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Aging in cells
In the aging brain, things just slow down. Enzymes that synthesize neurotransmitters become less active. Neurogenesis decreases. Vesicules become less efficient. The myelin sheath changes composition, affecting the transmission of electrical signals.
Up to 20% of some parts of the hippocampus, which is involved with emotion and learning, may be lost.
Within the neuron, the protoplasm outside the nucleus can start to fill with helical protein filaments known as neurofibrillary tangles, which impact normal cell functioning and contribute to such as Alzheimer's disease.
Many cells in the body normally reproduce by dividing. Cellular senescence or replicative senescence is the phenomenon whereby cells stop dividing, typically after about 50 divisions. Senescent cells are usually larger, with bigger nuclei.
In the brain, neurons cannot replicate but supporting cells such as glia (which do replicate) help repair brain damage. When these cells cannot replicate then brain decay can occur.
As cells divide, DNA telomeres (the looped region of repetitive DNA at the end of chromosomes) shorten. This is believed to limit the number of replications. Some cells, including stem cells and their progeny, avoid this problem by using the enzyme telemerase to add new repeats to the chromosome ends.
Other factors that lead to senescence include chromatin decondensation, DNA damage, oncogene activation and over-activation of mitogenic stimuli. Accumulation of mutations in somatic cells can also lead to senescence.
Apoptosis is the process of programmed cell death (as opposed to necrosis and injury-related traumatic cell death). Between 50 and 70 billion adult cells die each day (for children between 8 and 14 it is between 20 and 30 billion). It naturally happens when the cell is damaged somehow, is infected or is stressed somehow.
Cells also divide and reproduce, keeping the system in overall balance, although this happens much less in the brain (although there is some neurogenesis).
Apoptosis is also a defense again cancer, preventing replication of damaged cells. The decision for apoptosis comes from the cell itself, the surrounding tissue or the immune system.
There are various theories about the detail of cellular aging. Kowald and Kirkwood's (1996) Network Theory takes the broad view that aging is a combination of multiple factors.
Free radicals are any substance that have unpaired electrons and are thus thermodynamically unstable and very reactive. In cells they react with proteins, nucleic acids and (particularly) lipids, damaging the cell and its membrane.
Animal experiments have shown that reducing free radicals increases longevity. This has sparked a whole diet and health industry.
During transport to the inner mitochondrial membrane, oxygen molecules gain four electrons, leading to the creation of superoxide radicals. Some of these are converted to hydrogen peroxide, H2O2 which diffuses through cell walls and generates more free radicals, in particular the hydroxyl radical, HO•.
Oxygen-based free radicals plus non-radical oxidants (such as hydrogen peroxide) are called reactive oxygen species (ROS). These can also be caused by environmental pollution and radiation, as well as internal cell effects. Nitric oxide and peroxynitrate are reactive nitrogen species (RNS) as well as ROS. RNS reacts with amino acids, thus disrupting function.
Adenosine triphosphate (ATP) is produced as an energy source during the photosynthesis and cellular respiration and is consumed by many enzymes and many cellular processes. During its generation, electrons are transferred from reduced coenzymes to oxygen. Between 1 and 5% of this production escapes and results in the production of free radicals.
Redox, short for reduction-oxidation is the process whereby an atom has its oxidation number (the number of extra/reduced electrons) changed. Oxidation is the loss of electrons, whilst reduction is a gain in electrons.
Oxidative stress is an increased level of free radicals and comes from an imbalance between the production of reactive oxygen and the body's ability to detoxify the reactive intermediaries or repair resulting damage.
Cells also have defense mechanisms to combat oxidative damage, with antioxidants including vitamins A and E, glutathione (GSH), superoxide dismutase (SOD), catalyse and glutathione peroxidase.
These primary antioxidants remove free radicals, scavenging ROS and RNS, binding to metals ions or converting free radicals to less harmful forms.
Secondary antioxidants are enzymes that repair damage done by free radicals.
Neurons and other post-mitotic cells do not replicate and acquire nuclear and mitochondrial damage over time.
Over time, mitochondria cell become enlarged and membrane potential declines. They generate less energy and more ROS.
Mitochondrial membranes, proteins and DNA can be damaged by free radicals, leading to impaired electron transport and consequent apoptosis (cell death) when mitochondrial damage is severe.
As well as lipids, mitochondrial DNA (mtDNA), which encodes the electron transport chain, may be affected. mtDNA mutation is associated with a number of muscle and nervous tissue diseases.