Scrapie infection activates the replication of ecotropic, xenotropic, and polytropic murine leukemia virus (MuLV) in brains and spinal cords of senescence-accelerated mice: implication of MuLV in progression of scrapie pathogenesis

Senescence-accelerated mice (SAMP8) have a short life span, whereas SAMR1 mice are resistant to accelerated senescence. Previously it has been reported that the Akv strain of ecotropic murine leukemia virus (E-MuLV) was detected in brains of SAMP8 mice but not in brains of SAMR1 mice. In order to determine the change of MuLV levels following scrapie infection, we analyzed the E-MuLV titer and the RNA expression levels of E-MuLV, xenotropic MuLV, and polytropic MuLV in brains and spinal cords of scrapie-infected SAM mice. The expression levels of the 3 types of MuLV were increased in scrapie-infected mice compared to control mice; E-MuLV expression was detected in infected SAMR1 mice, but only in the terminal stage of scrapie disease. We also examined incubation periods and the levels of PrPSc in scrapie-infected SAMR1 (sR1) and SAMP8 (sP8) mice. We confirmed that the incubation period was shorter in sP8 (210+/-5 days) compared to sR1 (235+/-10 days) after intraperitoneal injection. The levels of PrPSc in sP8 were significantly greater than sR1 at 210+/-5 days, but levels of PrPSc at the terminal stage of scrapie in both SAM strains were virtually identical. These results show the activation of MuLV expression by scrapie infection and suggest acceleration of the progression of scrapie pathogenesis by MuLV.     

NMR-based metabonomic investigations into the metabolic profile of the senescence-accelerated mouse

In this work, metabonomic methods utilizing (1)H NMR spectroscopy and multivariate statistical technique have been applied to investigate the metabolic profiles of SAM. The serum metabolome of senescence-prone 8 (SAMP8), a murine model of age-related learning and memory deficits and Alzheimer's disease (AD), was compared with that of control, senescence-resistant 1 (SAMR1), which shows normal aging process. Serum samples were collected for study from both male and female 12-month-old SAMP8 and age matched SAMR1 ( n = 5). (1)H NMR spectra of serum were analyzed by pattern recognition using principal components analysis. The results showed that the serum metabolic patterns of SAMP8 and SAMR1 were significantly different due to strains and genders. Subtle differences in the endogenous metabolite profiles in serum between SAMP8 and SAMR1 were observed. The most important metabolite responsible for the strain separation was lack of inosine, which meant the protective function of anti-inflammation, immunomodulation and neuroprotection might be attenuated in SAMP8. Other differential metabolites observed between strains included decreased glucose, PUFA, choline, phosphocholine, HDL, LDL, D-3-hydoxybutyrate, citrate and pyruvate and increased lactate, SFA, alanine, methionine, glutamine and VLDL in serum of SAMP8 compared with those of SAMR1, suggesting perturbed glucose and lipid metabolisms in SAMP8. Besides the differences observed between the strains, an impact of gender on metabolism was also found. The females exhibited larger metabolic deviations than males and these gender differences in SAMP8 were much larger than in SAMR1. Higher levels of VLDL, lactate and amino acids and lower levels of HDL, LDL and unsaturated lipids were detected in female than in male SAMP8. These facts indicated that the metabolism disequilibrium in female and male SAMP8 was different and this may partly explain that females were more prone to AD than males. The results of this work may provide valuable clues to the understanding of the mechanisms of the senile impairment and the pathological changes of AD, as well as show the potential power of the combination of the NMR technique and the pattern recognition method for the analysis of the biochemical changes of certain pathophysiologic conditions.     

The level of butyrylcholinesterase activity increases and the content of the mRNA remains unaffected in brain of senescence-accelerated mouse SAMP8

Looking at cholinesterases (ChEs) changes in age-related mental impairment, the expression of ChEs in brain of senescence accelerated-resistant (SAMR1) and senescence accelerated-prone (SAMP8) mice was studied. Acetylcholinesterase (AChE) activity was unmodified and BuChE activity increased twofold in SAMP8 brain. SAMR1 brain contained many AChE-T mRNAs, less BuChE and PRiMA mRNAs and scant AChE-R and AChE-H mRNAs. Their content unchanged in SAMP8 brain. Amphiphilic (G(4)(A)) and hydrophilic (G(4)(H)) AChE and BuChE tetramers, besides amphiphilic dimers (G(2)(A)) and monomers (G(1)(A)) were identified in SAMR1 brain and their distribution was little modified in SAMP8 brain. Blood plasma does not seem to provide the excess of BuChE activity in SAMP8 brain; it probably arises from glial cell changes owing to astrocytosis.     

The Hippocampal Proteomic Analysis of Senescence-Accelerated Mouse: Implications of Uchl3 and Mitofilin in Cognitive Disorder and Mitochondria Dysfunction in SAMP8

Senescence-accelerated mouse prone 8 (SAMP8) is considered as a useful animal model for age-related learning and memory impairments. Hippocampus, a critical brain region associated with cognitive decline during normal aging and various neurodegenerative diseases, appeared a series of abnormalities in SAMP8. To investigate the molecular mechanisms underlying age-related cognitive disorders, we used 2-DE coupled with MALDI TOF/TOF MS to analyze the differential protein expression of the hippocampus of SAMP8 at 6-month-old compared with the age-matched SAM/resistant 1 (SAMR1) which shows normal aging process. Two proteins were found to be markedly changed in SAMP8 as compared to SAMR1: ubiquitin carboxyl-terminal hydrolase L3 (Uchl3), implicating in cytosolic proteolysis of oxidatively damaged proteins, was down-regulated while mitofilin, a vital protein for normal mitochondria function, exhibited four isoforms with a consistent basic shift of isoelectric point among the soluble hippocampal proteins in SAMP8 compared with SAMR1. The alterations were confirmed by Western blotting analysis. The analysis of their expression changes may shed light on the mechanisms of learning and memory deficits and mitochondrial dysfunction as observed in SAMP8.     

Kinetics of expression of infectious ecotropic, xenotropic, and mink cell focus-forming murine leukemia virus after 5-iododeoxyuridine induction of cells from high- and low-leukemia mouse strains

Endogenous murine leukemia virus (MuLV) was induced with 5-iododeoxyuridine (IdUrd) from the high-leukemia mouse strain AKR and from two low-leukemia strains, C3H/He and BALB/c. A virus-free cell line from strain AKR readily gave rise to infectious, XC-positive MuLV upon treatment with IdUrd, whereas cells from strains C3H/He and BALB/c produced replication-deficient, XC-negative MuLV. IdUrd-induced cells also produced xenotropic and mink cell focus-forming MuLV. Xenotropic virus emerged at a higher titer from both AKR and BALB/c cells during two discrete time intervals, first at day 3 after induction and a second time during spread of the induced ecotropic MuLV. Xenotropic and mink cell focus-forming MuLVs were also produced by IdUrd-induced C3H/He cells but required another round of infection in Sc-1 cells for detection. The in vitro infectivity of endogenous ecotropic MuLV isolated by IdUrd induction from C3H/He cells correlated with pathogenicity in the Fv-1-compatible, leukemia-negative mouse strain NFS/N. Thus, the virulence of endogenous ecotropic MuLV may be an important factor in determining the leukemia incidence in these inbred strains of mice.     

Senescence-Accelerated Mouse (SAM) with Special References to Neurodegeneration Models,SAMP8 and SAMP10 Mice

The SAM strains, a group of related inbred strains consisting of senescence-prone inbred strains (SAMP) and senescence-resistant inbred strains (SAMR), have been successfully developed by selective inbreeding of the AKR/J strain of mice donated by the Jackson laboratory in 1968. The characteristic feature of aging common to the SAMP and SAMR is accelerated senescence and normal aging, respectively. Furthermore, SAMP and SAMR strains of mice manifest various pathobiological phenotypes spontaneously. Among SAMP strains, SAMP8 and SAMP10 mice show age-related behavioral deterioration such as deficits in learning and memory, emotional disorders (reduced anxiety-like behavior and depressive behavior) and altered circadian rhythm associated with certain pathological, biochemical and pharmacological changes. Here, the previous and recent literature on SAM mice are reviewed with an emphasis on SAMP8 and SAMP10 mice. A spontaneous model like SAM with distinct advantages over the gene-modified model is hoped by investigators to be used more widely as a biogerontological resource to explore the etiopathogenesis of accelerated senescence and neurodegenerative disorders.     

Characterization of Senescence-Accelerated Mouse Prone 6 (SAMP6) as an Animal Model for Brain Research

The senescence-accelerated mouse (SAM) was developed by selective breeding of the AKR/J strain, based on a graded score for senescence, which led to the development of both senescence-accelerated prone (SAMP), and senescence-accelerated resistant (SAMR) strains. Among the SAMP strains, SAMP6 is well characterized as a model of senile osteoporosis, but its brain and neuronal functions have not been well studied. We therefore decided to characterize the central nervous system of SAMP6, in combination with different behavioral tests and analysis of its biochemical and pharmacological properties. Multiple behavioral tests revealed higher motor activity, reduced anxiety, anti-depressant activity, motor coordination deficits, and enhanced learning and memory in SAMP6 compared with SAMR1. Biochemical and pharmacological analyses revealed several alterations in the dopamine and serotonin systems, and in long-term potentiation (LTP)-related molecules. In this review, we discuss the possibility of using SAMP6 as a model of brain function.     

Differential expression of the liver proteome in senescence accelerated mice

The senescence-accelerated mouse (SAM) is a useful animal model to study aging or age-associated disorders due to its inherited aging phenotype. To investigate proteins involved in the aging process in liver, we compared the young (4- or 20-week old) and the aged group (50-week-old) of SAMP8 (short life span) and SAMR1 (control) mice, and identified 85 differentially expressed distinct proteins comprising antioxidation, glucose/amino acid metabolism, signal transduction and cell cycle systems using proteomics tools. For the antioxidation system, the aged SAMP8 mice showed a large increase in glutathione peroxidase and decreases in glutathione-S-transferase and peroxiredoxin, ranging from 2.5- to 5-fold, suggesting lower detoxification potentials for oxidants in the aged SAMP8 liver. Similarly, levels of key glycolytic enzymes decreased greatly in the aged SAMP8 compared to SAMR1, indicating a disturbance in glucose homeostasis that may be closely related to the typical deficits in learning and memory of the aged SAMP8. Protein profiles of amino acid metabolic enzymes suggest that accumulation of glutamine and glutamate in tissues of the aged SAMP8 may be due to hyperexpression of ornithine aminotransferase and/or glutamate dehydrogenase. Decreases in levels of proteins involved in signal transduction/apoptosis (e.g., cathepsin B) in the aged SAMP8 may support the previously proposed negative relationship between apoptosis and aging. However, the changes described above were not markedly seen in the young group of both strains. For cell cycle systems, levels of selenium binding protein increased about four-fold with age in SAMP8. Yet, almost no change occurred in either the young or the aged SAMR1, which may explain problems associated with cell proliferation and tissue regeneration in the aged SAMP8. In conclusion, composite profiles of key proteins involved in age-related processes enable assessment of accelerated senescence and the appearance of senescence-related pathologies in the aged SAMP8.     

加速衰老小鼠脑组织中的衰老相关基因的表达

从分子水平上研究衰老对大脑的影响有助于揭示机体衰老的分子机理 ,也有助于揭示衰老相关性脑功能异常的发生过程。本研究应用DDRT PCR方法研究衰老相关基因在SAM (Senescence acceleratedmouse)小鼠脑组织中表达的变化情况。在SAMR1TA、SAMP8/Ta、SAMP1 0 /Ta三个品系中 ,通过比较不同鼠龄SAMP1 0 /Ta (2、 4、 1 2、 1 8月龄 )的基因表达情况 ,发现在 4月龄和 1 2月龄分别有一个差异表达片段 ;对不同鼠龄的SAMP8/Ta (2、 4、 1 1月龄 )经差显比较 ,发现在 2月龄和 1 1月龄各有一差异表达片段。在不同品系的比较中发现了 1 6个差异性片段 ,分别属于SAMP1 0 /Ta (3个 )、SAMP8/Ta (6个 )和SAMR1TA (7个 )。测序结果经检索显示 ,它们分别与下列基因转录产物同源 :热休克识别蛋白 70、ATP依赖性线粒体RNA螺旋酶、DleumRNA、小鼠X染色体RP2 3 334C4克隆DNA序列、还原型辅酶Q 细胞色素c还原酶复合物 7 2kD亚单位、 6 0S核糖体蛋白L2 1、FIS、苯基烷基胺钙离子拮抗物结合蛋白、岩藻糖基转移酶 9、胶质细胞源性神经营养因子家族受体α1、内切核酸酶 /逆转录酶、PER1蛋白相关超级融原核蛋白、中心体蛋白CG NAP、转铁蛋白重链基因、巢蛋白 2基因、DNA依赖性蛋白激酶催化亚单位基因 prkdc     

Seeking for Senile-Related Gene Expression in Cerebral Tissue of Senescence-Accelerated Mouse

1. A better understanding of the molecular effect on aging in the brain may help reveal important aspects of organism aging, as well as the processes that lead to aging-related brain dysfunction. In this study, the aging-specific expression genes of the murine cerebrum were investigated by using the technique of DDRT-PCR in two senescence-accelerated mouse strains, SAMP10/Ta and SAMR1TA.2. Through comparing gene expression profile among the age, 2, 4, 12, and 18 month of the SAMP10/Ta strain, four differential fragments have been found, and comparing gene expression profile between the two mouse strains, 24 fragments have been detected, 7 and 17 of them belong to SAMP10/Ta and SAMR1TA, respectively.3. Sequencing analysis indicated that most of those fragments are homologous with some of certain gene cDNA that are related with senile. The data obtained from this study suggest that many genes are involved in the senile process and accelerate senescence phenotypic pathologies in SAMP10/Ta.     

The effect of aging on the mineral status of female SAMP1 and SAMR1

The effect of aging on the status of macrominerals and trace elements in tissues was studied using two strains (SAMP1 and SAMR1) of senescence accelerated mouse. Two-month-old, 6-mo-old, and 10-mo-old female SAMP1 and SAMR1 mice were fed a commercial diet. Iron, zinc, copper, calcium, magnesium, phosphorus, sulfur, sodium, and potassium concentrations in blood, liver, kidney, brain, and tibia of the mice were determined. The copper concentration in the brain was significantly increased with age in SAMP1 and SAMR1. In addition, the brain copper levels in SAMP1 were significantly higher than that in SAMR1 at respective ages. The calcium concentration in the kidney was significantly increased with age, but the copper and phosphorus concentrations significantly decreased with age in SAMP1 and SAMR1. In the liver of SAMR1, all minerals measured in this study except for sodium and potassium were significantly decreased with age. In addition, all mineral concentrations in the liver of 2-mo-old mice in SAMR1 except for copper and sodium were markedly higher than those in SAMP1 of the same age. These results suggest that the genetic factor is related to the age-associated mineral changes in tissues.     

Age-related changes in blood pressure in the senescence-accelerated mouse (SAM): aged SAMP1 mice manifest hypertensive vascular disease

Age-related changes in systolic blood pressure were assessed, using the senescence-accelerated mouse (SAM) model for aging research with strains SAMR1, SAMP1, and SAMP8. Each of the strains manifested a characteristic change in blood pressure with age. The SAMR1 strain, with normal aging, did not have chronologic changes from 2 to 27 months of age. The SAMP1 strain, with accelerated senescence, had a significant increase in blood pressure with age, and some (8 of 39) mice manifested hypertensive vascular disease characterized by high blood pressure, cardiac hypertrophy, and arteriolar fibrinoid necrosis at 11 to 14 months of age. The gradual increase in blood pressure after 8 to 10 months was considered to be preceded by progressive renal changes, from glomerulonephritis to contraction of the kidney, suggesting that the high blood pressure in the SAMP1 strain was of renal origin. Blood pressure in the SAMP8 strain, with age-related deficits in learning and memory, gradually decreased after 5 to 7 months of age, and was suggested to be due to the astrogliotic changes in response to spongiform degeneration in the medulla oblongata at 11 to 14 and 15 to 18 months of age.     

Proteomic analysis for protein carbonyl as an indicator of oxidative damage in senescence-accelerated mice

The senescence-accelerated prone mouse strain 8 (SAMP8) exhibits a remarkable age-accelerated deterioration in learning and memory. In this study, we identified carbonyl modification, a marker of protein oxidation, in liver and brain of SAMP8 from peptide mass fingerprints using MALDI-TOF mass spectrometry in combination with LC-MS/MS analysis. Carbonyl modification of Cu,Zn-superoxide dismutase (Cu,Zn-SOD) in liver at 3 month and hippocampal cholinergic neurostimulating peptide precursor protein (HCNP-pp) in brain at 9 month were higher in SAMP8 compared with control SAMR1. We demonstrated carbonyl modification of purified Cu,Zn-SOD increased by the reaction with H₂O₂. Therefore, progressive accumulation of oxidative damage to Cu,Zn-SOD, may cause dysfunction of defense systems against oxidative stress in SAMP8 with a higher oxidative states, leading to acceleration of aging. Furthermore, carbonyl modification of HCNP-pp may be involved in pathophysiological alterations associated with deterioration in the learning and memory in the brain seen in SAMP8.     

Immunocytochemical evaluation of the blood-brain barrier to endogenous albumin in the olfactory bulb and pons of senescence-accelerated mice (SAM)

The blood-brain barrier (BBB) to endogenous albumin was studied in the olfactory bulb and pons of the senescence-accelerated prone (SAMP8) mouse and senescence-accelerated resistant (SAMR1) mouse strains by using a quantitative immunocytochemical procedure. Ultrathin sections of Lowicryl K4M-embedded samples were exposed to anti-mouse albumin antiserum followed by protein A-gold. Morphometric analysis of the electron micrographs revealed that in the olfactory bulb of both groups of animals, especially in the internal granular layer, some percentage of capillaries and slightly larger microvessels showed leakage of albumin. However, this percentage was larger in SAMP8 than in SAMR1 mice. In the pons, no significant differences in the permeability of blood microvessels were observed in both groups of mice, although a small fraction of capillaries in SAMP8 mice showed limited extravasation of blood plasma albumin. These observations indicate that the BBB in the olfactory bulb of control and SAMP8 mice is not as tight as it is in the pons or in the previously examined cerebral cortex. The labelling density of the neuropil was slightly higher than in the cerebral cortex, suggesting that albumin may have extravasated locally, in addition to having acces to the parenchyma of the olfactory bulb and pons from neighbouring areas supplied with the non-BBB-type of microvasculature. Furthermore, the data obtained suggest that there is limited (segmental), premature agerelated impairment of the BBB function in SAMP8 mice.     

Type C Retrovirus Released from Porcine Primary Peripheral Blood Mononuclear Cells Infects Human Cells

As part of the evaluation of porcine cells, tissues, and organs intended for transplantation into humans, we investigated the conditions required to induce expression and release of porcine endogenous retrovirus (PoEV) from primary cells. Pigs contain endogenous retroviral sequences encoding infectious retrovirus, yet little is known about the conditions required to activate the expression and release of PoEV from primary cells. We show here that mitogenic activation of peripheral blood mononuclear cells (PBMC) isolated from the National Institutes of Health (NIH) miniature pig and the Yucatan pig resulted in the activation and release of an infectious type C retrovirus. Coculture of activated porcine PBMC with pig or human cell lines resulted in the transfer and expression of PoEV-specific sequences and the establishment of a productive infection. Sequence comparison of portions of the PoEV pol gene expressed in pig cell lines productively infected with virus derived from NIH miniature pig and Yucatan pig PBMC revealed marked similarity, suggesting that one or a few loci may be capable of being activated to yield an infectious virus. These findings demonstrate that the presence of endogenous viruses in source animals needs to be carefully considered when the infectious disease potential of xenotransplantation is being assessed.     

A replication-defective variant of Moloney murine leukemia virus. I. Biological characterization.

We have studied the virus produced by a clone, termed 8A, that was isolated from a culture of murine sarcoma virus-transformed mouse cells after superinfection with Moloney murine leukemia virus (MuLV-M). Clone 8A produced high levels of type C virus particles, but only a low titer of infectious murine sarcoma virus and almost no infectious MuLV. When fresh cultures of mouse cells were infected with undiluted clone 8A culture fluids, they released no detectable pogeny virus for several weeks after infection. Fully infectious MuLV was then produced in these cultures. This virus was indistinguishable from MuLV-M by nucleic acid hybridization tests and in its insensitivity to Fv-1 restriction. It also induced thymic lymphomas in BALB/c mice. To explain these results, we propose that cone 8A is infected with a replication-defective variant of MuLV-M. Particles produced by clone 8A, containing this defective genome, can establish an infection in fresh cells but cannot produce progency virus at detectable levels. Several weeks after infection, the defect in the viral genome is corrected by back-mutation or by recombination with endogenous viral genomes, resulting in the formation of fully infectious progeny MuLV. The progeny MuLV'S that arose in two different experiments were found to be genetically different from each other. This is consistent with the hypothesis that, in each experiment, the progeny virus is formed clone 8A cells and assayed for infectivity by the calcium phosphate transfection technique. No detectable MuLV was produced by cells treated with this DNA. This finding, along with positive results obtained in control experiments, indicates that clone 8A cells do not contain a normal MuLV provirus.     

Curcumin prevents mitochondrial dysfunction in the brain of the senescence-accelerated mouse-prone 8

The aging brain suffers mitochondrial dysfunction and a reduced availability of energy in the form of ATP, which in turn may cause or promote the decline in cognitive, sensory, and motor function observed with advancing age. There is a need for animal models that display some of the pathological features of human brain aging in order to study their prevention by e.g. dietary factors. We thus investigated the suitability of the fast-aging senescence-accelerated mouse-prone 8 (SAMP8) strain and its normally aging control senescence-accelerated mouse-resistant 1 (SAMR1) as a model for the age-dependent changes in mitochondrial function in the brain. To this end, 2-months old male SAMR1 (n = 10) and SAMP8 mice (n = 7) were fed a Western type diet (control groups) for 5 months and one group of SAMP8 mice (n = 6) was fed an identical diet fortified with 500 mg curcumin per kg. Dissociated brain cells and brain tissue homogenates were analyzed for malondialdehyde, heme oxygenase-1 mRNA, mitochondrial membrane potential (MMP), ATP concentrations, protein levels of mitochondrial marker proteins for mitochondrial membranes (TIMM, TOMM), the mitochondrial permeability transition pore (ANT1, VDAC1, TSPO), respiration complexes, and fission and fusion (Fis, Opa1, Mfn1, Drp1). Dissociated brain cells isolated from SAMP8 mice showed significantly reduced MMP and ATP levels, probably due to significantly diminished complex V protein expression, and increased expression of TSPO. Fission and fusion marker proteins indicate enhanced mitochondrial fission in brains of SAMP8 mice. Treatment of SAMP8 mice with curcumin improved MMP and ATP and restored mitochondrial fusion, probably by up-regulating nuclear factor PGC1α protein expression. In conclusion, SAMP8 compared to SAMR1 mice are a suitable model to study age-dependent changes in mitochondrial function and curcumin emerges as a promising nutraceutical for the prevention of neurodegenerative diseases that are accompanied or caused by mitochondrial dysfunction.     

Proliferative Senescence of Embryo Fibroblasts of Japanese Senescence Accelerated Mice is Accompanied by Parallel Decreasing of the Response to Various Growth Factors

The Japanese senescence accelerated mice (SAM) are a group of the low-longevity mouse lines and represent a new convenient model for studying the senescence process. We studied the proliferation of embryo fibroblasts of SAMP1 and SAMR1 mouse lines. It was shown that fibroblasts of the shortest longevity line SAMP1 have a markedly decreased proliferative potential of the mean 8.7 population doublings, whereas fibroblasts of a relatively high-longevity line SAMR1 have an average proliferative potential of 12.3 doublings. The fibroblast senescence in both lines is accompanied by simultaneous lowering of the cell proliferative response to the blood serum, epidermal, fibroblast, and platelet-derived growth factors. At initial stages of the cell culture growth, lines SAMP1 and SAMR1 exhibit the same reactions to growth factors, but already beginning from the fifth doubling, the SAMP1 cell response is sharply decreased as compared with SAMR1. Lowering of the proliferative reaction is accompanied by decreased phosphorylation of tyrosine in the cell proteins responsible for the mitogenic reaction. Thus, the parallel decrease in the proliferative response to different growth factors during fibroblast senescence is most likely due to the emergence of a regulatory block at common stages of the mitogenic signal transduction.     

Proliferative senescence of embryo fibroblasts of Japanese senescence accelerated mice (SAM) is accompanied by parallel decreasing of response to various growth factors

The Japanese senescence accelerated mice (SAM) are a group of the low-longevity mouse lines and represent a new convenient model for studying the senescence process. We studied the proliferation of embryo fibroblasts of SAMP1 and SAMR1 mouse lines. It was shown that fibroblasts of the shortest longevity line SAMP1 have a markedly decreased proliferative potential of the mean 8.7 population doublings, whereas fibroblasts of a relatively high-longevity line SAMR1 have an average proliferative potential of 12.3 doublings. The fibroblast senescence in both lines is accompanied by a simultaneous lowering of the cell proliferative response to the blood serum, epidermal, fibroblast, and platelet-derived growth factors. At initial stages of the cell culture growth, lines SAMP1 and SAMR1 exhibit the same reactions to growth factors, but already beginning from the fifth doubling, the SAMP1 cell response is sharply decreased as compared with SAMR1. Lowering the proliferative reaction is accompanied by a decreased phosphorylation of tyrosine in the cell proteins responsible for mitogenic reaction. Thus, the parallel decrease of proliferative response to different growth factors during fibroblast senescence is most likely due the emergence of a regulatory block at common stages of the mitogenic signal transduction.