Decline In Physiological Function Research Articles

Application of mesenchymal stem cell therapy for aging frailty: from mechanisms to therapeutics.

Aging frailty is a complex geriatric syndrome that becomes more prevalent with advancing age. It constitutes a major health problem due to frequent adverse outcomes. Frailty is characterized by disruption of physiological homeostasis and progressive decline of health status. Multiple factors contribute to development of frailty with advancing age, including genome instability, DNA damage, epigenetic alternations, stem cell exhaustion, among others. These interrelated factors comprehensively result in loss of tissue homeostasis and diminished reserve capacity in frailty. Therefore, the aged organism gradually represents symptoms of frailty with decline in physiological functions of organs. Notably, the brain, cardiovascular system, skeletal muscle, and endocrine system are intrinsically interrelated to frailty. The patients with frailty may display the diminished reserves capacity of organ systems. Due to the complex pathophysiology, no specific treatments have been approved for prevention of this syndrome. At such, effective strategies for intervening in pathogenic process to improve health status of frail patients are highly needed. Recent progress in cell-based therapy has greatly contributed to the amelioration of degenerative diseases related to age. Mesenchymal stem cells (MSCs) can exert regenerative effects and possess anti-inflammatory properties. Transplantation of MSCs represents as a promising therapeutic strategy to address the pathophysiologic problems of frail syndrome. Currently, MSC therapy have undergone the phase I and II trials in human subjects that have endorsed the safety and efficacy of MSCs for aging frailty. However, despite these positive results, caution is still needed with regard to potential to form tumors, and further large-scale studies are warranted to confirm the therapeutic efficacy of MSC therapy.

A model for studying cutaneous wound healing and resilience to aging: Ear punch biopsy in old mice.

Resilience to aging is a biological event that precedes age-related decline in physiological function and is defined as an organism's ability to respond to physical stress with increasing age. There is a need to identify factors that may predict resilience for enhancing and maintaining healthy aging. Older people often experience delayed wound healing beause of compromised tissue repair and immune response. Therefore preclincal models may be of value to investigate the relationship between cutaneous wound healing and resilience to aging. This brief report descibes an ear punch biopsy model of cutaneous wound healing in aging mice and shows that mice with biopsy ear wounds that heal more quickly have better cognition, increased strength and better running endurance later in life.

Aging and Neurodegenerative Disease: Is the Adaptive Immune System a Friend or Foe?

Neurodegenerative diseases of the central nervous system (CNS) are characterized by progressive neuronal death and neurological dysfunction, leading to increased disability and a loss of cognitive or motor functions. Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis have neurodegeneration as a primary feature. However, in other CNS diseases such as multiple sclerosis, stroke, traumatic brain injury, and spinal cord injury, neurodegeneration follows another insult, such as demyelination or ischaemia. Although there are different primary causes to these diseases, they all share a hallmark of neuroinflammation. Neuroinflammation can occur through the activation of resident immune cells such as microglia, cells of the innate and adaptive peripheral immune system, meningeal inflammation and autoantibodies directed toward components of the CNS. Despite chronic inflammation being pathogenic in these diseases, local inflammation after insult can also promote endogenous regenerative processes in the CNS, which are key to slowing disease progression. The normal aging process in the healthy brain is associated with a decline in physiological function, a steady increase in levels of neuroinflammation, brain shrinkage, and memory deficits. Likewise, aging is also a key contributor to the progression and exacerbation of neurodegenerative diseases. As there are associated co-morbidities within an aging population, pinpointing the precise relationship between aging and neurodegenerative disease progression can be a challenge. The CNS has historically been considered an isolated, “immune privileged” site, however, there is mounting evidence that adaptive immune cells are present in the CNS of both healthy individuals and diseased patients. Adaptive immune cells have also been implicated in both the degeneration and regeneration of the CNS. In this review, we will discuss the key role of the adaptive immune system in CNS degeneration and regeneration, with a focus on how aging influences this crosstalk.

The precursor of PI(3,4,5)P3 alleviates aging by activating daf-18(Pten) and independent of daf-16

Aging is characterized by the loss of homeostasis and the general decline of physiological functions, accompanied by various degenerative diseases and increased rates of mortality. Aging targeting small molecule screens have been performed many times, however, few have focused on endogenous metabolic intermediates—metabolites. Here, using C. elegans lifespan assays, we conducted a worm metabolite screen and identified an eukaryotes conserved metabolite, myo-inositol (MI), to extend lifespan, increase mobility and reduce fat content. Genetic analysis of enzymes in MI metabolic pathway suggest that MI alleviates aging through its derivative PI(4,5)P2. MI and PI(4,5)P2 are precursors of PI(3,4,5)P3, which is negatively related to longevity. The longevity effect of MI is dependent on the tumor suppressor gene, daf-18 (homologous to mouse Pten), independent of its classical pathway downstream genes, akt or daf-16. Furthermore, we found MI effects on aging and lifespan act through mitophagy regulator PTEN induced kinase-1 (pink-1) and mitophagy. MI’s anti-aging effect is also conserved in mouse, indicating a conserved mechanism in mammals.

HUBUNGAN DUKUNGAN KELUARGA DENGAN ACTIVITY DAILY LIVING PADA LANSIA DENGAN KOMPLIKASI HIPERTENSI (Di Desa Banjarejo Kecamatan Rejoso Kabupaten Nganjuk)

Introduction : Elderly often experience the decline of physiological functions one of them changes in the cardiovascular system so that trigger the occurrence of hypertension. This decine in physiological function leads to a decrease in the ability to perform activity daily living suPch as self-care.The purpose of this research is to know the Family Support Relationship with Activity Daily Living in Elderly with Hypertension Complication in Banjarejo Village, Rejoso District, Nganjuk Regency. Methode :Research design correlation with cross sectional shortcuts. Implemented on 9 - 12 May 2018 at Posyanduelderly in Banjarejo Village District RejosoNganjuk District with a population of 50 elderly who suffer complications of hypertension. The sampling technique used is total sampling. Total population of 37 and who suffer from hypertension with the number of samples is 37 respondents. Independent variable of family support with questionnaire and dependent variable is daily living activity with Bartel Index. Data analysis using spearmen rank test with significance α = 0,05. Result :The results showed that 37 respondents were almost half of 15 respondents (40,5%) family support with enough category and almost of 20 respondents (54,1%) experienced daily living activity with the category of mild dependence. Statistical test results obtained p value = 0,000 ≤ α = 0.05 with r = 0.598 so Ha accepted means the level of seedang relationship. Conclusions : Good support in the care of the elderly by always including the patient in every action done every day so that patients do not feel bored. The better the family support the better the patient in fulfilling Activity Daily Living in the elderly with complications of hypertension. Keyword : family support, daily living activity, elderly, and hypertension.

Whole beetroot consumption reduces systolic blood pressure and modulates diversity and composition of the gut microbiota in older participants

BackgroundAge-associated decline in physiological function has been identified as the main factor increasing disease risk, including cardiovascular (CVD) and gastrointestinal tract (GIT) diseases. Nutritional interventions encompassing dietary inorganic nitrates, such as nitrate rich beetroot may reduce the risk for CVD and GIT. ObjectiveAssess the impact of whole beetroot on blood pressure (BP), microbiota profile and functional measures (physical and bowel). DesignThirty-six healthy participants were recruited (mean age 67 ± 6 years; body mass index (BMI) 25 ± 2 kg/m2) and assigned randomly to a beetroot (n = 19) or control group (n = 17). Beetroot group consumed 150 g of whole beetroot and a medium-sized banana and the control group consumed a medium-sized banana every second day for 8 weeks. Resting BP, microbiota profiling, physical activity, urinary nitrate, short-chain fatty acids (SCFA) and Bristol Stool Score (BSS) were measured at 0, 4 and 8 weeks. Plasma nitrate was measured at weeks 0 and 8. ResultsThe beetroot group had a resting systolic BP reduction of 8.0 mmHg (p = 0.03), lower relative abundance of the phyla Bacteroidetes (p = 0.04), and a higher relative abundance of genus Alistipes (p = 0.03), increased Shannon diversity index (p = 0.03), fibre intake of 7 g/day (p < 0.01), nitrate intake 145 mg/day (p < 0.01), urinary nitrate of 460 μmol/L (p = 0.02) and SCFA concentrations (p < 0.05). However, 8 weeks of beetroot consumption did not have any impact upon functional measures, urine or plasma nitrate and BSS. ConclusionIn a randomised controlled trial, consuming whole beetroot for 8 weeks resulted in modification of risk factors for CVD and GIT disorders in older participants. Physical measures were unaffected and further assessment of more sensitive measures of functional performance are required to ascertain if whole beetroot may offer additional physiological benefits in older populations. Although the data here is promising, further mechanistic studies and larger clinical trials are required to confirm the findings.

RNAAgeCalc: A multi-tissue transcriptional age calculator.

Biological aging reflects decline in physiological functions and is an effective indicator of morbidity and mortality. Numerous epigenetic age calculators are available, however biological aging calculators based on transcription remain scarce. Here, we introduce RNAAgeCalc, a versatile across-tissue and tissue-specific transcriptional age calculator. By performing a meta-analysis of transcriptional age signature across multi-tissues using the GTEx database, we identify 1,616 common age-related genes, as well as tissue-specific age-related genes. Based on these genes, we develop new across-tissue and tissue-specific age predictors. We show that our transcriptional age calculator outperforms other prior age related gene signatures as indicated by the higher correlation with chronological age as well as lower median and median error. Our results also indicate that both racial and tissue differences are associated with transcriptional age. Furthermore, we demonstrate that the transcriptional age acceleration computed from our within-tissue predictor is significantly correlated with mutation burden, mortality risk and cancer stage in several types of cancer from the TCGA database, and offers complementary information to DNA methylation age. RNAAgeCalc is available at http://www.ams.sunysb.edu/~pfkuan/softwares.html#RNAAgeCalc, both as Bioconductor and Python packages, accompanied by a user-friendly interactive Shiny app.

Protective mechanism against age-associated changes in the peripheral nerves

AimsSenescence is the normal decline in physiological functions due to aging that results in cell dysfunction. However, age-associated changes in peripheral nerves have not been elucidated. We observed histological changes in the sciatic nerves of young and older mice to investigate how peripheral nerves changed with age, and we evaluated protective mechanisms of peripheral nerves against aging. Main methodsSciatic nerves were collected from female C57BL/6 mice at the ages of 8 weeks (young group) and 78 weeks (aged group) and examined histologically. Using hematoxylin and eosin staining, the number and density of sciatic nerve axons were evaluated. Through immunofluorescence staining, the expression of nerve-specific proteins, oxidative stress markers, and a neuronal aging marker (REST/NRSF) were investigated, and the intensity of fluorescence was quantified. The differences between the groups were assessed, and age-associated peripheral nerve changes were evaluated. Statistical analysis was performed using the Mann–Whitney U test. Key findingsAlthough the number and density of axons did not differ significantly between the groups, they were lower in the aged group than in the young group. In addition, the fluorescence intensity of each marker did not differ significantly between the groups, but the expression of REST/NRSF alone was significantly higher in the aged group than in the young group (p < 0.05). SignificanceThis study suggested that peripheral nerve functions are preserved by the expression of REST/NRSF, which increases with age. Because oxidative stress did not change, the protective effects of REST/NRSF are considered to be related to oxidative stress.

The Immune Response Against Human Cytomegalovirus Links Cellular to Systemic Senescence.

Aging reflects long-term decline in physiological function and integrity. Changes arise at a variable pace governed by time-dependent and -independent mechanisms that are themselves complex, interdependent and variable. Molecular decay produces inferior cells that eventually dominate over healthy counterparts in tissues they comprise. In a form of biological entropy, progression from molecular through cellular to tissue level degeneration culminates in organ disease or dysfunction, affecting systemic health. To better understand time-independent contributors and their potential modulation, common biophysical bases for key molecular and cellular changes underlying age-related physiological deterioration must be delineated. This review addresses the potential contribution of cytomegalovirus (CMV)-driven T cell proliferation to cellular senescence and immunosenescence. We first describe molecular processes imposing cell cycle arrest, the foundation of cellular senescence, then focus on the unique distribution, phenotype and function of CMV-specific CD8+ T cells in the context of cellular senescence and “inflammaging”. Their features position CMV infection as a pathogenic accelerant of immune cell proliferation underlying immune senescence. In human immunodeficiency virus (HIV) infection, where increased inflammation and exaggerated anti-CMV immune responses accelerate immune senescence, CMV infection has emerged as a major factor in unhealthy aging. Thus, we speculate on mechanistic links between CMV-specific CD8+ T-cell expansion, immune senescence and prevalence of age-related disorders in HIV infection.

Inflammatory biomarkers of frailty.

Frailty is a functional term that describes a decline in physiological functions that leads to dependency, vulnerability to stressors, high risk for adverse health outcomes, increased risk of falls, and increased morbidity and mortality. The central role of inflammation and the cross-talk between frailty and sarcopenia have led to a condition termed physical frailty, in which muscle atrophy is viewed as the biological substratum of physical frailty. Different paradigms of ageing, including "inflamm-ageing", "oxi-inflamm-ageing", and "inflamm-inactivity" reveal inflammation as a common driver of age-related frailty. The key role of inflammation in frailty conditions have led to numerous studies screening for potential inflammatory biomarkers of frailty. This review summarizes the present knowledge of inflammatory biomarkers that are considered promising tools to evaluate frailty. Inflammatory biomarkers for different pathophysiological pathways have been identified, and can be divided into markers of inflammation, oxidative stress, muscle protein turnover and physical inactivity. Described candidate inflammatory biomarkers could support diagnosis, prognosis, and therapeutic decisions in frail elderly. Furthermore, exercise training and nutritional counselling could be implemented in the standard care of the elderly in order to prevent, delay, or ameliorate frailty and to reduce the levels of blood inflammatory biomarkers. Such tools and decision-making outcomes would improve selection and treatment of the elderly and contribute to the ultimate goal - healthy ageing.

The effect of elderly simulated gastrointestinal in vitro digestion (SGID) on the antioxidant properties of different cheese matrices

AbstractThe world's population is getting older. By 2050 it is projected that 22% of the global population will be over 60 years of age. Aging is characterized by a decline in physiological functions and an increase in malnutrition and associated disease. Oxidative stress is associated with several age-related conditions, including cardiovascular disease, obesity, neurodegenerative disease and cancer. The negative effects of reactive oxygen species (ROS) are neutralized by antioxidants, which can be endogenously synthesised or consumed through the diet. Cheese is a nutritious dairy food and previous research has highlighted the antioxidant potential of some cheese types. Physiological changes associated with age can impact digestion processes, thus the ability to efficiently release bioactive compounds, including antioxidants, may be impaired with age. Cheese products varying by milk source, texture and fat content were subjected to simulated gastrointestinal in vitro digestion (SGID) using a modified model to account for physiological changes associated with aging. The antioxidant potential of undigested and digested cheese (n = 11) was determined in vitro using DPPH radical scavenging, ferric reducing antioxidant power (FRAP) and total phenolic content (TPC) assays. Cellular antioxidant potential was also investigated using the reduced glutathione assay (GSH) in the human macrophage cell line (U937). Experiments were carried out in triplicate. Statistical analysis by T-test demonstrated that digestion significantly increased (P &lt; 0.05) FRAP and TPC of all cheese products analysed. Of the eleven cheese products investigated, goats’ cheese displayed a significant increase (P &lt; 0.05) in radical scavenging properties (89.8% inhibition). Low fat white cheddar had significantly higher (P &lt; 0.05) GSH levels compared to full fat white cheddar (0.16 ± 0.01, 0.11 ± 0.01 μmol GSH/mg protein, respectively). Findings from this study suggest that despite physiological changes associated with age, cheese digestates retain, and in some cases, possess higher antioxidant potential than undigested samples. Cheese demonstrates potential as a functional food for the elderly by neutralizing the negative effects associated with age-related oxidative stress.

The plasma metabolome as a predictor of biological aging in humans

Chronological age is an important predictor of morbidity and mortality; however, it is unable to account for heterogeneity in the decline of physiological function and health with advancing age. Several attempts have been made to instead define a "biological age" using multiple physiological parameters in order to account for variation in the trajectory of human aging; however, these methods require technical expertise and are likely too time-intensive and costly to be implemented into clinical practice. Accordingly, we sought to develop a metabolomic signature of biological aging that could predict changes in physiological function with the convenience of a blood sample. A weighted model of biological age was generated based on multiple clinical and physiological measures in a cohort of healthy adults and was then applied to a group of healthy older adults who were tracked longitudinally over a 5-10-year timeframe. Plasma metabolomic signatures were identified that were associated with biological age, including some that could predict whether individuals would age at a faster or slower rate. Metabolites most associated with the rate of biological aging included amino acid, fatty acid, acylcarnitine, sphingolipid, and nucleotide metabolites. These results not only have clinical implications by providing a simple blood-based assay of biological aging, but also provide insight into the molecular mechanisms underlying human healthspan.

INVESTIGATING DYNAMICS OF AGE-ASSOCIATED TRANSCRIPTIONAL NETWORKS WITH INTERVENTIONS TARGETING AGING

Biological aging is characterized by a progressive decline in physiological function from molecular to organismal levels, manifesting through adaptive transcriptional networks. We present an overview of the complex regulation of transcriptional networks in species- and tissue-specific aging. We aimed to: 1) capture the age-associated changes in gene-gene connectivity, and 2) evaluate the effect of two interventions targeting biological aging (metformin, acarbose) on the regulation of gene networks. Aim 1) Using RNA-Seq we modeled co-expression networks and identified differentially co-expressed gene-pairs between young, middle-aged and older-aged groups. Aim 2) Using short-term clinical studies in older humans (metformin: MILES-trial; acarbose: SAIL-trial), and complementary mouse studies, we revealed the genes and novel pathways underlying the drugs’ effects on biological aging in muscle and adipose. Importantly, these interventions shifted transcripts to a more youthful expression. Overall, we provide evidence of age-associated gene-network topology changes and identify upstream transcriptional factors affected by age-targeting drugs.

The protective function of non-coding DNA in DNA damage accumulation with age and its roles in age-related diseases.

Aging is a progressive decline of physiological function in tissue and organ accompanying both accumulation of DNA damage and reduction of non-coding DNA. Peripheral non-coding DNA/heterochromatin has been proposed to protect the genome and centrally-located protein-coding sequences in soma and male germ cells against radiation and the invasion of exogenous nucleic acids. Therefore, this review summarizes the reduction of non-coding DNA/heterochromatin (including telomeric DNA and rDNA) and DNA damage accumulation during normal physiological aging and in various aging-related diseases. Based on analysis of data, it is found that DNA damage accumulation is roughly negatively correlated with the reduction of non-coding DNA and therefore speculated that DNA damage accumulation is likely due to the reduction of non-coding DNA protection in genome defense during aging. Therefore, it is proposed here that means to increase the total amount of non-coding DNA and/or heterochromatin prior to the onset of these diseases could potentially better protect the genome and protein-coding DNA, reduce the incidence of aging-related diseases, and thus lead to better health during aging.

Allostatic load and ageing: linking the microbiome and nutrition with age-related health.

Ageing is a process of decline in physiological function and capability over time. It is an anticipated major burden on societal health-care costs due to an increasingly aged global population. Accelerated biological ageing is a feature of age-related morbidities, which also appear to share common underpinning features, including low-grade persistent inflammation, phosphate toxicity, diminished Nrf2 activity, a depleted metabolic capability, depressed mitochondrial biogenesis and a low diversity gut microbiome.Social, psychological, lifestyle and nutritional risk factors can all influence the trajectory of age-related health, as part of an individual's exposome, which reflects the interplay between the genome and the environment. This is manifest as allostatic (over)load reflecting the burden of lifestyle/disease at both a physiological and molecular level. In particular, age-related genomic methylation levels and inflammatory status reflect exposome differences. These features may be mediated by changes in microbial diversity. This can drive the generation of pro-inflammatory factors, such as TMAO, implicated in the 'diseasome' of ageing. Additionally, it can be influenced by the 'foodome', via nutritional differences affecting the availability of methyl donors required for maintenance of the epigenome and by the provision of nutritionally derived Nrf2 agonists. Both these factors influence age-related physiological resilience and health. This offers novel insights into possible interventions to improve health span, including a rage of emerging senotherapies and simple modifications of the nutritional and environmental exposome. In essence, the emerging strategy is to treat ageing processes common to the diseasome of ageing itself and thus preempt the development or progression of a range of age-related morbidities.

'Obesageing': Linking obesity & ageing.

Obesity is one of the leading causes of preventable mortalities in many parts of the globe. The rise in geriatric population due to better treatment opportunities has also emerged as a major public health challenge. Both of these health challenges have impacted developed as well as developing countries. Obesity is attributed as a powerful risk factor of a variety of health problems such as cardiovascular diseases, hypertension, type 2 diabetes, dementia, neuropsychiatric diseases and many more. On the other hand, ageing is a natural process involving a gradual decline in physiological functions and is associated with similar co-morbidities as obesity. This review discusses about the commonalities (termed as ‘Obesageing') between the pathological phenomenon of obesity and normal physiological process of ageing. A unique rodent model of obesageing has been developed (WNIN/Ob) that has characteristics of morbid obesity as well as premature ageing. Such a novel animal model would facilitate the understanding of the complex interplay of different mechanisms that are common to obesity and ageing and help to devise strategies in future to tackle the growing burden of obesity and ageing.

Editorial introductions

Editorial introductions

Anti-aging Effects of Select Botanicals: Scientific Evidence and Current Trends

As skin ages, there is a decline in physiologic function. These changes are induced by both intrinsic (chronologic) and extrinsic (predominately UV-induced) factors. Botanicals offer potential benefits to combat some of the signs of aging. Here, we review select botanicals and the scientific evidence behind their anti-aging claims. Botanicals may offer anti-inflammatory, antioxidant, moisturizing, UV-protective, and other effects. A multitude of botanicals are listed as ingredients in popular cosmetics and cosmeceuticals, but only a select few are discussed here. These were chosen based on the availability of scientific data, personal interest of the authors, and perceived “popularity” of current cosmetic and cosmeceutical products. The botanicals reviewed here include argan oil, coconut oil, crocin, feverfew, green tea, marigold, pomegranate, and soy.

The age-regulated zinc finger factor ZNF367 is a new modulator of neuroblast proliferation during embryonic neurogenesis

Global population aging is one of the major social and economic challenges of contemporary society. During aging the progressive decline in physiological functions has serious consequences for all organs including brain. The age-related incidence of neurodegenerative diseases coincides with the sharp decline of the amount and functionality of adult neural stem cells. Recently, we identified a short list of brain age-regulated genes by means of next-generation sequencing. Among them znf367 codes for a transcription factor that represents a central node in gene co-regulation networks during aging, but whose function in the central nervous system (CNS), is completely unknown. As proof of concept, we analysed the role of znf367 during Xenopus laevis neurogenesis. By means of a gene loss of function approach limited to the CNS, we suggested that znf367 might act as a key controller of the neuroblast cell cycle, particularly in the progression of mitosis and spindle checkpoint. A candidate gene approach based on a weighted-gene co-expression network analysis, revealed fancd2 and ska3 as possible targets of znf367. The age-related decline of znf367 correlated well with its role during embryonic neurogenesis, opening new lines of investigation also in adult neurogenesis to improved maintenance and even repair of neuronal function.

Wasting in Chronic Kidney Disease – a Complex Issue

AbstractChronic kidney disease (CKD) has become a global health burden and is associated with increased morbidity and mortality. In particular, wasting is highly prevalent in later stages of the illness with muscle loss being a common problem. The aetiology and progression of this wasting is complex and multiple states have been identified linked to wasting in CKD. These include: ‘malnutrition’, ‘disease‐related malnutrition’, ‘protein‐energy wasting’, ‘cachexia’, ‘sarcopenia’, ‘frailty’ and ‘muscle wasting‘. The purpose of this paper is to review these terms in the context of CKD. Common features include weight loss, loss of muscle mass and muscle function principally driven by CKD disease specific factors and inflammatory mediators. Disease‐related malnutrition would appear to be a more appropriate term for CKD than malnutrition as it take in to consideration disease specific factors such as inflammation for example. Frailty is commonly associated with age‐related decline in physiological function. Development of novel screening tools measuring across multiple domains of nutritional status, muscle and physical function may be useful in CKD. Research into potential treatments are currently underway with focus on multi‐modal therapies including nutrition, resistance training and anabolic drugs such as myostatin blockade and selective androgen receptor modulators. A better understanding of different states and terms may help guide assessment and treatment opportunities for patients.