Membrane Hypothesis Research Articles

Mitochondrial DNA deletions associated with aging and presbyacusis.

The membrane hypothesis of aging proposes an association between reactive oxygen metabolites and aging processes. Reactive oxygen metabolites are a normal by-product of oxidative phosphorylation and are also formed under conditions of ischemia, hypoperfusion, and as a result of environmental contaminants. Among the many detrimental activities of reactive oxygen metabolites, also known as free oxygen radicals, is direct damage to mitochondrial DNA. Progressive accumulation of mitochondrial DNA damage renders cells unable to conduct oxidative phosphorylation reactions effectively, thereby leading to a bioenergetically deficient cell. Over time, mitochondrial DNA damage accumulates and leads to cellular dysfunction with subsequent organ failure, aging, and ultimately, death. This sequence forms the basis of the membrane hypothesis of aging. To determine if the membrane hypothesis of aging may be involved in the development of presbyacusis. Fischer rats from 4 age groups were tested for auditory sensitivity using the auditory brainstem response. Brain, stria vascularis, and auditory nerve tissues were harvested and mitochondrial DNA was amplified to identify the highly conserved cytochrome b and ND1-16S ribosomal RNA segment of the NADH genes, as well as a 4834-base pair (bp) deletion associated with aging. Fischer rats (n=28) from 4 age groups were used: young (2-4 months [n=9]), mid-young (9-11 months [n=5]), mid-old (18-20 months [n=5]), and old (30-34 months [n=9]). The results demonstrate a progressive reduction in auditory sensitivity with age. The mitochondrial DNA studies identify a significant increase in the presence of the 4834-bp deletion in the aged subjects compared with the young. These findings raise the possibility that the 4834-bp deletion may be associated with presbyacusis, as well as with aging.

The membrane hypothesis of aging: its relevance to recent progress in genetic research.

This review outlines the main concepts of the membrane hypothesis of aging (MHA) developed over the past two decades. MHA offers a general cell biological mechanism to explain the main trends of age-dependent changes in terms of intracellular physicochemistry. An essential point in MHA is that the inevitable plasma membrane alterations result in the accumulation of dry mass in the intracellular space, a process that is essential to cellular development and organismal maturation, but which becomes a rate limiting factor above a certain physical density of the cell colloids. The main statements of the MHA are supported by recent developments in molecular genetics. Specifically, the great majority of the products of oncogenes and antioncogenes are localized to the plasma membrane, indicating a central role of the plasma membrane in mitotic regulation, cell differentiation and senescence.

The lipid membrane hypothesis of schizophrenia: implications for possible clinical breath tests

The diagnosis of disease on the basis of an altered profile of breath volatiles is a new area of clinical biochemistry. The membrane hypothesis of schizophrenia leads to a number of predictions about possible volatile biochemical markers for this condition. These molecules would arise from autoxidation of arachidonic acid and possibly other unsaturated fatty acids. Preliminary experimental studies in this area are reviewed. The results are encouraging and developments in analytical methodology, especially mass spectrometry and electronic nose technology, hold promise for an objective test for monitoring the progress of the disease and possibly for diagnosis

Progress in numerical modeling of the thermoforming process

AbstractA finite element code to simulate the thermoforming process was developed. A dynamic approach, a membrane hypothesis, and a second order explicit integration method were considered in developing the code. Tensile tests were carried out on a servohydraulic Instron device to validate hyperelastic and memory integral constitutive laws. An original experimental approach was designed and built to measure the displacement of the surface of the sheet at several points during the forming stage. A validation mold was instrumented to measure the in‐mold pressure profile during the forming process. Some preliminary attempts were carried out to consider the transient sheet heating stage and to evaluate its influence on the subsequent forming step. © 1995 John Wiley & Sons, Inc.

Stretch and inflation of hyperelastic membranes as applied to blow moldiing

AbstractThe free and confined inflation of isotropic homogeneour membranes of general shape are considered. The material is assumed to obey the Mooney‐Rivin constitutive model, and the resulting partial differential equations, governing the deformation field, are solved using a Galerkin based finite‐element procedure. The method is illustrated through examples of both free and conflined inflation, as well as simulationeus stretch and inflation. Measurements were carried out on the final thickness distributionof containers blow‐molded inour laboratory. These containers typically cover a wide range of geometry adn size, including bottles with handles. Comparison between theory and experiment leads generally to good agreement, despite the limitation of the membrane hypothesis.

An in vitro model of aging: the influence of increasing physical density on enzyme activities of trypsin, xanthine oxidase and superoxide dismutase.

The enzyme activities of trypsin (using an artificial substrate, Nalpha-benzoyl-L-arginine-ethylester = BAEE), xanthine oxidase (XOD) and superoxide dismutase (SOD) were measured in the absence and presence of various concentrations of the following inert, water-soluble polymer viscogens: polyvinylpyrrolidone (PVP-40), polyethyleneglycol (PEG-6000) and bovine serum albumin (BSA). Enzyme activities measured in the absence of viscogens were taken as 100%. In the presence of the viscogens, enzyme activities decreased considerably as follows: (i) Trypsin: to 2 or 12% in reaction mixtures containing 64 mg/ml PVP-40 or 481 mg/ml PEG-6000, respectively. (ii) XOD: to 29.3% in a reaction mixture containing 116 mg/ml PVP-40, to 68.9% in a medium containing 266 mg/ml PEG-6000, and 38.1% in the presence of 138 mg/ml BSA. (iii) SOD: to 40.0, 19.9 and 16.6% in the same media as listed for XOD, respectively. The observations are consistent with the predictions of the molecular enzyme kinetic model (MEKM), and are also of importance for the membrane hypothesis of aging, since the latter explains the loss of cell functions by an age-dependent increase of intracellular density which may cause serious enzyme inhibitions.

Resting membrane potentials: a student test of alternate hypotheses.

The frog sartorius muscle is a model tissue for demonstrating to physiology students the principles underlying both membrane phenomena and hypothesis testing. Myocytes can be impaled with conventional glass microelectrodes to measure membrane voltage (Vm). Further, Vm is observed as extracellular K+ is altered and a K+ channel blocker is added. After the experiment, students examine the underlying assumptions of the Nernst equilibrium and the Goldman-Hodgkin-Katz equation. They ultimately determine which of the two algorithms best predicts the measured Vm. In addition, students learn micromanipulation and impalement techniques. This experiment facilitates the student's understanding of membrane permeability, ionic gradients, and membrane voltage.

On membrane solutions for elevated shell-of-revolution tanks of certain meridional profiles

This paper reports the findings of research into the possibility of certain shell forms for elevated reservoirs, initially conducted on the basis of the membrane hypothesis. In order to place the methods used and the findings obtained firmly into context, the paper begins by a review of the conditions of applicability of membrane solutions. Then, on the basis of a rectangular coordinate system, general expressions for membrane stress resultants are developed for elevated liquid-filled tanks in the form of shells of revolution of arbitrary meridian profiles. These expressions are next applied to selected profiles with zero slope at the pole (consistent with the smoothness requirements of the membrane hypothesis), and of reasonable shape for containment. A general discussion of the validity of the results, particularly for locations around the poles, is followed by a comparison of the membrane-stress variations for tanks of the same height and circular plan area, based on typical values of these dimensions. Finally, by defining a form efficiency parameter η, the tank of most desirable profile (from among the cases studied) is suggested.

The membrane hypothesis of schizophrenia

The phospholipid structure of neuronal membranes is essential for normal functioning of the nervous system. Evidence is accumulating that phospholipid metabolism in both brain and red blood cells may be disturbed in schizophrenia. In particular, in patients with negative symptoms, levels of arachidonic acid and docosahexanoic acid in red blood cell membrane phospholipids are severely abnormal. The membrane hypothesis of schizophrenia may represent a new and fruitful paradigm for future research.

The potent free radical scavenger α-lipoic acid improves memory in aged mice: Putative relationship to NMDA receptor deficits

α-lipoic acid (α-LA) improved longer-term memory of aged female NMRI mice in the habituation in the open field test at a dose of 100 mg/kg body weight for 15 days. In a separate experiment, no such effect could be found for young mice. α-LA alleviated age-related NMDA receptor deficits ( B max) without changing muscarinic, benzodiazepine, and α 2-adrenergic receptor deficits in aged mice. The carbachol-stimulated accumulation of inositol monophosphates was not changed by the treatment with α-LA. These results give tentative support to the hypothesis that α-LA improves memory in aged mice, probably by a partial compensation of NMDA receptor deficits. Possible modes of action of α-LA based on its free radical scavenger properties are discussed in relation to the membrane hypothesis of aging.

Molecular interactions of anaesthetics with biological membranes

1. 1. There is not yet a consensus as to which of the neuronal membranes, which molecular component of any particular membrane or what specific function of the membrane is critical for general anaesthesia. 2. 2. However, when considering anaesthetic effects on different synapses, with neurotransmitter receptors, ion channels etc., the unifying central concept is action at a membrane level. 3. 3. This paper will review the general evidence for this unifying hypothesis, and consider the apparent exceptions and limitations. 4. 4. The membrane hypothesis is usually stated in the form of the Meyer and Overton “rule” relating anaesthetic potency to hydrophobic solubility. 5. 5. The relationship applies to inhaled anaesthetics with potencies over a 100,000-fold range and has been described as one of the most powerful correlations in biology. 6. 6. Finding additional compounds that confirm this correlation is not likely to elucidate further the anaesthetic mode of action, and concentrating on the apparent exceptions to the hypothesis may prove to be a better approach. 7. 7. The apparent exceptions to the membrane hypothesis include some of the physiological and convulsant gases as well as higher members of a homologous series of hydrophobic compounds above the so-called “cut-off” effect. 8. 8. The apparent limitations include two of the most widely used clinical agents—enflurane and isoflurane. 9. 9. This paper will include some new data characterizing the anaesthetic site of action using a diverse group of anaesthetics (including some of the exceptions already mentioned). 10. 10. The evidence is against an earlier hypothesis that there is a bimodal distribution of the molecular sites.

Pigment of the imagination: a history of phytochrome research

Daylength and flowering the 1930s spectral studies action spectra for floral induction action spectra for elongation growth photoreversibility the 1950s high-energy responses detection partial purification the properties of phytochrome phototransformation in vivo spectrophotometric studies seed germination and flowering photoperiodic timing mougeotia ode of action the Hartmann model large phytochrome the gene regulation hypothesis dark transformations localization properties of large phytochrome the membrane hypothesis high-irradiance responses the very low fluence response - a dimer model shade avoidance the chromophore native phytochrome native pr and pfr sequestered and ubiquitinated phytochrome multiple phytochromes gene regulation autoregulation phytochrome and flowering. Epiloque: weed control coloured mulch.

The infectivity of spongiform encephalopathies: does a modified membrane hypothesis account for lack of immune response?

Scrapie, the prototype of a group of diseases which have the unique property of being both hereditary and infectious, is also exceptional in that it fails to evoke an immune response. Purification of crude scrapie preparations revealed a strong association of infectivity with a membrane protein ('PrPsc'); but a protein with the same amino acid sequence ('PrPc') was subsequently also found in normal mammalian nervous tissue. It is postulated by some investigators that 'PrPsc' is itself the infectious agent, or the most important part thereof, but in papers making that proposal immunological aspects have not been addressed. Experimental evidence supporting the hypothesis of a membrane fragment as agent has likewise lately not been taken into account. A modified form of the membrane hypothesis could account for immunological as well as genetic aspects of these diseases.

The infectivity of spongiform encephalopathies: does a modified membrane hypothesis account for lack of immune response?

The infectivity of spongiform encephalopathies: does a modified membrane hypothesis account for lack of immune response?

The effects of the molecular environment on the kinetics of catalase reaction and its relevance to cell aging

Catalase-mediated oxygen evolution from H 2O 2 was measured with a Clark electrode in a closed, buffered aqueous medium in a properly designed experimental model. Addition of various molecules (bovine serum albumin, egg albumin, dextrane, starch and PEG-8000) in increasing concentrations up to greater than 20% by volume decreased the rate of oxygen evolution in a linear fashion, although there were some quantitative differences between the effects of various components. The rotational correlation time of the spin label TMPN in BSA and egg albumin increased considerably in both protein solutions indicating a very significant increase of the microviscosity of these media. The results are interpreted in terms of the molecular enzyme kinetic model (MEKM) predicting that apart from microviscosity, the average mass distribution and the distance of the nearest two lattice points formed by components of the medium are also inversely proportional to both the forward and backward rate constants of the formation of the enzyme-substrate complex. These observations, on one hand, lend further experimental support to the MEKM and on the other one, are consistent with the membrane hypothesis of aging which explains the loss of cell functions by an age-dependent increase of intracellular density.

The horizons of an interdisciplinary synthesis in experimental gerontology

This review summarizes the main points of an interdisciplinary, theoretically established approach to the problem of cell senescence, called membrane hypothesis of aging (MHA). The main knowledge and some new suggestions regarding the damaging and sometimes useful roles of the oxygen free radicals is outlined. The most important experimental results are listed, which harmonize with the MHA. It is emphasized that MHA is not an alternative to the other aging hypotheses but represents a synthesis of most of them. It is pointed out that the new drug design based on the MHA resulted in a useful new molecule which is able to improve the key cell parameters deteriorated by advancing age. The necessity of a closer international cooperation is emphasized, in order to achieve a breakthrough in experimental gerontology within this century.

Cholesterol accumulation in plasma membrane and changes of membrane enzyme activity of Acholeplasma laidlawii cells during culture ageing

The data presented in this report show that the microviscosity of the plasma membrane and the cholesterol/phospholipid molar ratio of its lipid bilayer increases during ageing of Acholeplasma laidlawii cultures. At the same time the age changes of other lipid componetns content do not correlate with the change of membrane viscosity. It is also shown that membrane enzyme activities of mycoplasma cell decrease with age. These results confirm the membrane hypothesis of ageing according to which increased microviscosity is the essential factor of cell ageing.

Effects of centrophenoxine on body composition and some biochemical parameters of demented elderly people as revealed in a double-blind clinical trial

A double-blind clinical trial was performed on 50 persons (25 men, 25 women, average age 77 years) suffering from dementias of medium level (DSM III, Category 1, ICD No. 299). All subjects were residents in an old age home. The patients were treated first for 2 weeks by placebo tablets. During this period, body composition parameters were determined and these data served as controls. This was then followed by an 8-week-long treatment with the nootropic drug, centrophenoxine (CPH), 2 g/day distributed in 2×2 tablets of Helfergin 500 (Promonta, Hamburg, F.R.G.), or placebo tablets of identical size. After 8 weeks the laboratory tests were repeated again. The randomization code for verum or placebo treatment was revealed only after completing the trial. Four dropouts occurred during the treatment period. The total body water, extracellular water volume and exchangable Na + were determined by means of radioisotope methods. Plasma volume (PV) was measured by indocyanine-green dilution test. Body weights were also recorded. From the above data further parameters could be calculated. Serum lipid data as well as several hormone levels were also checked in the blood samples. The main results were better performance in psychometric tests (Pék et al., 1989) and a significant increase of the average intracellular water content (2.2–2.5% by weight) in the verum-treated group. The rehydration of the intracellular mass due to CPH treatment is consistent with the OH •. free radical scavenger properties of CPH and the predictions of the membrane hypothesis of aging.

The structural behaviour of liquid-filled spherical vessels. Part 1: Background and theoretical preliminaries

This paper is the first of two articles which aim to conduct a comprehensive parametric study for the problem of thin spherical containers filled to capacity with liquid. The investigation places particular emphasis on the effect of the bending disturbances arising at the support location. The latter produces b in-plane and flexural stresses which must be added to those computed in accordance with the membrane hypothesis, i.e. the simplified theory that appears to provide the sole basis of most current design calculations. In the present article, the background to the problem is outlined and the necessary theoretical formulation given.

On the role of intracellular physicochemistry in quantitative gene expression during aging and the effect of centrophenoxine. A review

The turnover of proteins in biological systems is due mostly to an ever-occuring damaging (cross-linking) effect of the OH' free radicals. The replacement of the damaged proteins requires a continuous gene expression. A key issue of experimental gerontology is why the gene expression maintains the fidelity but loses the speed during aging. The membrane hypothesis of aging (MHA) proposes a cellular mechanism based on the fact that the more compact cellular structures (e.g., membranes) are damaged faster than the more diluted ones (e.g., cytosol). In addition, the cell membrane is exposed also to the residual heat-induced damage deriving from a frequent discharge of its electric polarity. Therefore, one can assume that even an extremely small incompleteness of the replacement of the damaged membrane components per turnover cycle may result in an error accumulation, which may be responsible first for the inhibition of growth, then for aging of cells. In agreement with this hypothesis, neurons display a life-long, gradual loss of the passive potassium permeability of the cell membrane, resulting in a continuous dehydration of the intracellular mass, i.e., an increase of physical density. Theory and experimental models show that this latter process causes a slowing down of all enzyme functions including those realizing the gene expression and the elimination of the damaged components. Increase of-the dry mass content of cells and tissues is an obligatory process for maturation; however, later on it leads to aging. The known nootropic effects of centrophenoxine (CPH) can be interpreted on the basis of the OH' radical scavenger properties of dimethylaminoethanol (DMAE) which is incorporated in the neuronal membranes of the brain in form of phosphatidyl-DMAE. The protective effects of CPH (and of similar, newly synthesized other drugs) on the membrane components can slow down the age-dependent deteriorations of the intracellular physicochemistry, in agreement with the predictions of the MHA.