Age-related Pathophysiological Changes Research Articles

Mechanisms of vascular aging

Vascular aging plays a key role in morbidity and mortality in the elderly. With age, the vasculature undergoes changes characterized by endothelial dysfunction, wall thickening, decreased elongation, and arterial stiffness. The review focuses on the main cellular and molecular mechanisms of aging, including oxidative stress, endothelial dysfunction, inflammation, increased arterial stiffness, and molecular genetic aspects. Their role in the pathogenesis of diseases associated with aging is considered. Some of the molecular mechanisms underlying these processes include increased expression and activation of matrix metalloproteinases, activation of transforming growth factor β1 signaling, increased levels of C-reactive protein, interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)α, and N-terminal pro B-type natriuretic peptide (NT-pro-BNP), and activation of proinflammatory signaling pathways. These events can be caused by vasoactive agents, such as angiotensin II and endothelin-1, the levels of which increase with aging. For prevention of cardiovascular diseases, it is important to understand the mechanisms underlying age-related pathophysiological changes in the blood vessels.

Metabolic Alteration in Aging Process: Metabolic Remodeling in White Adipose Tissue by Caloric Restriction

Caloric restriction (CR) improves whole-body metabolism, suppresses various age-related pathophysiological changes, and extends lifespan. The beneficial actions of CR are regulated in growth hormone (GH)/insulin-like growth factor-1 (IGF-1) signal-dependent and -independent manners. To clarify the GH/IGF-1-independent mechanism, we compared gene expression profiles in white adipose tissue (WAT) between CR and GH/IGF-1 suppression, and found that CR upregulated sterol regulatory element-binding protein 1c (SREBP-1c) regulatory gene expression. To validate the impact of SREBP-1c as a beneficial mediator of CR, we compared the responses to CR between wild-type and SREBP-1c knockout (KO) mice. CR extended lifespan, upregulated gene expression involved in FA biosynthesis, activated mitochondrial biogenesis, and suppressed oxidative stress predominantly in WAT. In contrast, most of these findings were not observed in KO mice. Furthermore, SREBP-1c was implicated in CR-associated mitochondrial activation through upregulation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis. Sirtuin-3 (SIRT3) regulates mitochondrial quality and is also involved in the beneficial actions of CR. We observed that CR upregulated the mature form of SIRT3 protein and mitochondrial intermediate peptidase (MIPEP), a mitochondrial signal peptidase (MtSPase), in WAT. MIPEP cleaved precursor form of SIRT3 to mature form, and activated certain mitochondrial matrix proteins, suggesting that MIPEP might contribute to maintenance of mitochondrial quality during CR via SIRT3 activation. Taken together, CR induces SREBP-1c-dependent metabolic remodeling, including enhancement of FA biosynthesis and mitochondrial activation, via PGC-1α, and improvement of mitochondria quality via Mipep in WAT, resulting in beneficial actions.

Accumulation of kynurenine elevates oxidative stress and alters microRNA profile in human bone marrow stromal cells.

Kynurenine, a metabolite of tryptophan breakdown, has been shown to increase with age, and plays a vital role in a number of age-related pathophysiological changes, including bone loss. Accumulation of kynurenine in bone marrow stromal cells (BMSCs) has been associated with a decrease in cell proliferation and differentiation, though the exact mechanism by which kynurenine mediates these changes is poorly understood. MiRNAs have been shown to regulate BMSC function, and accumulation of kynurenine may alter the miRNA expression profile of BMSCs. The aim of this study was to identify differentially expressed miRNAs in human BMSCs in response to treatment with kynurenine, and correlate miRNAs function in BMSCs biology through bioinformatics analysis. Human BMSCs were cultured and treated with and without kynurenine, and subsequent miRNA isolation was performed. MiRNA array was performed to identify differentially expressed miRNA. Microarray analysis identified 50 up-regulated, and 36 down-regulated miRNAs in kynurenine-treated BMSC cultures. Differentially expressed miRNA included miR-1281, miR-330-3p, let-7f-5p, and miR-493-5p, which are important for BMSC proliferation and differentiation. KEGG analysis found up-regulated miRNA targeting glutathione metabolism, a pathway critical for removing oxidative species. Our data support that the kynurenine dependent degenerative effect is partially due to changes in the miRNA profile of BMSCs.

Impacts of Aging on Anemia Tolerance, Transfusion Thresholds, and Patient Blood Management.

Evidence-based patient blood management guidelines commonly recommend restrictive hemoglobin thresholds of 70 to 80 g/L for asymptomatic adults. However, most transfusion trials have enrolled adults across a broad age span, with few exclusive to older adults. Our recent meta-analysis of transfusion trials that focused on older adults paradoxically found lower mortality and fewer cardiac complications when these patients were managed using higher hemoglobin thresholds. We postulate that declining cardiac output with age contributes to deteriorating oxygen delivery capacity which impacts anemia-associated outcomes in older adults and propose a model to explain this age-related difference. We reviewed evidence concerning the pathophysiology of aging to explore the disparity in transfusion trial outcomes related to hemoglobin thresholds in different age groups. The literature was searched for normative cardiac output values at different ages in healthy adults. Using normative peak cardiac output data, we modeled oxygen delivery capacity in young, middle-aged, and older adults at a range of hemoglobin levels. Cardiovascular and pulmonary systems are impacted by age-related pathophysiological changes. Diminishing peak cardiac output associated with aging reduces the maximal oxygen delivery achievable under metabolic stress. Hence, at low hemoglobin levels, older adults are more susceptible to tissue hypoxia than younger adults. Our model predicts that an older adult with a hemoglobin of 100 g/L has a similar peak oxygen delivery capacity to a young adult with a hemoglobin of 70 g/L. Age-related pathophysiological changes provide some explanation as to why older adults have a lower tolerance for anemia than younger adults. This indicates the need for patient blood management hemoglobin thresholds specific to older as distinct from younger adults. The primary application of this model is in the consideration of patients rehabilitating to life outside hospital. It is important to note that pathophysiological changes associated with critical illness and major surgery are more complex than can be described in a simple model based on cardiac output and hemoglobin concentration. However, our review of oxygen transport and delivery in health and disease states allows the model to be considered in the context of treatment decisions for anemic adults in a range of hospital and community settings.

SREBP-1c-Dependent Metabolic Remodeling of White Adipose Tissue by Caloric Restriction.

Caloric restriction (CR) delays the onset of many age-related pathophysiological changes and extends lifespan. White adipose tissue (WAT) is not only a major tissue for energy storage, but also an endocrine tissue that secretes various adipokines. Recent reports have demonstrated that alterations in the characteristics of WAT can impact whole-body metabolism and lifespan. Hence, we hypothesized that functional alterations in WAT may play important roles in the beneficial effects of CR. Previously, using microarray analysis of WAT from CR rats, we found that CR enhances fatty acid (FA) biosynthesis, and identified sterol regulatory element-binding protein 1c (SREBP-1c), a master regulator of FA synthesis, as a mediator of CR. These findings were validated by showing that CR failed to upregulate factors involved in FA biosynthesis and to extend longevity in SREBP-1c knockout mice. Furthermore, we revealed that SREBP-1c is implicated in CR-associated mitochondrial activation through the upregulation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis. Notably, these CR-associated phenotypes were observed only in WAT. We conclude that CR induces SREBP-1c-dependent metabolic remodeling, including the enhancement of FA biosynthesis and mitochondrial activation, via PGC-1α in WAT, resulting in beneficial effects.

PACAP deficiency as a model of aging.

Dysregulation of neuropeptides may play an important role in aging-induced impairments. In the long list of neuropeptides, pituitary adenylate cyclase-activating polypeptide (PACAP) represents a highly effective cytoprotective peptide that provides an endogenous control against a variety of tissue-damaging stimuli. PACAP has neuro- and general cytoprotective effects due to anti-apoptotic, anti-inflammatory, and antioxidant actions. As PACAP is also a part of the endogenous protective machinery, it can be hypothesized that the decreased protective effects in lack of endogenous PACAP would accelerate age-related degeneration and PACAP knockout mice would display age-related degenerative signs earlier. Recent results support this hypothesis showing that PACAP deficiency mimics aspects of age-related pathophysiological changes including increased neuronal vulnerability and systemic degeneration accompanied by increased apoptosis, oxidative stress, and inflammation. Decrease in PACAP expression has been shown in different species from invertebrates to humans. PACAP-deficient mice display numerous pathological alterations mimicking early aging, such as retinal changes, corneal keratinization and blurring, and systemic amyloidosis. In the present review, we summarize these findings and propose that PACAP deficiency could be a good model of premature aging.

How various concentrations of nutrients affect basal redox homeostasis of fruit flies according to gender and aging.

We evaluated the effects of type of nutrients on redox status according to age and gender in Drosophila melanogaster. Flies were raised on different dose of sucrose and fixed concentration of protein containing media and separated according to their gender and age. Redox status biomarkers such as protein carbonyl groups, dityrosine, kynurenine, lipid hydroperoxides, advanced glycation end products, and Cu,Zn superoxide dismutase were assessed. We found that all of the males had higher levels of basal oxidative stress biomarkers except protein carbonyl. On the other hand, Cu,Zn-superoxide dismutase activity was elevated. We found that high concentration of sucrose leads to impaired redox status. We also observed that high protein content in sucrose-based media fecundity rate was increased and also transition to adult flies and survival ratio were decreased. Further studies are needed to focus on evaluation of the relation between median life span, nutritional mechanisms, and redox status biomarkers. PRACTICAL APPLICATIONS: Aging is characterized by functional decline in whole body system. Unfortunately, many of the life span extension strategies may lead to age-related disorders. It is widely accepted that impaired redox homeostasis is one of the signs of age-related pathophysiological changes. Due to difficulties in the establishment and validation of mimetic aging models in rodents, D. melanogaster is becoming/getting widely used model organism in gerontological studies. Currently, high protein and low carbohydrate-based nutrition regimes have become one of the most popular nutritional choice in aging population. Favorable nutrition type is considered one of the important factors for preventing age-related pathologies and promote healthy aging. In this study, we aimed to evaluate redox modulatory effects of different nutrition types as combination of various sucrose and constant protein concentration on basal redox status in D. melanogaster. Due to evolutionally conservation, we hypothesize that similar findings may be observed in aging population. Favorable nutrition type may ameliorate or postpone age-related degenerative processes and promote healthy aging.

Hydration and outcome in older patients admitted to hospital (The HOOP prospective cohort study).

Background: older adults are susceptible to dehydration due to age-related pathophysiological changes. We aimed to investigate the prevalence of hyperosmolar dehydration (HD) in hospitalised older adults, aged ≥65 years, admitted as an emergency and to assess the impact on short-term and long-term outcome.Methods: this prospective cohort study was performed on older adult participants who were admitted acutely to a large UK teaching hospital. Data collected included the Charlson comorbidity index (CCI), national early warning score (NEWS), Canadian Study of Health and Aging (CSHA) clinical frailty scale and Nutrition Risk Screening Tool (NRS) 2002. Admission bloods were used to measure serum osmolality. HD was defined as serum osmolality >300 mOsmol/kg. Participants who were still in hospital 48 h after admission were reviewed, and the same measurements were repeated.Results: a total of 200 participants were recruited at admission to hospital, 37% of whom were dehydrated. Of those dehydrated, 62% were still dehydrated when reviewed at 48 h after admission. Overall, 7% of the participants died in hospital, 79% of whom were dehydrated at admission (P = 0.001). Cox regression analysis adjusted for age, gender, CCI, NEWS, CSHA and NRS demonstrated that participants dehydrated at admission were 6 times more likely to die in hospital than those euhydrated, hazards ratio (HR) 6.04 (1.64–22.25); P = 0.007.Conclusions: HD is common in hospitalised older adults and is associated with poor outcome. Coordinated efforts are necessary to develop comprehensive hydration assessment tools to implement and monitor a real change in culture and attitude towards hydration in hospitalised older adults.

Patterns of cardiovascular drugs prescribed for an elderly Swedish population

To the Editor,Cardiovasculardiseases(CVDs),suchascoronaryheartdisease,atri-alfibrillation,heartfailureandstroke, are increasingly commonaspeo-ple age. Therefore, cardiovascular drugs are the most frequentlyprescribed medications for preventive and therapeutic purposesamong older adults [1]. However, several factors make cardiovasculardrug treatment in elderly people complicated. Age-related pathophysi-ological changes in the cardiovascular system, liver and kidney can af-fect the pharmacokinetics and pharmacodynamics of commonly useddrugs, which makes older persons more vulnerable to adverse drugevents [2]. Additionally, most clinical trials have been conducted inyounger and healthier patient populations, leaving limited evidenceon the benefits and harms of prescribing cardiovascular drugs to frailolder patients. Indeed, cardiovascular drugs are responsible for a largeproportion of adverse drug reactions (ADRs) among older people.Therefore, monitoring cardiovascular drug therapy among older popu-lation is crucial to help reduce ADRs. A few observational studies havedescribedtheuseofspecificcardiovasculardrugs(i.e.,beta-blockers,di-uretics) among the oldest-old [3,4], but there is a lack of largepopulation-based studies that provide an assessment of a broad rangeof prescribed cardiovascular drugs within older people from a generalpopulation. In this study, we aim to investigate the patterns of use ofcardiovascular drugs with respect to age, sex and CVDs among olderpeople (≥60 years) in a Swedish cohort.DatawerefromthebaselinesurveyoftheSwedishNationalstudyonAgingandCareinKungsholmen(SNAC-K)(www.snac-k.se).TheSNAC-KwasapprovedbytheRegionalEthicalReviewBoardinStockholm,andinformed consent was obtained from all participants. The SNAC-K par-ticipants included elderly people aged ≥60 years, living either in insti-tutions or in their own homes in the Kungsholmen district in centralStockholm, Sweden [5]. The sampling was stratified into different agecohorts and years of interval for assessment, i.e., a six-year interval fortheyounger-age cohorts (60,66, 72, and 78 years)and a three-yearin-terval for the older-age cohorts (81, 84, 87, 90, 93, 96, and 99+ years).Of the 5111 persons who were initially invited for participation,4590 were alive and eligible, and 3363 (73.3%) eventually participatedin the baseline examination (March 2001–June 2004). Data onage, sex, education, lifestyle factors, medical conditions (e.g., diabetes,high cholesterol, hypertension, CVDs), and current use of medications(e.g., antihypertensive agents, lipid-lowering agents) were collectedthrough interviews by nurses and clinical examinations by physicians[5]. Information on the use of medications was further verified byinspecting drug prescriptions and containers. Heart failure, coronaryheart disease (CHD), atrial fibrillation, and stroke were considered themain CVDs. Information on history of CVDs was taken from either self-reports or the computerized inpatient register system that covers allhospitals in Sweden since 1969. Medications were classified accordingto the Anatomical Therapeutic Chemical (ATC) classification system[6]. The classes of cardiovascular drugs included antithrombotic agents(ATC code B01), cardiac therapy (C01), diuretics (C03), beta-blockers(C07), calcium channel blockers (C08), renin–angiotensin system(RAS)-acting agents (C09), and lipid-lowering drugs (C10). The crudeprevalence of drug use was standardized using the local age- and sex-specificcensusdataoftheKungsholmencommunity.Descriptivestatis-tics were performed by using IBM SPSS Statistics 22 for Windows (IBMSPSS Inc., Chicago, Illinois, USA).Ofalltheparticipants,15hadmissinginformationondruguse,leav-ing3348 peopleforthisanalysis.Themeanageofparticipantswas74.3(SD, 11.2) years, and 64.8% were women.Overall, antithrombotic agents were most commonly prescribed(26.4%), followed by diuretics (21.7%) and beta-blockers (19.2%). Theprevalence of the use of other classes of cardiovascular drugs was

Age-Related Pathophysiological Changes in Rats with Unilateral Renal Agenesis

Affected rats of the unilateral urogenital anomalies (UUA) strain show renal agenesis restricted to the left side. To determine whether unilateral renal agenesis is a risk factor for the progression of renal insufficiency, we studied age-related pathophysiological alterations in affected rats. Although body growth and food intake were normal, polydipsia and polyuria with low specific gravity were present at 10 weeks and deteriorated further with age. Blood hemoglobin concentrations were normal, though there was slight erythropenia with increased MCV and MCH. Although hypoalbuminemia, hypercholesterolemia, azotemia, and hypermagnesemia were manifested after age 20 weeks, neither hyperphosphatemia nor hypocalcemia was observed. Plasma Cre and UN concentrations gradually increased with age. Cre clearance was almost normal, whereas fractional UN excretion was consistently lower than normal. Proteinuria increased with age, and albumin was the major leakage protein. In addition to cortical lesions, dilated tubules, cast formation, and interstitial fibrosis were observed in the renal medulla of 50 week-old affected rats. Renal weight was increased 1.7-fold and glomerular number 1.2-fold compared with normal rats. These findings show that the remaining kidney in UUA rats is involved not only in compensatory reactions but experiences pathophysiological alterations associated with progressive renal insufficiency.

Age-related pathophysiological changes in rat oligomeganephronic hypoplastic kidney

Rat male hypogonadism (hgn/hgn) is accompanied by oligomeganephronic hypoplastic kidney (HPK), in which each kidney contains one quarter the number of nephrons present in a normal kidney. The nephrons of the HPK are extremely hypertrophied. These characters were apparently common to human oligomeganephronia (OMN). To determine the age-related changes in renal pathophysiology in HPK rats, we measured several parameters of renal function at 70 days, 140 days, 210 days, and 280 days of age. At all time points, relative kidney weight was significantly smaller in HPK rats than in their normal litter mates. In HPK rats, both polyuria and polydipsia became more severe with advancing age. Although creatinine clearance (Ccr) and urinary nitrogen clearance (Cun) were significantly lower in HPK than in normal rats, the values did not decrease with age. A severe form of glomerulosclerosis, as well as interstitial infiltration and cystic dilation of tubules with proteinaceous luminal casts, was observed in the inner cortex and medulla of HPK rats at advanced age. In these animals the surface glomeruli retained their functional architecture but were hypertrophied. Both mean blood pressure (MBP) and proteinuria became more elevated with age in HPK rats, and their urine samples included considerable amounts of high molecular weight protein. These results suggest that the HPK rat is a suitable model of human OMN.