Chapter 4 explains that much what we think we know about the aging process comes from studying rare diseases of premature aging, such as Hutchinson–Gilford progeria syndrome, Bloom syndrome, Werner syndrome, Cockayne syndrome, dyskeratosis congenita, Fanconi anemia, Wolfram syndrome, and xeroderma pigmentosum. Lessons learned from these rare diseases are summarized in Chapter 4.
From Chapter 4:
I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.4.4.3 Rule—On a cellular basis, aging is a process confined to non-renewable cell populations. Brief Rationale—Long-lived cells that cannot replace themselves, such as fully differentiated neurons, muscle cells, and cartilage cells, have no biological destiny other than degeneration and death.As non-dividing cells undergo wear and tear, or suffer damage that cannot be repaired, they will die. The tissues in which these damaged cells reside will function with diminished capacity. For example, osteoarthritis is a chronic disease that occurs from repeated episodes of bone crunching on its cartilage cushion within joints. Osteoarthritis occurs primarily in weight-bearing joints, such as knees and hips. Over a lifetime, the cartilage is frayed and eroded. Injured chondrocytes do not divide, or they divide with insufficient zest to restore a normal cartilaginous cushion. As erosion of the cartilaginous lining continues, an inflammatory reaction develops in the joint. The inflammatory reaction produces pain, swelling, and associated clinical symptoms.
Consider oocytes. All of the oocytes that a woman will produce are present in utero, reaching a peak of about 7 million cells at 5 months’ gestation. After the peak is reached, about 3 months before birth, the oocytes begin to die; they are not replaced. The number of live oocytes declines until the number falls below a threshold of 1000, triggering menopause [28]. In this instance, as in every other example of human tissues undergoing aging, the process involves cells that cannot regenerate.
Frailty is a universal feature of old age. After the age of about 50, muscle mass gradually declines. The frailty associated with extreme aging is due, in part, to progressive sarcopenia. Muscle cells atrophy (i.e., reduce their size), die, and are not renewed. Frailty occurs because muscle cells were not designed to renew themselves continuously and indefinitely.
It was once thought that the brain cells you were born with are the same cells that you will die with; that brain cells do not divide. It is now known that regeneration (i.e., the growth of new neurons) occurs throughout life. This may be so, but new growth comes from reserve cells, not from fully differentiated neurons. Cell division cannot occur in a cell that becomes very large, like a neuron, and has appendages (i.e., an axon and dendrites) extending to and from other cells, sometimes over great distances (up to several feet in the case of motor neurons innervating foot muscles). Axons are ensheathed by a dependent network of periaxonal cells (i.e., oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system). Neurons are transfixed anatomically, and cannot round up to divide. Hence, the fully mature neuron has little or no regenerative opportunity. Consequently, many of the cellular changes that we associate with aging take place in neurons. The dementia that accompanies aging is due to the inability of injured neurons to repair or replace
The tauopathies are disorders wherein tau protein accumulates within neurons. Tau proteins are involved in the stabilization of microtubules in every cell throughout the body, but they accumulate to the greatest extent in the neurons of the central nervous system. If a fully differentiated neuron cannot clear its tau proteins, it will suffer progressive damage, leading to cell death. Though tau proteins are ubiquitous, the tauopathies always develop as neurodegenerative disorders. Examples of diseases in which tau proteins are found include: Alzheimer’s disease, progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, dementia pugilistica, a form of Parkinsonism known as Lytico–Bodig disease or as Parkinson–dementia complex of Guam, a form of Parkinsonism linked to chromosome 17, frontotemporal dementia, frontotemporal lobar degeneration, Hallervorden–Spatz disease, lipofuscinosis, meningioangiomatosis, Pick’s disease, a rare tumor of neurons known as ganglioglioma [29], subacute sclerosing panencephalitis, lead encephalopathy, tangle-predominant dementia, and tuberous sclerosis.
Agin The prion diseases are another example of disorders that target non-dividing neurons. The term prion was introduced in 1982 by Stanley Prusiner [30]. Prions are the only infectious agent that contains neither DNA nor RNA. A prion is a misfolded protein that can serve as a template for proteins of the same type to misfold, producing globs of non-functioning protein, causing cells to degenerate. The site of greatest accumulation of prion protein is in brain cells. Though few scientists would consider prions to be organisms, living or otherwise, they are undoubtedly transmissible infectious agents. The most common mode of transmission of prion disease is through the consumption of brains of infected animals.
The cells of the body that are most vulnerable to prion disease are the neurons of the brain. The reason for the particular sensitivity of neurons to prion disease relates to the limited ability of neurons to replicate (i.e., to replace damaged neurons with new neurons), reconnect (to replace damaged connections between a neuron and other cells), and to remove degenerated cells and debris. There are five known prion diseases of humans, and all of them produce encephalopathies characterized by decreasing cognitive ability and impaired motor coordination. They are: Kuru, Creutzfeldt–Jakob disease, bovine spongiform encephalopathy (known in humans as new variant Creutzfeldt–Jakob disease), Gerstmann–Straussler–Scheinker syndrome, and fatal familial insomnia. At present, all of the prion diseases are progressive and fatal. Prions have been observed in fungi, where their accumulation does not seem to produce any deleterious effect, and may even be advantageous to the organism [31].
In Section 4.3, we listed the many causative mechanisms underlying the rare diseases of premature aging. Without exception, every disease of premature aging creates a defect in the normal process of cellular renewal. If we understood how to control and maintain stem cell renewal, a feat that nematodes seem to have mastered, then we might understand how to defeat the aging process. In Chapter 7, we will be discussing cancer, another disorder of cell renewal. Whereas aging is a disease of cells that cannot divide, cancer is a disease of cells that cannot stop dividing.
- Jules J. Berman, Ph.D., M.D. tags: rare disease, common disease, aging, ageing, cell renewal, cancer, cause of aging, biology of aging, orphan disease, orphan drugs
