Molecular Mechanism of Aging
Neurological Degeneration
Our nervous system consists of much more than interlinked neurons. Glial cells like Schwann cells and oligodenadrocytes manufacture myelin, an insulating substance, which wraps around the axons connecting neurons. Astrocytes are other glial cells that regulate the wrapping process.
Neurological degeneration can take many forms which become increasingly manifest with age. During the human life span there is a 10% decrease in the weight of the brain due to both loss of cells & fluids in the cerebrum. Neuronal loss, due to the accumulation of damage–such as oxidative damage–may be the main cause of brain aging. Even without neuronal death, biochemical and structural changes compromise neuron function. With age, what changes could be the complex network of connections between nerve cells. Phenotypes of neurological degeneration include a number of age-related neurological diseases such as Alzheimer’s disease, Parkinson’s disease and macular degeneration. All forms of memory loss and senile dementia, some mental illness fall in this category as well. Increased stimulus response times in aging people can make driving and even walking dangerous. Degeneration of neuron systems in the inner ear can make it difficult for older people to maintain their balance. They frequently fall and hurt themselves. Orthopedic injuries associated with falling constitute one of the major maladies of the aged leading to loss of normal functionality and nursing home occupancy.
Our body has an internal mechanism of maintaining and replenishing our nervous system through neurogenesis. Neurogenesis takes place throughout the life of a mammal in two major brain structures: the dentate gyrus of the hippocampus and the subventricular zone of the forebrain. In these regions neural progenitor cells continuously divide and give birth to new neurons and glial cells. In the mammalian brain, neural progenitor cells are multipotent. They can differentiate into neurons, astrocytes or oligodendrocytes. Maintaining a sufficient and consistent rate of neurogenesis in the brain, particularly in the hippocampus, is important for the maintenance of (cognitive) health.
Neurogenesis is tied to circadian rhythms and time-of-day dependent. The cell-cycle of neurogenesis appears to be tied to daily light-related circadian cycles, with neural progenitor cells entering the cell cycle continually, but passing through into the M phase and generating new neurons mainly at night (at least in rats). It is speculated that irregularities in daily cycles and disrupted sleep may interfere with neurogenesis.
In addition, hippocampal neurogenesis is affected by other environmental factors as well. Stress factors like radiation, integrity of circadian gene expression, emotional states and hormonal signals and life style can affect neurogenesis. Neurogenesis is positively affected by regular daily rhythms, learning, voluntary exercise, good physical environment, antioxidant-rich diet, and by ingesting certain mood-stabilizing agents including lithium and fluoxetine (Prozac). It is negatively affected by involuntary stress, oxidative stress (free radical), radiation, toxicity and several types of chemotherapy. Also, oxidative environment favors the production of astrocytes over the production of neurons.
The rate of neurogenesis tends to decline with advancing age in old mammals, as well as the number of functional neurons. Insufficient or irregular neurogenesis is thought to be a causative factor in bipolar disease and other mood disorders. It is thought that health and longevity of glial cells is as important as that of neurons for mental health maintenance. Multiple sclerosis and cerebral palsy, for example are known to be diseases associated with malfunctioning glial cells. And improper myelin formation possibly contributes to several other mental illnesses such as autism, schizophrenia and bipolar disease. It is interesting that taking mood stabilizers like fluoxetine may not only inhibit serotonin uptake but also result in accelerated neurogenesis.
The decline of neurogenesis in people with advancing age may be a programmed mechanism. The genetic and cell-biology basis of neurogenesis is being explored extensively. It appears that the Bcl-2 gene functions to regulate development and survival of neurons in the central nervous system and is very important for neurogenesis. Also, it appears that expression of NF-κB, is important for neurogenesis. Unfortunately there is a paradox in that the same mechanisms that promote neurogenesis, like expression of Bcl-2 and NF-κB, can also promote carcinogenesis. The Ink4a proteins, which are increasingly active with age, suppress those mechanisms leading to increased protection against cancers with age, but at the cost of decreased neurogenesis and decreased proliferation of other somatic stem cell types.
