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Results for “replicative lifespan”

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PubMed2005

Infectivity enhanced, hTERT promoter-based conditionally replicative adenoviruses are useful for SCLC treatment.

Treatment of advanced small-cell lung cancer (SCLC) remains one of the major challenges in current medicine because of the high morbidity and mortality of the disease. Advanced stage lung cancer is refractory to conventional therapies and it also has an extremely poor prognosis. As a result, new therapeutic approaches are needed. Telomere maintenance to the regulation of replicative lifespan strongly implies that alterations in telomere biology play an important role during malignant transformation. Cancers that exhibit high levels of telomerase activity, such as all of the SCLC, were examined in a previous study. In this study, we turned the expression of human telomerase reverse transcriptase (hTERT) by tumors to a therapeutic advantage using a conditionally replication-competent adenovirus (CRAd) in which the expression of E1 (early region 1) is controlled by the hTERT promoter. This virus achieved good levels of viral replication in SCLC cells and induced a substantial anticancer effect in vitro and in vivo. As a further enhancement, the cancer cell killing effect was improved with a tropism modification of the virus to express the knob domain of Ad3 (serotype 3 adenovirus), and this improved infectivity for cancer cells. Conversely, the hTERT promoter has low activity in normal tissues, and the CRAd caused no damage to normal lung fibroblast cells. Since the telomerase activity is common in many types of cancers, these CRAds may be applicable to a wide range of tumors. We concluded that the use of hTERT promoter-based CRAds may be a potentially effective strategy for cancer treatment.

Adenoviridae↗

PubMed1981

Aging in vitro and D-glucose uptake kinetics of diploid human fibroblasts.

By use of a rapid technique, initial rates of D-glucose transport were obtained during the lifespan in vitro of a commercially available strain of human embryo lung fibroblasts (Flow 2000). The apparent Km of the D-glucose carrier did not change during senescence in vitro: x = 1.8 mM (range 1.3-2.3) in phase II, x = 1.8 mM (range 1.5-2.2) in phase III. Transport rates remained constant in stationary phase II cultures, which had completed between 30% and 80% of their replicative lifespan. A wide variation, however, was observed in terminally differentiated cells (phase III), which showed a two- to threefold increase in average cell size and protein content. In some senescent cultures, glucose transport calculated on a per cell basis was also two- to threefold increased, while it was strongly decreased (-75%) in others. When calculated per unit of cell water, protein, and surface area, respectively, transport rates in phase III cultures ranged from values established for stationary phase II cultures down to very low values. Detaching cells flushed off from senescent cultures did not show measurable rates of glucose transport into the inulin impermeable cell space. Present evidence argues against the idea that an impairment of D-glucose transport might precede loss of replicative potential in aging human fibroblasts. Instead our data indicate that the transport capacity of cell membrane finally decreases during postreplicative senescence in terminally differentiated cells.

Biological Transport↗

PubMed2003

Telomeres and telomerase in aging, regeneration and cancer.

The finding that telomere shortening limits the replicative lifespan of primary human cells has fueled speculations that telomere shortening plays a role during aging and regeneration of tissues in vivo. Support for this hypothesis comes from studies showing telomere shortening in a variety of human tissues as a consequence of aging and chronic disease. Studies in telomerase-deficient mice have given first experimental support that telomere shortening limits the replicative potential of organs and tissues in vivo and have identified telomerase as a promising target to treat regenerative disorders induced by telomere shortening. A potential downside of such an approach could be the development of malignant tumors, which has been linked to reactivation of telomerase in human cancers. In telomerase-deficient mice, telomere shortening showed a dual role in tumorigenesis, enhancing the initiation of tumors by induction of chromosomal instability but inhibiting tumor progression by induction of DNA-damage responses. The success in using telomerase activation for the treatment of regenerative disorders could depend on which of the mechanisms of telomere shortening is dominantly effecting carcinogenesis.

Animals↗

PubMed1980

Retesting the commitment theory of cellular aging.

The commitment theory of human fibroblast aging predicts that 55 percent of cells will be nondividing at the middle to late stages of the replicative lifespan; in the present study, however, fewer than 10 percent were nondividing. The fact that no immortal diploid cells have yet been reported is also at odds with the theory. Available data on the variable life-span of clones and mass cultures, the dependence of longevity on population size, and the predominance of certain cell types at termination of a culture are compatible with simpler theories, which support the idea that the limited replicative life-span of diploid fibroblasts is a valid model for organismic aging.

Cell Differentiation↗

PubMed2005

Potential involvement of oxidative stress in cartilage senescence and development of osteoarthritis: oxidative stress induces chondrocyte telomere instability and downregulation of chondrocyte function.

Oxidative stress leads to increased risk for osteoarthritis (OA) but the precise mechanism remains unclear. We undertook this study to clarify the impact of oxidative stress on the progression of OA from the viewpoint of oxygen free radical induced genomic instability, including telomere instability and resulting replicative senescence and dysfunction in human chondrocytes. Human chondrocytes and articular cartilage explants were isolated from knee joints of patients undergoing arthroplastic knee surgery for OA. Oxidative damage and antioxidative capacity in OA cartilage were investigated in donor-matched pairs of intact and degenerated regions of tissue isolated from the same cartilage explants. The results were histologically confirmed by immunohistochemistry for nitrotyrosine, which is considered to be a maker of oxidative damage. Under treatment with reactive oxygen species (ROS; 0.1 micromol/l H2O2) or an antioxidative agent (ascorbic acid: 100.0 micromol/l), cellular replicative potential, telomere instability and production of glycosaminoglycan (GAG) were assessed in cultured chondrocytes. In tissue cultures of articular cartilage explants, the presence of oxidative damage, chondrocyte telomere length and loss of GAG to the medium were analyzed in the presence or absence of ROS or ascorbic acid. Lower antioxidative capacity and stronger staining of nitrotyrosine were observed in the degenerating regions of OA cartilages as compared with the intact regions from same explants. Immunostaining for nitrotyrosine correlated with the severity of histological changes to OA cartilage, suggesting a correlation between oxidative damage and articular cartilage degeneration. During continuous culture of chondrocytes, telomere length, replicative capacity and GAG production were decreased by treatment with ROS. In contrast, treatment with an antioxidative agent resulted in a tendency to elongate telomere length and replicative lifespan in cultured chondrocytes. In tissue cultures of cartilage explants, nitrotyrosine staining, chondrocyte telomere length and GAG remaining in the cartilage tissue were lower in ROS-treated cartilages than in control groups, whereas the antioxidative agent treated group exhibited a tendency to maintain the chondrocyte telomere length and proteoglycan remaining in the cartilage explants, suggesting that oxidative stress induces chondrocyte telomere instability and catabolic changes in cartilage matrix structure and composition. Our findings clearly show that the presence of oxidative stress induces telomere genomic instability, replicative senescence and dysfunction of chondrocytes in OA cartilage, suggesting that oxidative stress, leading to chondrocyte senescence and cartilage ageing, might be responsible for the development of OA. New efforts to prevent the development and progression of OA may include strategies and interventions aimed at reducing oxidative damage in articular cartilage.

Aged↗

PubMed2003

The impact of brewing yeast cell age on fermentation performance, attenuation and flocculation.

Individual cells of the yeast Saccharomyces cerevisiae exhibit a finite replicative lifespan, which is widely believed to be a function of the number of divisions undertaken. As a consequence of ageing, yeast cells undergo constant modifications in terms of physiology, morphology and gene expression. Such characteristics play an important role in the performance of yeast during alcoholic beverage production, influencing sugar uptake, alcohol and flavour production and also the flocculation properties of the yeast strain. However, although yeast fermentation performance is strongly influenced by the condition of the yeast culture employed, until recently cell age has not been considered to be important to the process. In order to ascertain the effect of replicative cell age on fermentation performance, age synchronised populations of a lager strain were prepared using sedimentation through sucrose gradients. Each age fraction was analysed for the ability to utilise fermentable sugars and the capacity to flocculate. In addition cell wall properties associated with flocculation were determined for cells within each age fraction. Aged cells were observed to ferment more efficiently and at a higher rate than mixed aged or virgin cell cultures. Additionally, the flocculation potential and cell surface hydrophobicity of cells was observed to increase in conjunction with cell age. The mechanism of ageing and senescence in brewing yeast is a complex process, however here we demonstrate the impact of yeast cell ageing on fermentation performance.

Alcian Blue↗

PubMed2003

Growth and differentiation of rat bone marrow stromal cells: does 5-azacytidine trigger their cardiomyogenic differentiation?

OBJECTIVE: The potential use of bone marrow stromal cells (MSCs) as a cellular therapy for chronic cardiac diseases relies on the ability of the cell to replicate extensively in vitro and to give rise to myogenic cells that can replace the damaged cardiomyocytes. For this reason the present study investigated the replication lifespan and chemical-induced cardiomyogenic differentiation of rat MSCs in vitro. METHODS: The primary and the successively passaged Wistar rat MSCs were exposed to different concentrations (3, 5 and 10 microM) of 5-azacytidine using different methods (single- or repeat-treatment). The growth properties and the fate of the cells were compared to their untreated counterparts by cell counting, immunocytochemistry and Western analysis. RESULTS: When seeded at a density of 2845 cells/cm(2) and cultured under common conditions, rat MSCs could be expanded up to 21.94 cell doublings in 30 days of successive subcultures. This was accompanied by a gradual loss of their replication ability with passages. When treated with 5-azacytidine for 24 h at day 3 of primary culture and the first subculture, the growth properties of the MSCs were not obviously affected. Neither the spontaneously beating cells nor the formation of myotubes were found in the primary and first passaged MSCs after a single treatment with 5-azacytidine and in cultures which underwent repeated 5-azacytidine-treatments during continuous subculturing to passage 2. The expressions of cardiac troponin I, cardiac myosin heavy chain and connexin 43 by the 5-azacytidine-treated MSCs were also undetectable at both immunocytochemistry and Western blot levels. The specificity and reliability of the detection methods were technically confirmed with cultured rat cardiomyocytes. CONCLUSIONS: Rat MSCs cannot be extensively expanded in vitro or be induced to differentiate in an expected cardiomyogenic way by 5-azacytidine-treatment, if the cells are not immortalized.

Animals↗

PubMed2005

Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins.

Sir2 is a NAD+-dependent protein deacetylase that extends lifespan in yeast and worms. This study examines seven human proteins homologous to Sir2 (SIRT1 through SIRT7) for cellular localization, expression profiles, protein deacetylation activity, and effects on human cell lifespan. We found that: 1) three nuclear SIRT proteins (SIRT1, SIRT6, and SIRT7) show different subnuclear localizations: SIRT6 and SIRT7 are associated with heterochromatic regions and nucleoli, respectively, where yeast Sir2 functions; 2) SIRT3, SIRT4, and SIRT5 are localized in mitochondria, an organelle that links aging and energy metabolism; 3) cellular p53 is a major in vivo substrate of SIRT1 deacetylase, but not the other six SIRT proteins; 4) SIRT1, but not the other two nuclear SIRT proteins, shows an in vitro deacetylase activity on histone H4 and p53 peptides; and 5) overexpression of any one of the seven SIRT proteins does not extend cellular replicative lifespan in normal human fibroblasts or prostate epithelial cells. This study supports the notion that multiple human SIRT proteins have evolutionarily conserved and nonconserved functions at different cellular locations and reveals that the lifespan of normal human cells, in contrast to that of lower eukaryotes, cannot be manipulated by increased expression of a single SIRT protein.

Cell Line↗

PubMed1985

Methylation patterns in the gene for the alpha subunit of chorionic gonadotropin are inherited with variable fidelity in clonal lineages of human fibroblasts.

Cytosine methylation in DNA of an endogenous single-copy gene locus, the alpha-subunit of human chorionic gonadotropin (alpha-hCG), was assessed in a mass culture and individual clonal lineages of human diploid fibroblasts. Progressive hypomethylation at -CCGG- sites in this gene occurred during the replicative lifespan of the mass culture and was shown to arise randomly during clonal expansion. Thus, some clones and subclones lost -CCGG- methylation in the alpha-hCG gene region while others maintained essentially complete methylation. These data indicate significant interclonal variability in the fidelity with which DNA methylation is transmitted in an endogenous gene.

5-Methylcytosine↗

PubMed2006

Telomere length dynamics in normal hematopoiesis and in disease states characterized by increased stem cell turnover.

Telomeres both reflect and limit the replicative lifespan of normal somatic cells. Immature sub-populations of human CD34+38- hematopoietic stem cell (HSC) can be identified in vitro based on their growth kinetics and telomere length. Fluorescence in situ hybridization and flow cytometry (flow-FISH) has been used to characterize telomere length dynamics as a surrogate marker for HSC turnover in vivo. Investigations in normal steady-state hematopoiesis provided the basis for follow-up studies in model scenarios characterized by increased HSC turnover. Disorders with underlying malignant transformation of HSC (e.g., chronic myeloid leukemia (CML)) can be discriminated from disease states with increased HSC turnover rates secondary to depletion of the stem cell compartment, for example, as in defined bone marrow failure syndromes. In some of these model scenarios, the degree of telomere shortening can be correlated with disease duration, disease stage and severity as well as with response to disease-modifying treatment strategies. Whether increased telomere shortening represents a causal link between HSC turnover, replicative senescence and/or the induction of genetic instability in acquired HSC disorders remains to be shown. However, data from congenital disorders, like dyskeratosis congenita (DKC), suggest that disturbed telomere maintenance may play a role for replicative exhaustion of the HSC pool in vivo.

Animals↗

PubMedDate not supplied

Homologous recombination is elevated in some Werner-like syndromes but not during normal in vitro or in vivo senescence of mammalian cells.

Werner syndrome (WS) is a recessive genetic condition associated with markedly reduced replicative lifespans of cells in culture, high chromosomal instability in vivo and in vitro, and premature appearance of many characteristics of normal aging, including an increased incidence of cancer. We have monitored plasmid homologous recombination frequencies in diploid fibroblasts from 6 Werner or Werner-like syndrome patients, following transfection with a plasmid substrate containing 2 overlapping fragments of the TN5 Neor gene. Plasmid DNA recovered from these cells was then assayed for homologous recombination by (a) transformation of recA- bacteria to Ampr (indicating total viable plasmid) or Neor (indicating viable recombinant plasmid), and (b) by limited-cycle polymerase chain reaction (PCR) to co-amplify a recombinant fragment containing the overlap region, and a control region of the same plasmid, without bacterial transformation. Bacterial assay data indicated that recombination rates in 3 of the 6 WS strains were significantly elevated above normal controls; 4 of 6 appeared elevated by PCR assay. The highest-recombination WS strain showed evidence of reduced degradation of transfected plasmid DNA. For this small sample of WS strains, clinical severity of WS was not well correlated with recombination rate as determined by either assay (Pearson r = 0.78, not significant, for PCR assay); elevated recombination may, however, define a subset of WS at greatest risk for cancer and/or atherosclerosis. PCR assay of a hyperoxia-resistant HeLa cell line, displaying substantially increased chromosome breakage, indicated increased recombination between direct-repeat fragments. Nevertheless, elevated recombination in WS strains is unlikely to be secondary to impaired replicative capacity characteristic of WS cells, or to defective repair of chromosome damage which is increased in WS, since recombination in non-WS strains was unaffected by passage level or repeated UV irradiation.

Adult↗

PubMed1993

Accumulation of insulin-like growth factor binding protein-3 in conditioned medium of human fibroblasts increases with chronologic age of donor and senescence in vitro.

We have found that insulin-like growth factor binding protein-3 (IGFBP-3) accumulates to higher levels in medium conditioned by a strain of normal fibroblasts at late passage (LP) and a strain derived from subjects with Werner syndrome (WS) of premature aging, compared to medium conditioned by the same normal cells at early passage (EP) (Goldstein et al., Proc. Natl. Acad. Sci. USA, 88:9680-9684, 1991). To explore the generality of this phenomenon with respect to chronological age of donor (in vivo aging) and LP (in vitro senescence) we assayed IGFBP-3 in medium conditioned by 18 normal fibroblast strains at EP and LP and two WS strains at the midpoint of their curtailed replicative lifespans and assessed IGFBP-3 mRNA levels in cells by Northern analysis. The lowest accumulations of IGFBP-3 were found in medium conditioned by fetal cells with progressively increasing amounts postnatally; direct correlations between IGFBP-3 levels and donor age were seen in EP cells 3 days after subculture (during logarithmic growth) r = 0.80, P < 0.001, and 7 days after subculture (at confluence) r = 0.77, P < 0.001. With two exceptions, conditioned medium of cell strains accumulated more IGFBP-3 at LP; IGFBP-3 levels correlated with chronological age after 3 days, r = 0.50, P = 0.05, and after 7 days, r = 0.75, P < 0.001. IGFBP-3 content of WS culture medium fell within the range of LP normal cells. Cumulative IGFBP-3 levels were inversely proportional to the thymidine labeling index, a measure of proliferative vigor. With some exceptions IGFBP-3 mRNA levels were commensurate with the amount of IGFBP-3 accumulated in the medium, suggesting that distal translational and posttranslational mechanisms also regulate IGFBP-3 production in some strains. The trend toward augmented IGFBP-3 output of fibroblasts as a direct function of chronological age and in vitro senescence and as an inverse function of proliferative vigor is consistent with the known inhibitory effect of excess IGFBP-3 on IGF-mediated DNA synthesis and the reduced regenerative potential that is evident during biological aging in vivo.

Aging↗

PubMed1994

Senescence and cell density of human diploid fibroblasts influence metabolism of insulin-like growth factor binding proteins.

In order to analyze changes in metabolism of insulin-like growth factor binding proteins (IGFBPs) related to cell senescence and cell density, we compared human diploid fibroblasts (HDF) in the proliferatively vigorous first half (young cells) and senescent HDF in the last 10% (old cells) of the replicative lifespan after seeding cells over an eightfold range and proliferation to high density. Increasing the seeding cell density of both young and old HDF led to elevated rates of IGFBP-3 secretion, an increasing ratio of the 42/38 kDa species of IGFBP-3, and degradation of all species of IGFBPs derived from both the fetal bovine serum component of the culture medium and from HDF. At a given seeding density old HDF produced more IGFBP-3 and degraded more IGFBPs than young HDF. IGFBP-4 was degraded by a protease that appeared to be different from the protease(s) involved in degradation of the other IGFBPs. Young HDF at all seeding densities contained a cell-associated 29 kDa IGFBP, whereas this protein could not be detected in old cells. Thus, although certain changes in IGFBP metabolism are similar in young HDF seeded at high densities and in old HDF, young and old phenotypes can be distinguished by characteristic qualitative and quantitative changes in IGFBPs derived from fetal bovine serum and from HDF.

Blotting, Western↗

PubMed2001

A stochastic model of cell replicative senescence based on telomere shortening, oxidative stress, and somatic mutations in nuclear and mitochondrial DNA.

Human diploid fibroblast cells can divide for only a limited number of times in vitro, a phenomenon known as replicative senescence or the Hayflick limit. Variability in doubling potential is observed within a clone of cells, and between two sister cells arising from a single mitotic division. This strongly suggests that the process by which cells become senescent is intrinsically stochastic. Among the various biochemical mechanisms that have been proposed to explain replicative senescence, particular interest has been focussed on the role of telomere reduction. In the absence of telomerase--an enzyme switched off in normal diploid fibro-blasts-cells lose telomeric DNA at each cell division. According to the telomere hypothesis of cell senescence, cells eventually reach a critically short telomere length and cell cycle arrest follows. In support of this concept, forced expression of telomerase in normal fibroblasts appears to prevent cell senescence. Nevertheless, the telomere hypothesis in its basic form has some difficulty in explaining the marked stochastic variations seen in the replicative lifespans of individual cells within a culture, and there is strong empirical and theoretical support for the concept that other kinds of damage may contribute to cellular ageing. We describe a stochastic network model of cell senescence in which a primary role is played by telomere reduction but in which other mechanisms (oxidative stress linked particularly to mitochondrial damage, and nuclear somatic mutations) also contribute. The model gives simulation results that are in good agreement with published data on intra-clonal variability in cell doubling potential and permits an analysis of how the various elements of the stochastic network interact. Such integrative models may aid in developing new experimental approaches aimed at unravelling the intrinsic complexity of the mechanisms contributing to human cell ageing.

Cell Culture Techniques↗

PubMed2001

Profiles of random change during aging contain hidden information about longevity and the aging process.

Many different morphological and physiological changes occur during the yeast replicative lifespan. It has been proposed that change is a cause rather than an effect of aging. It is difficult to ascribe causality to processes that manifest themselves at the level of the entire organism, because of their global nature. Although causal connections can be established for processes that occur at the molecular level, their exact contributions are obscured, because they are immersed in a highly interactive network of processes. A top-down approach that can isolate crucial features of aging processes for further study may be a productive avenue. We have mathematically depicted the complicated and random changes that occur in cellular spatial organization during the lifespan of individual yeast cells. We call them budding profiles. This has allowed us to demonstrate that budding profiles are a highly individual characteristic, and that they are correlated with an individual cell's longevity. Additional information can be extracted from our model, indicating that random budding is associated with longevity. This expectation was confirmed, providing new avenues for exploring causal factors in yeast aging. The methodology described here can be readily applied to other aspects of aging in yeast and in higher organisms.

Animals↗

PubMed1997

Demonstration of cellular aging and senescence in serially passaged long-term cultures of human trabecular osteoblasts.

The proliferative capacity and cellular and biochemical characteristics of human trabecular bone osteoblasts were analysed throughout their replicative lifespan in vitro. Like several other cell types, human osteoblasts demonstrated a typical Hayflick phenomenon of cellular aging comprising a period of rapid proliferation until cumulative population doubling level (CPDL) 22 to 24, followed by a phase of slow growth and the final cessation of cell division at CPDL 32 to 34. Comparing young cells (less than 20% lifespan completed) and old cells (more than 90% lifespan completed) revealed a progressive increase in population doubling (PD) time, a decrease in attachment frequency, a decrease in the number of S-phase positive cells, a decrease in the rates of DNA, RNA and protein synthesis, an increase in the protein content per cell and an increased proportion of senescence-specific beta-galactosidase positive cells. While osteoblastic production of collagen type I decreased progressively during aging, alkaline phosphatase activity dropped rapidly after the first few passages and then remained constant during the rest of the proliferative lifespan, Significant morphological changes from thin and spindle-shaped early passage young cells to large, flattened and irregularly shaped late passage old cells full of intracellular debris were observed. In comparison, osteoblasts established from an osteoporotic bone sample showed a maximum CPDL of less than 5, had a longer PD time and exhibited abnormal senescent morphology. Thus, we have demonstrated for the first time that human osteoblasts, like several other diploid cell types, have a limited proliferative capacity in vitro and undergo aging and senescence as measured by various cellular and biochemical markers. In addition, preliminary studies show that cells from osteoporotic bone have a severely reduced proliferative capacity. This model of bone cell aging facilitates study of the molecular mechanisms of osteoblast senescence as well as factors related to osteoblast dysfunction in patients with osteoporosis.

Adolescent↗

PubMed1992

Impaired S-phase transit of Werner syndrome cells expressed in lymphoblastoid cell lines.

The clinical phenotype of Werner's syndrome (WS) includes short stature, premature cataracts, skin atrophy, osteoporosis, graying and loss of hair, neoplasia, diabetes mellitus, and arteriosclerosis. Cultured cells from patients with this autosomal recessive disorder exhibit chromosomal instability and a markedly reduced replicative lifespan and growth rate. To elucidate the cell cycle alterations associated with the growth deficit, we continuously labeled lymphoid cell lines from five WS patients and from four healthy adult controls with 5-bromodeoxyuridine. Bivariate Hoechst 33258/ethidium bromide flow cytometry revealed a 2.4-h prolongation in the minimal duration of the S phase of WS cells (P less than 0.005). Moreover, the fraction of proliferating cells irreversibly arrested in the S phase (5.4% vs 1.4% in controls) was significantly elevated in WS (P less than 0.001). Other cell cycle compartments were not significantly affected in WS cell lines. As a partial test of the hypothesis that the WS phenotype is due to a defect in DNA topoisomerase I (topo I) or DNA topoisomerase II (topo II) we exposed lymphoid cells from a healthy control to the topo I inhibitor camptothecin or to the topo II inhibitor 4'-(9-acridinylamino)methanesulfon-m-anisidine. The cell kinetic alterations elicited by these compounds differed from that exhibited by untreated WS patients. Thus, a primary defect in topo I or II is unlikely in WS. Our cell cycle results, however, provide important evidence that the biochemical genetic lesion is in fact expressed in lymphoblastoid cell lines, the most readily available cells from such subjects.

Adult↗

PubMed1979

Increased growth of human fibroblasts and arterial smooth muscle cells from diabetic patients related to diabetic serum factors and cell origin.

Fibroblasts from 3 diabetic patients (DF) grew faster, resulting in higher cell counts in the stationary phase than fibroblasts from 3 age-matched healthy volunteers (NF). This difference was apparent when DF or NF were cultured in either diabetic (DS) or normal serum (NS). Diabetic serum increased growth of both DF and NF compared with normal serum. Total protein content per plate paralleled the increase of cell number per plate in relation to cell origin and serum type. DS increased growth and total protein per plate in the arterial smooth muscle cell line from a non-diabetic patient in a way similar to in DF and NF. It is concluded that increased growth of DF in vivo could result in an increased turnover of vascular cells with a shortened replicative lifespan, leading to an accumulation of basal lamina. This effect would be even further accentuated by exposure of DF to DS. Taken together with the increased protein synthesis the accelerated development of diabetic angiopathy could be the final consequence.

Adolescent↗