Model Of Human Aging Research Articles

The companion dog as a model for inflammaging: a cross-sectional pilot study.

Inflammaging, the chronic, progressive proinflammatory state associated with aging, has been associated with multiple negative health outcomes in humans. The pathophysiology of inflammaging is complex; however, it is often characterized by high serum concentrations of inflammatory mediators such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, and C-reactive protein (CRP). Few studies have evaluated the effects of age on inflammatory cytokines in companion dogs, and most of these studies included dogs of a single breed. In this cross-sectional study, we measured multiple circulating inflammatory markers and hematological parameters in banked serum samples from 47 healthy companion dogs of various breeds enrolled in the Dog Aging Project. Using univariate linear models, we investigated the association of each of these markers with age, sex, body weight, and body condition score (BCS), a measure of obesity in the dog. Serum IL-6, IL-8, and TNF-α concentrations were all positively associated with age. Lymphocyte count was negatively associated with age. Platelet count had a negative association with body weight. IL-2, albumin, cholesterol, triglyceride, bilirubin, S100A12, and NMH concentrations were not associated with age, weight, BCS, or sex after adjustment for multiple comparisons. Our findings replicate previous findings in humans, including increases in IL-6 and TNF-α with age, giving more evidence to the strength of the companion dog as a model for human aging.

Sex differences in symptom presentation and their impact on diagnostic accuracy in Werner syndrome.

Whether sex differences exist in hereditary progeroid syndromes remains unclear. In this study, we investigated sex differences in patients with Werner syndrome (WS), a model of human aging, using patient data at the time of diagnosis. The presence of six cardinal signs in the diagnostic criteria was retrospectively evaluated. We found that the percentage of patients with all cardinal signs was higher in males than in females (54.2% vs. 21.2%). By the age of 40 years, 57.1% of male patients with WS presented with all the cardinal signs, whereas none of the female patients developed all of them. In particular, the frequency of having a high-pitched, hoarse voice, a characteristic of WS, was lower in female patients. The positive and negative predictive values for clinical diagnosis were 100% for males and females, indicating the helpfulness of diagnostic criteria regardless of sex. More female patients than male (86.7% vs. 64%) required genetic testing for their diagnosis because their clinical symptoms were insufficient, suggesting the importance of genetic testing for females even if they do not show typical symptoms of WS. Finally, the frequency of abnormal voice was lower in patients with WS harboring the c.3139-1G > C homozygous mutation. These results indicate, for the first time, that there are sex differences in the phenotypes of hereditary progeroid syndromes. The analysis of this mechanism in this human model of aging may lead to the elucidation of sex differences in the various symptoms of normal human aging. Geriatr Gerontol Int 2024; 24: 161-167.

Morbidity and mortality in elderly dogs – a model for human aging

Over the last decades, canines have experienced a marked increase in their lifespan, mirroring human populations. Several authors have pointed out the domestic dog as a suitable animal model for geropathology translational research. The aim of this study is to assess age-related morbidities and mortality in a population of 269 elderly canines (130 males and 139 females) submitted to necropsy. The organic systems exhibiting the higher number of age-related morbidities were the reproductive, cardiovascular and urinary systems and, in females, also the mammary gland. The prevalence of cardiovascular and urinary disease was significantly higher in males and mammary lesions were exclusively found in females. Urinary disease was more frequent in small breeds dogs, while peritoneum and male genital morbidities were significantly higher in larger breeds. Hyperplastic and degenerative lesions were common morbidities found in this elderly dog population. The main cause of death was neoplasia, which accounted for almost half of the deaths. Cardiovascular and urinary pathology also emerged as a frequent cause of mortality. These findings partially parallel data obtained for human species, displaying cancer and cardiovascular pathology as major causes of disease and death in elderlies. Our data reinforce the potential of the domestic dog for further translational investigations on gerontology, meeting the concept of One Health.

Effects of Age and Social Adversity on Immune Cell Populations in a Non-Human Primate Model of Human Aging

Significant hallmarks of aging are immune function decline and rising cumulative inflammation. These immunosenescent signatures are also found in individuals who experience chronic social adversity, independently of age. However, no studies to date have examined how social adversity alters immune function across the lifespan –data that are essential to identify the molecular routes through which social adversity might lead to increased aging-related disease. Over a two-year period, we investigated how age and social adversity (quantified by low social status) affected immunity. We measured immune cell proportions at baseline and their gene regulation after in vitro stimulation with pathogen molecules that stimulated both Th1 and Th2 immune responses in a population of free-ranging rhesus macaques. We first performed flow cytometry on peripheral whole blood to quantify changes on immune cell proportions across the lifespan (n=235) and in animals of different social statuses (n=141). We found significant decreases in CD20+ B cells and CD3+/CD4+ T cell proportions with age, suggesting diminished antibody production and adaptive immune responses in older individuals. Age-associated increases in CD3+/CD8+, CD3+/CD4+/CD25+ T regulatory cells and CD14-/CD16+/HLA-DR+ non-classical monocytes indicated heightened baseline inflammation in older animals. Social adversity recapitulated the effects of aging in CD14+/CD16-/HLA-DR+ classical monocytes, indicating immune deficits in phagocytosis and pathogen clearance in older and lower status individuals. Using RNA-seq, our stimulations (n=1,320) will allow us to identify molecular immune pathways that are disrupted by age and social adversity, similarities in response between age and adversity, and how the effect of adversity varies across the lifespan.

Atherosclerosis and Cardiovascular Diseases in Progeroid Syndromes.

Hutchinson–Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the representative genetic progeroid syndromes and have been widely studied in the field of aging research. HGPS is a pediatric disease in which premature aging symptoms appear in early childhood, and death occurs at an average age of 14.5 years, mainly due to cardiovascular disease (CVD). Conversely, WS patients exhibit accelerated aging phenotypes after puberty and die in their 50s due to CVD and malignant tumors. Both diseases are models of human aging, leading to a better understanding of the aging-associated development of CVD. In this review, we discuss the pathogenesis and treatment of atherosclerotic diseases presented by both progeroid syndromes with the latest findings.

Simulated microgravity accelerates aging in Saccharomyces cerevisiae

The human body experiences physiological changes under microgravity environment that phenocopy aging on Earth. These changes include early onset osteoporosis, skeletal muscle atrophy, cardiac dysfunction, and immunosenescence, and such adaptations to the space environment may pose some risk to crewed missions to Mars. To investigate the effect of microgravity on aging, many model organisms have been used such as the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and mice. Herein we report that the budding yeast Saccharomyces cerevisiae show decreased replicative lifespan (RLS) under simulated microgravity in a clinostat. The reduction of yeast lifespan is not a result of decreased tolerance to heat shock or oxidative stress and could be overcome either by deletion of FOB1 or calorie restriction, two known interventions that extend yeast RLS. Deletion of the sirtuin gene SIR2 worsens the simulated microgravity effect on RLS, and together with the fob1Δ mutant phenotype, it suggests that simulated microgravity augments the formation of extrachromosomal rDNA circles, which accumulate in yeast during aging. We also show that the chronological lifespan in minimal medium was not changed when cells were grown in the clinostat. Our data suggest that the reduction in longevity due to simulated microgravity is conserved in yeast, worms, and flies, and these findings may have potential implications for future crewed missions in space, as well as the use of microgravity as a model for human aging.

Building, testing, and learning from network models of human aging

We have developed computational models of human aging that are based on complex networks of interactions between health attributes of individuals. Our “generic network model” (GNM) captures the population level exponential increase of mortality with age in Gompertz’s law together with the exponential decrease of health as measured by the frailty index (FI). Our GNM includes only random accumulation of damage, with no programmed aging. Our GNM allows large populations of model individuals to be quickly generated with detailed individual health trajectories. This allows us to explore individual damage propagation in detail. To facilitate comparison with observational data, we have also developed and tested new approaches to binarizing continuous-valued health data. To extract the most information out of available cross-sectional or longitudinal data, we have also reconstructed interactions from generalized network models that can predict individual health trajectories and mortality.

Size discrimination in adult zebrafish (Danio rerio): Normative data and individual variation

In humans, aging and neurodegenerative diseases have been found to be associated with impairment in both mathematical abilities and estimation of continuous quantities such as size, weight or distance. Zebrafish (Danio rerio) is rapidly becoming a model for human aging and brain disorders but we currently lack any instrument for rapid assessment of quantity estimation abilities in this species. Here we developed a simple method based on spontaneous preference of zebrafish for using the larger available hole to pass an obstacle. We collected a large amount of data from small groups of zebrafish moving between compartments of their tank and we used these normative data to compare the performance of individually tested fish. Zebrafish significantly discriminated size ratios from 0.60 to 0.91 with their performance decreasing while increasing the size ratio between the smaller and the larger hole presented. On average, individually tested fish showed the same performance, but a large inter-individual variability was observed. Test-retest analyses revealed a good reliability of this test, with 0.60 and 0.75 ratios being the most informative. Experience did not affect individual performance, suggesting the suitability of this test to measure the longitudinal changes and the effects of pharmacological treatments on cognitive abilities.

THE EFFECTS OF AGE AND SIZE ON THE COMPANION DOG METABOLOME: ROLES OF TRYPTOPHAN AND FATTY ACID METABOLISM

Recently, the companion dog has been promoted as an ideal animal model for human aging. Dogs show an interesting phenomenon where smaller individuals are longer lived than their larger counterparts. However, many of the underlying molecular mechanisms that influence aging and longevity in the dog are unknown. To begin to uncover these physiological changes, we completed the largest metabolomics study to date in the companion dog. Here, we collected blood plasma samples from companion dogs in three in the United States for metabolomics analysis. We then looked at the effects of age and size on the metabolome to develop new hypotheses about healthy canine aging. Our most striking differences were found with regards to geographic location in the canine metabolome, in which metabolic profiles were more similar between dogs in the same city than across cities. After controlling for this location effect, we found a strong signal of amino acid metabolism, specifically tryptophan metabolism, associated with weight in the dog where metabolites in the tryptophan metabolism pathway were always higher in small, long-lived dogs. Future studies will directly investigate the role of tryptophan metabolism in model organisms.

The companion dog as a model for human aging and mortality

SummaryAround the world, human populations have experienced large increases in average lifespan over the last 150 years, and while individuals are living longer, they are spending more years of life with multiple chronic morbidities. Researchers have used numerous laboratory animal models to understand the biological and environmental factors that influence aging, morbidity, and longevity. However, the most commonly studied animal species, laboratory mice and rats, do not experience environmental conditions similar to those to which humans are exposed, nor do we often diagnose them with many of the naturally occurring pathologies seen in humans. Recently, the companion dog has been proposed as a powerful model to better understand the genetic and environmental determinants of morbidity and mortality in humans. However, it is not known to what extent the age‐related dynamics of morbidity, comorbidity, and mortality are shared between humans and dogs. Here, we present the first large‐scale comparison of human and canine patterns of age‐specific morbidity and mortality. We find that many chronic conditions that commonly occur in human populations (obesity, arthritis, hypothyroidism, and diabetes), and which are associated with comorbidities, are also associated with similarly high levels of comorbidity in companion dogs. We also find significant similarities in the effect of age on disease risk in humans and dogs, with neoplastic, congenital, and metabolic causes of death showing similar age trajectories between the two species. Overall, our study suggests that the companion dog may be an ideal translational model to study the many complex facets of human morbidity and mortality.

Mito-mice∆ and mitochondrial DNA mutator mice as models of human osteoporosis caused not by aging but by hyperparathyroidism.

Mitochondrial DNA (mtDNA) mutator mice showing accelerated accumulation of mtDNA with somatic mutations are potentially useful models of human aging, whereas mito-miceΔ showing accelerated accumulation of mtDNA with a deletion mutation (ΔmtDNA) are potentially useful models of mitochondrial diseases but not human aging, even though both models express an age-associated decrease in mitochondrial respiration. Because osteoporosis is the only premature aging phenotype observed in mtDNA mutator mice with the C57BL/6J nuclear genetic background, our previous study precisely examined its expression spectra and reported that both mtDNA mutator mice and mito-miceΔ, but not aged mice, developed decreased cortical bone thickness. Moreover, decreased cortical bone thickness is usually not seen in aged humans but is commonly seen in the patients with hyperparathyroidism caused by oversecretion of parathyroid hormone (PTH). In the present study, we showed higher concentrations of blood PTH in mtDNA mutator mice and mito-miceΔ than in aged mice. We also found that both models developed decreased mitochondrial respiration in the duodenum or renal tubules, which would lead to hypocalcemia, oversecretion of PTH, and ultimately osteoporosis. Thus, mtDNA mutator mice and mito-miceΔ may be useful models of human osteoporosis caused not by aging but by hyperparathyroidism.

Model organisms: Short-lived excitement.

A collection of genomic tools helps researchers exploit a short-lived fish species as a model for human aging.

Age is just a number! Or is it?

Age is just a number! Or is it?

Recent Insights into Spindle Function in Mammalian Oocytes and Early Embryos1

Errors in chromosome segregation in oocytes and early embryos lead to embryo aneuploidy, which contributes to early pregnancy loss. At the heart of chromosome segregation is the spindle, a dynamic biomechanical machine fashioned from microtubules, which is tasked with gathering and sorting chromosomes and dispatching them to the daughter cells at the time of cell division. Understanding the causes of segregation error in the oocyte and early embryo will undoubtedly hinge on a thorough understanding of the mechanism of spindle assembly and function in these highly specialized cellular environments. The recent advent of live imaging approaches to observe chromosome segregation in real-time in oocytes and embryos, paired with gene-silencing techniques and specific inhibition for assessing the function of a protein of interest, has led to a substantial advance in our understanding of chromosome segregation in early mammalian development. These studies have uncovered numerous mechanistic differences between oocytes, embryos, and traditional model systems. In addition, a flurry of recent studies using naturally aged mice as the model for human aging have begun to shed light on the increased levels of aneuploidy seen in embryos from older mothers. Here we review these recent developments and consider what has been learned about the causes of chromosome missegregation in early development.

Beyond Fat Grafting

The concept of aging and the mechanisms responsible for soft tissue aging have become progressively more important as the world's population ages and demands a higher quality of life. Although molecular mechanisms of aging have been evaluated in model organisms, specific genomic, genetic, and epigenetic modifications that can be translated to normal human tissue aging have yet to be identified. We propose that adipose tissue is an excellent model with which to investigate molecular aging pathways. The goal of this study is to demonstrate that primary human adipose tissue can serve as a model of human aging, and further, can be used to detect differences in genomic transcriptional profiling between cell types in adipose tissue as well as between youthful and older age groups. Subcutaneous adipose tissue was excised during cosmetic procedures from healthy patients. Adipocytes and stromal vascular fractions from the anterior abdomen were isolated from 3 young (26-39 years) and 3 old (52-64 years) patients and analyzed for genome-wide transcriptional differences between varying ages and cell types using the Affymetrix GeneChip Human Gene Chip 1.0ST. Genes specific to adipocytes were more highly expressed in adipocytes than in stromal vascular fractions, validating that adipose tissue should be examined in a cell-specific manner. An increase in overall gene expression was observed among patients in the older age group, consistent with senescence-related chromatin dysregulation. Principal components analysis revealed no clear delineation between age groups and a clear separation by cell type. Analysis of variance revealed cell type as the most significant variable in transcriptional differences, whereas age-related differences were a distant second. Gene Ontology categories of the most significantly modified genes included RNA splicing and mRNA metabolism, plasma membrane, and mitochondrial metabolism. Primary adipose tissue is an effective model for the study of the molecular mechanisms of human aging. Our findings are consistent with the hypothesis that epigenetic modifications play a more important role than transcriptional modifications in early human adipose tissue aging. Our future studies will examine the contribution of specific epigenetic markers to human adipose tissue aging and promise to advance approaches in regenerative medicine, and the prevention and treatment of aging.

Nonhuman Primate Calorie Restriction

Calorie restriction (CR) is the only dietary intervention that repeatedly extends both median and maximal lifespan in a broad range of species. Although there has been considerable interest in CR and its ability to retard aging, the mechanism has remained elusive. In contrast to studies in rodent and nonmammalian systems that are now beginning to provide mechanistic insights into how CR promotes longevity, the efficacy of CR in delaying primate aging has yet to be fully demonstrated. Here we review some of the insights from CR studies in short-lived species. We describe the advantages of using the rhesus monkey as a model for human aging and detail how CR can be successfully implemented in this species. We discuss the findings from our ongoing longitudinal study and outline the effects to date of CR on rhesus monkey health. Finally, we highlight the importance of primate studies in the context of aging research and its potential to advance our understanding of human aging and health.

Donor age reflects the replicative lifespan of human fibroblasts in culture

Human fibroblasts, which have a finite lifespan in cultures, have been widely used as a model system for cellular aging, and frequently used as one model of human aging. But whether cellular aging contributes to organismal aging has been controversial. To reinvestigate this question, we cultured human fibroblasts from the skin of one individual volunteer collected at different ages. Over a period of 27 years (donor age 36 years to 62 years), we obtained skin cells four times at appropriate intervals, and established eight fibroblast lines. These human fibroblasts have presented evidence for a correlation between donor age and proliferative lifespan in vitro. This result parallels the fact that telomeric DNA size cultured fibroblasts decrease with the increase in donor age. These cell lines had a normal diploid human chromosome constitution and will be useful in studies of human biology including aging.

Effect of Gender on Main Clinical Chemistry Parameters in Aged Rats

Clinical laboratory data are crucially important for the diagnosis, prognosis and therapy of aging-related diseases. The age-dependent changes in the findings of routine clinical-chemistry analyses may influence the evaluation of health status of the elderly people. Serum endogenous antioxidant levels and lipid profiles are considered to be related to the progress of age-related diseases. Analyses of these routine parameters are also important for the evaluation in the elderly. Although the analyses of serum biochemical parameters are important, there have been not enough data on changes in the levels of parameters with aging in both genders. However, elderly people generally suffer from aging-related diseases or may be using some medication that interferes with the accuracy of the result; it is thus preferred that the same procedures be applied in aged rats as a model of human aging. Aged Sprague-Dawley rats (24 months) of both genders were used in the current study. Serum total protein, albumin, bilirubin, uric acid, lipid profiles, iron, and total iron-binding capacity levels were determined on the same day of collection by standard clinical chemistry laboratory methods. Serum endogenous antioxidant parameters such as uric acid and bilirubin levels varied with gender in spite of almost no changes in the serum albumin and total iron binding capacity levels. Among the main parameters studied, lipid profile, conjugated bilirubin, and uric acid levels of male rats were significantly higher than in the aged female group. On the other hand, serum unconjugated bilirubin and iron levels were all found to be lower in the aged male group. Our findings support our conviction that serum biochemical parameters of aged rats have a controlling role in differing regulating mechanisms through gender differences. The gender-related data on these main serum clinical chemistry parameters in aged rats would be useful in studies of aging-related disorders using this model.

The Canine (Dog) Model of Human Aging and Disease: Dietary, Environmental and Immunotherapy Approaches

Aged dogs (beagles) develop losses in executive function, learning and memory. The severity of decline in these cognitive domains represents a spectrum that captures normal aging, mild cognitive impairment and early/mild Alzheimer's disease (AD) in humans. In parallel, dogs naturally accumulate several types of neuropathology (although not all) consistent with human brain aging and AD including cortical atrophy, neuron loss, loss of neurogenesis, amyloid-beta (Abeta) plaques, cerebral amyloid angiopathy and oxidative damage. Many of these neuropathological features correlate with the extent of cognitive decline in a brain region-dependent manner. Dogs are ideally suited for longitudinal studies, and we provide a summary of the beneficial effects of an antioxidant diet, behavioral enrichment, and Abeta immunotherapy. In addition, combinatorial treatment approaches can be a powerful strategy for improving brain function through enhancement of multiple molecular pathways.

Clinical Relevance of Transgenic Mouse Models for Aging Research

Studies on transgenic mice have shown them to be useful models for human aging- and age-related diseases. Life span end points in yeast and Caenorhabditis elegans can identify highly conserved genes that promote longevity when their functions are lost and which can readily be manipulated in the mouse. Protein kinase A is an example of a highly conserved gene that has age-delaying effects when specific subunits are suppressed or removed in the mouse, suggesting that loss of function may be a rational pharmacologic target. Gain of function is also an attractive clinical approach because expression levels of some vital genes may decrease in an age-related manner. The antioxidant enzyme catalase can delay aging when the human gene is inserted into mitochondria of mice. Other antioxidant genes are of interest in this system, both individually and in combination with catalase. A challenging aspect is to determine how to deliver catalase, as well as other gene products, into the mitochondria in the clinical setting. A number of new and exciting genes will most likely be investigated as clinical antiaging targets as the result of a forward genetic life span screening approach in invertebrates and a reverse genetic life span approach in the mouse.