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1.
Yeast cells, like mammalian cells, enlarge steadily as they age. Unabated cell growth can promote cellular senescence; however, the significance of the relationship between size and cellular lifespan is not well understood. Herein, we report a genetic link between cell size, growth rate and lifespan. Mutations that increase cell size concomitantly increase growth rate and decrease lifespan. As a result, large cells grow, divide and age dramatically faster than small cells. Conversely, small cell mutants age slowly and are long-lived. Investigation of the mechanisms involved suggests that attainment of a maximal size modulates lifespan. Indeed, cumulative results revealed that life expectancy is size-dependent, and that the rate at which cells age is determined in large part by the amount of cell growth per generation.  相似文献   

2.
Comment on: Murakami C, et al. Cell Cycle 2012; 11:3087-96.  相似文献   

3.
Nicotinamide extends replicative lifespan of human cells   总被引:3,自引:0,他引:3  
Kang HT  Lee HI  Hwang ES 《Aging cell》2006,5(5):423-436
We found that an ongoing application of nicotinamide to normal human fibroblasts not only attenuated expression of the aging phenotype but also increased their replicative lifespan, causing a greater than 1.6-fold increase in the number of population doublings. Although nicotinamide by itself does not act as an antioxidant, the cells cultured in the presence of nicotinamide exhibited reduced levels of reactive oxygen species (ROS) and oxidative damage products associated with cellular senescence, and a decelerated telomere shortening rate without a detectable increase in telomerase activity. Furthermore, in the treated cells growing beyond the original Hayflick limit, the levels of p53, p21WAF1, and phospho-Rb proteins were similar to those in actively proliferating cells. The nicotinamide treatment caused a decrease in ATP levels, which was stably maintained until the delayed senescence point. Nicotinamide-treated cells also maintained high mitochondrial membrane potential but a lower respiration rate and superoxide anion level. Taken together, in contrast to its demonstrated pro-aging effect in yeast, nicotinamide extends the lifespan of human fibroblasts, possibly through reduction in mitochondrial activity and ROS production.  相似文献   

4.
This past decade has seen the identification of numerous conserved genes that extend lifespan in diverse species, yet the number of compounds that extend lifespan is relatively small. A class of compounds called STACs, which were identified as activators of Sir2/SIRT1 NAD+-dependent deacetylases, extend the lifespans of multiple species in a Sir2-dependent manner and can delay the onset of age-related diseases such as cancer, diabetes and neurodegeneration in model organisms. Plant-derived STACs such as fisetin and resveratrol have several liabilities, including poor stability and relatively low potency as SIRT1 activators. To develop improved STACs, stilbene derivatives with modifications at the 4' position of the B ring were synthesized using a Horner-Emmons-based synthetic route or by hydrolyzing deoxyrhapontin. Here, we describe synthetic STACs with lower toxicity toward human cells, and higher potency with respect to SIRT1 activation and lifespan extension in Saccharomyces cerevisiae. These studies show that it is possible to improve upon naturally occurring STACs based on a number of criteria including lifespan extension.  相似文献   

5.
Three conditions which influence both the aggregation rate and the final size of aggregates of dissociated embryonic chick retina cells were studied to determine whether there was a strict relationship between these two variables. The length of trypsinization time, age of the embryo, and concentration of chondroitin sulfate in the medium under some conditions showed an inverse relationship between their influence on aggregation rate and the final size of the aggregates; conditions favoring more rapid aggregation reduced the size of aggregates formed by 24 hr. Embryonic liver cells also showed this inverse relationship when cultured with chondroitin sulfate. These observations and other similar observations in the literature emphasize that when interpreting the action of exogenous promoters or inhibitors of cell aggregation, attention should be given to the possibility that there might not be a direct relationship between initial rate and final size.  相似文献   

6.
7.
Summary and conclusion The coefficient of correlation between cell length and percentage mitosis in root-tips ofZea mays was found to be high and negative: r=–0·577±0·075. This value taken together with correlated data justifies the generality that cell division and cell size are inversely related. An analysis of the bases of the relation brings the conclusion that in an increasing cell population where growth in cell number and growth in cell size are taking place simultaneously, cell division is the independent and cell size the dependent variable. That is to say, other things being equal, the size of the cells is a result of the rate of cell multiplication. The explanation of this is given in the text.  相似文献   

8.
Population growth rate and its determinants: an overview   总被引:8,自引:0,他引:8  
We argue that population growth rate is the key unifying variable linking the various facets of population ecology. The importance of population growth rate lies partly in its central role in forecasting future population trends; indeed if the form of density dependence were constant and known, then the future population dynamics could to some degree be predicted. We argue that population growth rate is also central to our understanding of environmental stress: environmental stressors should be defined as factors which when first applied to a population reduce population growth rate. The joint action of such stressors determines an organism's ecological niche, which should be defined as the set of environmental conditions where population growth rate is greater than zero (where population growth rate = r = log(e)(N(t+1)/N(t))). While environmental stressors have negative effects on population growth rate, the same is true of population density, the case of negative linear effects corresponding to the well-known logistic equation. Following Sinclair, we recognize population regulation as occurring when population growth rate is negatively density dependent. Surprisingly, given its fundamental importance in population ecology, only 25 studies were discovered in the literature in which population growth rate has been plotted against population density. In 12 of these the effects of density were linear; in all but two of the remainder the relationship was concave viewed from above. Alternative approaches to establishing the determinants of population growth rate are reviewed, paying special attention to the demographic and mechanistic approaches. The effects of population density on population growth rate may act through their effects on food availability and associated effects on somatic growth, fecundity and survival, according to a 'numerical response', the evidence for which is briefly reviewed. Alternatively, there may be effects on population growth rate of population density in addition to those that arise through the partitioning of food between competitors; this is 'interference competition'. The distinction is illustrated using a replicated laboratory experiment on a marine copepod, Tisbe battagliae. Application of these approaches in conservation biology, ecotoxicology and human demography is briefly considered. We conclude that population regulation, density dependence, resource and interference competition, the effects of environmental stress and the form of the ecological niche, are all best defined and analysed in terms of population growth rate.  相似文献   

9.
10.
Immunosenescence is the consequence of the continuous attrition caused by chronic antigenic stress. The most important characteristics of immunosenescence (accumulation of memory and effector T cells, reduction of naive T cells, shrinkage of T cell repertoire, reduction of the immunological space) are compatible with this assumption. Immunosenescence can be taken as proof that the beneficial effects of the immune system, devoted to the neutralization of harmful agents early in life, become detrimental late in life, in a period not foreseen by evolution. This perspective could explain the mechanisms of the ageing process as well as the pathogenesis of age-related diseases.  相似文献   

11.
Human fibroblasts, which have a finite lifespan in cultures, have been widely used as a model system for cellular aging, and frequently used as one model of human aging. But whether cellular aging contributes to organismal aging has been controversial. To reinvestigate this question, we cultured human fibroblasts from the skin of one individual volunteer collected at different ages. Over a period of 27 years (donor age 36 years to 62 years), we obtained skin cells four times at appropriate intervals, and established eight fibroblast lines. These human fibroblasts have presented evidence for a correlation between donor age and proliferative lifespan in vitro . This result parallels the fact that telomeric DNA size cultured fibroblasts decrease with the increase in donor age. These cell lines had a normal diploid human chromosome constitution and will be useful in studies of human biology including aging.  相似文献   

12.
BACKGROUND AND AIMS: Sub-arctic mountain birch Betula pubescens var. pumila communities in the North Atlantic region are of variable stature, ranging from prostrate scrubs to forests with trees up to 12 m high. Four hypotheses were tested, relating growth and population characteristics of sub-arctic birch woodland and scrub to tree stature; i.e. the variable stature of birch woods is due to differences in (1) the mean growth rate; (2) the age-related patterns of growth rate; (3) the life expectancy of stems; or (4) the tree form. Methods: A stratified random sample of 300 birch trees was drawn from the total population of indigenous birch woodlands and scrub in Iceland, yielding 286 valid sample genets. The population was divided into three sub-populations with dominant trees 0-2, 2-4 and 4-12 m tall, referred to as birch scrub, birch scrub-woodland and birch forest, respectively. KEY RESULTS: Trees in the scrub population were of more contorted growth form than birch in the scrub-woodland and forest populations. Mean growth rates, mean age and median life expectancies increased significantly with sub-population of greater tree stature. At the population level, annual increment and longevity of birch stems was apparently interrelated as the stems in vigorously growing birch sub-populations had a longer life expectancy than those of slower growth. However, no difference was observed between sub-populations in age-related patterns of extension growth rate. CONCLUSIONS: The results were consistent with hypotheses (1), (3) and (4), but hypothesis (2) was rejected. Hence, mountain birch of more vigorous growth attains a greater stature than birch of lesser increment due to faster extension growth rate and a longer lifespan. In addition, the more contorted stem form of scrub populations contributes to their low stature.  相似文献   

13.
The amount of large and old trees has decreased in the boreal forests during the last centuries of forestry. Such trees are important habitats for epiphytic lichens and there is a growing concern for lichen species that are associated with large and old trees. However, only little is known about the relative importance of tree size versus age as determinants of lichen diversity. Here we have determined the size, age and growth rate of 157 Norway spruce trees and recorded the occurrence of epiphytic lichen species on their branches and lower stems. The study includes crustose lichens and was done in two old-growth forests in SE Norway. Tree age and tree size were the parameters that explained the largest part of epiphytic lichen diversity. Only the growth rate of the most recent time period, i.e. 1984–2004, showed a statistically significant relationship to diversity. There was no indication of a stabilising species number with increasing tree age. Slow-growing and old trees were, however, mainly of importance to the lichen species growing on stems, and this set of species were in general adversely affected by a large amount of branches. The opposite was the case for the species that were confined to branches as their diversity increased when the amount of branches increased. Our study adds empirical data to support the importance of large and old trees as bearers of biodiversity in boreal forests. Site preservation and patch retention of groups of old and large trees is recommended as measures to maintain epiphytic lichen diversity.  相似文献   

14.
Newly synthesized membrane proteins are constantly sorted from the endoplasmic reticulum (ER) to various membranous compartments. How proteins specifically enrich at the inner nuclear membrane (INM) is not well understood. We have established a visual in vitro assay to measure kinetics and investigate requirements of protein targeting to the INM. Using human LBR, SUN2, and LAP2β as model substrates, we show that INM targeting is energy-dependent but distinct from import of soluble cargo. Accumulation of proteins at the INM relies on both a highly interconnected ER network, which is affected by energy depletion, and an efficient immobilization step at the INM. Nucleoporin depletions suggest that translocation through nuclear pore complexes (NPCs) is rate-limiting and restricted by the central NPC scaffold. Our experimental data combined with mathematical modeling support a diffusion-retention–based mechanism of INM targeting. We experimentally confirmed the sufficiency of diffusion and retention using an artificial reporter lacking natural sorting signals that recapitulates the energy dependence of the process in vivo.  相似文献   

15.
Uncleaved signal-anchor sequences of membrane proteins inserted into the endoplasmic reticulum initiate the translocation of either the amino-terminal or the carboxyl-terminal polypeptide segment across the bilayer. Which topology is acquired is not determined by the apolar segment of the signal but rather by the hydrophilic sequences flanking it. To study the role of charged residues in determining the membrane topology, the insertion of mutants of the asialoglycoprotein receptor H1, a single-spanning protein with a cytoplasmic amino terminus, was analyzed in transfected COS-7 cells. When the charged amino acids flanking the hydrophobic signal were mutated to residues of opposite charge, half the polypeptides inserted with the inverted orientation. When, in addition, the amino-terminal domain of the mutant protein was truncated, approximately 90% of the polypeptides acquired the inverted topology. The transmembrane orientation appears to be primarily determined by the charges flanking the signal sequence but is modulated by the domains to be translocated.  相似文献   

16.
17.
It has been reported that the replicative lifespan of human fibroblasts can be substantially extended by supplementing the growth medium with hydrocortisone or increased levels of serum proteins. These observations have been made only on cell populations transferred many times at high cell density, and cumulative population doublings have been recorded, rather than a more direct measure of cell division potential. We have measured the replicative potential of human fibroblasts cultured so as to avoid conditions of high cell density, medium depletion, and departure from exponential growth. Two fetal lung and two newborn foreskin fibroblast strains were serially passaged in the presence or absence of hydrocortisone (HC), epidermal growth factor (EGF), and fibroblast growth factor (FGF) until they senesced. At each passage cells were plated at densities sufficiently low that colony-forming efficiency could be calculated. We determined cumulative population doublings and also estimated the number of cell generations attained under each condition. FGF caused small but possibly significant changes, while HC and EGF failed to substantially alter replicative lifespan. The reported effect of HC on the doubling potential of fetal lung fibroblasts is therefore not an inevitable action of this hormone on the senescence mechanism, but may instead depend for its apparent activity on the passage regimen used. The fibroblast's insensitivity to EGF as a modulator of replicative potential, as compared with the keratinocyte, whose lifespan can be tripled by EGF, implies that the mechanisms limiting the replicative potential of these two cell types are not identical.  相似文献   

18.
Mutants of the Escherichia coli initiator tRNA (tRNA(fMet)) have been used to examine the role of the anticodon and discriminator base in in vivo aminoacylation of tRNAs by cysteinyl-tRNA synthetase. Substitution of the methionine anticodon CAU with the cysteine anticodon GCA was found to allow initiation of protein synthesis by the mutant tRNA from a complementary initiation codon in a reporter protein. Sequencing of the protein revealed that cysteine comprised about half of the amino acid at the N terminus. An additional mutation, converting the discriminator base of tRNA(GCAfMet) from A73 to the base present in tRNA(Cys) (U73), resulted in a 6-fold increase in the amount of protein produced and insertion of greater than or equal to 90% cysteine in response to the complementary initiation codon. Substitution of C73 or G73 at the discriminator position led to insertion of little or no cysteine, indicating the importance of U73 for recognition of the tRNA by cysteinyl-tRNA synthetase. Single base changes in the anticodon of tRNA(GCAfMet) containing U73 from GCA to UCA, GUA, GCC, and GCG (changes underlined) eliminated or dramatically reduced cysteine insertion by the mutant initiator tRNA indicating that all three cysteine anticodon bases are essential for specific aminoacylation of the tRNA with cysteine in vivo.  相似文献   

19.
20.
In eukaryotes, most nuclear DNA replication proceeds bidirectionally from multiple origins of replication. A unit of DNA, replicated by two replication forks from a single origin, is termed a replicon. Using results from DNA fiber autoradiography we show a novel positive correlation between replicon size and the rate of replication fork movement in root meristem nuclei of 13 grass species. Although there is interspecific variation in replicon size, it is balanced by similar variation in the rate of replication fork progression.  相似文献   

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