracellular folate homeostasis and mass generation under different metabolic scenarios.

Computationally Modelling Cholesterol Metabolism and Atherosclerosis.

Cardiovascular disease (CVD) is the leading cause of death globally. The underlying pathological driver of CVD is atherosclerosis. The primary risk factor for atherosclerosis is elevated low-density lipoprotein cholesterol (LDL-C). Dysregulation of cholesterol metabolism is synonymous with a rise in LDL-C. Due to the complexity of cholesterol metabolism and atherosclerosis mathematical models are routinely used to explore their non-trivial dynamics. Mathematical modelling has generated a wealth of useful biological insights, which have deepened our understanding of these processes. To date however, no model has been developed which fully captures how whole-body cholesterol metabolism intersects with atherosclerosis. The main reason for this is one of scale. Whole body cholesterol metabolism is defined by macroscale physiological processes, while atherosclerosis operates mainly at a microscale. This work describes how a model of cholesterol metabolism was combined with a model of atherosclerotic plaque formation. This new model is capable of reproducing the output from its parent models. Using the new model, we demonstrate how this system can be utilized to identify interventions that lower LDL-C and abrogate plaque formation.

An evolutionary perspective of lifespan and epigenetic inheritance.

In the last decade epigenetics has come to the fore as a discipline which is central to biogerontology. Age associated epigenetic changes are routinely linked with pathologies, including cardiovascular disease, cancer, and Alzheimer's disease; moreover, epigenetic clocks are capable of correlating biological age with chronological age in many species including humans. Recent intriguing empirical observations also suggest that inherited epigenetic effects could influence lifespan/longevity in a variety of organisms. If this is the case, an imperative exists to reconcile lifespan/longevity associated inherited epigenetic processes with the evolution of ageing. This review will critically evaluate inherited epigenetic effects from an evolutionary perspective. The overarching aim is to integrate the evidence which suggests epigenetic inheritance modulates lifespan/longevity with the main evolutionary theories of ageing.

Dietary restriction and ageing: Recent evolutionary perspectives.

Dietary restriction (DR) represents one of the most robust interventions for extending lifespan. It is not known how DR increases lifespan. The prevailing evolutionary hypothesis suggests the DR response redirects metabolic resources towards somatic maintenance at the expense of investment in reproduction. Consequently, DR acts as a proximate mechanism which promotes a pro-longevity phenotype. This idea is known as resource reallocation. However, growing findings suggest this paradigm could be incomplete. It has been argued that during DR it is not always possible to identify a trade-off between reproduction and lifespan. It is also suggested the relationship between reproduction and somatic maintenance can be uncoupled by the removal or inclusion of specific nutrients. These findings have created an imperative to re-explore the nexus between DR and evolutionary theory. In this review I will address this evolutionary conundrum. My overarching objectives are fourfold: (1) to outline some of the evidence for and against resource reallocation; (2) to examine recent findings which have necessitated a theoretical re-evaluation of the link between life history theory and DR; (3) to present alternatives to the resource reallocation model; (4) to present emerging variables which potentially influence how DR effects evolutionary trade-offs.

Modeling cholesterol metabolism and atherosclerosis.

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality among Western populations. Many risk factors have been identified for ASCVD; however, elevated low-density lipoprotein cholesterol (LDL-C) remains the gold standard. Cholesterol metabolism at the cellular and whole-body level is maintained by an array of interacting components. These regulatory mechanisms have complex behavior. Likewise, the mechanisms which underpin atherogenesis are nontrivial and multifaceted. To help overcome the challenge of investigating these processes mathematical modeling, which is a core constituent of the systems biology paradigm has played a pivotal role in deciphering their dynamics. In so doing models have revealed new insights about the key drivers of ASCVD. The aim of this review is fourfold; to provide an overview of cholesterol metabolism and atherosclerosis, to briefly introduce mathematical approaches used in this field, to critically discuss models of cholesterol metabolism and atherosclerosis, and to highlight areas where mathematical modeling could help to investigate in the future. This article is categorized under: Cardiovascular Diseases > Computational Models.

DNA methylation in genes associated with the evolution of ageing and disease: A critical review.

Ageing is characterised by a physical decline in biological functioning which results in a progressive risk of mortality with time. As a biological phenomenon, it is underpinned by the dysregulation of a myriad of complex processes. Recently, however, ever-increasing evidence has associated epigenetic mechanisms, such as DNA methylation (DNAm) with age-onset pathologies, including cancer, cardiovascular disease, and Alzheimer's disease. These diseases compromise healthspan. Consequently, there is a medical imperative to understand the link between epigenetic ageing, and healthspan. Evolutionary theory provides a unique way to gain new insights into epigenetic ageing and health. This review will: (1) provide a brief overview of the main evolutionary theories of ageing; (2) discuss recent genetic evidence which has revealed alleles that have pleiotropic effects on fitness at different ages in humans; (3) consider the effects of DNAm on pleiotropic alleles, which are associated with age related disease; (4) discuss how age related DNAm changes resonate with the mutation accumulation, disposable soma and programmed theories of ageing; (5) discuss how DNAm changes associated with caloric restriction intersect with the evolution of ageing; and (6) conclude by discussing how evolutionary theory can be used to inform investigations which quantify age-related DNAm changes which are linked to age onset pathology.

The Interdependency and Co-Regulation of the Vitamin D and Cholesterol Metabolism.

Vitamin D and cholesterol metabolism overlap significantly in the pathways that contribute to their biosynthesis. However, our understanding of their independent and co-regulation is limited. Cardiovascular disease is the leading cause of death globally and atherosclerosis, the pathology associated with elevated cholesterol, is the leading cause of cardiovascular disease. It is therefore important to understand vitamin D metabolism as a contributory factor. From the literature, we compile evidence of how these systems interact, relating the understanding of the molecular mechanisms involved to the results from observational studies. We also present the first systems biology pathway map of the joint cholesterol and vitamin D metabolisms made available using the Systems Biology Graphical Notation (SBGN) Markup Language (SBGNML). It is shown that the relationship between vitamin D supplementation, total cholesterol, and LDL-C status, and between latitude, vitamin D, and cholesterol status are consistent with our knowledge of molecular mechanisms. We also highlight the results that cannot be explained with our current knowledge of molecular mechanisms: (i) vitamin D supplementation mitigates the side-effects of statin therapy; (ii) statin therapy does not impact upon vitamin D status; and critically (iii) vitamin D supplementation does not improve cardiovascular outcomes, despite improving cardiovascular risk factors. For (iii), we present a hypothesis, based on observations in the literature, that describes how vitamin D regulates the balance between cellular and plasma cholesterol. Answering these questions will create significant opportunities for advancement in our understanding of cardiovascular health.

Electrochemically detecting DNA methylation in the EN1 gene promoter: implications for understanding ageing and disease.

There is a growing need for biomarkers which predict age-onset pathology. Although this is challenging, the methylome offers significant potential. Cancer is associated with the hypermethylation of many gene promoters, among which are developmental genes. Evolutionary theory suggests developmental genes arbitrate early-late life trade-offs, causing epimutations that increase disease vulnerability. Such genes could predict age-related disease. The aim of this work was to optimise an electrochemical procedure for the future investigation of a broad range of ageing-related pathologies. An electrochemical approach, which adopted three analytical techniques, was used to investigate DNA methylation in the engrailed-1 (EN1) gene promoter. Using synthetic single-stranded DNA, one technique was able to detect DNA at concentrations as low as 10 nM, with methylation status distinguishable at concentrations >25 nM. A negative correlation could be observed between % methylation of a heterogeneous solution and the key electrochemical parameter, charge transfer resistance (Rct; r = -0.982, P<0.01). The technique was applied to the breast cancer cell line Michigan Cancer Foundation-7 (MCF-7), where a similar correlation was observed (r = -0.965, P<0.01). These results suggest electrochemistry can effectively measure DNA methylation at low concentrations of DNA. This has implications for the future detection of age-related disease.

Cholesterol Homeostasis: An In Silico Investigation into How Aging Disrupts Its Key Hepatic Regulatory Mechanisms.

The dysregulation of intracellular cholesterol homeostasis is associated with several age-related diseases, most notably cardiovascular disease (CVD). Research in this area has benefitted from using computational modelling to study the inherent complexity associated with the regulation of this system. In addition to facilitating hypothesis exploration, the utility of modelling lies in its ability to represent an array of rate limiting enzymatic reactions, together with multiple feedback loops, which collectively define the dynamics of cholesterol homeostasis. However, to date no model has specifically investigated the effects aging has on this system. This work addresses this shortcoming by explicitly focusing on the impact of aging on hepatic intracellular cholesterol homeostasis. The model was used to investigate the experimental findings that reactive oxygen species induce the total activation of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR). Moreover, the model explored the impact of an age-related decrease in hepatic acetyl-CoA acetyltransferase 2 (ACAT2). The model suggested that an increase in the activity of HMGCR does not have as significant an impact on cholesterol homeostasis as a decrease in hepatic ACAT2 activity. According to the model, a decrease in the activity of hepatic ACAT2 raises free cholesterol (FC) and decreases low-density lipoprotein cholesterol (LDL-C) levels. Increased acetyl CoA synthesis resulted in a reduction in the number of hepatic low-density lipoprotein receptors, and increased LDL-C, FC, and cholesterol esters. The rise in LDL-C was restricted by elevated hepatic FC accumulation. Taken together these findings have important implications for healthspan. This is because emerging clinical data suggest hepatic FC accumulation is relevant to the pathogenesis of non-alcoholic fatty liver disease (NAFLD), which is associated with an increased risk of CVD. These pathophysiological changes could, in part, help to explain the phenomenon of increased mortality associated with low levels of LDL-C which have been observed in certain studies involving the oldest old (≥85 years).

Effects of obesity on cholesterol metabolism and its implications for healthy ageing.

The last few decades have witnessed a global rise in the number of older individuals. Despite this demographic shift, morbidity within this population group is high. Many factors influence healthspan; however, an obesity pandemic is emerging as a significant determinant of older people's health. It is well established that obesity adversely affects several metabolic systems. However, due to its close association with overall cardiometabolic health, the impact that obesity has on cholesterol metabolism needs to be recognised. The aim of the present review is to critically discuss the effects that obesity has on cholesterol metabolism and to reveal its significance for healthy ageing.

Data-driven selection and parameter estimation for DNA methylation mathematical models.

Epigenetics is coming to the fore as a key process which underpins health. In particular emerging experimental evidence has associated alterations to DNA methylation status with healthspan and aging. Mammalian DNA methylation status is maintained by an intricate array of biochemical and molecular processes. It can be argued changes to these fundamental cellular processes ultimately drive the formation of aberrant DNA methylation patterns, which are a hallmark of diseases, such as cancer, Alzheimer's disease and cardiovascular disease. In recent years mathematical models have been used as effective tools to help advance our understanding of the dynamics which underpin DNA methylation. In this paper we present linear and nonlinear models which encapsulate the dynamics of the molecular mechanisms which define DNA methylation. Applying a recently developed Bayesian algorithm for parameter estimation and model selection, we are able to estimate distributions of parameters which include nominal parameter values. Using limited noisy observations, the method also identified which methylation model the observations originated from, signaling that our method has practical applications in identifying what models best match the biological data for DNA methylation.

Disrupting folate metabolism reduces the capacity of bacteria in exponential growth to develop persisters to antibiotics.

Bacteria can survive high doses of antibiotics through stochastic phenotypic diversification. We present initial evidence that folate metabolism could be involved with the formation of persisters. The aberrant expression of the folate enzyme gene fau seems to reduce the incidence of persisters to antibiotics. Folate-impaired bacteria had a lower generation rate for persisters to the antibiotics ampicillin and ofloxacin. Persister bacteria were detectable from the outset of the exponential growth phase in the complex media. Gene expression analyses tentatively showed distinctive profiles in exponential growth at times when bacteria persisters were observed. Levels of persisters were assessed in bacteria with altered, genetically and pharmacologically, folate metabolism. This work shows that by disrupting folate biosynthesis and usage, bacterial tolerance to antibiotics seems to be diminished. Based on these findings there is a possibility that bacteriostatic antibiotics such as anti-folates could have a role to play in clinical settings where the incidence of antibiotic persisters seems to drive recalcitrant infections.

Computational modelling folate metabolism and DNA methylation: implications for understanding health and ageing.

Dietary folates have a key role to play in health, as deficiencies in the intake of these B vitamins have been implicated in a wide variety of clinical conditions. The reason for this is folates function as single carbon donors in the synthesis of methionine and nucleotides. Moreover, folates have a vital role to play in the epigenetics of mammalian cells by supplying methyl groups for DNA methylation reactions. Intriguingly, a growing body of experimental evidence suggests that DNA methylation status could be a central modulator of the ageing process. This has important health implications because the methylation status of the human genome could be used to infer age-related disease risk. Thus, it is imperative we further our understanding of the processes which underpin DNA methylation and how these intersect with folate metabolism and ageing. The biochemical and molecular mechanisms, which underpin these processes, are complex. However, computational modelling offers an ideal framework for handling this complexity. A number of computational models have been assembled over the years, but to date, no model has represented the full scope of the interaction between the folate cycle and the reactions, which governs the DNA methylation cycle. In this review, we will discuss several of the models, which have been developed to represent these systems. In addition, we will present a rationale for developing a combined model of folate metabolism and the DNA methylation cycle.

The Interplay Between Cholesterol Metabolism and Intrinsic Ageing.

The last few decades have witnessed remarkable progress in our understanding of ageing. From an evolutionary standpoint it is generally accepted that ageing is a non-adaptive process which is underscored by a decrease in the force of natural selection with time. From a mechanistic perspective ageing is characterized by a wide variety of cellular mechanisms, including processes such as cellular senescence, telomere attrition, oxidative damage, molecular chaperone activity, and the regulation of biochemical pathways by sirtuins. These biological findings have been accompanied by an unrelenting rise in both life expectancy and the number of older people globally. However, despite age being recognized demographically as a risk factor for healthspan, the processes associated with ageing are routinely overlooked in disease mechanisms. Thus, a central goal of biogerontology is to understand how diseases such as cardiovascular disease (CVD) are shaped by ageing. This challenge cannot be ignored because CVD is the main cause of morbidity in older people. A worthwhile way to examine how ageing intersects with CVD is to consider the effects ageing has on cholesterol metabolism, because dysregualted cholesterol metabolism is the key factor which underpins the pathology of CVD. The aim of this chapter is to outline a hypothesis which accounts for how ageing intersects with intracellular cholesterol metabolism. Moreover, we discuss the implications of this relationship for the onset of disease in the 'oldest old' (individuals ≥85 years of age). We conclude the chapter by discussing the important role mathematical modelling has to play in improving our understanding of cholesterol metabolism and ageing.

LDL-C levels in older people: Cholesterol homeostasis and the free radical theory of ageing converge.

The cardiovascular disease (CVD) risk factor, low density lipoprotein cholesterol (LDL-C) increases with age, up until the midpoint of life in males and females. However, LDL-C can decrease with age in older men and women. Intriguingly, a recent systematic review also revealed an inverse association between LDL-C levels and cardiovascular mortality in older people; low levels of LDL-C were associated with reduced risk of mortality. Such findings are puzzling and require a biological explanation. In this paper a hypothesis is proposed to explain these observations. We hypothesize that the free radical theory of ageing (FRTA) together with disrupted cholesterol homeostasis can account for these observations. Based on this hypothesis, dysregulated hepatic cholesterol homeostasis in older people is characterised by two distinct metabolic states. The first state accounts for an older person who has elevated plasma LDL-C. This state is underpinned by the FRTA which suggests there is a decrease in cellular antioxidant capacity with age. This deficiency enables hepatic reactive oxidative species (ROS) to induce the total activation of HMG-CoA reductase, the key rate limiting enzyme in cholesterol biosynthesis. An increase in cholesterol synthesis elicits a corresponding rise in LDL-C, due to the downregulation of LDL receptor synthesis, and increased production of very low density lipoprotein cholesterol (VLDL-C). In the second state of dysregulation, ROS also trigger the total activation of HMG-CoA reductase. However, due to an age associated decrease in the activity of cholesterol-esterifying enzyme, acyl CoA: cholesterol acyltransferase, there is restricted conversion of excess free cholesterol (FC) to cholesterol esters. Consequently, the secretion of VLDL-C drops, and there is a corresponding decrease in LDL-C. As intracellular levels of FC accumulate, this state progresses to a pathophysiological condition akin to nonalcoholic fatty liver disease. It is our conjecture this deleterious state has the potential to account for the inverse association between LDL-C level and CVD risk observed in older people.

Modelling the molecular mechanisms of aging.

The aging process is driven at the cellular level by random molecular damage that slowly accumulates with age. Although cells possess mechanisms to repair or remove damage, they are not 100% efficient and their efficiency declines with age. There are many molecular mechanisms involved and exogenous factors such as stress also contribute to the aging process. The complexity of the aging process has stimulated the use of computational modelling in order to increase our understanding of the system, test hypotheses and make testable predictions. As many different mechanisms are involved, a wide range of models have been developed. This paper gives an overview of the types of models that have been developed, the range of tools used, modelling standards and discusses many specific examples of models that have been grouped according to the main mechanisms that they address. We conclude by discussing the opportunities and challenges for future modelling in this field.

Aging and computational systems biology.

Aging research is undergoing a paradigm shift, which has led to new and innovative methods of exploring this complex phenomenon. The systems biology approach endeavors to understand biological systems in a holistic manner, by taking account of intrinsic interactions, while also attempting to account for the impact of external inputs, such as diet. A key technique employed in systems biology is computational modeling, which involves mathematically describing and simulating the dynamics of biological systems. Although a large number of computational models have been developed in recent years, these models have focused on various discrete components of the aging process, and to date no model has succeeded in completely representing the full scope of aging. Combining existing models or developing new models may help to address this need and in so doing could help achieve an improved understanding of the intrinsic mechanisms which underpin aging.

A mathematical model of microbial folate biosynthesis and utilisation: implications for antifolate development.

The metabolic biochemistry of folate biosynthesis and utilisation has evolved into a complex network of reactions. Although this complexity represents challenges to the field of folate research it has also provided a renewed source for antimetabolite targets. A range of improved folate chemotherapy continues to be developed and applied particularly to cancer and chronic inflammatory diseases. However, new or better antifolates against infectious diseases remain much more elusive. In this paper we describe the assembly of a generic deterministic mathematical model of microbial folate metabolism. Our aim is to explore how a mathematical model could be used to explore the dynamics of this inherently complex set of biochemical reactions. Using the model it was found that: (1) a particular small set of folate intermediates are overrepresented, (2) inhibitory profiles can be quantified by the level of key folate products, (3) using the model to scan for the most effective combinatorial inhibitions of folate enzymes we identified specific targets which could complement current antifolates, and (4) the model substantiates the case for a substrate cycle in the folinic acid biosynthesis reaction. Our model is coded in the systems biology markup language and has been deposited in the BioModels Database (MODEL1511020000), this makes it accessible to the community as a whole.

Obesity and the dysregulation of fatty acid metabolism: implications for healthy aging.

INTRODUCTION: The population of the world is aging. In 2010, an estimated 524 million people were aged 65 years or older representing eight percent of the global population. By 2050, this number is expected to nearly triple to approximately 1.5 billion, 16 percent of the world's population. Although people are living longer, the quality of their lives are often compromised due to ill-health. Areas covered: Of the conditions which compromise health as we age, obesity is at the forefront. Over half of the global older population were overweight or obese in 2010, significantly increasing the risk of a range of metabolic diseases. Although, it is well recognised excessive calorie intake is a fundamental driver of adipose tissue dysfunction, the relationship between obesity; intrinsic aging; and fat metabolism is less understood. In this review we discuss the intersection between obesity, aging and the factors which contribute to the dysregulation of whole-body fat metabolism. Expert commentary: Being obese disrupts an array of physiological systems and there is significant crosstalk among these. Moreover it is imperative to acknowledge the contribution intrinsic aging makes to the dysregulation of these systems and the onset of disease.