3. MEDICAL BIOLOGY:
MISREGULATION OF MITOSIS AND HUMAN AGING
The idea that human aging is controlled by genes is not the
end but the beginning of research: Does the aging process involve
one gene, or a fixed group of specific genes, or groups of
various genes at different times and in different individuals?
The term "messenger RNA" refers to the ribonucleic acid
molecule transcribed from DNA that carries the coded information
specifying the sequence of amino acids in a protein. Since the
various messenger RNAs present in any cell can be isolated and
identified, the population of present messenger RNAs can be used
to establish a profile of the active genes of that cell.
Fibroblasts are a type of connective tissue cell secreting
structural proteins such as collagen, the proteins forming a
matrix in which the fibroblasts become embedded. These cells can
be easily obtained from skin, and they can be easily cultured
outside the body.
Progeria (Hutchinson-Gilford disease; Hutchinson-Gilford
syndrome; premature senility syndrome) is a condition of
precocious aging, with onset at birth or early childhood, the
condition characterized by growth retardation, a senile
appearance with dry wrinkled skin, early occurrence of
*atherosclerosis in blood vessels, and premature death (usually
before the age of 20) due to coronary artery disease. The disease
is apparently genetic, but the details of the etiology are not
clear.
In this context, the term "phenotype" refers to the specific
individuality of an organism as determined by the interaction
during development between its genetic constitution (genotype)
and the environment.
In this context, the term "mitosis" refers to the entire
cell division phase of the cell cycle, with "cell cycle"
referring to the entire life history of a single cell from
mitosis to mitosis, including the sequence of intervening phases.
In this context, the term "postmitotic cells" refers to cells
that normally do not undergo mitosis once they have fully
differentiated (e.g., neurons and muscle cells).
... ... D.H. Ly et al (4 authors at 2 installations, US) report
an analysis of aging correlates in human genetic profiles, the
authors making the following points:
1) The authors measured messenger RNA levels in actively
dividing fibroblasts isolated from young, middle-age, and old-age
humans and humans with progeria. Messenger RNA levels were
analyzed with high-density *oligonucleotide arrays containing
probes for more than 6000 known human genes.
2) The authors report their results suggest that an altered
expression profile of genes involved in mitosis occurs with age,
and that these changes result in increased rates of *somatic
mutation, leading to numerical and structural *chromosome
aberrations and mutations that manifest themselves as an aging
phenotype.
3) The authors suggest that these chromosome pathologies,
which begin to occur in dividing cells relatively early in life
(but in the postreproductive stage), may lead to misregulation of
key structural, signaling, and metabolic genes associated with
the aging phenotype, such as the apparent misregulations
characteristic of *osteoporosis, *Alzheimer's disease,
*arthritis, etc. Misregulation of this sort is expected to
increase in each round of cell division, and it may be propagated
to other normal mitotic cells (e.g., *leukocytes, *epithelial
cells, *glial cells, etc.) and postmitotic cells (e.g., neurons,
muscles, etc.) through changes in the *extracellular matrix and
oxidized fatty acid derivatives that affect signaling pathways.
Aging, the authors suggest, may therefore occur gradually and in
mosaic patterns, rather than as a uniform phenomenon
characteristic of cancerous growth (which is clonal -- deriving
from a single mutated progenitor cell)
4) The authors conclude: "Additional studies are required
before we can understand the aging process in complex organisms,
both in mitotic and postmitotic tissue, but the studies reported
here highlight important mechanisms that may contribute to aging
and age-related problems."
-----------
D.H. Ly et al: Mitotic misregulation and human aging.
(Science 31 Mar 00 287:2486)
QY: Richard A. Lerner, Scripps Research Institute 619-784-1000.
-----------
Text Notes:
... ... *atherosclerosis: "Arteriosclerosis" is a generic term
for several diseases in which the arterial wall becomes thickened
and loses elasticity, and "atherosclerosis" is a form of
arteriosclerosis characterized by patchy thickening (atheroma) in
the subintimal layer (i.e., immediately below the innermost layer
[intima]) of medium and large arteries, the thickening capable of
reducing or obstructing blood flow.
... ... *oligonucleotide arrays: (DNA microarrays) DNA
microarrays are chips containing hundreds or thousands of gene
snippets laid out in precise arrays that provide rapid snapshots
of the expression of whole suites of genes. The general method in
microarray analysis is to a) isolate messenger RNAs (mRNAs)
produced by a genome; b) convert mRNA into complementary DNA
(cDNA); c) add a fluorescent tag to the cDNA for tracking
purposes; d) wash a solution of tagged cDNAs over a DNA
microarray chip. Each DNA snippet on the chip will bind the cDNA
from the corresponding gene, and by measuring the fluorescences
arrayed on the chip, the profile of gene expression is revealed.
... ... *somatic mutation: In general, a mutation occurring in
non-germ cells, which means the mutation is not transmitted to
the next generation of individuals (but is transmitted to the
next generation of cells of that type).
... ... *chromosome: In cells with chromosomes, the
chromosomes are the physical structures into which DNA is
organized and on which genes are carried.
... ... *osteoporosis: A generalized progressive diminution of
bone density (bone mass per unit volume) that causes skeletal
weakness. The ratio of mineral to organic elements is unchanged.
The major clinical manifestations of osteoporosis are bone
fractures resulting from a reduction below the fracture threshold
of the amount of bone available for mechanical support.
... ... *Alzheimer's disease: There are various forms of dementia
produced by various causes. Alzheimer-type dementia (Alzheimer's
disease) is apparently related to what appear to be specific
cellular and histological degenerative processes, with loss of
cells from several specific brain areas, the brain showing
moderate to marked atrophy. Memory loss is the most prominent
early symptom.
... ... *arthritis: In general, inflammation of a joint or a
state characterized by inflammation of joints.
... ... *leukocytes: White blood cells, of which there are
various types.
... ... *epithelial cells: In animals, "epithelial cells" compose
the cell layers that form the interface between a tissue and the
external environment, for example, the cells of the skin, the
lining of the intestinal tract, and the lung airway passages.
... ... *glial cells: Cells of the central and peripheral nervous
system that metabolically support neurons. Such cells also
produce the multiple membrane layers called myelin and enfold
certain nerve cell axons with it.
... ... *extracellular matrix: In general, the extracellular
matrix is a layer consisting mainly of proteins and
glycosaminoglycans that form a sheet underlying endothelial and
epithelial cells. The molecular constituents of the matrix are
secreted by cells in the vicinity. Endothelial cells are the
cells that line blood vessels.
-------------------
Summary & Notes by SCIENCE-WEEK http://scienceweek.com 9Jun00
For more information: http://scienceweek.com/swfr.htm
-------------------
Related Background:
ON NEW APPROACHES TO HUMAN AGING
It is probably safe to say that research on the biological basis
of human aging will remain a central interest in the sciences as
long as there is any research at all. However, despite the
general public attention to the subject, it is only during the
past few decades that cell biologists have begun a vigorous
attempt to understand the aging process. A major reason for this
is that the new knowledge provided during the past 40 years by
molecular biology concerning fundamental cellular processes
suggests that an understanding of the biological basis of human
aging is indeed possible. The cell biologist Leonard Hayflick
(University of California San Francisco, US) first demonstrated
in the 1960s that the mortality of biological cells is either
directly or indirectly programmed in each cell, and that this is
an important aspect of the aging of human tissues (see related
background material below). Hayflick now presents a provocative
essay on the subject, the author making the following points:
1) The author points out that in the past 100 years life
expectancy at birth in developed countries has increased from
approximately 48 years to 76 years, the same gain that occurred
over the previous 1900 years. But this progress has neither
advanced nor resulted from our understanding of aging. Instead,
it is the control of infectious diseases of the young that
explains the increase in life expectancy during the 20th century.
2) The author suggests that the failure to distinguish
between the diseases of old age and the aging process is
widespread even in the scientific community. The virtual
resolution of various childhood diseases such as poliomyelitis
and iron-deficiency anemia did not increase our knowledge of
childhood development. Similarly, the resolution of the leading
causes of death in old age -- cardiovascular disease, stroke, and
cancer -- are unlikely to advance our knowledge of the aging
process.
3) The author suggests that one example of the consequences
for science policy of the failure to distinguish research on age-
associated diseases from research on the fundamental biology of
aging is that "it is virtually impossible to raise funds for
research on aging, because in the minds of policy-makers and the
public no one suffers or dies from it." More than half of the
budget of the US National Institute on Aging is spent on
Alzheimer's disease, yet the elimination of this disease "will
have only a trivial impact on life expectancy and will not
advance our knowledge of the fundamental biology of aging." The
author suggests that greater attention must be given to a
question that is rarely posed: Why are old cells more vulnerable
to disease than young cells?
4) The author concludes: "The resolution of all causes of
death currently written on the death certificates of those older
than 65 will result in an increase in life expectancy of only
about 15 years. An increase in our knowledge of how age changes
occur does not put a 15-year limit on what is possible."
-----------
Leonard Hayflick: New Approaches to Old Age.
(Nature 27 Jan 00 403:365)
QY: Leonard Hayflick, Univ. of Calif. San Francisco 415-476-4044.
-------------------
Summary by SCIENCE-WEEK http://scienceweek.com 14Apr00
For more information: http://scienceweek.com/swfr.htm
-------------------
Related Background:
CELLULAR AGING: DONOR AGE AND CELLULAR REPLICATION LIFESPAN
Fibroblasts are a type of connective tissue cell, secreting
structural proteins such as collagen, the proteins forming a
matrix in which the fibroblasts become embedded. These cells can
be easily obtained from skin, and they can be easily cultured
outside the body. Normal human fibroblasts have a finite
replicative lifespan in vitro (i.e., they divide a finite number
of times), and this has been postulated to be a cellular
manifestation of aging of the human organism. Several studies
have indeed shown an inverse relationship between donor age (the
age of the persons from which cultured cells are derived) and
fibroblast culture replicative lifespan. But in all cases the
correlation was weak, and with few exceptions the health status
of the donors was unknown. Thus, the relationship between the
replicative lifespan and the age of the donor from which the
cells are derived has remained equivocal (*Note #1).
... ... V.J. Cristofalo et al (5 authors at 2 installations, US)
now report a study of the replicative lifespan of 124 skin
fibroblast cell lines established from donors of different ages.
All donors were medically examined and were declared "healthy"
(according to Baltimore Longitudinal Study of Aging protocols) at
the time the biopsies were taken. The authors report that both
long- and short-lived cell lines were observed in all age groups,
but no significant correlation between the proliferative
potential of the cell lines and donor age was found. A comparison
of multiple cell lines established from the same donors at
different ages also failed to reveal any significant trends
between proliferative potential and donor age. The authors
suggest their results clearly indicate that if health status and
biopsy conditions are controlled, the replicative lifespan of
fibroblasts in culture does not correlate with donor age.
-----------
V.J. Cristofalo et al: Relationship between donor age and the
replicative lifespan of human cells in culture: A reevaluation.
(Proc. Natl. Acad. Sci. US 1 Sep 98 95:10614)
QY: Vincent J. Cristofalo, Center for Gerontological Research,
Alleghany University of the Health Sciences, Philadelphia, PA
19129 US.
-----------
Text Notes:
... ... *Note #1: The possibility that the process of cell aging
and death is under genetic control was first suggested by Leonard
Hayflick in 1961. Hayflick reported that normal human fibroblasts
apparently have an intrinsic limit to the number of times they
can proliferate, with human fibroblasts removed from an embryo
and grown in culture dividing approximately 50 times before they
deteriorate and die. In contrast, human fibroblasts removed from
adults multiply only 15 to 30 times before dying. Also,
fibroblasts removed from young children suffering from Werner's
syndrome (a rare disease that causes premature aging) divide only
2 to 10 times in culture. Further evidence for a relationship
between aging and the replicative capacity of cells was provided
by the discovery that the number of replications in culture is
apparently related to the lifespan of organism. For example,
cultured cells of the Galapagos tortoise, whose maximum life span
is approximately 175 years, divide more than 100 times in
culture, whereas cells from the mouse, whose maximum life
expectancy is only a few years, divide fewer than 30 times in
culture. The correlation roughly holds for other species as well.
-------------------
Summary & Notes by SCIENCE-WEEK http://scienceweek.com 16Oct98
-------------------
Related Background:
BIOLOGY OF AGING: ON TELOMERES AND REPLICATIVE SENESCENCE
Telomeres are defined ends of chromosomes that contain specific
repeated DNA sequences. They are essential for normal chromosome
replication, and since their length shortens a bit with each
replication, they are believed to be involved in the aging of the
cell. Telomerase is an enzyme that repairs damage to telomeres,
and it is thought by some that cancerous cells may have mutant
telomerase, the mutant enzyme conferring immortality on the
cancer cell. ... ... In a review of cell senescence, the aging of
cell cultures, and the immortalization of mammalian cells, John
M. Sedivy (Brown University, US) makes the following points: 1)
Finite replicative lifespan (senescence) of mammalian cells in
culture is a phenomenon that has generated much curiosity since
its description. The obvious significance of senescence to
organismal aging and the development of cancer has engendered a
long-lasting and lively debate about its mechanisms. 2) Three
classical observations are usually cited to argue that in vitro
replicative senescence is a phenomenon with biological
significance: a) the correlation of in vitro lifespan with the
age of the donor; b) the correlation of in vitro lifespan with
the average life expectancy of species; and, c) the reduced in
vitro lifespan of cells from patients afflicted with premature
aging syndromes. 3) Two major theories have been used to explain
limited replicative capacity. The first hypothesis invokes the
gradual accumulation of mutations, and the second hypothesis
invokes the existence of a molecular clock (or clocks) that can
keep track of cell divisions. The second theory is now believed
to be generally true. 4) It is known that cell senescence can be
overcome, because many cell lines in common laboratory use are
quite obviously immortal. Rodent cells can overcome senescence
spontaneously. Human, chicken, bovine, and horse cells rarely, if
ever, immortalize spontaneously. 5) Certain viral or biochemical
interventions in human cell cultures can overcome cell
senescence, typically by causing 20 to 30 extra population
doublings. At the end of this extended lifespan, there is a
decline and death of the culture in 4 to 6 weeks, which has been
termed "crisis". Senescent cells, on the other hand, can be
maintained in vitro in a viable non-proliferative state for very
long periods of time (reports of from 4 to 6 months, and up to 2
years). 6) The author suggests it is amazing that in spite of
very long periods of apparent "immortality", the senescent
program in cells remains intact in cells in which senescence has
been overridden, so that on removal of the overriding agent, the
program is capable of establishing rapid growth arrest. 7) The
current prevailing hypothesis for the nature of the molecular
clock involved in cell senescence is the attrition of telomeres.
*Germ cells, and some key *stem cells, are known to express
telomerase catalytic activity, whereas the majority of somatic
cells lack it. Murine (mouse) embryonic stem cells express
telomerase and are functionally immortal, and elimination of
telomerase eventually results in loss of proliferation. 8) The
author proposes that immortalization of human cells requires a
bypass of both cell senescence and crisis, whereas in rodent
cells cell crisis does not exist and culture lifespan is limited
only by senescence. 9) Evidence indicates that, at least in human
cells, telomere length appears to be linked critically to the
triggering of senescence. The author suggests that although it
remains to be rigorously demonstrated, this strongly implies that
activation of telomerase can result in one-step immortalization.
In conclusion, the author states the two most significant
questions in this field: a) Does cell senescence limit organismal
lifespan? And, b) Is telomerase expression necessary for cancer
progression in vivo?
QY: John M. Sedivy [john_sedivy@brown.edu]
(Proc. Natl. Acad. Sci. US 4 Aug 98 95:9078)
(Science-Week 4 Sep 98)
-----------
Text Notes:
... ... *Germ cells: Any cell from which gametes (sperm cells and
egg cells) are derived. All other cells are called "somatic"
cells.
... ... *stem cells: In general, a stem cell is any precursor
cell, a form prior to cell differentiation. E.g., stem cells in
bone marrow that give rise to blood cells.
-------------------
Summary & Notes by SCIENCE-WEEK http://scienceweek.com 4Sep98
For more information: http://scienceweek.com/swfr.htm
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