Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “aging hallmarks”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 181 records · Page 10Linked to original sources

Reduced primary T lymphopoiesis in 3-month-old lurcher mice: sign of premature ageing of thymus?

OBJECTIVE: The nervous, endocrine and immune systems are functionally interconnected so that they may form a complex metasystem. Abnormalities within the neuroendocrine compartment can thus affect immune mechanisms and vice versa. The Lurcher-type mutation in mice has a profound impact on brain development in both homozygous and heterozygous individuals, which is followed by immune system changes. We investigated whether macroscopic changes in the thymus size were associated with an altered thymocyte development or with changes in peripheral T cell subset distribution. METHODS: CD3, CD4 and CD8 expressions on thymocytes and peripheral T cells were compared with those in wild-type and Lurcher heterozygous C3H mice using surface immunophenotyping and flow cytometry. Galanthus nivalis agglutinin binding to thymocytes was measured at the same time. RESULTS: While no differences between experimental groups were observed in 1-month-old mice, a critical reduction of numbers of thymocytes and namely double-positive cells occurred before the age of 3 months in Lurcher mice, which was accompanied by thymus involution. Interestingly, this was not accompanied by significant differences in major T subset proportions in the peripheral lymphatic tissue. CONCLUSIONS: We interpret our observations as hallmarks of premature thymus ageing in heterozygous Lurcher mice with only a marginal effect in the periphery in early adulthood.

Aging↗

Aging, neuroendocrine function, and osteoporosis.

Osteoporosis may occur in both women and men. Osteoporosis is defined as age-related involutional bone loss that exceeds that observed in the normal population of the same age and sex. The hallmark of the disease is a reduction in mineralized bone matrix. Osteoporosis is a multifactorial disease and can be considered the result of impaired coordination of bone remodeling ("resorption/formation coupling"). This review describes the role of systemic hormones and local acting mediators, including neuropeptides and neurotransmitters, in the control of bone turnover. Furthermore the significance of age-related (neuro)endocrine dysfunction for bone remodeling and consequently for development of osteoporosis is discussed.

Aging↗

Functional deficits in basal ganglia of children with attention-deficit/hyperactivity disorder shown with functional magnetic resonance imaging relaxometry.

Attention-deficit/hyperactivity disorder is a highly heritable and prevalent neuropsychiatric disorder estimated to affect 6% of school-age children. Its clinical hallmarks are inattention, hyperactivity and impulsivity, which often respond substantially to treatment with methylphenidate or dextroamphetamine. Etiological theories suggest a deficit in corticostriatal circuits, particularly those components modulated by dopamine. We developed a new functional magnetic resonance imaging procedure (T2 relaxometry) to indirectly assess blood volume in the striatum (caudate and putamen) of boys 6-12 years of age in steady-state conditions. Boys with attention-deficit/hyperactivity disorder had higher T2 relaxation time measures in the putamen bilaterally than healthy control subjects. Relaxation times strongly correlated with the child's capacity to sit still and his accuracy in accomplishing a computerized attention task. Daily treatment with methylphenidate significantly changed the T2 relaxation times in the putamen of children with attention-deficit/hyperactivity disorder, although the magnitude and direction of the effect was strongly dependent on the child's unmedicated activity state. There was a similar but nonsignificant trend in the right caudate. T2 relaxation time measures in thalamus did not differ significantly between groups, and were not affected by methylphenidate. Attention-deficit/hyperactivity disorder symptoms may be closely tied to functional abnormalities in the putamen, which is mainly involved in the regulation of motor behavior.

Attention Deficit Disorder with Hyperactivity↗

Ultraviolet-B irradiation and matrix metalloproteinases: from induction via signaling to initial events.

Effects of sunlight have fascinated researchers for decades because nearly every living thing on earth is likely to be exposed to sunlight and the ultraviolet (UV) fraction of it. In addition to detrimental long-term effects such as immunosuppression and skin cancer, premature aging of the skin (photoaging) is a well-documented consequence of exposure to UVA and UVB. Photoaged skin is biochemically characterized by an overgrowth of abnormal elastic fibers in the dermis and by a dramatic decrease of distinct collagen types. Ultraviolet irradiation induces delayed UV-responsive genes, among them matrix metalloproteinases, which degrade macromolecules of the extracellular matrix, a hallmark in carcinogenesis and aging. We are interested in UVB-triggered initial events and in subsequent signaling resulting in enhanced expression of two major members of the matrix metalloproteinase family, the interstitial collagenase (MMP-1) and stromelysin-1 (MMP-3), in human dermal fibroblasts. Especially, these skin cells play a central role in connective tissue breakdown in photoaging and as stromal cells in tumor invasion and metastasis by means of their capability to produce matrix metalloproteinases. In this review, we will focus on UVB-triggered induction of matrix metalloproteinases, the so far identified components of the UVB-modulated signal transduction pathway(s), and the UVB irradiation-associated generation of reactive oxygen species (ROS). Finally, a potentially novel aspect in UVB irradiation-mediated expression of interstitial collagenase and stromelysin-1-namely, the involvement of reactive nitrogen species (RNS)-is discussed.

Gene Expression Regulation, Enzymologic↗

Women with a reduced ovarian complement may have an increased risk for a child with Down syndrome.

Advanced maternal age is the only well-established risk factor for trisomy 21 Down syndrome (DS), but the basis of the maternal-age effect is not known. In a population-based, case-control study of DS, women who reported surgical removal of all or part of an ovary or congenital absence of one ovary were significantly more likely to have delivered a child with DS than were women who did not report a reduced ovarian complement (odds ratio 9.61; 95% confidence interval 1.18-446.3). Because others have observed that women who have had an ovary removed exhibit elevated levels of FSH and similar hallmarks of advanced maternal age, our finding suggests that the physiological status of the ovary is key to the maternal-age effect. In addition, it suggests that women with a reduced ovarian complement should be offered prenatal diagnosis.

Adolescent↗

Naturopathic treatment for ear pain in children.

OBJECTIVE: Otitis media is 1 of the most frequent diseases of early infancy and childhood and 1 of the most common reasons for children to visit a physician. In the past 2 decades, there has been a substantial increase in the diagnosis of otitis media worldwide. In the United States, 93% of all children have had at least 1 episode of acute otitis media (AOM) by 7 years of age. Otalgia is the hallmark of AOM. Most affected children either complain of earache or manifest behavior that the parents interpret as indicating ear pain. Treatment of the ear pain early in the course of AOM decreases both parental anxiety and the child's discomfort and accelerates the healing process. The objective of this study was to determine the efficacy and tolerability of naturopathic versus traditional treatment for the management of otalgia commonly associated with AOM in children. METHODS: The study was designed as a double-blind trial in an outpatient community clinic. A total of 171 children who were aged 5 to 18 years and had otalgia and clinical findings associated with middle-ear infection were studied. The children were randomly assigned to receive treatment with Naturopathic Herbal Extract Ear Drops (NHED) or anesthetic ear drops, with or without amoxicillin. On enrollment, the children were assigned by computer-numbered randomization to receive NHED (contents: allium sativum, verbascum thapsus, calendula flores, hypericum perfoliatum, lavender, and vitamin E in olive oil) 5 drops 3 times daily, alone (group A) or together with a topical anesthetic (amethocaine and phenazone in glycerin) 5 drops 3 times daily (group B), or oral amoxicillin 80 mg/kg/d (maximum 500 mg/dose) divided into 3 doses with either NHED 5 drops 3 times daily (group C) or topical anesthetic 5 drops 3 times daily (group D). A double-blind design was used, and all ear drops were placed in identical bottles. Treatment was initiated by the nurse in all cases. A single physician (M.S.) evaluated and treated all of the patients included in the study and recorded all of the data. The presence or absence of ear pain was assessed over 3 days with a visual analog scale. Ear pain was assessed by a specially devised observational instrument based on previous reports. One side of the instrument consisted of a linear numbered scale, from 1 (no pain) to 10 (worst possible pain), and a corresponding color scale, ranging from blue to dark red. The reverse side contained a scale of 5 facial expressions, ranging from broad smile (no pain) to a sad and crying face (worst possible pain), and a corresponding color scale, ranging from blue to dark red. RESULTS: There were no significant between-group differences in patient age or gender, degree of fever, main symptoms, associated symptoms, and severity or laterality of acute otitis media. Each group had a statistically significant improvement in ear pain over the course of the 3 days. Patients who were given ear drops alone had a better response than patients who were given ear drops together with amoxicillin. Results were better in the NHED group than in the controls. Nevertheless, the findings indicated that the pain was mostly (80%) self-limited and could be explained simply by the time elapsed. The American Academy of Otolaryngology-Head and Neck Surgery guidelines recommend topical medications as the first line of treatment for ear pain in the absence of systemic infection or serious underlying disease. Because no evidence was found that systemic antibiotics alone improved treatment outcome, if antibiotics do not change the natural course of otitis media, then the main goal of treatment, as in the present study, should be to alleviate the ear pain. The alternative, naturopathic herbal extract medications, may offer many new possibilities in the management of ear pain associated with AOM. Primary care physicians should be aware that at least 10% of their patients may have tried 1 or more forms of alternative/complementary medicine before presenting for consultation. As it was widely reported in the medical literature, these herb, these herbal extracts have the potential to meet all of the requirements of appropriate medication that could be routinely used in the pediatric patient, namely in vitro bacteriostatic and bacteriocidal activity against common pathogens, immunostimulation ability, antioxidant activity, and anti-inflammatory effects. They are also well-absorbed with good penetration into the tissue surrounding the tympanic membrane. They have been found to enhance local immunologic activity. Finally, herbal extracts are well-tolerated (owing to their long elimination time), easy to administer, and less expensive than the new antibiotics. There are no documented side effects. On the basis of our findings that the group with the most significant treatment effects (NHED with topical anesthetic) explained only 7.3% of the total pain reduction, we propose that sometimes the general practitioner or pediatrician needs to give the human body a chance to repair itself. Nevertheless, if the physician believes that there is an indication for some treatment, especially if the parents are anxious, then a local treatment such as one used in our study might be adequate. CONCLUSIONS: This study suggests that in cases of ear pain caused by AOM in children in which active treatment, besides a simple 2- to 3-day waiting period, is needed, an herbal extract solution may be beneficial. Concomitant antibiotic treatment is apparently not contributory.

Acute Disease↗

Increased susceptibility to sporadic Parkinson's disease by a certain combined alpha-synuclein/apolipoprotein E genotype.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders affecting about 1% of Western populations older than age 50. The pathological hallmark of PD are Lewy bodies, that is, intracytoplasmic inclusion bodies in affected neurons of the substantia nigra. Recently, alpha-synuclein (alpha-SYN) has been identified as the main component of Lewy bodies in sporadic PD, suggesting involvement in neurodegeneration via protein accumulation. The partially overlapping pathology of PD and Alzheimer's disease, as well as striking structural similarities of alpha-SYN and apolipoprotein E, which is a major risk factor for late-onset Alzheimer's disease, prompted us to investigate the influence of different alpha-SYN and apolipoprotein E alleles for developing sporadic PD. We performed association studies in 193 German PD patients and 200 healthy control subjects matched for age, sex, and origin. A polymorphism in the promoter region of the alpha-SYN gene (NACP-Rep1) as well as of the closely linked DNA markers D4S1647 and D4S1628 revealed significant differences in the allelic distributions between PD patients and the control group. Furthermore, the Apo epsilon4 allele but not the Th1/E47 promoter polymorphism of the apolipoprotein E gene was significantly more frequent among early-onset PD patients (age at onset, <50 years) than in late-onset PD. Regarding the combination of the Apo epsilon4 allele and allele 1 of the alpha-SYN promoter polymorphism, a highly significant difference between the group of PD patients and control individuals has been found, suggesting interactions or combined actions of these proteins in the pathogenesis of sporadic PD. PD patients harboring this genotype have a 12.8-fold increased relative risk for developing PD during their lives.

Aged↗

Protective effects of estrogen in a rat model of age-related cataracts.

Women have a higher incidence of cataracts, and epidemiologic data suggest that the increased risk may be caused by a lack of estrogen in postmenopausal years. We have examined the effects of estrogen on methylnitrosourea (MNU)-induced cataractogenesis in Sprague-Dawley rats. Animals were ovariectomized, injected with MNU, and treated with estradiol or estrone by a continuous-release, subcutaneous Silastic implant, or they received an empty Silastic implant (no hormone). In the no-hormone group, rats developed opaque lenses approximately 6 months after MNU treatment. By 8 months, 74% (14/19) of the no-hormone rats had evident opacity in one or both eyes by simple gross inspection; 58% (22/38) of the eyes in this group were opaque. Estradiol or estrone treatment reduced the incidence of cataractous eyes to 12% or 25%, respectively. Lenses were examined under a dissecting microscope for light transmission. The lenses of the group treated with no hormone had light transmission of 26% +/- 9.2%, whereas lenses from the estradiol-treated animals had light transmission of 72% +/- 5.8%. Histological examination revealed that the anterior cortices of the opaque lenses were disrupted and showed the hallmark signs of age-related cataracts; in addition, some eyes that appeared clear by macroscopic examination showed the early histologic signs of cataractogenesis. It was demonstrated with reverse transcription-PCR that lens cells express both alpha and beta types of estrogen receptor, suggesting that the protective effects of the hormones may be a direct, receptor-mediated phenomenon. Thus, the MNU-treated, ovariectomized rat serves as a model for age-related cataractogenesis, and observation of a clear protective effect of estrogens in this system supports the implications of epidemiologic data.

Aging↗

Matrix gene expression and decompensated heart failure: the aged SHR model.

Impaired functional performance despite hypertrophic enlargement, and an excessive accumulation of extracellular matrix, are hallmarks of the decompensated failing heart. Age is the leading risk factor for heart failure, and there is evidence suggesting that a number of age-associated changes in the cardiac phenotype predispose the heart to failure. The spontaneously hypertensive rat (SHR) exhibits compensated cardiac hypertrophy followed by a transition to heart failure in the last quartile of the lifespan, and thus provides a useful model of the transition from stable compensated hypertrophy to decompensated heart failure in the context of aging. The transition to failure in the SHR is accompanied by marked changes in the expression of an array of genes in the heart, including increased expression of a number of genes associated with the extracellular matrix. Drug treatments that prevent or reverse matrix gene expression in the SHR heart improve myocardial function and survival. The aged SHR model of decompensated heart failure has provided insight into the role of the extracellular matrix in the transition to failure, and can be useful to further investigate the mechanistic bases of heart failure, as well as to evaluate the potential efficacy of novel therapeutic approaches to the treatment of heart failure.

Aging↗

S100 proteins in Corpora amylacea from normal human brain.

Corpora amylacea (C.A.) also named polyglucosan bodies (P.B.) are one of the hallmarks of normal brain aging. Although their functions are not yet clear, C.A. increase in number in patients suffering from neurodegenerative diseases. C.A. contain 88% of hexoses and 4% of proteins. Most of the proteins in C.A. are aging or stress proteins such as heat shock proteins, ubiquitinated proteins and advanced glycation end products which are also proinflammatory products. Stimulated by the potential role played by some S100 proteins in the inflammatory process which may be triggered in C.A., we investigated, by immunohistochemistry, the presence of different S100 proteins (S100A1, S100A2, S100A3, S100A4, S100A5, S100A6, S100A8, S100A9, S100A12 and S100B) in C.A. from normal human brain. Among the ten S100 proteins analyzed, nine (S100A) were detected in C.A. Three S100 proteins (S100A8, S100A9, S100A12) which are highly expressed in activated macrophages and used as inflammatory markers were detected in C.A. S100A8 was, in addition, found in thick neuronal processes from the pons. One (S100B) could not be found in C.A. although it was highly expressed in astrocytes. In C.A., the staining intensity was estimated by computer-assisted microscopy and gave the following order: S100A1 congruent withS100A8 congruent with S100A9>S100A5> or =S100A4>S100A12>S100A6> S100A2=S100A3. The potential inflammatory role played by S100 proteins in C.A. is discussed.

Adult↗

A new view of diabetic retinopathy: a neurodegenerative disease of the eye.

Diabetic retinopathy (DR) is a common complication of diabetes and a leading cause of legal blindness in working-age adults. The clinical hallmarks of DR include increased vascular permeability, leading to edema, and endothelial cell proliferation. Much of the research effort has been focused on vascular changes, but it is becoming apparent that other degenerative changes occur beyond the vascular cells of the retina. These include increased apoptosis, glial cell reactivity, microglial activation, and altered glutamate metabolism. When occurring together, these changes may be considered as neurodegenerative and could explain some of the functional deficits in vision that begin soon after the onset of diabetes. This review will present the current evidence that neurodegeneration of the retina is a critical component of DR. There are two basic hypotheses that account for loss of cells in the neural retina. First, the loss of blood-retinal barrier integrity, which initially manifests as an increase in vascular permeability, causes a failure to control the composition of the extracellular fluid in the retina, which in turn leads to edema and neuronal cell loss. Alternatively, diabetes has a direct effect on metabolism within the neural retina, leading to an increase in apoptosis, which in turn causes breakdown of the blood-retinal barrier. It is not clear which hypothesis will be found to be correct, and, in fact, it is likely that vascular permeability and neuronal apoptosis are closely linked components of DR. However, the gradual loss of neurons suggests that progress of the disease is ultimately irreversible, since these cells cannot usually be replaced. In light of this possibility, new treatments for DR should be preventive in nature, being implemented before overt clinical symptoms develop. While vascular permeability is the target that is primarily considered for new treatments of DR, evidence presented here suggests that apoptosis of neurons is also an essential target for pharmacological studies. The vision of people with diabetes will be protected only when we have discovered a means to prevent the gradual but constant loss of neurons within the inner retina.

Animals↗

Stable overexpression of manganese superoxide dismutase in mitochondria identifies hydrogen peroxide as a major oxidant in the AP-1-mediated induction of matrix-degrading metalloprotease-1.

Reactive oxygen species (ROS) are important second messengers for the induction of several genes in a variety of physiological and pathological conditions. Here we addressed the question of whether isolated, unbalanced overexpression of the antioxidant enzyme manganese superoxide dismutase (Mn-SOD) may modulate signal transduction cascades, finally leading to connective tissue degradation, a hallmark in carcinogenesis and aging. Therefore, we generated stably Mn-SOD-overexpressing fibroblasts with an up to 4. 6-fold increase in Mn-SOD activity. The Mn-SOD-overexpressing cells revealed specific resistance to the superoxide anion (O-(2))-generating agent paraquat, whereas no resistance to UVA-generated oxidative stress was found. Treatment of the Mn-SOD-overexpressing cells with various ROS-generating systems resulted (due to the enhanced dismutation of superoxide anion to hydrogen peroxide) in an up to 9.5-fold increase in matrix-degrading metalloprotease-1 (MMP-1) mRNA levels. A similar increase in MMP-1 mRNA was also seen when the intracellular H(2)O(2) concentration was increased by the inhibition of different H(2)O(2)-detoxifying pathways. Furthermore, prooxidant conditions led to a strong induction of c-jun and c-fos mRNA levels resulting in a 4-fold higher transactivation of the transcription factor AP-1 in the Mn-SOD-overexpressing cells. Collectively, we have found that enhanced Mn-SOD activity, via an unbalanced H(2)O(2) overproduction and detoxification, induces MMP-1 mRNA levels, and this effect is at least partly mediated by the DNA recognition sequence AP-1.

Cell Line↗

Prevention of hypertension.

This review summarizes papers and reports published during the past year that contribute important knowledge or perspectives about prevention of elevated arterial blood pressure. Emphasis is on controlled intervention trials, particularly the large, multicenter Trials of Hypertension Prevention-Phase I, but all relevant randomized trials known to the author are included. Observational epidemiologic studies that are cross-sectional, eg, the INTERSALT study and the US Pitt County Study, or longitudinal, eg, the large Health Professionals Followup Study and the National Health and Nutrition Examination Survey (I) Epidemiologic Followup Study, are also discussed. The recent evidence, when viewed in the context of the previously accumulated literature, supports the recommendations of two recent expert reports to the effect that 1) much knowledge is available to help avoid the rise of blood pressure with age that is the hallmark of the epidemic of hypertension in industrialized societies, and 2) efforts should be particularly directed toward control of obesity, increased physical activity, reduced salt intake, and moderation of alcohol use.

Diet↗

The possible role of tissue-type plasminogen activator (tPA) and tPA blockers in the pathogenesis and treatment of Alzheimer's disease.

Alzheimer's disease (AD) is the leading cause of cognitive decline in aged individuals. The pathological hallmarks of AD include the formation of neurofibrillary tangles, along with senile plaques that are mainly composed of the amyloid-beta (Abeta) peptide. Several lines of evidence implicate the tPA/plasmin system in AD. One type of cell death observed in AD is excitotoxic neuronal damage, and the tPA/plasmin system participates in excitotoxic cell death. Recent in vitro experiments report that the addition of aggregated Abeta peptide to primary cortical neurons leads to the up-regulation of tPA mRNA expression. Additionally, plasmin (activated by tPA) attenuates Abeta neurotoxicity by degrading the peptide and rendering it inactive. However, there is no evidence to demonstrate an in vivo contribution of the tPA/plasmin system in AD. We are currently examining the effects of the tPA/plasmin system on the deposition and toxicity of the Abeta peptide with in vivo paradigms of AD. We hope to define the contribution of the tPA/plasmin system in the development of AD pathology.

Alzheimer Disease↗

Leptin enhances the calcification of vascular cells: artery wall as a target of leptin.

Leptin, the product of the ob gene, regulates food intake, energy expenditure, and other physiological functions of the peripheral tissues. Leptin receptors have been identified in the hypothalamus and in extrahypothalamic tissues. Increased circulating leptin levels have been correlated with cardiovascular disease, obesity, aging, infection with bacterial lipopolysaccharide, and high-fat diets. All these conditions have also been correlated with increased vascular calcification, a hallmark of atherosclerotic and age-related vascular disease. In addition, the differentiation of marrow osteoprogenitor cells is regulated by leptin. Thus, we hypothesized that leptin may regulate the calcification of vascular cells. In this report, we tested the effects of leptin on a previously characterized subpopulation of vascular cells that undergo osteoblastic differentiation and calcification in vitro. When treated with leptin, these calcifying vascular cells had a significant 5- to 10-fold increase in alkaline phosphatase activity, a marker of osteogenic differentiation of osteoblastic cells. Prolonged treatment with leptin enhanced the calcification of these cells, further supporting the pro-osteogenic differentiation effects of leptin. Furthermore, the presence of the leptin receptor on calcifying vascular cells was demonstrated using reverse transcriptase polymerase chain reaction, immunocytochemistry, and Western blot analysis. We also identified the presence of leptin receptor in the mouse artery wall, localized to subpopulations of medial and adventitial cells, and the expression of leptin by artery wall cells and atherosclerotic lesions in mice. Taken together, these results suggest that leptin regulates the osteoblastic differentiation and calcification of vascular cells and that the artery wall may be an important peripheral tissue target of leptin action.

Alkaline Phosphatase↗

Angiotensin II augments advanced glycation end product-induced pericyte apoptosis through RAGE overexpression.

Advanced glycation end product (AGE)-their receptor (RAGE) and angiotensin II (AII) are implicated in diabetic retinopathy. However, a crosstalk between the two is not fully understood. In vivo, AGE injection stimulated RAGE expression in the eye of spontaneously hypertensive rats, which was blocked by an AII-type 1 receptor blocker, telmisartan. In vitro, AII-type 1 receptor-mediated reactive oxygen species generation elicited RAGE gene expression in pericytes through NF-kappaB activation. Further, AII augmented AGE-induced pericyte apoptosis, the earliest hallmark of diabetic retinopathy. Our present study may implicate a crosstalk between AGE-RAGE system and AII in diabetic retinopathy.

Angiotensin II↗

Aging exacerbates neointimal formation, and increases proliferation and reduces susceptibility to apoptosis of vascular smooth muscle cells in mice.

OBJECTIVES: In response to injury, aging mediates exaggerated neointimal formation, the pathologic hallmark of obliterative vascular diseases. We assessed the development of neointima in a model of mechanical vascular injury in aging mice (18 months old) and young mice (2 months old). To investigate the mechanisms by which aging affects neointimal formation, we also carried out a set of in vitro studies to characterize the biologic properties of vascular smooth muscle cells (VSMCs) derived from aging and young mice. METHODS: Aging and young mice were subjected to wire injury to the carotid artery. Four weeks later injured arteries were harvested, and neointimal formation was histologically assessed. The profiles of angiogenesis-related genes between aortic VSMCs derived from aging and young mice were compared with complementary DNA arrays. Expression of platelet-derived growth factor receptor-alpha (PDGFR-alpha) and proliferation in response to platelet-derived growth factor-BB (PDGF-BB) by VSMCs were assessed. Susceptibility to apoptosis in aging and young VSMCs in response to nitric oxide and serum starvation was investigated. In addition, the level of apoptosis in neointimal VSMCs (by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay) was compared between aging and young animals. RESULTS: When compared with young mice, aging mice exhibited exaggerated neointimal formation (intima-media ratio, 1.17 +/- 0.57 vs 0.49 +/- 0.16; P < .0001). Aging VSMCs expressed higher levels of PDGFR-alpha (12.0% +/- 2.7% vs 3.2 +/- 0.67%; P = .034) and greater proliferative response (4-fold increase) to PDGF-BB, compared with young VSMCs. However, aging VSMCs were less susceptible to apoptosis when subjected to serum starvation (75% less) and exposure to nitric oxide (50% less). Furthermore, there was more apoptosis in the neointima of young arteries than in their aging counterparts (8.75% +/- 3.3% vs 2.8% +/- 1.9; P = .021). CONCLUSIONS: Age-dependent increases in PDGFR-alpha may alter VSMC proliferation, and when coupled with resistance to apoptosis could contribute to exaggerated neointima formation in aging animals. Of significance, our findings in the mouse will enable application of abundant molecular tools afforded by this species to further dissect the mechanisms of exaggerated neointimal formation associated with aging. CLINICAL RELEVANCE: Neointimal formation is the pathologic hallmark of obliterative vascular diseases, including primary atherosclerosis, post stent restenosis, graft occlusion after vascular bypass procedures, and transplant allograft vasculopathy. Aging is an independent risk factor for development of cardiovascular diseases, and aging exaggerates neointimal formation after vascular injury. Understanding the mechanisms responsible for this phenomenon may facilitate prevention or provide new therapies for vascular occlusive diseases, which are so prevalent in the aging population. Our ability to reproduce the model in the mouse will no doubt facilitate such understanding.

Aging↗

Effects of xerosis and ageing on epidermal proliferation and differentiation.

The hallmarks of dry skin (xerosis) are scaliness and loss of elasticity. Decreased hydration and a disturbed lipid content of the stratum corneum are also well-known features. The frequency of dry skin increases with ageing. The aim of this study was to examine if these known features of dry skin are related to changes in epidermal proliferation and differentiation. In addition, age-related changes in normal and in dry skin were examined: 62 volunteers were divided by clinical grading and biophysical measurements into groups with young/normal, young/dry, aged/normal and aged/dry skin. Biopsy samples from the lower legs (most severe dryness) were examined by two-dimensional gel electrophoresis and by immunohistochemistry for epidermal proliferation, epidermal keratins and cornified envelope proteins. There was a slight increase in proliferation in both groups with dry skin compared with normal skin of the corresponding age. In aged/normal compared with young/normal skin there was a significant decrease in proliferation. However, epidermal proliferation was the same in aged/dry skin as in young/normal skin. For epidermal differentiation, an age-independent decrease of keratins K1 and K10 and an associated increase in the basal keratins K5 and K14 was detected in dry skin. There was also an age-independent premature expression of the cornified envelope protein involucrin. In contrast, loricrin expression was not influenced by dry skin conditions. In summary, epidermal proliferation was significantly decreased in aged/normal compared with young/normal skin. Dry skin showed significant changes in the epidermal expression of basal and differentiation-related keratins, and a premature expression of involucrin irrespective of age.

Adult↗