scholarly journals Age-related changes to macrophages are detrimental to fracture healing

2019 ◽  
Author(s):  
Daniel Clark ◽  
Sloane Brazina ◽  
Frank Yang ◽  
Diane Hu ◽  
Erene Niemi ◽  
...  
Keyword(s):  
Fracture Healing ◽  
The Elderly ◽  
Fracture Site ◽  
Rna Seq ◽  
Fracture Callus ◽  
Age Related ◽  
The Impact ◽  
Old Mice ◽  
Age Related Changes ◽  
Young Mice

AbstractThe elderly population suffers from higher rates of complications during fracture healing that result in increased morbidity and mortality. Inflammatory dysregulation is associated with increased age and is a contributing factor to the myriad of age-related diseases. Therefore, we investigated age-related changes to an important cellular regulator of inflammation, the macrophage, and the impact on fracture healing outcomes. We demonstrated that old mice (24 months) have delayed fracture healing with significantly less bone and more cartilage compared to young mice (3 months). The quantity of infiltrating macrophages into the fracture callus was similar in old and young mice. However, RNA-seq analysis demonstrated distinct differences in the transcriptomes of macrophages derived from the fracture callus of old and young mice, with an upregulation of M1/pro-inflammatory genes in macrophages from old mice as well as dysregulation of other immune-related genes. Preventing infiltration of the fracture site by macrophages in old mice improved healing outcomes, with significantly more bone in the calluses of treated mice compared to age-matched controls. After preventing infiltration by macrophages, the macrophages within the fracture callus were collected and examined via RNA-seq analysis, and their transcriptome resembled macrophages from young calluses. Taken together, infiltrating macrophages from old mice demonstrate detrimental age-related changes, and depleting infiltrating macrophages can improve fracture healing in old mice.

scholarly journals AGE-RELATED CHANGES TO MACROPHAGES AFFECT FRACTURE HEALING

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S83-S83
Author(s):  
Daniel Clark ◽  
Theodore Miclau ◽  
Mary Nakamura ◽  
Ralph Marcucio
Keyword(s):  
Older Adults ◽  
Fracture Healing ◽  
Inflammatory Cytokine ◽  
Cytokine Expression ◽  
Fracture Callus ◽  
Inflammatory Phase ◽  
Age Related ◽  
Anti Inflammatory ◽  
Old Mice ◽  
Age Related Changes

Abstract Fracture healing follows a strict temporal sequence characterized by an initial inflammatory phase. Perturbation of the inflammatory phase may be responsible for the poorer fracture healing outcomes in older adults. Herein, we examine age-related changes to the macrophage during fracture healing. Macrophages regulate inflammation through pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes. Anti-inflammatory activity is promoted via activation of triggering receptor expressed on myeloid cells 2 (TREM2). Tibia fractures were made in old (24 months) and young (3 months) mice. Immune cells from the fracture callus were analyzed via RNAseq and FACS, and fracture healing was evaluated histologically. Old mice demonstrated significantly delayed fracture healing compared to young (p<0.05). The quantity of infiltrating macrophages into the fracture callus was similar in young and old mice. However, 1222 genes were significantly differentially regulated (FDR<0.1) in callus macrophages from old mice compared to young, and old macrophages demonstrated a more pro-inflammatory phenotype. TREM2 expression was increased in macrophages after fracture in both groups but was significantly less in old mice compared to young via RNAseq and FACS (FDR<0.1, p<0.05). TREM2-/- mice demonstrated increased pro-inflammatory cytokine expression within the callus with resulting significant delays in fracture healing compared to age-matched controls (p<0.05). Inhibition of macrophage infiltration into the fracture callus significantly improved fracture healing in old mice compared to age-matched controls. Age-related changes to macrophages, including increased pro-inflammatory cytokine expression and dysregulated TREM2 expression, may explain fracture healing deficits observed in older adults. Therapeutically targeting macrophages may improve management of fractures in older adults.

Abstract T P136: Potential Contributors to the Declining Impact of Stroke Risk Factors with Age: Implications for Stroke Epidemiology in the Elderly

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
George Howard ◽  
Mary Cushman ◽  
Maciej Banach ◽  
Brett M Kissela ◽  
David C Goff ◽  
...  
Keyword(s):  
Risk Factors ◽  
Risk Factor ◽  
Stroke Risk ◽  
Multivariable Analysis ◽  
The Elderly ◽  
Stroke Risk Factors ◽  
Age Related ◽  
Increased Risk ◽  
The Impact ◽  
Age Related Changes

Purpose: The importance of stroke research in the elderly is increasing as America is “graying.” For most risk factors for most diseases (including stroke), the magnitude of association with incident events decreases at older ages. Potential changes in the impact of risk factors could be a “true” effect, or could be due to methodological issues such as age-related changes in residual confounding. Methods: REGARDS followed 27,748 stroke-free participants age 45 and over for an average of 5.3 years, during which 715 incident strokes occurred. The association of the “Framingham” risk factors (hypertension [HTN], diabetes, smoking, AFib, LVH and heart disease) with incident stroke risk was assessed in age strata of 45-64 (Young), 65-74 (Middle), and 75+ (Old). For those with and without an “index” risk factor (e.g., HTN), the average number of “other” risk factors was calculated. Results: With the exception of AFib, there was a monotonic decrease in the magnitude of the impact across the age strata, with HTN, diabetes, smoking and LVH even becoming non-significant in the elderly (Figure 1). However, for most factors, the increasing prevalence of other risk factors with age impacts primarily those with the index risk factor absent (Figure 2, example HTN as the “index” risk factor). Discussion: The impact of stroke risk factors substantially declined at older ages. However, this decrease is partially attributable to increases in the prevalence of other risk factors among those without the index risk factor, as there was little change in the prevalence of other risk factors in those with the index risk factor. Hence, the impact of the index risk factor is attenuated by increased risk in the comparison group. If this phenomenon is active with latent risk factors, estimates from multivariable analysis will also decrease with age. A deeper understanding of age-related changes in the impact of risk factors is needed.

scholarly journals Effect of age on susceptibility to Salmonella Typhimurium infection in C57BL/6 mice

2009 ◽  
Vol 58 (12) ◽  
pp. 1559-1567 ◽  
Author(s):  
Zhihong Ren ◽  
Raina Gay ◽  
Adam Thomas ◽  
Munkyong Pae ◽  
Dayong Wu ◽  
...  
Keyword(s):  
Immune Response ◽  
Ex Vivo ◽  
The Elderly ◽  
Mesenteric Lymph ◽  
Age Related ◽  
Serovar Typhimurium ◽  
Lymph Node Cells ◽  
Old Mice ◽  
Effect Of Age ◽  
Young Mice

Ageing is associated with a decline in immune function, which predisposes the elderly to a higher incidence of infections. Information on the mechanism of the age-related increase in susceptibility to Salmonella enterica serovar Typhimurium (S. Typhimurium) is limited. In particular, little is known regarding the involvement of the immune response in this age-related change. We employed streptomycin (Sm)-pretreated C57BL/6 mice to develop a mouse model that would demonstrate age-related differences in susceptibility and immune response to S. Typhimurium. In this model, old mice inoculated orally with doses of 3×108 or 1×106 c.f.u. S. Typhimurium had significantly greater S. Typhimurium colonization in the ileum, colon, Peyer's patches, spleen and liver than young mice. Old mice had significantly higher weight loss than young mice on days 1 and 2 post-infection. In response to S. Typhimurium infection, old mice failed to increase ex vivo production of IFN-γ and TNF-α in the spleen and mesenteric lymph node cells to the same degree as observed in young mice; this was associated with their inability to maintain the presence of neutrophils and macrophages at a ‘youthful’ level. These results indicate that Sm-pretreated C57BL/6 old mice are more susceptible to S. Typhimurium infection than young mice, which might be due to impaired IFN-γ and TNF-α production as well as a corresponding change in the number of neutrophils and macrophages in response to S. Typhimurium infection compared to young mice.

Abstract 429: Thoracic Aortic Smooth Muscle Cell Phenotype and Contractility are Altered With Aging

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Jason B Wheeler ◽  
Robert E Stroud ◽  
Elizabeth K Nadeau ◽  
Rupak Mukherjee ◽  
John S Ikonomidis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Cellular Proliferation ◽  
Primary Cultures ◽  
Cell Phenotype ◽  
Age Related ◽  
Age Dependent ◽  
Old Mice ◽  
Age Related Changes ◽  
Young Mice

Background: Age-related changes in the thoracic aorta, including alterations in medial extracellular matrix (ECM) in terms of increased collagen and reduced medial cellularity, are associated with a loss of contractility in isolated smooth muscle cells (SMCs). SMCs can regulate both the passive ECM content and mechanical properties of the aorta. However, the age-dependent effects on cellular proliferation, migration, adhesion, and gene expression (phenotype) of aortic SMCs remains unknown. Accordingly, the goal of this study was to determine the age-dependent changes in these characteristics of aortic SMCs. Methods/Results: Primary cultures of SMCs were established from thoracic aortic explants harvested from 6 month (n=6) and 21 month old (n=6) C57BL/6 mice. Cellular proliferation (by Cyquant assay), migration (Boyden chamber), and adhesion (on a cell culture treated surface) were reduced in the SMCs from old mice compared to those from young mice. Expression of ECM remodeling genes, including ECM proteins, matrix metalloproteinases, and tissue inhibitors of MMPs, produced a distinct genotypic profile between old and young SMCs (Figure). Conclusions: Findings from this study demonstrated that thoracic aortic SMCs from old mice are phenotypically distinct compared to those from young mice. Further, the changes in gene expression with age are consistent with the ECM changes observed in the aorta. Future studies will be required to define the role of these age-related changes in aortic SMC phenotype in aortopathies.

The Contribution of Macrophages in Old Mice to Periodontal Disease

2021 ◽  
pp. 002203452110094
Author(s):  
D. Clark ◽  
B. Halpern ◽  
T. Miclau ◽  
M. Nakamura ◽  
Y. Kapila ◽  
...  
Keyword(s):  
Bone Loss ◽  
Periodontal Disease ◽  
Detrimental Effect ◽  
Macrophage Depletion ◽  
Age Related ◽  
Disease Induction ◽  
Disease Recovery ◽  
Old Mice ◽  
Age Related Changes ◽  
Young Mice

The prevalence of periodontal disease increases with age. Systemic inflammatory dysregulation also increases with age and has been reported to contribute to the myriad of diseases and conditions that become more prevalent with advanced age. As periodontal disease involves a dysregulated host inflammatory response, the age-related inflammatory dysregulation may contribute to the pathogenesis of periodontal disease in aging populations. However, our understanding of what drives the age-related inflammatory dysregulation is limited. Here, we investigate the macrophage and its contribution to periodontal disease in old and young mice using a ligature-induced periodontal disease model. We demonstrate that control old mice present with an aged periodontal phenotype, characterized by increased alveolar bone loss and increased local inflammatory cytokine expression compared to young mice. Macrophages were demonstrated to be present in the periodontium of old and young mice in equal numbers in controls, during disease induction, and during disease recovery. However, it appears age may have a detrimental effect on macrophage activity during disease recovery. Depletion of macrophages during disease recovery in old mice resulted in decreased inflammatory cytokines within the gingiva and decreased bone loss as measured by micro–computed tomography. In young mice, macrophage depletion during disease recovery had no beneficial or detrimental effect. Macrophage depletion during disease induction resulted in decreased disease severity similarly in young and old mice. Findings from this work support the diverse roles of macrophages in disease induction as well as the active roles of disease recovery, including the resolution of inflammation. Here, we conclude that age-related changes to the macrophage appear to be detrimental to the recovery from disease and may explain, in part, the age-related increase in prevalence of periodontal disease. Future studies examining the specific intrinsic age-related changes to the macrophage will help identify therapeutic targets.

scholarly journals Impact of aging on gene expression response to x-ray irradiation using mouse blood

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Constantinos G. Broustas ◽  
Axel J. Duval ◽  
Sally A. Amundson
Keyword(s):  
Gene Expression ◽  
Differentially Expressed Genes ◽  
Differentially Expressed ◽  
X Rays ◽  
Gene Expression Response ◽  
X Ray ◽  
The Impact ◽  
Old Mice ◽  
Radiation Biodosimetry ◽  
Young Mice

AbstractAs a radiation biodosimetry tool, gene expression profiling is being developed using mouse and human peripheral blood models. The impact of dose, dose-rate, and radiation quality has been studied with the goal of predicting radiological tissue injury. In this study, we determined the impact of aging on the gene expression profile of blood from mice exposed to radiation. Young (2 mo) and old (21 mo) male mice were irradiated with 4 Gy x-rays, total RNA was isolated from whole blood 24 h later, and subjected to whole genome microarray analysis. Pathway analysis of differentially expressed genes revealed young mice responded to x-ray exposure by significantly upregulating pathways involved in apoptosis and phagocytosis, a process that eliminates apoptotic cells and preserves tissue homeostasis. In contrast, the functional annotation of senescence was overrepresented among differentially expressed genes from irradiated old mice without enrichment of phagocytosis pathways. Pathways associated with hematologic malignancies were enriched in irradiated old mice compared with irradiated young mice. The fibroblast growth factor signaling pathway was underrepresented in older mice under basal conditions. Similarly, brain-related functions were underrepresented in unirradiated old mice. Thus, age-dependent gene expression differences should be considered when developing gene signatures for use in radiation biodosimetry.

scholarly journals Regenerative Medicine Approaches for Age-Related Muscle Loss and Sarcopenia: A Mini-Review

Gerontology ◽  
2017 ◽  
Vol 63 (6) ◽  
pp. 580-589 ◽  
Author(s):  
Juan Diego Naranjo ◽  
Jenna L. Dziki ◽  
Stephen F. Badylak
Keyword(s):  
Regenerative Medicine ◽  
Treatment Options ◽  
The Elderly ◽  
Signaling Molecules ◽  
Current Treatment ◽  
Muscle Physiology ◽  
Age Related ◽  
Increased Risk ◽  
And Function ◽  
Age Related Changes

Sarcopenia is a complex and multifactorial disease that includes a decrease in the number, structure and physiology of muscle fibers, and age-related muscle mass loss, and is associated with loss of strength, increased frailty, and increased risk for fractures and falls. Treatment options are suboptimal and consist of exercise and nutrition as the cornerstone of therapy. Current treatment principles involve identification and modification of risk factors to prevent the disease, but these efforts are of limited value to the elderly individuals currently affected by sarcopenia. The development of new and effective therapies for sarcopenia is challenging. Potential therapies can target one or more of the proposed multiple etiologies such as the loss of regenerative capacity of muscle, age-related changes in the expression of signaling molecules such as growth hormone, IGF-1, myostatin, and other endocrine signaling molecules, and age-related changes in muscle physiology like denervation and mitochondrial dysfunction. The present paper reviews regenerative medicine strategies that seek to restore adequate skeletal muscle structure and function including exogenous delivery of cells and pharmacological therapies to induce myogenesis or reverse the physiologic changes that result in the disease. Approaches that modify the microenvironment to provide an environment conducive to reversal and mitigation of the disease represent a potential regenerative medicine approach that is discussed herein.

scholarly journals A cross-sectional study on interference control: age affects reactive control but not proactive control

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e8365 ◽  
Author(s):  
Yanfang Peng ◽  
Qin Zhu ◽  
Biye Wang ◽  
Jie Ren
Keyword(s):  
Middle Ages ◽  
Middle Age ◽  
The Elderly ◽  
Efficiency Score ◽  
Interference Control ◽  
Reactive Control ◽  
Cross Sectional ◽  
Age Related ◽  
The Difference ◽  
The Impact

Background Working memory updating (WMU), a controlled process to continuously adapt to the changing task demand and environment, is crucial for cognitive executive function. Although previous studies have shown that the elderly were more susceptible to cognitive interference than the youngsters, the picture of age-related deterioration of WMU is incomplete due to lack of study on people at their middle ages. Thus, the present study investigated the impact of age on the WMU among adults by a cross-sectional design to verify whether inefficiency interference control accounts for the aging of WMU. Methods In total, 112 healthy adults were recruited for this study; 28 old adults (21 female) ranging from 60 to 78 years of age; 28 middle-age adults (25 female) ranging from 45 to 59 years of age; 28 adults (11 female) ranging from 26 to 44 years of age; and 28 young adults (26 female) ranging from 18 to 25 years of age. Each participant completed a 1-back task. The inverse efficiency score was calculated in various sequences of three trials in a row to quantify the performance of WMU for adults of various ages. Results Inverse efficiency score of both young groups (young adult and adult) were significantly shorter than the old group in both Repeat-Alternate (RA, including □□○ and ○○□) and Alternate-Alternate (AA, including ○□○ and □○□) sequential patterns and they were additionally better than the middle-age group in AA sequential pattern. Conclusion With the increase of difficulty in the task, the difference in reactive interference control between young and middle age was gradually revealed, while the difference between young and old remained to apparent. The degradation of WMU aging may begin from middle-age and presents selective impairment in that only reactive interference control, but not proactive interference control, shows pronounced age-related decline. The preliminary results can inform future studies to further explore the whole lifespan trajectories of cognitive functions.

scholarly journals The Impact of Long‐Term Physical Activity on Age‐Related Changes in Protein and Gene Expression

2008 ◽  
Vol 22 (S1) ◽  
Author(s):  
Ian R Lanza ◽  
Daniel K Short ◽  
Kevin R Short ◽  
Yan W Asmann ◽  
Sreekumar Raghavakaimal ◽  
...  
Keyword(s):  
Gene Expression ◽  
Physical Activity ◽  
Age Related ◽  
The Impact ◽  
Age Related Changes

Impact of Tuberculosis in Elderly Population

2018 ◽  
pp. 326-338
Author(s):  
Gagan Chooramani ◽  
Pooja Singh
Keyword(s):  
Clinical Characteristics ◽  
Elderly Population ◽  
The Elderly ◽  
World Health ◽  
Tuberculosis Patients ◽  
Disease Outcomes ◽  
Age Related ◽  
Health Organization ◽  
The Impact ◽  
Poor Memory

The World Health Organization has declared that the spread of tuberculosis is a global emergency. Despite the implementation of strong tuberculosis-control initiatives by WHO, this highly infectious disease continues to affect all vulnerable populations, including the elderly population. Adverse social factors and poor living conditions also affect the elderly much more than the young. The clinical characteristics of tuberculosis in older adults can be unusual and may be confused with age-related illnesses. Various factors related to old age can also cause complications in the diagnosis, treatment, and disease outcomes for tuberculosis patients. The contributory factors may be poor memory, deafness, mental confusion, or impairment of speech. In addition, therapy for tuberculosis in elderly individuals is challenging because of the increased incidence of adverse drug reactions. Hence, understanding the impact of these substantial aspects will help to overcome the problem of tuberculosis in the elderly population.

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