Severity Of Age-related Diseases Research Articles

PENG ZU Study on Healthy Aging in China (PENG ZU Cohort): Design and Goals.

Life expectancy is increasing, leading to the continuous aging of the population in China. Enhancing the health status of the older population is crucial to achieving healthy aging. The primary objective of the PENG ZU Study on Healthy Aging in China (PENG ZU Cohort) is to understand the natural progression of health status among the aging Chinese population. Specifically, the PENG ZU cohort aims to identify and validate multidimensional aging markers, uncover the underlying mechanisms of systemic aging and functional decline, and develop novel strategies and measures to delay functional decline and adverse health outcomes, while maintaining overall good health. The PENG ZU cohort consists of 26,000 individuals aged 25 to 89 years from seven major geographical regions in China. Diversified data and biospecimens are collected according to standardized procedures at baseline and follow-up visits. Baseline recruitment for the PENG ZU cohort was completed in October 2021. The extensive analysis of multidimensional health-related data and bioresources collected from the cohort is anticipated to develop methods for evaluating functional status and elucidating multilevel, cross-scale interactions and regulatory mechanisms of healthy aging. The findings from this study will enhance the understanding of health changes due to aging, facilitate efficient and effective interventions to maintain functional ability, and reduce the incidence and severity of age-related diseases, thereby further promoting healthy aging.

Radiological Assessment of Morphological Changes of Lumbar Spine: From First to 9th Decade of Life.

Analysis of lumbar spine radiograms of 1,496 Jeju islanders of Korea. To look into the age- and gender-matched incidences of morphological changes and their severities. There have been several prior research on the prevalence and severity of age-related diseases, both related and unrelated. Those offer some fundamental clinical data for clinicians. Radiograms of 1,496 patients (555 males and 941 females) from the first to 9th decade were examined for this study. Sagittal and coronal alignment, disc space narrowing, spur formation including diffuse idiopathic spinal hyperostosis (DISH), spondylolisthesis, and ballooned discs associated with biconcave bodies due to osteoporosis were among the parameters of lumbar spine morphologies examined on high-quality radiographs by both human observers and computers. The alignment of the lumbar spine altered after birth and set at growth maturity, and then the curve was maintained till the end of the 5th decade afterward and the curve gradually hypolordotic. There were three types of coronal alignment abnormalities can be seen: idiopathic, osteopathic, and discogenic (degenerative lumbar scoliosis [DLS]). DLS developed after 6th decade. There was no scoliosis associated with spondylolysis or the post-laminofacetectomy period. Disc space narrowing and corporal spur formation were not seen till the end of 3rd decade comparatively speaking, the corporal spurs generated in the non-scoliotic spine were smaller than those in the scoliotic spine. DISH began to appear in the 5th-decade patients and its incidences increased gradually afterward. Porosis-related vertebral body collapse started to happen after 6th decade. There are three different types of spondylolisthesis: anterior, posterior, and lateral. The lateral slip occurred only in the scoliotic spine. All types were related to degenerative discs. It has been shown that the morphology of the lumbar spine changes throughout time.

Genetic variation in ALDH4A1 is associated with muscle health over the lifespan and across species.

The influence of genetic variation on the aging process, including the incidence and severity of age-related diseases, is complex. Here, we define the evolutionarily conserved mitochondrial enzyme ALH-6/ALDH4A1 as a predictive biomarker for age-related changes in muscle health by combining Caenorhabditis elegans genetics and a gene-wide association scanning (GeneWAS) from older human participants of the US Health and Retirement Study (HRS). In a screen for mutations that activate oxidative stress responses, specifically in the muscle of C. elegans, we identified 96 independent genetic mutants harboring loss-of-function alleles of alh-6, exclusively. Each of these genetic mutations mapped to the ALH-6 polypeptide and led to the age-dependent loss of muscle health. Intriguingly, genetic variants in ALDH4A1 show associations with age-related muscle-related function in humans. Taken together, our work uncovers mitochondrial alh-6/ALDH4A1 as a critical component to impact normal muscle aging across species and a predictive biomarker for muscle health over the lifespan.

New Insights into the Roles and Mechanisms of Spermidine in Aging and Age-Related Diseases.

High incidences of morbidity and mortality associated with age-related diseases among the elderly population are a socio-economic challenge. Aging is an irreversible and inevitable process that is a risk factor for pathological progression of diverse age-related diseases. Spermidine, a natural polyamine, plays a critical role in molecular and cellular interactions involved in various physiological and functional processes. Spermidine has been shown to modulate aging, suppress the occurrence and severity of age-related diseases, and prolong lifespan. However, the precise mechanisms through which spermidine exerts its anti-aging effects have not been established. In this review, we elucidate on the mechanisms and roles underlying the beneficial effects of spermidine in aging from a molecular and cellular perspective. Moreover, we provide new insights into the promising potential diagnostic and therapeutic applications of spermidine in aging and age-related diseases.

Diet-based strategies, informed by genetics, to improve healthspan

Diet is one of the most variable aspects of life history, as most individuals have a large diversity of choices, varying in the type and amount that they ingest. In the short-term, diet can affect metabolism and energy levels. However, in the long run, the net deficiency or excess of calories from diet can influence the progression and severity of age-related diseases. An old and yet still debated question is: how do specific dietary choices impact health- and lifespan? It is clear that genetics can play a critical role - perhaps just as important as diet choices. For example, poor diet in combination with genetic susceptibility can lead to metabolic disorders, such as obesity and type 2 diabetes. We have identified the existence of diet-gene pairs, where the consequence of mutating a specific gene is only realized on specific diets. Although only a handful of these diet-gene pairs have been characterized, there are potentially thousands of such interactions, which may explain the variability in the rates of aging in humans and the incidence and severity of age-related diseases.

Conserved aging-related signatures of senescence and inflammation in different tissues and species.

Increasing evidence indicates that chronic inflammation and senescence are the cause of many severe age-related diseases, with both biological processes highly upregulated during aging. However, until now, it has remained unknown whether specific inflammation- or senescence-related genes exist that are common between different species or tissues. These potential markers of aging could help to identify possible targets for therapeutic interventions of aging-associated afflictions and might also deepen our understanding of the principal mechanisms of aging. With the objective of identifying such signatures of aging and tissue-specific aging markers, we analyzed a multitude of cross-sectional RNA-Seq data from four evolutionarily distinct species (human, mouse and two fish) and four different tissues (blood, brain, liver and skin). In at least three different species and three different tissues, we identified several genes that displayed similar expression patterns that might serve as potential aging markers. Additionally, we show that genes involved in aging-related processes tend to be tighter controlled in long-lived than in average-lived individuals. These observations hint at a general genetic level that affect an individual’s life span. Altogether, this descriptive study contributes to a better understanding of common aging signatures as well as tissue-specific aging patterns and supplies the basis for further investigative age-related studies.

The Continuum of Aging and Age-Related Diseases: Common Mechanisms but Different Rates.

Geroscience, the new interdisciplinary field that aims to understand the relationship between aging and chronic age-related diseases (ARDs) and geriatric syndromes (GSs), is based on epidemiological evidence and experimental data that aging is the major risk factor for such pathologies and assumes that aging and ARDs/GSs share a common set of basic biological mechanisms. A consequence is that the primary target of medicine is to combat aging instead of any single ARD/GSs one by one, as favored by the fragmentation into hundreds of specialties and sub-specialties. If the same molecular and cellular mechanisms underpin both aging and ARDs/GSs, a major question emerges: which is the difference, if any, between aging and ARDs/GSs? The hypothesis that ARDs and GSs such as frailty can be conceptualized as accelerated aging will be discussed by analyzing in particular frailty, sarcopenia, chronic obstructive pulmonary disease, cancer, neurodegenerative diseases such as Alzheimer and Parkinson as well as Down syndrome as an example of progeroid syndrome. According to this integrated view, aging and ARDs/GSs become part of a continuum where precise boundaries do not exist and the two extremes are represented by centenarians, who largely avoided or postponed most ARDs/GSs and are characterized by decelerated aging, and patients who suffered one or more severe ARDs in their 60s, 70s, and 80s and show signs of accelerated aging, respectively. In between these two extremes, there is a continuum of intermediate trajectories representing a sort of gray area. Thus, clinically different, classical ARDs/GSs are, indeed, the result of peculiar combinations of alterations regarding the same, limited set of basic mechanisms shared with the aging process. Whether an individual will follow a trajectory of accelerated or decelerated aging will depend on his/her genetic background interacting lifelong with environmental and lifestyle factors. If ARDs and GSs are manifestations of accelerated aging, it is urgent to identify markers capable of distinguishing between biological and chronological age to identify subjects at higher risk of developing ARDs and GSs. To this aim, we propose the use of DNA methylation, N-glycans profiling, and gut microbiota composition to complement the available disease-specific markers.

Gene-diet interactions and aging in C. elegans

Diet is the most variable aspect of life history, as most individuals have a large diversity of food choices, varying in the type and amount that they ingest. In the short-term, diet can affect metabolism and energy levels. However, in the long run, the net deficiency or excess of calories from diet can influence the progression and severity of age-related diseases. An old and yet still debated question is: how do specific dietary choices impact health- and lifespan? It is clear that genetics can play a critical role — perhaps just as important as diet choices. For example, poor diet in combination with genetic susceptibility can lead to metabolic disorders, such as obesity and type 2 diabetes. Recent work in Caenorhabditis elegans has identified the existence of diet-gene pairs, where the consequence of mutating a specific gene is only realized on specific diets. Many core metabolic pathways are conserved from worm to human. Although only a handful of these diet-gene pairs has been characterized, there are potentially hundreds, if not thousands, of such interactions, which may explain the variability in the rates of aging in humans and the incidence and severity of age-related diseases.

Prophylactic Nrf2 Activation Halts Progression of the Severe Adult Phenotype of Sickle Cell Disease in Transgenic Mice

Transition from pediatric to adult care is associated with poor prognosis and a sharp rise in mortality in sickle cell disease (SCD). Hitherto, mechanisms that promote the severe adult phenotype of SCD have not been defined. We performed a longitudinal cohort study in thirty-two Townes transgenic mice (SS; n=16, AA; n=16) aged 1 month through to 10 months to identify prognostic factors of SCD severity. Thirty-eight percent of the SS mice died during this period while all the control AA mice survived (Log-rank Mantel Cox test, p<0.01). Hemoglobin (Hb) concentration declined sharply at 3 months in the SS mice while it remained unchanged in the age-matched AA mice. Worsening anemia was concomitant with increased concentrations of multiple markers of intravascular hemolysis including plasma heme (p=0.0019), plasma Hb (p=0.002), and lactate dehydrogenase, LDH (p=0.032) as the SS mice reached adulthood. Collectively, these data identified hemolytic stress as a component of the adult phenotype of SCD. An age-dependent increase in the concentration of vascular cell adhesion molecule-1 (VCAM-1) in the plasma of SS animals (p<0.05), but not in AA mice highlighted vascular inflammation as another component of the severe adult phenotype of SCD. We confirmed the link between age-related disease severity and vascular inflammation by demonstrating a 2-fold higher concentration of vascular endothelial cadherin (sVE-cad) in the plasma of SS mice at 3-months compared to the steady-sate values of the same marker when the mice were one month old (p<0.05). Since nuclear factor erythroid-2 factor 2 (Nrf2) controls the antioxidant response to hemolytic stress, we tested the hypothesis that this factor may influence the progression of SCD. We generated bone marrow chimeric sickle mice devoid of Nrf2 activity in the endothelium and in other non-hematopoietic tissues. The resulting chimeras had markedly more severe intravascular hemolysis and vascular inflammation defined by higher concentrations of sVCAM-1 (p<0.01) and sVE-cad (p<0.01) than age-matched SS mice with a full complement of Nrf2 activity. Next, we determined whether prophylactic activation of Nrf2 in 1 month SS mice would slow down the disease severity seen in adulthood. A group of newly weaned SS mice aged ~1 month were randomized to receive the Nrf2 activator 3H-1, 2-dithiole-3-thione (D3T; n=8), or a DMSO vehicle by oral gavage (0.5 mmole/kg, 3x/week). After eight weeks of treatment the Hb dropped by <2% in the D3T group compared to a 10% drop in the vehicle group. In addition, D3T treatment blunted the age-related worsening of intravascular hemolysis, which we initially observed in the longitudinal cohort, and confirmed in the vehicle treated animals, by the elevations in plasma heme (p<0.01), plasma Hb (p<0.01), plasma bilirubin (p<0.05) and LDH (p<0.05). Remarkably, D3T treatment reduced the mean plasma sVCAM-1 at 3 month (731.8±28.2) from a significantly higher value when the same animals were aged 1 month (882.4±36; p<0.01, n=8), as well as stabilizing the plasma concentration of sVE-cad with aging. On the contrary, both sVCAM-1 and sVE-cad levels rose significantly during the adult transition in the vehicle-treated SS mice (p<0.001). Overall, our data identify Nrf2 as an attractive therapeutic target to slowing down the progression of SCD during the pediatric to adult transition. DisclosuresArcher:Global Blood Therapeutics: Consultancy.

Whole-transcriptome analysis of mouse adipose tissue in response to short-term caloric restriction.

Caloric restriction (CR) has been shown to extend the lifespan of many species by improving cellular function and organismal health. Additionally, fat reduction by CR may play an important role in lengthening lifespan and preventing severe age-related diseases. Interestingly, CR induced the greatest transcriptome change in the epididymal fat of mice in our study. In this transcriptome analysis, we identified and categorized 446 genes that correlated with CR level. We observed down-regulation of several signaling pathways, including insulin/insulin-like growth factor 1 (insulin/IGF-1), epidermal growth factor (EGF), transforming growth factor beta (TGF-β), and canonical wingless-type mouse mammary tumor virus integration site (Wnt). Many genes related to structural features, including extracellular matrix structure, cell adhesion, and the cytoskeleton, were down-regulated, with a strong correlation to the degree of CR. Furthermore, genes related to the cell cycle and adipogenesis were down-regulated. These biological processes are well-identified targets of insulin/IGF-1, EGF, TGF-β, and Wnt signaling. In contrast, genes involved in specific metabolic processes, including the tricarboxylic acid cycle and the electron transport chain were up-regulated. We performed in silico analysis of the promoter sequences of CR-responsive genes and identified two associated transcription factors, Paired-like homeodomain 2 (Pitx2) and Paired box gene 6 (Pax6). Our results suggest that strict regulation of signaling pathways is critical for creating the optimal energy homeostasis to extend lifespan.

Time trends for risk of severe age-related diseases in individuals with and without HIV infection in Denmark: a nationwide population-based cohort study

Whether the reported high risk of age-related diseases in HIV-infected people is caused by biological ageing or HIV-associated risk factors such as chronic immune activation and low-grade inflammation is unknown. We assessed time trends in age-standardised and relative risks of nine serious age-related diseases in a nationwide cohort study of HIV-infected individuals and population controls. We identified all HIV-infected individuals in the Danish HIV Cohort Study who had received HIV care in Denmark between Jan 1, 1995, and June 1, 2014. Population controls were identified from the Danish Civil Registration System and individually matched in a ratio of nine to one to the HIV-infected individuals for year of birth, sex, and date of study inclusion. Individuals were included in the study if they had a Danish personal identification number, were aged 16 years or older, and were living in Denmark at the time of study inclusion. Data for study outcomes were obtained from the Danish National Hospital Registry and the Danish National Registry of Causes of Death and were cardiovascular diseases (myocardial infarction and stroke), cancers (virus associated, smoking related, and other), severe neurocognitive disease, chronic kidney disease, chronic liver disease, and osteoporotic fractures. We calculated excess and age-standardised incidence rates and adjusted incidence rate ratios of outcomes for time after HIV diagnosis, highly active antiretroviral therapy (ART) initiation, and calendar time. The regression analyses were adjusted for age, sex, calendar time, and origin. We identified 5897 HIV-infected individuals and 53,073 population controls; median age was 36·8 years (IQR 30·6-44·4), and 76% were men in both cohorts. Dependent on disease, the HIV cohort had 55,050-57,631 person-years of follow-up and the population controls had 638,204-659,237 person-years of follow-up. Compared with the population controls, people with HIV had high excess and relative risk of all age-related diseases except other cancers. Overall, the age-standardised and relative risks of cardiovascular diseases, cancers, and severe neurocognitive disease did not increase substantially with time after HIV diagnosis or ART initiation. Except for chronic kidney diseases, the age-standardised and relative risks of age-related diseases did not increase with calendar time. Severe age-related diseases are highly prevalent in people with HIV, and continued attention and strategies for risk reduction are needed. The findings from our study do not suggest that accelerated ageing is a major problem in the HIV-infected population. Preben og Anna Simonsens Fond, Novo Nordisk Foundation, Danish AIDS Foundation, Augustinus Foundation, and Odense University Hospitals Frie Fonds Midler.

Inducible Knock Out of Pregnancy-Associated Plasma Protein-A Gene Expression in the Adult Mouse: Effect on Vascular Injury Response

Pregnancy-associated plasma protein-A (PAPP-A) enhances local IGF signaling through its ability to proteolyze inhibitory IGF binding proteins. In vivo, PAPP-A (like IGF) appears to exhibit antagonistic pleiotropy; ie, it has beneficial effects early in life but detrimental effects later in life. Accordingly, PAPP-A knockout (KO) mice are born as proportional dwarfs and have diminished reproductive vigor and reduced peak bone mass acquisition at puberty. On the other hand, PAPP-A KO mice live approximately 30% longer than their wild-type littermates, with decreased incidence and severity of age-related diseases and resistance to adverse responses of vascular injury. To be able to distinguish the impact of PAPP-A deficiency in the adult from that in early life, we developed a mouse model suitable for inducible Cre recombinase-mediated excision of the PAPP-A gene. In this study, we characterize the conditional PAPP-A KO mouse model for efficacy of tamoxifen-induced floxed PAPP-A excision in various tissues of adult mice and demonstrate a significant (P = .0001) reduction of neointimal formation in these mice after unilateral carotid artery ligation.

The role of the T cell in age-related inflammation

Ageing is accompanied by alterations to T-cell immunity and also by a low-grade chronic inflammatory state termed inflammaging. The significance of these phenomena is highlighted by their being predictors of earlier mortality. We have recently published that the proinflammatory cytokine TNFα is a strong inducer of CD4(+) T-cell senescence and T-cell differentiation, adding to the growing body of literature implicating proinflammatory molecules in mediating these critical age-related T-cell alterations. Moreover, the inflammatory process is also being increasingly implicated in the pathogenesis of many common and severe age-related diseases, including cancer, cardiovascular diseases and type 2 diabetes. Furthermore, major age-related risk factors for poor health, such as obesity, stress and smoking, are also associated with an upregulation in systemic inflammatory markers. We propose the idea that the ensuing inflammatory response to influenza infection propagates cardiovascular diseases and constitutes a major cause of influenza-related mortality. While inflammation is not a negative phenomenon per se, this age-related dysregulation of inflammatory responses may play crucial roles driving age-related pathologies, T-cell immunosenescence and CMV reactivation, thereby underpinning key features of the ageing process.

Molecular Mechanism of Dietary Restriction in Neuroprevention and Neurogenesis: Involvement of Neurotrophic Factors.

Dietary restriction (DR) is the most efficacious intervention for retarding the deleterious effects of aging. DR increases longevity, decreases the occurrence and severity of age-related diseases, and retards the physiological decline associated with aging. The beneficial effects of DR have been mostly studied in non-neuronal tissues. However, several studies have showed that DR attenuate neuronal loss after several different insults including exposure to kainate, ischemia, and MPTR Moreover, administration of the non-metabolizable glucose analog 2-deoxy-D-glucose (2DG) could mimic the neuroprotective effect of DR in rodent, presumably by limiting glucose availability at the cellular level. Based on the studies of chemically induced D.R., it has been proposed that the mechanism whereby DR and 2DG protect neurons is largely mediated by stress response proteins such as HSP70 and GRP78 which are increased in neurons of rats and mice fed a DR regimen. In addition, D.R., as mild metabolic stress, could lead to the increased activity in neuronal circuits and thus induce expression of neurotrophic factors. Interestingly, such increased neuronal activities also enhance neurogenesis in the brains of adult rodents. In this review, we focus on what is known regarding molecular mechanisms of the protective role of DR in neurodegenerative diseases and aging process. Also, we propose that DR is a mild cellular stress that stimulates production of neurotrophic factors, which are major regulators of neuronal survival, as well as neurogenesis in adult brain.

Living longer: age retardation and autonomy

Research into human ageing is a growing field of research with two central foci: geriatric medicine works to reduce the incidence and severity of age-related diseases and disabilities by devising adequate therapeutic and preventive strategies. A second focus, this time in the emerging field of biogerontology, is to bring about a general retardation of the ageing process and by this increase the average and maximum human lifespan. This contribution looks into the second focus, i.e. the possibility of age retardation which, for the time being, is merely hypothetical. After outlining research strategies studying age retardation in animal experiments, it will ask how extending human life by technological interventions might play out on the individual, familial and social level. The central concern here will be autonomy-linked issues, seeing that in debates concerning the ethical implications of age-retarding techniques the argument from autonomy is one of the main arguments in favour of the prolongation of human life. In particular, this contribution will assess whether the argument from autonomy does, in fact, unequivocally support the recourse to age-retarding techniques.

Alzheimer's, Atherosclerosis, and Aggregates: A Role for Bacterial Degradation

Several of the most prevalent and severe age-related diseases, notably Alzheimer's disease and atherosclerosis, feature the accumulation of non-degradable aggregates within the lysosomes of disease-affected cells. At an early point in disease progression, the breakdown of lysosomal contents by the resident catabolic enzymes stops working properly. A return of lysosomal enzymatic activity to pre-disease levels may restore aggregate elimination. In this review, a method of bioremediation-derived lysosomal enzyme enhancement is proposed, featuring the cellular introduction of microbial-isolated enzymes, or xenoenzymes. The benefits and challenges of using xenoenzymes to break down aggregates are discussed. As the size of our elderly population grows, the incidence of age-related diseases will increase, necessitating the exploration of radical, but potentially powerful, therapeutic strategies.

Echocardiographic abnormalities and disease severity in Fabry's disease

Fabry's disease is an X-linked recessive genetic deficiency of the enzyme alpha-galactosidase A, which leads to the pathologic deposition of neutral glycosphingolipids in lysosomes of the vascular endothelium of the heart, brain and kidney. The disease is progressive in hemizygous male patients, with increasing involvement of the major organs leading to death. Because cardiac involvement is a constant feature, echocardiograms were performed on 35 patients with Fabry's disease, 23 hemizygotes (aged 28.6 +/- 14 years) and 12 heterozygotes (aged 31.6 +/- 6 years), to determine whether cardiac involvement could be detected noninvasively. The results demonstrated that hemizygous male patients had a greater aortic root diameter, thicker interventricular septum and greater ventricular mass than did heterozygous female patients. Left ventricular mass per square meter of body surface area correlated well with clinical disease severity (r = 0.68, p less than 0.05), suggesting progressive glycosphingolipid deposition. Older heterozygotes (greater than 25 years old) had more severe evidence of cardiac disease than did younger male patients. Although mitral valve prolapse was identified in 12 (54%) of 23 male hemizygotes and in 7 (58%) of 12 female heterozygotes its presence did not correlate with clinical disease severity or other echocardiographic variables. Therefore, echocardiographic evidence of Fabry's disease appears to correlate with age-related disease severity and may be a useful noninvasive marker to follow disease progression and possible regression when appropriate therapy becomes available.