In June, 2014, my book, entitled
Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.
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:
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.
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.
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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
