FAP
Prolyl endopeptidase FAP (EC 3.4.21.26) (170 kDa melanoma membrane-bound gelatinase) (Dipeptidyl peptidase FAP) (EC 3.4.14.5) (Fibroblast activation protein alpha) (FAPalpha) (Gelatine degradation protease FAP) (EC 3.4.21.-) (Integral membrane serine protease) (Post-proline cleaving enzyme) (Serine integral membrane protease) (SIMP) (Surface-expressed protease) (Seprase) [Contains: Antiplasmin-cleaving enzyme FAP, soluble form (EC 3.4.14.5) (EC 3.4.21.-) (EC 3.4.21.26) (APCE)]
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We previously showed that lifelong rapamycin treatment of short-lived Apc mice, a model for familial adenomatous polyposis, resulted in a normal lifespan. Apc mice develop colon polyps with a low frequency but can be converted to a colon cancer model by dextran sodium sulfate (DSS) treatments (Apc -DSS model). We asked, what effect would pretreatment of Apc mice with chronic rapamycin prior to DSS exposure have on survival and colonic neoplasia? Forty-two ppm enteric formulation of rapamycin diet exacerbated the temporary weight loss associated with DSS treatment in both sexes. However, our survival studies showed that chronic rapamycin treatment significantly extended lifespan of Apc -DSS mice (both sexes) by reductions in colon neoplasia and prevention of anemia. Rapamycin also had prophylactic effects on colon neoplasia induced by azoxymethane and DSS in C57BL/6 males and females. Immunoblot assays showed the expected inhibition of complex 1 of mechanistic or mammalian target of rapamycin (mTORC1) and effectors (S6K→rpS6 and S6K→eEF2K→eEF2) in colon by lifelong rapamycin treatments. To address the question of cell types affected by chronic enteric rapamycin treatment, immunohistochemistry analyses demonstrated that crypt cells had a prominent reduction in rpS6 phosphorylation and increase in eEF2 phosphorylation relative controls. These data indicate that enteric rapamycin prevents or delays colon neoplasia in Apc DSS mice through inhibition of mTORC1 in the crypt cells.
Keywords
- Aging
- Crypt stem cells
- eEF2K
- mTORC1
- rpS6
Idiopathic inflammatory myopathies cause progressive muscle weakness and degeneration. Since high-dose glucocorticoids might not lead to full recovery of muscle function, physical exercise is also an important intervention, but some exercises exacerbate chronic inflammation and muscle fibrosis. It is unknown how physical exercise can have both beneficial and detrimental effects in chronic myopathy. Here we show that senescence of fibro-adipogenic progenitors (FAPs) in response to exercise-induced muscle damage is needed to establish a state of regenerative inflammation that induces muscle regeneration. In chronic inflammatory myopathy model mice, exercise does not promote FAP senescence or resistance against tumor necrosis factor-mediated apoptosis. Pro-senescent intervention combining exercise and pharmacological AMPK activation reverses FAP apoptosis resistance and improves muscle function and regeneration. Our results demonstrate that the absence of FAP senescence after exercise leads to muscle degeneration with FAP accumulation. FAP-targeted pro-senescent interventions with exercise and pharmacological AMPK activation may constitute a therapeutic strategy for chronic inflammatory myopathy.
MeSH Terms
- Aging
- Animals
- Apoptosis
- Exercise Therapy
- Female
- Humans
- Mesenchymal Stem Cells
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Muscle, Skeletal
- Muscular Diseases
- Regeneration
Fibro-adipogenic progenitors (FAPs), a muscle-resident stem cell population, have recently emerged as important actors of muscle regeneration by interacting with myogenic progenitors (MPs) to promote the formation of new muscle fibers. However, FAPs are also considered as main contributors of intramuscular fibrotic and fat depositions, resulting in a poor quality of muscles and a defective regeneration in aging and Duchenne Muscular Dystrophy disease (DMD). Therefore, the understanding of the control of FAP fate is an important aspect of muscle repair and homeostasis, but little is known in humans. We wondered the extent to which human FAP proliferation, adipogenesis and fibrogenesis can be regulated by human myogenic progenitors (MPs) in physiological and pathological contexts. FAPs and MPs were isolated from skeletal muscles of healthy young or old donors and DMD patients. FAP/MP contact co-cultures and conditioned-media from undifferentiated MPs or differentiated myotubes were assessed on both proliferation and fibro-adipogenic differentiation of FAPs. We showed that soluble molecules released by MPs activate the phosphoinositide 3-kinase (PI3Kinase)/Akt pathway in FAPs, resulting in the stimulation of FAP proliferation. FAP differentiation was regulated by MP-derived myotubes through the secretion of pro-fibrogenic factors and anti-adipogenic factors. Importantly, the regulation of FAP adipogenic and fibrogenic fates by myotubes was found to be mediated by Smad2 phosphorylation and the gene expression of glioma-associated oncogene homolog 1 (GLI1). Surprisingly, the regulations of proliferation and differentiation were disrupted for FAPs and MPs derived from aged individuals and patients with DMD. Our results highlight a novel crosstalk between FAPs and the myogenic lineage in humans that could be crucial in the formation of adipocyte and myofibroblast accumulation in dystrophic and aged skeletal muscle.
MeSH Terms
- Adipogenesis
- Adolescent
- Adult
- Adult Stem Cells
- Aged
- Aging
- Cells, Cultured
- Child
- Child, Preschool
- Female
- Humans
- Infant
- Male
- Middle Aged
- Muscle Development
- Muscular Dystrophy, Duchenne
- Myoblasts
- Young Adult
Keywords Adipocytes; Myofibroblasts; Muscle progenitors; Myopathies
Fibroblast growth factor (FGF)21 is promptly induced by short fasting in animal models to regulate glucose and fat metabolism. Data on FGF21 in humans are inconsistent and FGF21 has not yet been investigated in old patients with cachexia, a complex syndrome characterized by inflammation and weight loss. The aim of this study was to explore the association of FGF21 with cachexia in old patients compared with their healthy counterparts. Serum FGF21 and its inactivating enzyme fibroblast activation protein (FAP)-α were measured with enzyme-linked immunoassays. Cachexia was defined as ≥5% weight loss in the previous 3 mo and concurrent anorexia (Council on Nutrition appetite questionnaire). We included 103 patients with and without cachexia (76.9 ± 5.2 y of age) and 56 healthy controls (72.9 ± 5.9 y of age). Cachexia was present in 16.5% of patients. These patients had significantly higher total FGF21 levels than controls (952.1 ± 821.3 versus 525.2 ± 560.3 pg/mL; P = 0.012) and the lowest FGF21 levels (293.3 ± 150.9 pg/mL) were found in the control group (global P < 0.001). Although FAP-α did not differ between the three groups (global P = 0.082), bioactive FGF21 was significantly higher in patients with cachexia (global P = 0.002). Risk factor-adjusted regression analyses revealed a significant association between cachexia and total (β = 649.745 pg/mL; P < 0.001) and bioactive FGF21 (β = 393.200 pg/mL; P <0.001), independent of sex, age, and body mass index. Patients with cachexia exhibited the highest FGF21 levels. Clarification is needed to determine whether this is an adaptive response to nutrient deprivation in disease-related cachexia or whether the increased FGF21 values contribute to the catabolic state.
MeSH Terms
- Aged
- Aged, 80 and over
- Cachexia
- Cross-Sectional Studies
- Female
- Fibroblast Growth Factors
- Gelatinases
- Humans
- Male
- Membrane Proteins
- Pilot Projects
- Prospective Studies
- Serine Endopeptidases
- Weight Loss
Keywords
- Aging
- Anorexia
- Biomarker
- Cachexia
- Fibroblast growth factor 21
Research on age-related regenerative failure of skeletal muscle has extensively focused on the phenotypes of muscle stem cells (MuSCs). In contrast, the impact of aging on regulatory cells in the MuSC niche remains largely unexplored. Here, we demonstrate that aging impairs the function of mouse fibro-adipogenic progenitors (FAPs) and thereby indirectly affects the myogenic potential of MuSCs. Using transcriptomic profiling, we identify WNT1 Inducible Signaling Pathway Protein 1 (WISP1) as a FAP-derived matricellular signal that is lost during aging. WISP1 is required for efficient muscle regeneration and controls the expansion and asymmetric commitment of MuSCs through Akt signaling. Transplantation of young FAPs or systemic treatment with WISP1 restores the myogenic capacity of MuSCs in aged mice and rescues skeletal muscle regeneration. Our work establishes that loss of WISP1 from FAPs contributes to MuSC dysfunction in aged skeletal muscles and demonstrates that this mechanism can be targeted to rejuvenate myogenesis.
MeSH Terms
- Adipocytes
- Adipogenesis
- Aging
- Animals
- CCN Intercellular Signaling Proteins
- Cells, Cultured
- Humans
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Muscle, Skeletal
- Proto-Oncogene Proteins
- Stem Cells
Keywords
- CCN4
- WISP1
- aging
- fibro-adipogenic progenitors
- matricellular signaling
- muscle stem cells
- regeneration
- satellite cell
- skeletal muscle
- stem cell niche
Fibro-adipogenic progenitors (FAPs) are an interstitial cell population in adult skeletal muscle that support muscle regeneration. During development, interstitial muscle connective tissue (MCT) cells support proper muscle patterning, however the underlying molecular mechanisms are not well understood and it remains unclear whether adult FAPs and embryonic MCT cells share a common lineage. We show here that mouse embryonic limb MCT cells expressing the transcription factor Osr1, differentiate into fibrogenic and adipogenic cells in vivo and in vitro defining an embryonic FAP-like population. Genetic lineage tracing shows that developmental Osr1 cells give rise to a subset of adult FAPs. Loss of Osr1 function leads to a reduction of myogenic progenitor proliferation and survival resulting in limb muscle patterning defects. Transcriptome and functional analyses reveal that Osr1 cells provide a critical pro-myogenic niche via the production of MCT specific extracellular matrix components and secreted signaling factors.
MeSH Terms
- Aging
- Animals
- Body Patterning
- Connective Tissue
- Embryo, Mammalian
- Extracellular Matrix Proteins
- Extremities
- Gene Expression Regulation
- Mice
- Muscle Development
- Myoblasts
- Signal Transduction
- Transcription Factor 4
- Transcription Factors
Identification of cost-effective interventions to maintain muscle mass, muscle strength, and physical performance during muscle wasting and aging is an important public health challenge. It requires understanding of the cellular and molecular mechanisms involved. Muscle-deconditioning processes have been deciphered by means of several experimental models, bringing together the opportunities to devise comprehensive analysis of muscle wasting. Studies have increasingly recognized the importance of fatty infiltrations or intermuscular adipose tissue for the age-mediated loss of skeletal-muscle function and emphasized that this new important factor is closely linked to inactivity. The present review aims to address three main points. We first mainly focus on available experimental models involving cell, animal, or human experiments on muscle wasting. We next point out the role of intermuscular adipose tissue in muscle wasting and aging and try to highlight new findings concerning aging and muscle-resident mesenchymal stem cells called fibro/adipogenic progenitors by linking some cellular players implicated in both FAP fate modulation and advancing age. In the last part, we review the main data on the efficiency and molecular and cellular mechanisms by which exercise, replacement hormone therapies, and β-hydroxy-β-methylbutyrate prevent muscle wasting and sarcopenia. Finally, we will discuss a potential therapeutic target of sarcopenia: glucose 6-phosphate dehydrogenase.
MeSH Terms
- Adipose Tissue
- Aging
- Animals
- Apoptosis
- Dietary Supplements
- Exercise
- Glucosephosphate Dehydrogenase
- Hormone Replacement Therapy
- Humans
- Mitochondria
- Models, Animal
- Models, Theoretical
- Muscle, Skeletal
- Sarcopenia
- Signal Transduction
- Valerates
- Weightlessness
Keywords
- Beta-hydroxy-beta-methylbutyrate (HMB)
- Exercise
- Intermuscular adipose tissue (IMAT)
- Microgravity
- Muscle disuse
- Sarcopenia
Senile systemic amyloidosis (SSA) is a form of amyloidosis associated with aging, and is characterized by deposition of amyloid fibrils derived from wild-type transthyretin. Amyloid deposition is mainly seen in the myocardium, resulting in arrhythmia (atrial fibrillation) and/or heart failure. Previously, SSA was thought to represent a disease of aged patients over 80 years only; however, recent studies have indicated that SSA also affects much younger patients, with an onset around 50 years. In addition, a number of patients with SSA present with carpal tunnel syndrome (CTS), often several years prior to the onset of heart failure. Hence, CTS may be a key symptom suggestive of SSA, and amyloid deposits should always be confirmed in the operation specimens obtained during carpal tunnel release surgery in CTS patients aged over 50 years. Recently, effective drugs such as tafamidis and diflunisal, which stabilize the structure of the transthyretin tetramer, have been established in FAP patients, and therapeutic effectiveness of these drugs is also anticipated for SSA patients.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Amyloidosis
- Animals
- Biopsy
- Disease Models, Animal
- Humans
- Middle Aged
- Organ Specificity
- Prealbumin
Mutation of a single copy of the adenomatous polyposis coli (APC) gene results in familial adenomatous polyposis (FAP), which confers an extremely high risk for colon cancer. Apc(Min/ ) mice exhibit multiple intestinal neoplasia (MIN) that causes anemia and death from bleeding by 6 months. Mechanistic target of rapamycin complex 1 (mTORC1) inhibitors were shown to improve Apc(Min/ ) mouse survival when administered by oral gavage or added directly to the chow, but these mice still died from neoplasia well short of a natural life span. The National Institute of Aging Intervention Testing Program showed that enterically targeted rapamycin (eRapa) extended life span for wild-type genetically heterogeneous mice in part by inhibiting age-associated cancer. We hypothesized that eRapa would be effective in preventing neoplasia and extend survival of Apc(Min/ ) mice. We show that eRapa improved survival of Apc(Min/ ) mice in a dose-dependent manner. Remarkably, and in contrast to previous reports, most of the Apc(Min/ ) mice fed 42 parts per million eRapa lived beyond the median life span reported for wild-type syngeneic mice. Furthermore, chronic eRapa did not cause detrimental immune effects in mouse models of cancer, infection, or autoimmunity, thus assuaging concerns that chronic rapamycin treatment suppresses immunity. Our studies suggest that a novel formulation (enteric targeting) of a well-known and widely used drug (rapamycin) can dramatically improve its efficacy in targeted settings. eRapa or other mTORC1 inhibitors could serve as effective cancer preventatives for people with FAP without suppressing the immune system, thus reducing the dependency on surgery as standard therapy.
MeSH Terms
- Adenomatous Polyposis Coli
- Animals
- Chemistry, Pharmaceutical
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Female
- Genes, APC
- Intestinal Mucosa
- Longevity
- Mechanistic Target of Rapamycin Complex 1
- Melanoma, Experimental
- Mice
- Mice, Inbred C57BL
- Multiprotein Complexes
- Neoplasm Transplantation
- Sirolimus
- TOR Serine-Threonine Kinases
- Time Factors
Age and sex differences are closely related to the onset of senile systemic amyloidosis (SSA) caused by wild-type (WT) transthyretin (TTR). However, the effects of these differences on the amyloid formation mechanism in familial amyloid polyneuropathy (FAP) caused by variant TTR, have remained unclear. To elucidate age and sex differences in FAP, we investigated biochemical characteristics of amyloid deposits in different tissue sites of FAP by proteomic analysis. We used shotgun liquid chromatography/tandem mass spectrometry to analyze the proportions of variant and WT TTR in amyloid deposits in different tissues, such as cardiac, kidney, peripheral nerves, and gastrointestinal tissues, from 23 autopsied FAP cases. The analysis revealed a highly significant correlation between the proportion of WT TTR and age at autopsy in cardiac tissues, whereas the analysis indicated no correlation in kidney, peripheral nerves, and gastrointestinal tissues. In addition, we demonstrated age-related significantly increased WT TTR deposits, but not variant TTR deposits, in cardiac tissues of male patients. Taken together, these data suggest that both age and sex differences affect cardiac amyloid formation, mainly derived from WT TTR, in FAP.
MeSH Terms
- Adult
- Age Factors
- Amyloid Neuropathies, Familial
- Female
- Humans
- Male
- Middle Aged
- Myocardium
- Prealbumin
- Proteomics
- Sex Characteristics
- Young Adult
Keywords
- Aging
- Amyloidosis
- Familial amyloidotic polyneuropathy
- Proteome
- Sex differences
- Transthyretin
Neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), familial adenomatous polyposis (FAP), von Hippel-Lindau syndrome (VHL), and Gorlin syndrome (GS) are single gene diseases that predispose to early onset tumours. Few studies have assessed the effect of these diseases on life expectancy. This study's aim was to assess this effect, and to test the hypothesis that genetic registers increase survival. NF1, NF2, VHL, FAP, and GS patients were identified through the North West Regional Genetic Register Service and the North West Cancer Intelligence Service. Information on benign and malignant tumours, and deaths were obtained. Kaplan-Meier curves were used to show actuarial survival rates for each disease, compared to the local population, and in patients diagnosed pre/post the regional genetic register. Log rank (Mantel-Cox) tests were used to compare survival between groups. Life expectancies were significantly reduced for all diseases investigated compared with the local population (80.0 years) (p=0.05). GS had the longest life expectancy at 73.4 years, followed by NF1 at 71.5 years, NF2 at 69.0 years, FAP at 63.6 years, and VHL at 52.5 years. Patients diagnosed after establishment of the genetic register had an increase in survival compared to those diagnosed pre-1990: NF2 (14.7 years), FAP (13.9 years), VHL (16.3 years), and GS (11.2 years). Life expectancy for all five diseases was less than normal, although in recent years this reached the level of the local population in GS. Although there have been improvements in all conditions which may in part be attributable to better targeted care through the genetic register service, more needs to be done to address the very poor life expectancy in VHL.
MeSH Terms
- Cause of Death
- Female
- Humans
- Life Expectancy
- Male
- Neoplastic Syndromes, Hereditary
- Registries
- Survival Analysis
- Survival Rate
Gastric sensorymotor dysfunctions have been implicated in the pathophysiology of some functional gastrointestinal disorders, such as functional dyspepsia and irritable bowel syndrome. Therefore, we hypothesized that abnormal gastric emptying and impaired antral motility are possible underlying mechanisms of symptoms in children with functional abdominal pain (FAP). Hundred and two children [37 (36.3%) males, 4-14 years, mean 7.8 years, SD 2.7 years] fulfilling Rome III criteria for FAP were recruited for this study. An age and sex compatible group of healthy children (n = 20) were selected as controls [8 (40%) males, 4-14 years, mean 8.4 years, SD 3.0 years]. Liquid gastric emptying rate (GER) and antral motility parameters (amplitude of antral contractions, frequency of antral contractions and antral motility index) were assessed using a previously reported ultrasound method. Average GER (42.1% vs 66.2% in controls), amplitude of antral contractions (56.5% vs 89%), frequency of contractions per 3 min (8.5 vs 9.3), and antral motility index (4.9 vs 8.3) were significantly lower in patients with FAP compared with controls (P < 0.01). Fasting antral area was higher in patients (1.4 vs 0.6, P < 0.0001). GER negatively correlated with the scores obtained for severity of abdominal pain (r = -0.29, P = 0.004). Gastric emptying rate and antral motility parameters were significantly impaired in patients with FAP and GER negatively correlated with symptom severity. These findings highlight the possible role of gastrointestinal motility abnormalities in the pathophysiology of childhood FAP.
MeSH Terms
- Abdominal Pain
- Adolescent
- Age of Onset
- Aging
- Child
- Child, Preschool
- Chronic Disease
- Gastric Emptying
- Gastrointestinal Motility
- Humans
- Male
- Pain Measurement
- Pyloric Antrum
- Recurrence
- Retrospective Studies
NTG (nitroglycerine) is used in routine tilt testing to elicit a vasovagal response. In the present study we hypothesized that with increasing age NTG triggers a more gradual BP (blood pressure) decline due to a diminished baroreflex-buffering capacity. The purpose of the present study was to examine the effect of NTG on baroreflex control of BP in patients with distinct age-related vasovagal collapse patterns. The study groups consisted of 29 patients (16-71 years old, 17 females) with clinically suspected VVS (vasovagal syncope) and a positive tilt test. Mean FAP (finger arterial pressure) was monitored continuously (Finapres). Left ventricular SV (stroke volume), CO (cardiac output) and SVR (systemic vascular resistance) were computed from the pressure pulsations (Modelflow). BRS (baroreflex sensitivity) was estimated in the time domain. In the first 3 min after NTG administration, BP was well-maintained in all patients. This implied an adequate arterial resistance response to compensate for steeper reductions in SV and CO with increasing age. HR (heart rate) increased and the BRS decreased after NTG administration. The rate of mean FAP fall leading to presyncope was inversely related to age (r=0.51, P=0.005). Accordingly, patients with a mean FAP fall >1.44 mmHg/s (median) were generally younger compared with patients with a slower mean FAP-fall (30 /-10 years compared with 51 /-17 years; P=0.001). The main determinant of the rate of BP fall on approach of presyncope was the rate of fall in HR (r=0.75, P<0.001). It was concluded that, in older patients, sublingual NTG provokes a more gradual BP decline compared with younger patients. This gradual decline cannot be ascribed to failure of the baroreflex-buffering capacity with increasing age. Age-related differences in the laboratory presentation of a vasovagal episode depend on the magnitude of the underlying bradycardic response.
MeSH Terms
- Adolescent
- Adult
- Age Factors
- Aged
- Aging
- Baroreflex
- Blood Pressure
- Cardiac Output
- Female
- Head-Down Tilt
- Humans
- Male
- Middle Aged
- Nitroglycerin
- Syncope, Vasovagal
- Tilt-Table Test
- Vascular Resistance
- Vasodilation
- Vasodilator Agents
Although aging is closely related with the onset of senile systemic amyloidosis (SSA) caused by wild-type transthyretin (TTR), the effect of aging on amyloid formation has remained unclear in familial amyloidotic polyneuropathy (FAP), caused by variant- and wild-type TTR. The aim of this study was to elucidate the effects of aging and/or other factors in FAP on amyloid formation in the lung, one of the most important target organs of amyloid deposition in SSA. Pulmonary amyloid distribution was determined using 19 autopsied lung samples from patients with FAP amyloidogenic TTR (ATTR) V30M, the most common type of FAP. Amyloid deposition was observed around the walls of the bronchi/ bronchioles, the pulmonary arteries, and the pulmonary veins, while no amyloid deposits could be found around the lymphatics. In addition, amyloid deposition in the alveolar regions was a characteristic finding in aged patients with FAP ATTR V30M (average ages of the patients with amyloid positive vs. negative: 50.55 /- 8.75 vs. 39.75 /- 4.17 years old, p < 0.005), similar to the finding in one SSA patient. These results suggest that aging could play an important role in the progression of pulmonary amyloid formation in FAP ATTR V30M.
MeSH Terms
- Adult
- Aged, 80 and over
- Aging
- Amyloidosis
- Amyloidosis, Familial
- Female
- Humans
- Lung
- Lung Diseases
- Male
- Middle Aged
- Point Mutation
- Prealbumin
We investigated the occurrence of ventricular late potentials (LPs) in patients with familial amyloidotic polyneuropathy (FAP) and the possible association with ventricular arrhythmia on Holter electrocardiography and echocardiographic data. Fifty-five patients and 94 healthy controls were studied. LP were found in 46% of the FAP patients older than 60 years and in 15% of the controls (P = .02), whereas no difference was found in individuals younger than 60 years. The occurrence of LP was associated with nonsustained ventricular arrhythmia in the older FAP patients (P = .04). Older patients with LP had increased ventricular septum thickness (P = .02) and left posterior wall thickness (P = .01), as compared with those without LP. In conclusion, ventricular LPs are common in the FAP patients older than 60 years and associated with nonsustained ventricular arrhythmia and increased thickness of the left ventricular wall. Long-term follow-up studies are required to find the prognostic significance of these new findings.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Amyloid Neuropathies, Familial
- Arrhythmias, Cardiac
- Electrocardiography
- Electrocardiography, Ambulatory
- Female
- Humans
- Male
- Middle Aged
- Sweden
- Ventricular Function, Left
Glaucoma is a common cause of blindness affecting at least 66 million people worldwide. Pigmentary glaucoma is one of the most common forms of secondary glaucoma, and its pathogenesis remains unclear. Interleukin-18 (IL-18) is an important regulator of innate and acquired immune responses and plays an important role in inflammatory/autoimmunity diseases. Using the DBA/2J mouse as an animal model of human pigmentary glaucoma, we demonstrated for the first time that the expression of the IL-18 protein and gene in the iris/ciliary body and level of IL-18 protein in the aqueous humor of DBA/2J mice are dramatically increased with age. This increase precedes the onset of clinical evidence of pigmentary glaucoma, implying a pathogenic role of inflammation/immunity in this disease. We also observed that activated NF-kappaB and phosphorylated MAPK are increased in the iris/ciliary body of DBA/2J mice, suggesting that both signaling pathways may be involved in IL-18 mediated pathogenesis of pigmentary glaucoma in the eyes of DBA/2J mice. In addition, matrix metalloproteinase-2 (MMP-2) expression in the iris/ciliary body and the activity of MMP-2 in the aqueous humor are increased whereas tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) expression in the iris/ciliary body is decreased, indicating that the degradation process is involved in this mouse model of pigmentary glaucoma. Furthermore, the expressions of apoptosis-related genes, caspase-8, Fas, FADD, FAP, and FAF, and the activity of caspase-3 are increased in the iris/ciliary body of DBA/2J mice. Elucidation of biochemical and molecular mechanisms of IL-18 participation in the pathogenesis of pigmentary glaucoma should provide approaches for developing improved and targeted treatments to ameliorate this blinding disease. The possibility that altered IL-18 expression in the eye of DBA/2J mice initiates and/or amplifies the pathogenesis of pigmentary glaucoma requires further investigation.
MeSH Terms
- Aging
- Animals
- Antigens, CD
- Antigens, Differentiation, T-Lymphocyte
- Apoptosis
- Ciliary Body
- Disease Models, Animal
- Gene Expression Regulation
- Glaucoma, Open-Angle
- Humans
- Interleukin-18
- Intraocular Pressure
- Iris
- Lectins, C-Type
- Matrix Metalloproteinase 2
- Mice
- Mice, Inbred C57BL
- Mice, Inbred DBA
- Mitogen-Activated Protein Kinases
- NF-kappa B
- Retinal Ganglion Cells
- Signal Transduction
- T-Lymphocytes
- Tissue Inhibitor of Metalloproteinase-1
To clarify the clinicopathological features of cardiac amyloidosis in transthyretin (TTR) familial amyloid polyneuropathy (FAP), 169 patients were divided into three groups. Group I consisted of 113 patients with ATTR Val30Met who originated from an endemic focus, II consisted of 36 patients with ATTR Val30Met in nonendemic areas, and III consisted of 20 patients who had non-Val30Met ATTRs with 15 different gene mutations. The median age of onset in Group I was 34 years. On our initial examination, only one 65-year-old female patient was found to be suffering from congestive heart failure. During the follow-up of 65 patients, 7 developed congestive heart failure, the average duration of their illness being 8.7 years. In Group II, the median age of onset was 53 years and 6 of the 36 patients were diagnosed as having cardiac amyloidosis in the course of this disease. In 20 autopsied patients with ATTR Val30Met, congestive heart failure was clinically seen in 6 of the 20 and all 6 showed considerably increased cardiac weight (500g or more). In Group III patients with non-Val30Met ATTRs, the median age of onset was 51.5 years and 14 of the 20 patients had cardiac amyloidosis with congestive heart failure on admission or soon after a definite diagnosis. Cardiac amyloidosis occurs in the classical form of FAP with ATTR Val30Met, especially in older patients, and is also a common clinical manifestation in FAP patients with non-Val30Met ATTRs. In the pathogenesis of cardiac amyloidosis in ATTR FAP, aging seems to play an important role.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Amyloid
- Amyloid Neuropathies, Familial
- Amyloidosis
- Cardiomyopathies
- Female
- Humans
- Male
- Middle Aged
- Mutation
- Polyneuropathies
- Prealbumin
- Retrospective Studies
This study reevaluates the risk of rectal cancer and the frequency of subsequent proctectomy for nonmalignant causes in patients with familial adenomatous polyposis (FAP) who have undergone colectomy with ileorectal anastomosis (IRA). Potential risk factors for rectal cancer in this setting are also examined, and recommendations for the choice of surgical procedure are made. The national polyposis registries in Denmark, Finland, The Netherlands, and Sweden included 659 patients undergoing surgery with IRA in 1940-1997. Kaplan-Meier analysis and Cox regression analysis were performed to evaluate cumulative risk, survival, and predictive risk factors. Rectal carcinoma was diagnosed in 47 patients, with a cumulative 40-year risk of 0.32. The cumulative risk according to chronologic age was 0.30 at age 60, and higher in patients undergoing surgery above age 25 (P = 0.0016). Chronologic age was the only independent risk factor (P = 0.0016). The cumulative 5-year survival rate after rectal carcinoma was 0.60. The apc mutation was known in 167 patients, of whom 7 had rectal cancer. The cumulative 40-year risk of secondary proctectomy was 0.70, and higher in patients with a mutation in codon 1250-1500 than outside this region (P = 0.005). However, all 7 rectal cancers were found in the latter group. None of the 18 patients with attenuated FAP (mutation in codon 0-200 or >1500) had a secondary proctectomy. IRA is recommended in (1) young patients with few rectal adenomas and a family history of a mild phenotype and (2) patients with attenuated FAP (a mutation in codon 0-200 or >1500), provided there is acceptance of life-long rectal surveillance. Patients with many rectal polyps and/or a family history of severe polyposis should be offered a restorative proctocolectomy with an ileal pouch-anal anastomosis.
MeSH Terms
- Adenoma
- Adenomatous Polyposis Coli
- Adolescent
- Adult
- Aged
- Aging
- Anastomosis, Surgical
- Child
- Colectomy
- Female
- Humans
- Ileum
- Male
- Middle Aged
- Mutation
- Rectal Neoplasms
- Rectum
- Reoperation
- Risk Factors
- Survival Analysis
The concept of an intrinsic "biological age" or "physiological age" is very important in comparative ecological and evolutionary studies, but its implementation has been problematic. Although many authors have discussed the importance of intrinsic measures of age over the past 75 years, only Reiss (1989 ) has proposed an operational definition in terms of cumulative metabolism; however, Reiss' measure cannot be easily applied to assessing the age of individual organisms. Measurement of the level of accumulation of fluorescent age pigments (particularly lipofuscins) in post-mitotic tissues, which seems to occur at a rate proportional to cumulative metabolism, in principle provides a mechanism for estimating the biological age of individual organisms. This study has shown that brain-tissue FAP levels vary in direct proportion to chronological age and body size within four species of poeciliid fishes, and has documented interspecific differences in rate of accumulation of fluorescent age pigments, differences that seem to be a function of the degrees of relatedness. Rather than proposing that FAP level by itself be used as a measure of biological age, however, I propose that it be used in conjunction with other estimates, such as chronological age and body size, to derive a composite "age factor."
MeSH Terms
- Aging
- Animals
- Body Constitution
- Body Weight
- Brain
- Cyprinodontiformes
- Female
- Fluorescent Dyes
- Lipofuscin
- Male
- Models, Biological
- Pigments, Biological
- Poecilia
- Species Specificity
- Spectrometry, Fluorescence
Human fibroblast activation protein (FAP), a member of the serine prolyl oligopeptidase family, is a type II cell surface glycoprotein selectively expressed by fibroblastic cells in areas of active tissue remodeling, such as the embryonic mesenchyme, areas of wound healing, the gravid uterus, and the reactive stroma of epithelial cancers. Homologues of FAP have been identified in the mouse and Xenopus laevis. FAP is a dual-specificity enzyme that acts as a dipeptidyl peptidase and collagenase in vitro. To explore the role of FAP in vivo, Fap(-/-) mice were generated by homologous recombination. RNase protection analysis and reverse transcription-PCR confirmed the absence of full-length Fap transcripts in mouse embryonic tissues. No FAP protein was detected in Fap(-/-) animals by immunohistochemistry, and no FAP-specific dipeptidyl peptidase activity was found. We report that Fap(-/-) mice are fertile, show no overt developmental defects, and have no general change in cancer susceptibility.
MeSH Terms
- Aging
- Animals
- Antigens, Neoplasm
- Biomarkers, Tumor
- Crosses, Genetic
- Embryo, Mammalian
- Embryo, Nonmammalian
- Embryonic and Fetal Development
- Female
- Fertility
- Fibroblasts
- Gelatinases
- Growth Substances
- Humans
- Male
- Membrane Proteins
- Mesoderm
- Mice
- Mice, Inbred Strains
- Mice, Knockout
- Recombination, Genetic
- Restriction Mapping
- Reverse Transcriptase Polymerase Chain Reaction
- Serine Endopeptidases
- Stem Cells
- Transcription, Genetic
- Xenopus laevis
Familial adenomatous polyposis is a genetically inherited disease with very high risk of colorectal cancer and with a large expression of multiple extracolonic malignancies. In recent years two surgical options are available for the treatment of FAP: total colectomy with ileorectal anastomosis and restorative proctocolectomy with ileoanal reservoir. The preservation of the rectum offers good quality of life and good functional results, but needs an accurate surveillance of the rectal stump and screening for the development of cancer. Restorative proctocolectomy is reserved for patients with large or confluent polyps of the rectum, for older patients and for those who had already had an ileorectal anastomosis and who develops subsequently large adenomas at increased risk for rectal cancer. Prophylactic procedures of surveillance, screening and surgery have reduced in patients at risk the incidence of colorectal cancer. But recently an increased number of malignant extracolonic tumors (gastric cancer, duodenal and periampullary cancer, small intestinal cancer, adrenal and thyroid cancer) and abdominal desmoid tumors, that causes a significant mortality, has been documented. The knowledge of the extracolonic features of FAP suggests a careful follow-up of the patients and the prevention and treatment of upper gastrointestinal cancers and desmoid disease.
MeSH Terms
- Adenomatous Polyposis Coli
- Humans
- Life Expectancy
- Postoperative Complications
- Proctocolectomy, Restorative
Despite the introduction of screening, surveillance, and prophylactic colectomy surgery, patients with familial adenomatous polyposis (FAP) are at risk of dying from other malignancies. In order to quantify this risk and identify the causes of mortality, a retrospective life table analysis was performed on 222 patients with familial adenomatous polyposis who had undergone a total colectomy and ileorectal anastomosis between 1948 and 1990. These FAP patients were compared with an age- and sex-matched group of the general population and a relative risk of dying was calculated. Of 222 patients, 53 have died. In a matched group of the general population the expected number of deaths would be 15.8. The relative risk of dying is therefore 3.35. There has been no significant improvement with time and the relative risk is greatest for female patients. The three main causes of mortality are upper gastrointestinal malignancy, desmoid disease, and perioperative complications. Further research should therefore be aimed at prevention and improved treatment of these in order to improve survival.
MeSH Terms
- Adenomatous Polyposis Coli
- Adolescent
- Adult
- Age Factors
- Aged
- Anastomosis, Surgical
- Colectomy
- Confidence Intervals
- Female
- Follow-Up Studies
- Humans
- Ileum
- Life Expectancy
- Male
- Middle Aged
- Odds Ratio
- Rectum
- Retrospective Studies
- Risk Factors
- Sex Factors
- Survival Rate
The purpose of this investigation was to determine whether vasodilator responses are attenuated and whether vasoconstriction is augmented with age in resistance vessels in the hindlimb of the dog. We examined blood flow (FAF) and pressure (FAP) responses in the femoral arterial system in older (109 /- 8-mo-old) and younger mature (31 /- 3-mo-old) female beagles during pentobarbital anesthesia. Vasodilator responses were evaluated during the intra-arterial administration of acetylcholine (ACh), which produces endothelium-dependent vasodilation, and albuterol, which mediates relaxation in vascular smooth muscle via beta-adrenoceptors. The vasoconstrictor response to phenylephrine (PE), an alpha-adrenergic agonist, was also examined. ACh and albuterol each induced dose-dependent vasodilation in the older and in the younger dogs. Resultant changes in neither FAF nor FAP were affected by age in response to either of these vasodilator substances. Likewise, reductions in femoral vascular resistance (FVR) in response to ACh or to albuterol were not age dependent. Vasodilation following induced hindlimb ischemia resulted in similar increases in FAF in both groups, but produced a greater reduction in FAP in older vs. younger dogs (P = 0.05). Similarly, FVR decreased more in the older beagles (P = 0.02). Vasoconstriction mediated by PE resulted in similar reductions in FAF in both age groups, but the increase in FAP was less at several PE doses in older vs. younger dogs (P < 0.05). However, increases in FVR in response to PE were not statistically different in the younger and older beagles.(ABSTRACT TRUNCATED AT 250 WORDS)
MeSH Terms
- Acetylcholine
- Aging
- Albuterol
- Animals
- Aorta
- Blood Pressure
- Dogs
- Dose-Response Relationship, Drug
- Female
- Femoral Artery
- Hindlimb
- Ischemia
- Muscle, Smooth, Vascular
- Muscles
- Norepinephrine
- Phenylephrine
- Regional Blood Flow
- Renin
- Vascular Resistance
- Vasoconstriction
- Vasodilation
The objective of this investigation was to examine whether fluorescent age pigment (FAP) was associated with the physiological rather than the chronological age of houseflies (Musca domestica) and to determine if the level of physical activity of individual flies was related to their FAP content. Distinction between the physiological age and the chronological age of the flies was made on the basis of flightlessness which occurs prior to death in all houseflies. Flies with shorter life expectancy become flightless earlier. Walking and flying activity of individual flies was measured by radar-Doppler instrumentation developed in this laboratory. The concentration of FAP, determined by fluorimetry, increased with age but the rate of increase was greater in flightless flies than in their flying cohorts of the same age. FAP content of individual flies tended to be greater in flies exhibiting relatively high levels of physical activity. The results of this study suggest that FAP concentration is associated with life expectancy and physical activity of houseflies.
MeSH Terms
- Aging
- Animals
- Fluorescence
- Houseflies
- Male
- Melanins
- Movement
- Pigments, Biological
The patterns of fluorescent age pigment (FAP) accumulation in response to gamma-irradiation were examined in adult male houseflies under conditions of relatively high and low levels of physical activity. Flies were exposed to 0, 20, 40, and 66 kR and their level of physical activity was altered by permitting or restricting flight activity. Under conditions of high activity the mean life span of flies exposed to 20 kR and 40 kR was greater than in the controls. The mean life span of high activity flies exposed to 66 kR and all groups of low activity irradiated flies was less than the control life span. The force of mortality as indicated by Gompertz slope was greater in high activity controls than in unirradiated flies maintained under low activity conditions. Gompertz slope was similar in corresponding high and low activity groups exposed to radiation. Radiation decreased the rate of FAP accumulation in high activity groups, but increased the rate of FAP accumulation under low activity conditions. The low activity control and low activity flies exposed to 20 kR had a lower FAP accumulation than the corresponding high activity groups at 14 days of age. At this age, low activity groups of flies exposed to 40 kR and 66 kR had concentrations of FAP that were similar to the corresponding high activity groups. These results indicate that radiation exposure decreased longevity by causing damage rather than by increasing the rate of aging.
MeSH Terms
- Aging
- Animals
- Dose-Response Relationship, Radiation
- Energy Metabolism
- Gamma Rays
- Houseflies
- Longevity
- Melanins
- Physical Exertion
- Pigments, Biological
The immunoperoxidase method, the autoclave method, and a newly developed alkaline-guanidine method were used to distinguish senile (SSA) and familial types (FAP) of prealbumin-related amyloidosis in formalin-fixed, paraffin-embedded tissue sections. Because all the amyloid deposits of SSA and FAP reacted positively with the antiprealbumin antiserum, a classification of the amyloid fibril proteins of FAP and SSA by immunohistochemistry, using polyclonal anti-prealbumin antisera, was not feasible. Both the senile and familial forms of amyloidosis showed unchanged Congophilia after prolonged autoclaving. In the alkaline-guanidine method, FAP amyloids were resistant to incubation for 2 hours. On the other hand, amyloid deposits of SSA lost the Congophilia and green birefringence with 2 hours' alkaline-guanidine treatment. Therefore, the autoclave method combined with the alkaline-guanidine method will considerably facilitate differentiation of SSA and FAP, without specific antisera.
MeSH Terms
- Aged
- Aging
- Alkalies
- Amyloidosis
- Guanidine
- Guanidines
- Histocytochemistry
- Humans
- Immunochemistry
- Prealbumin
A prealbumin (PA)-like protein was demonstrated in amyloid fibrils both from a patient with senile systemic amyloidosis (SSA) and from a patient in northern Sweden with familial amyloidotic polyneuropathy (FAP). The investigated properties of this protein were similar in the two types of fibrils. The protein had molecular weight, antigenic determinants, and at least one cysteinyl residue in common with the subunit of normal PA. In contrast to normal PA, it contained disulphide-linked subunits and was to some extent bound to the fibril via the cysteinyl residues. The noncovalent forces between its subunits were weaker than in normal PA. It constituted part of the previously described AScl protein of the SSA fibrils. Proteins with lower molecular weight than the PA monomer were major proteins in both SSA and FAP fibrils. These proteins had similar properties in the two kinds of fibril and may be derived from PA. PA in serum from Swedish patients with FAP and SSA was normal with regard to the isoelectric pH of the monomers and tetramers.
MeSH Terms
- Adult
- Aged
- Aging
- Amyloidosis
- Antigen-Antibody Reactions
- Chemical Phenomena
- Chemistry
- Electrophoresis, Polyacrylamide Gel
- Humans
- Isoelectric Focusing
- Male
- Middle Aged
- Molecular Weight
- Peripheral Nervous System Diseases
- Prealbumin
- Serum Amyloid A Protein
- Sweden
Sarcoplasmic reticulum (SR) from winter flounder (Pseudopleuronectes americanus) of various ages was investigated with regard to fluorescent age pigment (FAP), potential of enzymic lipid peroxidation, fatty acid composition, protein pattern and Ca2 -sequestering ability. FAP accumulation, protein pattern and Ca2 -sequestering ability were also evaluated after the SR were incubated in vitro with the peroxidizing cofactors: NADH, ADP and Fe3 . No difference in FAP content was observed in SR isolated from fish of different ages. However, a higher accumulation of FAP in muscle tissue from old fish was observed. A slow but significant increase in FAP in SR was observed when the SR from both young and old fish were incubated with peroxidizing cofactors. It was demonstrated that 4-year-old fish had higher levels of NADH-dependent lipid peroxidation in their SR than 2-year-old fish. No differences in fatty acid composition were observed in the SR of fish aged from 2 to 8 years old. Two species of high-molecular-weight protein were found to increase in SR isolated from aging fish. These species resembled the polymerized proteins derived after incubation of the SR with the peroxidizing cofactors. Ca2 -uptake decreased when the SR was incubated with peroxidizing cofactors, but the results are difficult to interpret since Ca2 -uptake of SR was affected by captive stress.
MeSH Terms
- Aging
- Animals
- Ca(2 ) Mg(2 )-ATPase
- Calcium
- Fatty Acids
- Female
- Flatfishes
- Flounder
- Lipid Peroxides
- Melanins
- Membrane Lipids
- Membrane Proteins
- Pigments, Biological
- Sarcoplasmic Reticulum
We have studied, by immunohistochemical methods using specific antisera, the development of three glycoproteins of human pancreatic secretion: lipase, carboxyl ester hydrolase (CEH) and the P19 protein (precursor of the non glycosylated protein X or "pancreatic thread/stone protein"). We have compared their development to that of trypsinogens (Tgs) and chymotrypsinogen A (ChTgA), as well as to that of FAP (feto acinar pancreatic protein), a glycoprotein associated with the differentiation of human pancreas. Our studies show the characteristic appearance and development of lipase, the immunoreactivity of which appears later (at the 21st week of pregnancy) than it does for Tgs and ChTg (at the 16th week of pregnancy). Moreover, the lipase labelling is first observed in a few acini dispersed in the pancreas and then spreads out progressively to be present in all the acini after the age of 15 days. By contrast, as soon as they appear, Tgs and ChTg are observed uniformly in all acinar cells. The intensities of the lipase, Tgs and ChTg labellings increase greatly at birth. The ontogenesis of CEH does not follow that of lipase but that of Tgs and ChTg. The ontogenesis of P19 is parallel to that of Tgs. As previously observed, FAP presents a maximal immunoreactivity at the 24th-27th weeks of pregnancy, which decreases slowly up until birth.
MeSH Terms
- Aging
- Calcium-Binding Proteins
- Carboxylesterase
- Carboxylic Ester Hydrolases
- Carrier Proteins
- Chymotrypsinogen
- Fetus
- Gestational Age
- Glycoproteins
- Humans
- Immunoenzyme Techniques
- Immunohistochemistry
- Infant
- Infant, Newborn
- Lipase
- Lithostathine
- Pancreas
- Protein Precursors
- Trypsinogen
Thirty-eight patients with familial adenomatous polyposis (FAP) were compared with 19 patients with ulcerative colitis (UC) for differences in illness-related variables, coping styles, psychiatric symptomatology, and intellectual performance. Patients with FAP had significantly less education, longer time since recent surgery, less psychiatric illness, and evidence of less preoccupation with their illness, as compared with UC patients. FAP patients with a positive family history (N = 28) scored significantly lower on both verbal and performance intellectual tests, even when taking education into account, compared with FAP patients without a family history (N = 9). The relevance of these findings to the ongoing monitoring and surveillance of patients with FAP is discussed.
MeSH Terms
- Adaptation, Psychological
- Adenomatous Polyposis Coli
- Adult
- Cognition Disorders
- Colitis, Ulcerative
- Humans
- Intelligence Tests
- Interview, Psychological
- Life Expectancy
- Mental Disorders
- Sick Role
- Surveys and Questionnaires