Age-related Disease States Research Articles

The Effects of Aging on Gut Microbiome Composition and Association With Age-Related Disease States: A Literature Review

The Effects of Aging on Gut Microbiome Composition and Association With Age-Related Disease States: A Literature Review

Blood-based epigenome-wide analyses of chronic low-grade inflammation across diverse population cohorts

Chronic inflammation is a hallmark of age-related disease states. The effectiveness of inflammatory proteins including C-reactive protein (CRP) in assessing long-term inflammation is hindered by their phasic nature. DNA methylation (DNAm) signatures of CRP may act as more reliable markers of chronic inflammation. We show that inter-individual differences in DNAm capture 50% of the variance in circulating CRP (N= 17,936, Generation Scotland). We develop a series of DNAm predictors of CRP using state-of-the-art algorithms. An elastic-net-regression-based predictor outperformed competing methods and explained 18% of phenotypic variance in the Lothian Birth Cohort of 1936 (LBC1936) cohort, doubling that of existing DNAm predictors. DNAm predictors performed comparably in four additional test cohorts (Avon Longitudinal Study of Parents and Children, Health for Life in Singapore, Southall and Brent Revisited, and LBC1921), including for individuals of diverse genetic ancestry and different age groups. The best-performing predictor surpassed assay-measured CRP and a genetic score in its associations with 26 health outcomes. Our findings forge new avenues for assessing chronic low-grade inflammation in diverse populations.

Vitamin B12 status and folic acid supplementation influence mitochondrial heteroplasmy levels in mice.

One-carbon metabolism is a complex network of metabolic reactions that are essential for cellular function including DNA synthesis. Vitamin B12 and folate are micronutrients that are utilized in this pathway and their deficiency can result in the perturbation of one-carbon metabolism and subsequent perturbations in DNA replication and repair. This effect has been well characterized in nuclear DNA but to date, mitochondrial DNA (mtDNA) has not been investigated extensively. Mitochondrial variants have been associated with several inherited and age-related disease states; therefore, the study of factors that impact heteroplasmy are important for advancing our understanding of the mitochondrial genome's impact on human health. Heteroplasmy studies require robust and efficient mitochondrial DNA enrichment to carry out in-depth mtDNA sequencing. Many of the current methods for mtDNA enrichment can introduce biases and false-positive results. Here, we use a method that overcomes these limitations and have applied it to assess mitochondrial heteroplasmy in mouse models of altered one-carbon metabolism. Vitamin B12 deficiency was found to cause increased levels of mitochondrial DNA heteroplasmy across all tissues that were investigated. Folic acid supplementation also contributed to elevated mitochondrial DNA heteroplasmy across all mouse tissues investigated. Heteroplasmy analysis of human data from the Framingham Heart Study suggested a potential sex-specific effect of folate and vitamin B12 status on mitochondrial heteroplasmy. This is a novel relationship that may have broader consequences for our understanding of one-carbon metabolism, mitochondrial-related disease and the influence of nutrients on DNA mutation rates.

The Human Extracellular Matrix Diseasome Reveals Genotype-Phenotype Associations with Clinical Implications for Age-Related Diseases.

The extracellular matrix (ECM) is earning an increasingly relevant role in many disease states and aging. The analysis of these disease states is possible with the GWAS and PheWAS methodologies, and through our analysis, we aimed to explore the relationships between polymorphisms in the compendium of ECM genes (i.e., matrisome genes) in various disease states. A significant contribution on the part of ECM polymorphisms is evident in various types of disease, particularly those in the core-matrisome genes. Our results confirm previous links to connective-tissue disorders but also unearth new and underexplored relationships with neurological, psychiatric, and age-related disease states. Through our analysis of the drug indications for gene-disease relationships, we identify numerous targets that may be repurposed for age-related pathologies. The identification of ECM polymorphisms and their contributions to disease will play an integral role in future therapeutic developments, drug repurposing, precision medicine, and personalized care.

Sex Differences in Aging and Associated Biomarkers.

Aging is a natural process defined by the gradual, time-dependent decline of biological and behavioural functions, for which individuals of the same chronological age show variability. The capacity of biological systems to continuously adjust for optimal functioning despite ever changing environments is essential for healthy aging, and variability in these adaptive homeostatic mechanisms may reflect such heterogeneity in the aging process. With an ever-increasing aging population, interest in biomarkers of aging is growing. Although no universally accepted definition of biomarkers of healthy aging exists, mediators of homeostasis are consistently used as measures of the aging process. As important sex differences are known to underlie many of these systems, it is imperative to consider that this may reflect, to some extent, the sex differences observed in aging and age-related disease states. This chapter aims to outline sex differences in key homeostatic domains thought to be associated with the pathophysiology of aging, often proposed as biomarkers of aging and age-related disease states. This includes considering sex-based differences and hormonal status with regards to the gonadal and adrenal endocrine systems and immune function.

Association of mitochondrial DNA levels with frailty and all-cause mortality.

Mitochondrial function is altered with age and variants in mitochondrial DNA (mtDNA) modulate risk for several age-related disease states. However, the association of mtDNA copy number, a readily available marker which reflects mitochondrial depletion, energy reserves, and oxidative stress, on aging and mortality in the general population has not been addressed. To assess the association between mtDNA copy number and two primary outcomes--prevalent frailty and all-cause mortality--we utilize data from participants who were from two multicenter, multiethnic, community-based, prospective studies--the Cardiovascular Health Study (CHS) (1989-2006) and the Atherosclerosis Risk in Communities (ARIC) study (1987-2013). A total of 4892 participants (43.3% men) from CHS and 11,509 participants (44.9% men) from ARIC self-identifying as white or black were included in the analysis. mtDNA copy number, the trait of interest, was measured using a qPCR-based method in CHS and an array-based method in ARIC from DNA isolated from whole blood in participants from both cohorts. In race-stratified meta-analyses, we observe a significant inverse association of mtDNA copy number with age and higher mtDNA copy number in women relative to men. Lower mtDNA copy number was also significantly associated with prevalent frailty in white participants from CHS (OR 0.91, 95% CI 0.85-0.97). Additionally, mtDNA copy number was a strong independent predictor of all-cause mortality in an age- and sex-adjusted, race-stratified analysis of 16,401 participants from both cohorts with a pooled hazard ratio of 1.47 (95% CI 1.33-1.62) for the lowest quintile of mtDNA copy number relative to the highest quintile. Key messages: Mitochondrial DNA (mtDNA) copy number is associated with age and sex. Lower mtDNA copy number is also associated with prevalent frailty. mtDNA copy number is a significant predictor of all-cause mortality in a multiethnic population.

Biochemical, Biomedical and Metabolic Aspects of Imidazole-Containing Dipeptides with the Inherent Complexity to Neurodegenerative Diseases and Various States of Mental Well-Being: A Challenging Correction and Neurotherapeutic Pharmaceutical Biotechnology for Treating Cognitive Deficits, Depression and Intellectual Disabilities.

The activities of carnosine (β-alanyl-L-histidine), carnosine imidazole containing dipeptide based derivatives (N-acetylcarnosine, carcinine, homocarnosine) and a carnosine degrading enzyme (serum carnosinase (EC 3.4.13.20); [human tissue carnosinase (EC 3.4.13.3), CN2 (CNDP2)] ) activities have been discrepantly linked to neuropathophysiological processes. Approximately 82% of the U.S. population will experience normal age-related cognitive decline, as compared to the precipitous losses that are associated with dementing disorders. Interventions designed to promote health and function through everyday activity and specific pharmaco-nutritional therapeutic treatments may enhance brain plasticity in key regions that support executive function. Cognitive health is multidimensional cascade of functions. It encompasses an array of functions, including general intellectual ability, memory, language, allowing a person to interact effectively and appropriately with the environment. The risk factors for reduced physical and cognitive functions in elderly people, as identified in longitudinal studies, relate to comorbidities, critical care situations, physical and psychosocial health, environmental conditions, social circumstances, nutrition, and lifestyle. Depression and dementia are both common in older adults; cognitive functioning declines slightly with normal aging; depression itself can be associated with cognitive impairment and dementia. In this study the role of carnosine and related neuron specific naturally-occurring endogenous imidazole-containing dipeptide pharmacoperones (N-acetylcarnosine, carcinine) is revealed presently in a surprisingly large amounts in long-lived human tissues to correct conformational abnormalities leading to distinct neurodegeneration and age-related disease states, treating cognitive deficits, depression and intellectual disabilities. Carnosine serves as a physiological buffering agent and a metal ion (e.g., zinc and copper) chelator, endowed with ferroxidase type activity; possess anti-aging functions, and free-radical scavenging activity, is capable of delaying senescence and extending the life-span of cultured human fibroblasts; is able to kill transformed cells and protect cells against aldehydes and amyloid peptide fragment. Carnosine and carcinine exhibit a well-documented anti-glycating activity against the glycation of proteins, including low-density lipoproteins, glucose degradation products, esterase, histones. A tissue carnosine-degrading enzyme (CN2) colocalized with the activity of histidine decarboxylase to histamine neurons in the hypothalamic tuberomammillary nucleus (TMN) plays a key role in the neuro-transmission and neuroregulation roles of imidazole-containing based dipeptides. Carnosine released from skeletal muscle during exercise may be transported into TMN-histamine neurons and hydrolyzed. Timing of carnosine present in the chicken broth, the specific patented nutraceutical composition (Can-C Plus™), 1% N-acetylcarnosine lubricant eye drops or 1% carcinine lubricant eye drops formulations are important targeting posology vehicles that are involved in many CNS functions through the central brain histamine system including the vision enhancement functions, physiological regulation of cognitive functions, arousal; anxiety; activation of the sympathetic nervous system; the stress-related release of hormones from the pituitary and of central aminergic neurotransmitters; antinociception; water retention and suppression of eating. The roles for the carnosine-stimulated/mediated neuronal histamine system are proposed as a danger and physiological response system active in protection from neurodegenerative diseases and in management of cognitive deficits, depression and intellectual disabilities.

O-GlcNAc transferase and O-GlcNAcase: achieving target substrate specificity.

O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) catalyze the dynamic cycling of intracellular, post-translational O-GlcNAc modification on thousands of Ser/Thr residues of cytosolic, nuclear, and mitochondrial signaling proteins. The identification of O-GlcNAc modified substrates has revealed a functionally diverse set of proteins, and the extent of O-GlcNAcylation fluctuates in response to nutrients and cellular stress. As a result, OGT and OGA are implicated in widespread, nutrient-responsive regulation of numerous signaling pathways and transcriptional programs. These enzymes are required for normal embryonic development and are dysregulated in metabolic and age-related disease states. While a recent surge of interest in the field has contributed to understanding the functional impacts of protein O-GlcNAcylation, little is known about the upstream mechanisms which modulate OGT and OGA substrate targeting. This review focuses on elements of enzyme structure among splice variants, post-translational modification, localization, and regulatory protein interactions which drive the specificity of OGT and OGA toward different subsets of the cellular proteome. Ongoing efforts in this rapidly advancing field are aimed at revealing mechanisms of OGT and OGA regulation to harness the potential therapeutic benefit of manipulating these enzymes' activities.

Tempol intake improves inflammatory status in aged mice.

Oxidative stress is associated with both healthy aging and age-related disease states. In connection with oxidative stress, immunity is also a major component as a result of the chronic, low-grade inflammation associated with the development of tissue aging. Here we show that long-term treatment with the antioxidant tempol extends life-span in mice. Tempol-treated mice exhibited a reduction in mortality at 20 months. Tempol drinking did not have any effect on body weight, amount of visceral adipose tissue, or plasma biochemical parameters in aged mice. Body temperature of aged control mice (which drank only water) was significantly lower than young mice, but this reduction of body temperature was partially restored in aged mice which drank tempol. Plasma thiobarbituric acid-reactive substances and C-reactive protein were significantly increased in the control aged mice compared with young mice, but levels of both were normalized by tempol drinking. One of the endogenous antioxidants, ascorbic acid, was significantly increased in the plasma of mice which consumed tempol. The proportion of CD4 lymphocytes in the blood of aged tempol-treated mice was partially increased in comparison to aged control mice. These results suggest that the reduction of mortality by tempol is due to amelioration of chronic inflammation and improved function of the immune system through antioxidant effects.

HTERT mutations associated with idiopathic pulmonary fibrosis affect telomerase activity, telomere length, and cell growth by distinct mechanisms

Telomerase is a ribonucleoprotein reverse transcriptase (RT) that synthesizes specific DNA repeats, or telomeric DNA, at the ends of chromosomes. Telomerase is minimally composed of a protein subunit, TERT, and an RNA component, TR. Aberrant telomerase activity has been associated with most human cancers and several premature aging diseases, such as idiopathic pulmonary fibrosis (IPF), a chronic, progressive, and fatal lung disease characterized by alveolar epithelial cell damage and fibrosis. Our study focuses on three hTERT mutations that were identified in a subset of patients with IPF, in which these patients also exhibited shorter telomeres compared with age-matched controls. We characterized how three IPF-associated hTERT mutations, V144M, R865C, and R865H, affected telomerase function both in vitro and in human cells. We demonstrated that the R865 residue is crucial for repeat addition processivity and thus telomere synthesis in telomerase-positive 293 cells and telomerase-negative BJ cells, consistent with its location in the hTERT nucleotide-binding motif. In contrast, while the V144M mutant did not exhibit any biochemical defects, this mutant was unable to elongate telomeres in human cells. As a result, our studies have identified hTERT V144 and R865 as two critical residues required for proper telomerase function in cells. Together, this may explain how inherited hTERT mutations can lead to shortened telomeres in patients with IPF and, thus, provide further insight into the role of naturally occurring telomerase mutations in the pathophysiology of certain age-related disease states.

Age-related alterations in forebrain mechanisms of chronic pain

We identified age-related changes in the activation within forebrain structures involved in cognition and the processing and modulation of pain following characterization of cognitive behaviors and the behavioral response to sensory stimuli in young (4 month), mid-life (16 month) and aged (24 months) FBN1 hybrid male rats. Cognition tests assessed exploratory behavior, locomotor activity, emotionality/reactivity, anxiety, fear, learning and memory (Open Field Behavior, Elevated Plus Maze) and the behavioral responses to mechanical (Von Frey) and thermal stimulation (Hargreaves) of the hindpaw. Behavioral results indicate that locomotor activity and learning is decreased and that pain sensitivity and anxiety increases with aging. We also identified changes in the activation of specific CNS structures under basal conditions (no stimulation) and in response to inflammatory pain (subcutaneous injection of 1.0% formalin) using autoradiographic measurement of regional cerebral blood flow as an index of neuronal activity. Specifically, we identified age-related changes in the activation within structures involved in nociceptive processing and mesolimbic dopamine regions associated with reward. In addition, we assessed these brain regions in all animals for the presence of apoptosis using an in-vivo fluorescent polycaspase marker (FAM-FLIVO™), an indicator of apoptotic changes in the nervous system. Apoptotic cell death within the same forebrain and brainstem ROIs described was confirmed by immunohistochemical TUNEL staining. Image analysis is ongoing and the findings will be presented at the meeting. Results from this study will provide important insights into the basic biology of the aging process and the pathophysiology of age-related disease states which may lead to the development of new target strategies for the diagnosis and treatment of chronic pain in an aging population. We identified age-related changes in the activation within forebrain structures involved in cognition and the processing and modulation of pain following characterization of cognitive behaviors and the behavioral response to sensory stimuli in young (4 month), mid-life (16 month) and aged (24 months) FBN1 hybrid male rats. Cognition tests assessed exploratory behavior, locomotor activity, emotionality/reactivity, anxiety, fear, learning and memory (Open Field Behavior, Elevated Plus Maze) and the behavioral responses to mechanical (Von Frey) and thermal stimulation (Hargreaves) of the hindpaw. Behavioral results indicate that locomotor activity and learning is decreased and that pain sensitivity and anxiety increases with aging. We also identified changes in the activation of specific CNS structures under basal conditions (no stimulation) and in response to inflammatory pain (subcutaneous injection of 1.0% formalin) using autoradiographic measurement of regional cerebral blood flow as an index of neuronal activity. Specifically, we identified age-related changes in the activation within structures involved in nociceptive processing and mesolimbic dopamine regions associated with reward. In addition, we assessed these brain regions in all animals for the presence of apoptosis using an in-vivo fluorescent polycaspase marker (FAM-FLIVO™), an indicator of apoptotic changes in the nervous system. Apoptotic cell death within the same forebrain and brainstem ROIs described was confirmed by immunohistochemical TUNEL staining. Image analysis is ongoing and the findings will be presented at the meeting. Results from this study will provide important insights into the basic biology of the aging process and the pathophysiology of age-related disease states which may lead to the development of new target strategies for the diagnosis and treatment of chronic pain in an aging population.

Reverse Transcribing the Code for Chromosome Stability

The linearity of eukaryotic chromosomes presents challenges to cells, as the presence of DNA "ends" poses problems for the DNA replication machinery and the cell's damage response systems. This year's Nobel Prize in Physiology or Medicine recognized groundbreaking studies establishing the telomere field as a crucial area of biomedical research.

Role of NFκB in age-related vascular endothelial dysfunction in humans

Role of NFκB in age-related vascular endothelial dysfunction in humans

Cellular Regulation of SIRT1

The intersection between regulatory pathways responsive to metabolic fluctuation on one hand, and to cellular stress on the other, is a fascinating area within which NAD/NADH responsive proteins play a major role [1, 2]. A key player amongst these is SIRT1, a member of the mammalian sirtuin family (SIRT1-7). SIRT1 is an NAD-dependent deacetylase with critical functions in the maintenance of homeostasis and cell survival. In this review I shall focus upon (i) the cellular regulation of SIRT1 expression and (ii) the cellular regulation of SIRT1 activity. In addition the distinction between basal and stress-induced functions will be addressed: do they simply reflect a sliding scale of response, or are they mechanistically distinct? Elevated levels of SIRT1 are evident in cancer and SIRT1 can function as a cancer-specific survival factor in human cell lines. However, in a mouse model SIRT1 is reported to function as a tumour suppressor. Possible explanations for this apparent discrepancy will be considered. Given the high profile of SIRT1 as a potential therapeutic target it is clearly important to clarify its basal functioning in relation to differentiation, cell type, intercellular communication, and to age-related disease states including neurodegeneration and cancer.

Aging and glycoxidant stress

Aging and related diseases are accompanied by increased Oxidative Stress (OS) and accumulation of Advanced Glycation End products (AGEs). One important component of AGEs accumulation with aging appears to be the sustained exposure to dietary AGE (dAGEs), which contributes to overloading of anti-AGE receptors and depletion of anti-oxidant reserves. In this review, we present experimental animal and human data which support this postulation. Lowering the content of AGEs in the normal diet significantly prevents AGEs accumulation and the increased OS caused by aging and also extends lifespan in mice. In humans, short-term trials indicate that a Low AGEs diet reduces oxidant burden and inflammatory markers. Long-term studies are in progress and will help establish definitive causality between age-related disease states and modern dietary practices in Western societies.

Is There A Relationship Between Insulin Resistance and Frailty Syndrome?

Due to the fact that the percentage of aged subjects in the populations of industrialized countries is dramatically increasing, the scientific community has been obligated to focus their attention on age related disease states and peculiar consequences of aging such as, frailty. Frailty is defined as a syndrome of decreased reserve and resistance to stressors and is clinically expressed as muscle weakness, poor exercise tolerance, factors related to body composition, sarcopenia, and lower extremity mobility. Some biochemical markers of frailty in older persons, including pro-inflammatory markers, hormones and free radicals have been suggested. However, there is growing evidence that a rise in insulin resistance [IR] occurs as individuals age and IR is not only considered a simple metabolic finding, but has been identified as a major risk factor for many age-related diseases due to altered lipid metabolism, increased inflammatory state, impaired endothelial functioning, pro-thrombotic status and atherosclerosis. Considering that IR is related to many of the clinical features of frailty such as, skeletal muscle weakness, lower extremity mobility disability, cognitive decline and body composition changes, we will analyze the relationships among IR and such individual components while highlighting potential pathophysiologic mechanisms of IR on the activation of the downward spiral of the frailty syndrome in older persons. In particular, we will address the issue that IR may also be considered a pivotal biological component of some clinical aspects of the frailty syndrome in aging individuals.

Effect of Inflammation on the Aging Microcirculation: Impact on Skeletal Muscle Blood Flow Control

To meet the metabolic demands of skeletal muscle, the vasculature supplying these vascular beds has to be connected to respond in a coordinated uniform manner, thus providing the necessary oxygen and nutrients during increased activity. The skeletal muscle microcirculation is the major resistance network controlling vascular blood supply and it is the integrity of the endothelium lining the blood vessels that is paramount in facilitating this action. Aging is a major risk factor for cardiovascular disease and is associated with significant increases in inflammatory agents that negatively impact the vasculature. Several inflammatory agents such as cytokines (tumor necrosis factor-a), advanced glycation products (AGEs), and matrix metalloproteinases (MMPs) along with storage cells for inflammatory mediators (mast cells) are associated with a chronic "low-grade inflammation" state that has been observed over the course of the aging process. Current research suggests that these age-related increases in inflammatory agents can disrupt the microvascular endothelium and thus impair blood flow. This impairment could exacerbate the common age-related disease states such as hypertension, diabetes, congestive heart failure, and sarcopenia, leading to increased mortality and morbidity.

Genetically engineered mice and their use in aging research.

Genetically engineered animal models have been and will continue to be invaluable for exploring the basic mechanisms involved in the aging process as well as in extending our understanding of diseases found to be more prevalent in the older human population. Continued development of such in vivo systems will allow scientists to further dissect the role genetic and environmental factors play in aging and in age-related disease states and to enhance our understanding of these processes. In this article we discuss techniques involved in the development of such models and review some examples of laboratory mouse strains that have been used to study either normal aging or select diseases associated with aging.