Oxidative stress

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Oxidative_stress 

 

Oxidative stress mechanisms in tissue injury. Free radical toxicity induced by xenobiotics and the subsequent detoxification by cellular enzymes (termination).

Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal redox state of cells can cause toxic effects through the production of peroxides and free radicals that damage all components of the cell, including proteins, lipids, and DNA. Oxidative stress from oxidative metabolism causes base damage, as well as strand breaks in DNA. Base damage is mostly indirect and caused by the reactive oxygen species (ROS) generated, e.g., O₂⁻ (superoxide radical), OH (hydroxyl radical) and H₂O₂ (hydrogen peroxide). Further, some reactive oxidative species act as cellular messengers in redox signaling. Thus, oxidative stress can cause disruptions in normal mechanisms of cellular signaling.

In humans, oxidative stress is thought to be involved in the development of ADHD, cancer, Parkinson's disease, Lafora disease, Alzheimer's disease, atherosclerosis, heart failure, myocardial infarction, fragile X syndrome, sickle-cell disease, lichen planus, vitiligo, autism, infection, chronic fatigue syndrome (ME/CFS), and depression and seems to be characteristic of individuals with Asperger syndrome. However, reactive oxygen species can be beneficial, as they are used by the immune system as a way to attack and kill pathogens. Short-term oxidative stress may also be important in prevention of aging by induction of a process named mitohormesis.

Chemical and biological effects

Chemically, oxidative stress is associated with increased production of oxidizing species or a significant decrease in the effectiveness of antioxidant defenses, such as glutathione. The effects of oxidative stress depend upon the size of these changes, with a cell being able to overcome small perturbations and regain its original state. However, more severe oxidative stress can cause cell death, and even moderate oxidation can trigger apoptosis, while more intense stresses may cause necrosis.

Production of reactive oxygen species is a particularly destructive aspect of oxidative stress. Such species include free radicals and peroxides. Some of the less reactive of these species (such as superoxide) can be converted by oxidoreduction reactions with transition metals or other redox cycling compounds (including quinones) into more aggressive radical species that can cause extensive cellular damage. Most long-term effects are caused by damage to DNA. DNA damage induced by ionizing radiation is similar to oxidative stress, and these lesions have been implicated in aging and cancer. Biological effects of single-base damage by radiation or oxidation, such as 8-oxoguanine and thymine glycol, have been extensively studied. Recently the focus has shifted to some of the more complex lesions. Tandem DNA lesions are formed at substantial frequency by ionizing radiation and metal-catalyzed H₂O₂ reactions. Under anoxic conditions, the predominant double-base lesion is a species in which C8 of guanine is linked to the 5-methyl group of an adjacent 3'-thymine (G[8,5- Me]T). Most of these oxygen-derived species are produced by normal aerobic metabolism. Normal cellular defense mechanisms destroy most of these. Repair of oxidative damages to DNA is frequent and ongoing, largely keeping up with newly induced damages. In rat urine about 74,000 oxidative DNA adducts per cell per day are excreted. However, there is a steady state level of oxidative damages, as well, in the DNA of a cell. There are about 24,000 oxidative DNA adducts per cell in young rats and 66,000 adducts per cell in old rats. Likewise, any damage to cells is constantly repaired. However, under the severe levels of oxidative stress that cause necrosis, the damage causes ATP depletion, preventing controlled apoptotic death and causing the cell to simply fall apart.

Polyunsaturated fatty acids, particularly arachidonic acid and linoleic acid, are primary targets for free radical and singlet oxygen oxidations. For example, in tissues and cells, the free radical oxidation of linoleic acid produces racemic mixtures of 13-hydroxy-9Z,11E-octadecadienoic acid, 13-hydroxy-9E,11E-octadecadienoic acid, 9-hydroxy-10E,12-E-octadecadienoic acid (9-EE-HODE), and 11-hydroxy-9Z,12-Z-octadecadienoic acid as well as 4-Hydroxynonenal while singlet oxygen attacks linoleic acid to produce (presumed but not yet proven to be racemic mixtures of) 13-hydroxy-9Z,11E-octadecadienoic acid, 9-hydroxy-10E,12-Z-octadecadienoic acid, 10-hydroxy-8E,12Z-octadecadienoic acid, and 12-hydroxy-9Z-13-E-octadecadienoic (see 13-Hydroxyoctadecadienoic acid and 9-Hydroxyoctadecadienoic acid). Similar attacks on arachidonic acid produce a far larger set of products including various isoprostanes, hydroperoxy- and hydroxy- eicosatetraenoates, and 4-hydroxyalkenals. While many of these products are used as markers of oxidative stress, the products derived from linoleic acid appear far more predominant than arachidonic acid products and therefore easier to identify and quantify in, for example, atheromatous plaques. Certain linoleic acid products have also been proposed to be markers for specific types of oxidative stress. For example, the presence of racemic 9-HODE and 9-EE-HODE mixtures reflects free radical oxidation of linoleic acid whereas the presence of racemic 10-hydroxy-8E,12Z-octadecadienoic acid and 12-hydroxy-9Z-13-E-octadecadienoic acid reflects singlet oxygen attack on linoleic acid. In addition to serving as markers, the linoleic and arachidonic acid products can contribute to tissue and/or DNA damage but also act as signals to stimulate pathways which function to combat oxidative stress.

Oxidant	Description
•O− 2, superoxide anion	One-electron reduction state of O 2, formed in many autoxidation reactions and by the electron transport chain. Rather unreactive but can release Fe2+ from iron-sulfur proteins and ferritin. Undergoes dismutation to form H 2O 2 spontaneously or by enzymatic catalysis and is a precursor for metal-catalyzed •OH formation.
H 2O 2, hydrogen peroxide	Two-electron reduction state, formed by dismutation of •O− 2 or by direct reduction of O 2. Lipid-soluble and thus able to diffuse across membranes.
•OH, hydroxyl radical	Three-electron reduction state, formed by Fenton reaction and decomposition of peroxynitrite. Extremely reactive, will attack most cellular components
ROOH, organic hydroperoxide	Formed by radical reactions with cellular components such as lipids and nucleobases.
RO•, alkoxy and ROO•, peroxy radicals	Oxygen centred organic radicals. Lipid forms participate in lipid peroxidation reactions. Produced in the presence of oxygen by radical addition to double bonds or hydrogen abstraction.
HOCl, hypochlorous acid	Formed from H 2O 2 by myeloperoxidase. Lipid-soluble and highly reactive. Will readily oxidize protein constituents, including thiol groups, amino groups and methionine.
ONOO-, peroxynitrite	Formed in a rapid reaction between •O− 2 and NO•. Lipid-soluble and similar in reactivity to hypochlorous acid. Protonation forms peroxynitrous acid, which can undergo homolytic cleavage to form hydroxyl radical and nitrogen dioxide.

Production and consumption of oxidants

One source of reactive oxygen under normal conditions in humans is the leakage of activated oxygen from mitochondria during oxidative phosphorylation. However, E. coli mutants that lack an active electron transport chain produced as much hydrogen peroxide as wild-type cells, indicating that other enzymes contribute the bulk of oxidants in these organisms. One possibility is that multiple redox-active flavoproteins all contribute a small portion to the overall production of oxidants under normal conditions.

Other enzymes capable of producing superoxide are xanthine oxidase, NADPH oxidases and cytochromes P450. Hydrogen peroxide is produced by a wide variety of enzymes including several oxidases. Reactive oxygen species play important roles in cell signalling, a process termed redox signaling. Thus, to maintain proper cellular homeostasis, a balance must be struck between reactive oxygen production and consumption.

The best studied cellular antioxidants are the enzymes superoxide dismutase (SOD), catalase, and glutathione peroxidase. Less well studied (but probably just as important) enzymatic antioxidants are the peroxiredoxins and the recently discovered sulfiredoxin. Other enzymes that have antioxidant properties (though this is not their primary role) include paraoxonase, glutathione-S transferases, and aldehyde dehydrogenases.

The amino acid methionine is prone to oxidation, but oxidized methionine can be reversible. Oxidation of methionine is shown to inhibit the phosphorylation of adjacent Ser/Thr/Tyr sites in proteins. This gives a plausible mechanism for cells to couple oxidative stress signals with cellular mainstream signaling such as phosphorylation.

Diseases

Oxidative stress is suspected to be important in neurodegenerative diseases including Lou Gehrig's disease (aka MND or ALS), Parkinson's disease, Alzheimer's disease, Huntington's disease, depression, autism, and multiple sclerosis. Indirect evidence via monitoring biomarkers such as reactive oxygen species, and reactive nitrogen species production indicates oxidative damage may be involved in the pathogenesis of these diseases, while cumulative oxidative stress with disrupted mitochondrial respiration and mitochondrial damage are related to Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases.

Oxidative stress is thought to be linked to certain cardiovascular disease, since oxidation of LDL in the vascular endothelium is a precursor to plaque formation. Oxidative stress also plays a role in the ischemic cascade due to oxygen reperfusion injury following hypoxia. This cascade includes both strokes and heart attacks. Oxidative stress has also been implicated in chronic fatigue syndrome (ME/CFS). Oxidative stress also contributes to tissue injury following irradiation and hyperoxia, as well as in diabetes. In hematological cancers, such as leukemia, the impact of oxidative stress can be bilateral. Reactive oxygen species can disrupt the function of immune cells, promoting immune evasion of leukemic cells. On the other hand, high levels of oxidative stress can also be selectively toxic to cancer cells.

Oxidative stress is likely to be involved in age-related development of cancer. The reactive species produced in oxidative stress can cause direct damage to the DNA and are therefore mutagenic, and it may also suppress apoptosis and promote proliferation, invasiveness and metastasis. Infection by Helicobacter pylori which increases the production of reactive oxygen and nitrogen species in human stomach is also thought to be important in the development of gastric cancer.

Antioxidants as supplements

The use of antioxidants to prevent some diseases is controversial. In a high-risk group like smokers, high doses of beta carotene increased the rate of lung cancer since high doses of beta-carotene in conjunction of high oxygen tension due to smoking results in a pro-oxidant effect and an antioxidant effect when oxygen tension isn't high. In less high-risk groups, the use of vitamin E appears to reduce the risk of heart disease. However, while consumption of food rich in vitamin E may reduce the risk of coronary heart disease in middle-aged to older men and women, using vitamin E supplements also appear to result in an increase in total mortality, heart failure, and hemorrhagic stroke. The American Heart Association therefore recommends the consumption of food rich in antioxidant vitamins and other nutrients, but does not recommend the use of vitamin E supplements to prevent cardiovascular disease. In other diseases, such as Alzheimer's, the evidence on vitamin E supplementation is also mixed. Since dietary sources contain a wider range of carotenoids and vitamin E tocopherols and tocotrienols from whole foods, ex post facto epidemiological studies can have differing conclusions than artificial experiments using isolated compounds. However, AstraZeneca's radical scavenging nitrone drug NXY-059 shows some efficacy in the treatment of stroke.

Oxidative stress (as formulated in Harman's free radical theory of aging) is also thought to contribute to the aging process. While there is good evidence to support this idea in model organisms such as Drosophila melanogaster and Caenorhabditis elegans, recent evidence from Michael Ristow's laboratory suggests that oxidative stress may also promote life expectancy of Caenorhabditis elegans by inducing a secondary response to initially increased levels of reactive oxygen species. The situation in mammals is even less clear. Recent epidemiological findings support the process of mitohormesis, however a 2007 meta-analysis indicating studies with a low risk of bias (randomization, blinding, follow-up) find that some popular antioxidant supplements (Vitamin A, Beta Carotene, and Vitamin E) may increase mortality risk (although studies more prone to bias reported the reverse).

The USDA removed the table showing the Oxygen Radical Absorbance Capacity (ORAC) of Selected Foods Release 2 (2010) table due to the lack of evidence that the antioxidant level present in a food translated into a related antioxidant effect in the body.

Metal catalysts

Metals such as iron, copper, chromium, vanadium, and cobalt are capable of redox cycling in which a single electron may be accepted or donated by the metal. This action catalyzes production of reactive radicals and reactive oxygen species. The presence of such metals in biological systems in an uncomplexed form (not in a protein or other protective metal complex) can significantly increase the level of oxidative stress. These metals are thought to induce Fenton reactions and the Haber-Weiss reaction, in which hydroxyl radical is generated from hydrogen peroxide. The hydroxyl radical then can modify amino acids. For example, meta-tyrosine and ortho-tyrosine form by hydroxylation of phenylalanine. Other reactions include lipid peroxidation and oxidation of nucleobases. Metal catalyzed oxidations also lead to irreversible modification of R (Arg), K (Lys), P (Pro) and T (Thr) Excessive oxidative-damage leads to protein degradation or aggregation.

The reaction of transition metals with proteins oxidated by Reactive Oxygen Species or Reactive Nitrogen Species can yield reactive products that accumulate and contribute to aging and disease. For example, in Alzheimer's patients, peroxidized lipids and proteins accumulate in lysosomes of the brain cells.

Non-metal redox catalysts

Certain organic compounds in addition to metal redox catalysts can also produce reactive oxygen species. One of the most important classes of these is the quinones. Quinones can redox cycle with their conjugate semiquinones and hydroquinones, in some cases catalyzing the production of superoxide from dioxygen or hydrogen peroxide from superoxide.

Immune defense

The immune system uses the lethal effects of oxidants by making the production of oxidizing species a central part of its mechanism of killing pathogens; with activated phagocytes producing both ROS and reactive nitrogen species. These include superoxide (•O⁻
₂), nitric oxide (•NO) and their particularly reactive product, peroxynitrite (ONOO-). Although the use of these highly reactive compounds in the cytotoxic response of phagocytes causes damage to host tissues, the non-specificity of these oxidants is an advantage since they will damage almost every part of their target cell. This prevents a pathogen from escaping this part of immune response by mutation of a single molecular target.

Male infertility

Sperm DNA fragmentation appears to be an important factor in the aetiology of male infertility, since men with high DNA fragmentation levels have significantly lower odds of conceiving. Oxidative stress is the major cause of DNA fragmentation in spermatozoa. A high level of the oxidative DNA damage 8-OHdG is associated with abnormal spermatozoa and male infertility.

Aging

In a rat model of premature aging, oxidative stress induced DNA damage in the neocortex and hippocampus was substantially higher than in normally aging control rats. Numerous studies have shown that the level of 8-OHdG, a product of oxidative stress, increases with age in the brain and muscle DNA of the mouse, rat, gerbil and human. Further information on the association of oxidative DNA damage with aging is presented in the article DNA damage theory of aging. However, it was recently shown that the fluoroquinolone antibiotic enoxacin can diminish aging signals and promote lifespan extension in nematodes C. elegans by inducing oxidative stress.

Origin of eukaryotes

The great oxygenation event began with the biologically induced appearance of oxygen in the earth's atmosphere about 2.45 billion years ago. The rise of oxygen levels due to cyanobacterial photosynthesis in ancient microenvironments was probably highly toxic to the surrounding biota. Under these conditions, the selective pressure of oxidative stress is thought to have driven the evolutionary transformation of an archaeal lineage into the first eukaryotes. Oxidative stress might have acted in synergy with other environmental stresses (such as ultraviolet radiation and/or desiccation) to drive this selection. Selective pressure for efficient repair of oxidative DNA damages may have promoted the evolution of eukaryotic sex involving such features as cell-cell fusions, cytoskeleton-mediated chromosome movements and emergence of the nuclear membrane. Thus the evolution of meiotic sex and eukaryogenesis may have been inseparable processes that evolved in large part to facilitate repair of oxidative DNA damages.

COVID-19 and cardiovascular injury

It has been proposed that oxidative stress may play a major role to determine cardiac complications in COVID-19.

See also

• Reductive stress
• Acatalasia
• Antioxidant
• Bruce Ames
• Denham Harman
• Malondialdehyde, an oxidative stress marker
• Mitochondrial free radical theory of aging
• Mitohormesis
• Nitric oxide
• Pro-oxidant
• Antioxidative stress

Aging brain

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Aging_brain 

Aging is a major risk factor for most common neurodegenerative diseases, including mild cognitive impairment, dementias including Alzheimer's disease, cerebrovascular disease, Parkinson's disease, and Lou Gehrig's disease. While much research has focused on diseases of aging, there are few informative studies on the molecular biology of the aging brain (usually spelled ageing brain in British English) in the absence of neurodegenerative disease or the neuropsychological profile of healthy older adults. However, research suggests that the aging process is associated with several structural, chemical, and functional changes in the brain as well as a host of neurocognitive changes. Recent reports in model organisms suggest that as organisms age, there are distinct changes in the expression of genes at the single neuron level. This page is devoted to reviewing the changes associated with healthy aging.

Structural changes

Aging entails many physical, biological, chemical, and psychological changes. Therefore, it is logical to assume the brain is no exception to this phenomenon. CT scans have found that the cerebral ventricles expand as a function of age. More recent MRI studies have reported age-related regional decreases in cerebral volume. Regional volume reduction is not uniform; some brain regions shrink at a rate of up to 1% per year, whereas others remain relatively stable until the end of the life-span. The brain is very complex, and is composed of many different areas and types of tissue, or matter. The different functions of different tissues in the brain may be more or less susceptible to age-induced changes. The brain matter can be broadly classified as either grey matter, or white matter. Grey matter consists of cell bodies in the cortex and subcortical nuclei, whereas white matter consists of tightly packed myelinated axons connecting the neurons of the cerebral cortex to each other and with the periphery.

Loss of neural circuits and brain plasticity

Brain plasticity refers to the brain's ability to change structure and function. This ties into the common phrase, "if you don't use it, you lose it," which is another way of saying, if you don't use it, your brain will devote less somatotopic space for it. One proposed mechanism for the observed age-related plasticity deficits in animals is the result of age-induced alterations in calcium regulation. The changes in our abilities to handle calcium will ultimately influence neuronal firing and the ability to propagate action potentials, which in turn would affect the ability of the brain to alter its structure or function (i.e. its plastic nature). Due to the complexity of the brain, with all of its structures and functions, it is logical to assume that some areas would be more vulnerable to aging than others. Two circuits worth mentioning here are the hippocampal and neocortical circuits. It has been suggested that age-related cognitive decline is due in part not to neuronal death but to synaptic alterations. Evidence in support of this idea from animal work has also suggested that this cognitive deficit is due to functional and biochemical factors such as changes in enzymatic activity, chemical messengers, or gene expression in cortical circuits.

Thinning of the cortex

Advances in MRI technology have provided the ability to see the brain structure in great detail in an easy, non-invasive manner in vivo. Bartzokis et al., has noted that there is a decrease in grey matter volume between adulthood and old age, whereas white matter volume was found to increase from age 19–40, and decline after this age. Studies using Voxel-based morphometry have identified areas such as the insula and superior parietal gyri as being especially vulnerable to age-related losses in grey matter of older adults. Sowell et al., reported that the first 6 decades of an individual's life were correlated with the most rapid decreases in grey matter density, and this occurred over dorsal, frontal, and parietal lobes on both interhemispheric and lateral brain surfaces. It is also worth noting that areas such as the cingulate gyrus, and occipital cortex surrounding the calcarine sulcus appear exempt from this decrease in grey matter density over time. Age effects on grey matter density in the posterior temporal cortex appear more predominantly in the left versus right hemisphere, and were confined to posterior language cortices. Certain language functions such as word retrieval and production were found to be located to more anterior language cortices, and deteriorate as a function of age. Sowell et al., also reported that these anterior language cortices were found to mature and decline earlier than the more posterior language cortices. It has also been found that the width of sulcus not only increases with age, but also with cognitive decline in the elderly.

Age-related neuronal morphology

There is converging evidence from cognitive neuroscientists around the world that age-induced cognitive deficits may not be due to neuronal loss or cell death, but rather may be the result of small region-specific changes to the morphology of neurons. Studies by Duan et al., have shown that dendritic arbors and dendritic spines of cortical pyramidal neurons decrease in size and/or number in specific regions and layers of human and non-human primate cortex as a result of age (Duan et al., 2003; morph). A 46% decrease in spine number and spine density has been reported in humans older than 50 compared with younger individuals. An electron microscopy study in monkeys reported a 50% loss in spines on the apical dendritic tufts of pyramidal cells in prefrontal cortex of old animals (27–32 years old) compared with young ones (6–9 years old).

Neurofibrillary tangles

Age-related neuro-pathologies such as Alzheimer's disease, Parkinson's disease, diabetes, hypertension and arteriosclerosis make it difficult to distinguish the normal patterns of aging. One of the important differences between normal aging and pathological aging is the location of neurofibrillary tangles. Neurofibrillary tangles are composed of paired helical filaments (PHF). In normal, non-demented aging, the number of tangles in each affected cell body is relatively low and restricted to the olfactory nucleus, parahippocampal gyrus, amygdala and entorhinal cortex. As the non-demented individual ages, there is a general increase in the density of tangles, but no significant difference in where tangles are found. The other main neurodegenerative contributor commonly found in the brain of patients with AD is amyloid plaques. However, unlike tangles, plaques have not been found to be a consistent feature of normal aging.

Role of oxidative stress

Main article: Oxidative stress

Cognitive impairment has been attributed to oxidative stress, inflammatory reactions and changes in the cerebral microvasculature. The exact impact of each of these mechanisms in affecting cognitive aging is unknown. Oxidative stress is the most controllable risk factor and is the best understood. The online Merriam-Webster Medical Dictionary defines oxidative stress as, "physiological stress on the body that is caused by the cumulative damage done by free radicals inadequately neutralized by antioxidants and that is to be associated with aging." Hence oxidative stress is the damage done to the cells by free radicals that have been released from the oxidation process.

Compared to other tissues in the body, the brain is deemed unusually sensitive to oxidative damage. Increased oxidative damage has been associated with neurodegenerative diseases, mild cognitive impairment and individual differences in cognition in healthy elderly people. In 'normal aging', the brain is undergoing oxidative stress in a multitude of ways. The main contributors include protein oxidation, lipid peroxidation and oxidative modifications in nuclear and mitochondrial DNA. Oxidative stress can damage DNA replication and inhibit repair through many complex processes, including telomere shortening in DNA components. Each time a somatic cell replicates, the telomeric DNA component shortens. As telomere length is partly inheritable, there are individual differences in the age of onset of cognitive decline.

DNA damage

At least 25 studies have demonstrated that DNA damage accumulates with age in the mammalian brain. This DNA damage includes the oxidized nucleoside 8-hydroxydeoxyguanosine (8-OHdG), single- and double-strand breaks, DNA-protein crosslinks and malondialdehyde adducts (reviewed in Bernstein et al.). Increasing DNA damage with age has been reported in the brains of the mouse, rat, gerbil, rabbit, dog, and human. Young 4-day-old rats have about 3,000 single-strand breaks and 156 double-strand breaks per neuron, whereas in rats older than 2 years the level of damage increases to about 7,400 single-strand breaks and 600 double-strand breaks per neuron.

Lu et al. studied the transcriptional profiles of the human frontal cortex of individuals ranging from 26 to 106 years of age. This led to the identification of a set of genes whose expression was altered after age 40. They further found that the promoter sequences of these particular genes accumulated oxidative DNA damage, including 8-OHdG, with age. They concluded that DNA damage may reduce the expression of selectively vulnerable genes involved in learning, memory and neuronal survival, initiating a pattern of brain aging that starts early in life.

Chemical changes

In addition to the structural changes that the brain incurs with age, the aging process also entails a broad range of biochemical changes. More specifically, neurons communicate with each other via specialized chemical messengers called neurotransmitters. Several studies have identified a number of these neurotransmitters, as well as their receptors, that exhibit a marked alteration in different regions of the brain as part of the normal aging process.

Dopamine

An overwhelming number of studies have reported age-related changes in dopamine synthesis, binding sites, and number of receptors. Studies using positron emission tomography (PET) in living human subjects have shown a significant age-related decline in dopamine synthesis, notably in the striatum and extrastriatal regions (excluding the midbrain). Significant age-related decreases in dopamine receptors D₁, D₂, and D₃ have also been highly reported. A general decrease in D₁ and D₂ receptors has been shown, and more specifically a decrease of D₁ and D₂ receptor binding in the caudate nucleus and putamen. A general decrease in D₁ receptor density has also been shown to occur with age. Significant age-related declines in dopamine receptors, D₂ and D₃ were detected in the anterior cingulate cortex, frontal cortex, lateral temporal cortex, hippocampus, medial temporal cortex, amygdala, medial thalamus, and lateral thalamus One study also indicated a significant inverse correlation between dopamine binding in the occipital cortex and age. Postmortem studies also show that the number of D₁ and D₂ receptors decline with age in both the caudate nucleus and the putamen, although the ratio of these receptors did not show age-related changes. The loss of dopamine with age is thought to be responsible for many neurological symptoms that increase in frequency with age, such as decreased arm swing and increased rigidity. Changes in dopamine levels may also cause age-related changes in cognitive flexibility.

Serotonin

Decreasing levels of different serotonin receptors and the serotonin transporter, 5-HTT, have also been shown to occur with age. Studies conducted using PET methods on humans, in vivo, show that levels of the 5-HT₂ receptor in the caudate nucleus, putamen, and frontal cerebral cortex, decline with age. A decreased binding capacity of the 5-HT₂ receptor in the frontal cortex was also found, as well as a decreased binding capacity of the serotonin transporter, 5-HHT, in the thalamus and the midbrain. Postmortem studies on humans have indicated decreased binding capacities of serotonin and a decrease in the number of S₁ receptors in the frontal cortex and hippocampus as well as a decrease in affinity in the putamen.

Glutamate

Glutamate is another neurotransmitter that tends to decrease with age. Studies have shown older subjects to have lower glutamate concentration in the motor cortex compared to younger subjects. A significant age-related decline especially in the parietal gray matter, basal ganglia, and to a lesser degree, the frontal white matter, has also been noted. Although these levels were studied in the normal human brain, the parietal and basal ganglia regions are often affected in degenerative brain diseases associated with aging and it has therefore been suggested that brain glutamate may be useful as a marker of brain diseases that are affected by aging.

Neuropsychological changes

Changes in orientation

Orientation is defined as the awareness of self in relation to one's surroundings Often orientation is examined by distinguishing whether a person has a sense of time, place, and person. Deficits in orientation are one of the most common symptoms of brain disease, hence tests of orientation are included in almost all medical and neuropsychological evaluations. While research has primarily focused on levels of orientation among clinical populations, a small number of studies have examined whether there is a normal decline in orientation among healthy aging adults. Results have been somewhat inconclusive. Some studies suggest that orientation does not decline over the lifespan. For example, in one study 92% of normal elderly adults (65–84 years) presented with perfect or near perfect orientation. However some data suggest that mild changes in orientation may be a normal part of aging. For example, Sweet and colleagues concluded that "older persons with normal, healthy memory may have mild orientation difficulties. In contrast, younger people with normal memory have virtually no orientation problems" (p. 505). So although current research suggests that normal aging is not usually associated with significant declines in orientation, mild difficulties may be a part of normal aging and not necessarily a sign of pathology.

Changes in attention

Many older adults notice a decline in their attentional abilities. Attention is a broad construct that refers to "the cognitive ability that allows us to deal with the inherent processing limitations of the human brain by selecting information for further processing" (p. 334). Since the human brain has limited resources, people use their attention to zone in on specific stimuli and block out others.

If older adults have fewer attentional resources than younger adults, we would expect that when two tasks must be carried out at the same time, older adults' performance will decline more than that of younger adults. However, a large review of studies on cognition and aging suggest that this hypothesis has not been wholly supported. While some studies have found that older adults have a more difficult time encoding and retrieving information when their attention is divided, other studies have not found meaningful differences from younger adults. Similarly, one might expect older adults to do poorly on tasks of sustained attention, which measure the ability to attend to and respond to stimuli for an extended period of time. However, studies suggest that sustained attention shows no decline with age. Results suggest that sustained attention increases in early adulthood and then remains relatively stable, at least through the seventh decade of life. More research is needed on how normal aging impacts attention after age eighty.

It is worth noting that there are factors other than true attentional abilities that might relate to difficulty paying attention. For example, it is possible that sensory deficits impact older adults' attentional abilities. In other words, impaired hearing or vision may make it more difficult for older adults to do well on tasks of visual and verbal attention.

Changes in memory

Main article: Memory and aging

Many different types of memory have been identified in humans, such as declarative memory (including episodic memory and semantic memory), working memory, spatial memory, and procedural memory. Studies done, have found that memory functions, more specifically those associated with the medial temporal lobe are especially vulnerable to age-related decline. A number of studies utilizing a variety of methods such as histological, structural imaging, functional imaging, and receptor binding have supplied converging evidence that the frontal lobes and frontal-striatal dopaminergic pathways are especially affected by age-related processes resulting in memory changes.

Changes in language

Changes in performance on verbal tasks, as well as the location, extent, and signal intensity of BOLD signal changes measured with functional MRI, vary in predictable patterns with age. For example, behavioral changes associated with age include compromised performance on tasks related to word retrieval, comprehension of sentences with high syntactic and/or working memory demands, and production of such sentences.

Genetic changes

Variation in the effects of aging among individuals can be attributed to both genetic and environmental factors. As in so many other science disciplines, the nature and nurture debate is an ongoing conflict in the field of cognitive neuroscience. The search for genetic factors has always been an important aspect in trying to understand neuro-pathological processes. Research focused on discovering the genetic component in developing AD has also contributed greatly to the understanding the genetics behind normal or "non-pathological" aging.

The human brain shows a decline in function and a change in gene expression. This modulation in gene expression may be due to oxidative DNA damage at promoter regions in the genome. Genes that are down-regulated over the age of 40 include:

• GluR1 AMPA receptor subunit
• NMDA R2A receptor subunit (involved in learning)
• Subunits of the GABA-A receptor
• Genes involved in long-term potentiation e.g. calmodulin 1 and CAM kinase II alpha.
• Calcium signaling genes
• Synaptic plasticity genes
• Synaptic vesicle release and recycling genes

Genes that are upregulated include:

• Genes associated with stress response and DNA repair
• Antioxidant defence

Epigenetic age analysis of different brain regions

The cerebellum is the youngest brain region (and probably body part) in centenarians according to an epigenetic biomarker of tissue age known as epigenetic clock: it is about 15 years younger than expected in a centenarian. By contrast, all brain regions and brain cells appear to have roughly the same epigenetic age in subjects who are younger than 80. These findings suggest that the cerebellum is protected from aging effects, which in turn could explain why the cerebellum exhibits fewer neuropathological hallmarks of age related dementias compared to other brain regions.

Delaying the effects of aging

The process of aging may be inevitable; however, one may potentially delay the effects and severity of this progression. While there is no consensus of efficacy, the following are reported as delaying cognitive decline:

• High level of education
• Physical exercise
• Staying intellectually engaged, i.e. reading and mental activities (such as crossword puzzles)
• Maintaining social and friendship networks
• Maintaining a healthy diet, including omega-3 fatty acids, and protective antioxidants.

"Super Agers"

Longitudinal research studies have recently conducted genetic analyses of centenarians and their offspring to identify biomarkers as protective factors against the negative effects of aging. In particular, the cholesteryl ester transfer protein (CETP) gene is linked to prevention of cognitive decline and Alzheimer's disease. Specifically, valine CETP homozygotes but not heterozygotes experienced a relative 51% less decline in memory compared to a reference group after adjusting for demographic factors and APOE status.

Cognitive reserve

Main article: Cognitive reserve

The ability of an individual to demonstrate no cognitive signs of aging despite an aging brain is called cognitive reserve. This hypothesis suggests that two patients might have the same brain pathology, with one person experiencing noticeable clinical symptoms, while the other continues to function relatively normally. Studies of cognitive reserve explore the specific biological, genetic and environmental differences which make one person susceptible to cognitive decline, and allow another to age more gracefully.

Nun Study

Main article: Nun Study

A study funded by the National Institute of Aging followed a group of 678 Roman Catholic sisters and recorded the effects of aging. The researchers used autobiographical essays collected as the nuns joined their Sisterhood. Findings suggest that early idea density, defined by number of ideas expressed and use of complex prepositions in these essays, was a significant predictor of lower risk for developing Alzheimer's disease in old age. Lower idea density was found to be significantly associated with lower brain weight, higher brain atrophy, and more neurofibrillary tangles.

Hypothalamus inflammation and GnRH

In a recent study (published May 1, 2013), it is suggested that the inflammation of the hypothalamus may be connected to our overall aging bodies. They focused on the activation of the protein complex NF-κB in mice test subjects, which showed increased activation as mice test subjects aged in the study. This activation not only affects aging, but affects a hormone known as GnRH, which has shown new anti-aging properties when injected into mice outside the hypothalamus, while causing the opposite effect when injected into the hypothalamus. It'll be some time before this can be applied to humans in a meaningful way, as more studies on this pathway are necessary to understand the mechanics of GnRH's anti-aging properties.

Inflammation

A study found that myeloid cells are drivers of a maladaptive inflammation element of brain-ageing in mice and that this can be reversed or prevented via inhibition of their EP2 signalling.

Aging Disparities

For certain demographics, the effects of normal cognitive aging are especially pronounced. Differences in cognitive aging might be tied to the lack of or reduced access to medical care and, as a result, suffer disproportionately from negative health outcomes. As the global population grows, diversifies, and grays, there is an increasing need to understand these inequities.

Race

African Americans

In the United States, Black and African American demographics suffer disproportionately from metabolic dysfunction with age. This has many downstream effects, but the most prominent of these is the toll on cardiovascular health. Metabolite profiles of the healthy aging index - a score that assesses neurocognitive function, among other correlates of health through the years - are associated with cardiovascular disease. Healthy cardiovascular function is critical for maintaining neurocognitive efficiency into old age. Attention, verbal learning, and cognitive set ability are related to diastolic blood pressure, triglyceride levels, and HDL cholesterol levels, respectively.

Latinos

The Latino demographic is most likely to suffer from metabolic syndrome - the combination of high blood pressure, high blood sugar, elevated triglyceride levels, and abdominal obesity - which not only increases the risk of cardiac events and type II diabetes but also is associated with lower neurocognitive function during midlife. Among different Latin heritages, frequency of the dementia-predisposing apoE4 allele was highest for Caribbean Latinos (Cubans, Dominicans, and Puerto Ricans) and lowest among mainland Latinos (Mexicans, Central Americans, and South Americans). Conversely, frequency of the neuroprotective apoE2 allele was highest for Caribbean Latinos and lowest for those of mainland heritage.

Indigenous Peoples

Indigenous populations are often understudied in research. Reviews of current literature studying natives in Australia, Brazil, Canada, and the United States from participants aged 45 to 94 years old reveal varied prevalence rates for cognitive impairment not related to dementia, from 4.4% to 17.7%. These results can be interpreted in the context of culturally biased neurocognitive tests, preexisting health conditions, poor access to healthcare, lower educational attainment, and/or old age.

Sex

Women

Compared to their male counterparts, women’s scores on the Mini Mental State Exam (MMSE) tend to decline at slightly faster rates with age. Males with mild cognitive impairment tend to show more microstructural damage than females with MCI, but seem to have a greater cognitive reserve due to larger absolute brain size and neuronal density. As a result, women tend to manifest symptoms of cognitive decline at lower thresholds than men do. This effect seems to be moderated by educational attainment - higher education is associated with later diagnosis of mild cognitive impairment as neuropathological load increases.

Transgender Individuals

LGBT elders face numerous disparities as they approach end-of-life. The transgender community fears the risk of hate crime, elder abuse, homelessness, loss of identity, and loss of independence as they age. As a result, depression and suicidality are particularly high within the demographic. Intersectionality - the overlap of several minority identities - can play a major role in health outcomes, as transgender people can be discriminated against for their race, sexuality, gender identity, and age. In the oldest old, these considerations are especially important - as members of this generation have survived through systematic prejudice and discrimination in a time where their identity was outlawed and labeled by the Diagnostic and Statistical Manual of Mental Disorders as a mental illness.

Socioeconomic status

Socioeconomic status is the interaction between social and economic factors. It has been demonstrated that sociodemographic factors can be used to predict cognitive profiles within older individuals to some extent.  This may be because families of higher socioeconomic status are equipped to provide their children with resources early on to facilitate cognitive development. For children in families of low SES, relatively small changes in parental income were associated with large changes in brain surface area; these losses were seen in areas associated with language, reading, executive functions, and spatial skills. Meanwhile, for children in families of high SES, small changes in parental income were associated with small changes in surface area within these regions. With respect to global cortical thickness, low SES children showed a curvilinear decrease in thickness with age while those of high SES demonstrated a steeper linear decline, suggesting that synaptic pruning is more efficient in the latter group. This trend was especially evident in the left fusiform and left superior temporal gyri - critical language and literacy supporting areas.

See also

• Aging movement control
• Life extension
• List of life extension related topics
• Neuropsychological test
• Reliability theory of aging and longevity
• Senescence
• Sensory stimulation therapy
• Software aging
• Neuroscience of aging

 

Productive forces

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Productive_forces 

Productive forces, productive powers, or forces of production (German: Produktivkräfte) is a central idea in Marxism and historical materialism.

In Karl Marx and Friedrich Engels' own critique of political economy, it refers to the combination of the means of labor (tools, machinery, land, infrastructure, and so on) with human labour power. Marx and Engels probably derived the concept from Adam Smith's reference to the "productive powers of labour" (see e.g. chapter 8 of The Wealth of Nations (1776)), although the German political economist Friedrich List also mentions the concept of "productive powers" in The National System of Political Economy (1841).

All those forces which are applied by people in the production process (body and brain, tools and techniques, materials, resources, quality of workers' cooperation, and equipment) are encompassed by this concept, including those management and engineering functions technically indispensable for production (as contrasted with social control functions). Human knowledge can also be a productive force.

Together with the social and technical relations of production, the productive forces constitute a historically specific mode of production.

Labor

Karl Marx emphasized that with few exceptions means of labour are not a productive force unless they are actually operated, maintained and conserved by living human labour. Without applying living human labour, their physical condition and value would deteriorate, depreciate, or be destroyed (an example would be a ghost town or capital depreciation due to strike action).

Capital itself, being one of the factors of production, comes to be viewed in capitalist society as a productive force in its own right, independent from labour, a subject with "a life of its own". Indeed, Marx sees the essence of what he calls "the capital relation" as being summarised by the circumstance that "capital buys labour", i.e. the power of property ownership to command human energy and labour-time, and thus of inanimate "things" to exert an autonomous power over people. What disappears from view is that the power of capital depends in the last instance on human cooperation.

"The production of life, both of one’s own in labour and of fresh life in procreation... appears as a double relationship: on the one hand as a natural, on the other as a social relationship. By social we understand the co-operation of several individuals, no matter under what conditions, in what manner and to what end. It follows from this that a certain mode of production, or industrial stage, is always combined with a certain mode of co-operation, or social stage, and this mode of co-operation is itself a “productive force.”

The productive power of cooperation comes to be viewed as the productive power of capital, because it is capital which forcibly organises people, rather than people organising capital. Marx regarded this as a supreme reification.

Unlike British classical economics, Marxian economics classifies financial capital as being an element of the relations of production, rather than the factors or forces of production ("not a thing, but a social relation between persons, established by the instrumentality of things").

Destructive forces

Marx and Engels did not believe that human history featured a continuous growth of the productive forces. Rather, the development of the productive forces was characterised by social conflicts. Some productive forces destroyed other productive forces, sometimes productive techniques were lost or destroyed, and sometimes productive forces could be turned into destructive forces:

"How little highly developed productive forces are safe from complete destruction, given even a relatively very extensive commerce, is proved by the Phoenicians, whose inventions were for the most part lost for a long time to come through the ousting of this nation from commerce, its conquest by Alexander and its consequent decline. Likewise, for instance, glass-painting in the Middle Ages. Only when commerce has become world commerce, and has as its basis large-scale industry, when all nations are drawn into the competitive struggle, is the permanence of the acquired productive forces assured. (...) Competition soon compelled every country that wished to retain its historical role to protect its manufactures [sic] by renewed customs regulations (the old duties were no longer any good against big industry) and soon after to introduce big industry under protective duties. Big industry universalised competition in spite of these protective measures (it is practical free trade; the protective duty is only a palliative, a measure of defence within free trade), established means of communication and the modern world market, subordinated trade to itself, transformed all capital into industrial capital, and thus produced the rapid circulation (development of the financial system) and the centralisation of capital. By universal competition it forced all individuals to strain their energy to the utmost. It destroyed as far as possible ideology, religion, morality, etc. and where it could not do this, made them into a palpable lie. It produced world history for the first time, insofar as it made all civilised nations and every individual member of them dependent for the satisfaction of their wants on the whole world, thus destroying the former natural exclusiveness of separate nations. It made natural science subservient to capital and took from the division of labour the last semblance of its natural character. It destroyed natural growth in general, as far as this is possible while labour exists, and resolved all natural relationships into money relationships. In the place of naturally grown towns it created the modern, large industrial cities which have sprung up overnight. Wherever it penetrated, it destroyed the crafts and all earlier stages of industry. It completed the victory of the commercial town over the countryside. [Its first premise] was the automatic system. [Its development] produced a mass of productive forces, for which private [property] became just as much a fetter as the guild had been for manufacture and the small, rural workshop for the developing craft. These productive forces received under the system of private property a one-sided development only, and became for the majority destructive forces; moreover, a great multitude of such forces could find no application at all within this system. (...) from the conception of history we have sketched we obtain these further conclusions: (1) In the development of productive forces there comes a stage when productive forces and means of intercourse are brought into being, which, under the existing relationships, only cause mischief, and are no longer forces of production but forces of destruction (machinery and money); and connected with this a class is called forth, which has to bear all the burdens of society without enjoying its advantages, which, ousted from society, is forced into the most decided antagonism to all other classes; a class which forms the majority of all members of society, and from which emanates the consciousness of the necessity of a fundamental revolution, the communist consciousness, which may, of course, arise among the other classes too through the contemplation of the situation of this class. (...) Both for the production on a mass scale of this communist consciousness, and for the success of the cause itself, the changing of men on a mass scale is, necessary, a change which can only take place in a practical movement, a revolution; this revolution is necessary, therefore, not only because the ruling class cannot be overthrown in any other way, but also because the class overthrowing it, can only in a revolution succeed in ridding itself of all the muck of ages, and become fitted to found society anew.

Marxist–Leninist definition in the Soviet Union

The Institute of Economics of the Academy of Sciences of the U.S.S.R., textbook (1957, p xiv) says that "[t]he productive forces reflect the relationship of people to the objects and forces of nature used for the production of material wealth." (italics added) While productive forces are a human activity, the concept of productive forces includes the concept that technology mediates the human-nature relationship. Productive forces do not include the subject of labor (the raw materials or materials from nature being worked on). Productive forces are not the same thing as the means of production. Marx identified three components of production: human labor, subject of labor, and means of labor (1967, p 174). Productive forces are the union of human labor and the means of labor; means of production are the union of the subject of labor and the means of labor. (Institute of Economics of the Academy of Sciences of the U.S.S.R., 1957, p xiii).

On the other hand, The Great Soviet Encyclopedia (1969-1978) states:

Society’s principal productive forces are people—the participants in social production, or the workers and the toiling masses in general (K. Marx and F. Engels, vol. 46, part 1, p. 403; V. I. Lenin, Poln. sobr. soch., 5th ed., vol. 38, p. 359). <…>

Through the purposeful expenditure of labor power in labor activity, human beings “objectify” or embody themselves in the material world. The material elements of the productive forces (the means of production and the means of consumption) are the product of human reason and labor. The means of production include the means of labor, which transmit human influence to nature, and the objects of labor, to which human labor is applied. The most important components of the means of labor are the instruments of labor (for example, tools, devices, and machines).

(From Productive forces. — The Great Soviet Encyclopedia: in 30 volumes. — Moscow: «Soviet Encyclopedia», 1969-1978.; English web-version of the article; original version in Russian)

According to this, productive forces have such structure:

• People (human labour power)
• Means (the material elements of the productive forces)
  • Means of production
    • Means of labour
      • Instruments of labour
    • Objects of labour (also known as Subject of labour)
  • Means of consumption

Marxism in USSR served as core philosophical paradigm or platform, and had been developing as a science. So different views, hypotheses and approaches were widely discussed, tested and refined with time.

Determinism

See article: Theory of productive forces

Reification of technology

Other interpretations, sometimes influenced by postmodernism and the concept of commodity fetishism have by contrast emphasized the reification of the powers of technology, said to occur by the separation of technique from the producers, and by falsely imputing human powers to technology as autonomous force, the effect being a perspective of inevitable and unstoppable technological progress operating beyond any human control, and impervious to human choices.

In turn, this is said to have the effect of naturalising and legitimating social arrangements produced by people, by asserting that they are technically inevitable. The error here seems to be that social relations between people are confused and conflated with technical relations between people and things, and object relations between things; but this error is said to be a spontaneous result of the operation of a universal market and the process of commercialization.

Productivity

Marx's concept of productive forces also has some relevance for discussions in economics about the meaning and measurement of productivity.

Modern economics theorises productivity in terms of the marginal product of the factors of production. Marx theorises productivity within the capitalist mode of production in terms of the social and technical relations of production, with the concept of the organic composition of capital and the value product. He suggests there is no completely neutral view of productivity possible; how productivity is defined depends on the values and interests people have. Thus, different social classes have different notions of productivity reflecting their own station in life, and giving rise to different notions of productive and unproductive labour.

Critique of technology

In the Romantic or ecological critique of technology, technical progress boosting productivity often does not mean human progress at all. The design of production technologies may not be suited to human needs or human health, or technologies may be used in ways which do more harm than good. In that case, productive forces are transformed into destructive forces.

Sometimes this view leads to cultural pessimism or a theory of "Small is beautiful" as proposed by E. F. Schumacher. Ideas about alternative technology are also proposed. All of this suggests that the technologies we have, are only options which have been chosen from different technical possibilities existing at the time, and that the same technologies can be used for good or for ill, in different contexts.

A technology may be chosen because it is profitable, and once adopted on a mass scale, it may be difficult to create alternatives to it, particularly because it becomes integrated with other technologies and a whole "life style" (e.g. petrol-fueled cars). Yet that may not mean that the technology is ultimately desirable for human life on earth.

Productive force determinism is then criticised on the ground that whatever technologies are adopted, these are the result of human choices between technical alternatives, influenced by the human interests and stakes existing at the time. What may be presented as a pre-determined "technical necessity" may in reality have more to do with considerations of political, sociological, or economic power.

Advocates of technological progress however argue that even if admittedly "progress may have its price", without technical innovation there would be no progress at all; the same people who criticize technology also depend on it for their everyday existence.