(The FASEB Journal. 1999;13:S167-S174.)
© 1999 FASEB
Age-dependent atrophy and microgravity travel: what do they have in common?
EUGENIA WANG1
The Bloomfield Center For Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital; and Department of Medicine, McGill University, Montréal, Québec, Canada
1Correspondence: Lady Davis Institute for Medical Research, 3755, chemin de la Côte Ste. Catherine Street, Montréal, Québec, Canada H3T 1E2. E-mail: cznu{at}musica.mcgill.ca
 |
ABSTRACT
|
|---|
Space travel and extending human lifespan are two of the many advances
of the twentieth century. However, both of these scientific wonders
exact a price for their gains; i.e. deleterious effects on normal
physiological processes. For example, both old age and prolonged
microgravity travel are associated with atrophy in heart, muscle, and
bone. The underlying signal transduction pathways, the control
mechanisms for the processes of proliferation, differentiation, and
apoptosis, may prove to be similarly altered in both old age and
microgravity travel. We suggest that the mechanical events involved in
space travel provide a telescopic compression of lifespan changes in
these tissues; if so, space travel provides an excellent opportunity to
investigate how long-term degeneration occurs on Earth. With the aid of
biochip technology for multi-factorial analysis, a platform can be
generated to create therapeutic modalities to contain, retard, reduce,
or prevent this tissue atrophy, either in space or on Earth.—Wang, E.
Age-dependent atrophy and microgravity travel: what do they have in
common?
Key Words: replicative senescence • high-throughput technology • nonlinear dynamics • microchips
|
INTRODUCTION
|
|---|
LIVING INTO THE EIGHTH DECADE of human lifespan and
venturing into the forbidden territory of space must be two of the
twentieth century's biggest advances to a nineteenth century man. The
dream of extending the human lifespan is being realized: the average
human lifespan has gained at least two decades in the last 50 years and
this trend will continue until ages in the eighties are considered
average. Concerning prolonged healthy living, we ask, By what means can
our society avoid having people spend their remaining lifespan
combating old-age diseases such as cardiovascular dysfunction,
neurological debility, bone and muscle atrophy, and cancer? Could
microgravity travel contribute to ourunderstanding of these
life-long earth-bound changes, and thus provide scientific means to
minimize the severity of the burden of old age?
|
REVIEW OF RECENT MOLECULAR FINDINGS ON THE CELLULAR AGING PROCESS
|
|---|
The dawn of the twenty-first century nostalgically
tempts us to review what we have gained in the past 100 years.
Medically, two major achievements are the extension of human lifespan
and the ability to address genetically associated diseases. Even as
late as the early 1900's, lifespan determination and time of death
were thought of as predestinated by the mysteries of nature, capable of
being addressed only by the immortals. Longevity, prolonged lifespan,
and freedom from disease in old age were simply thought of as gifts
from Mother Nature as a reward for good deeds. Genetic diseases were
then commonly thought of as a curse to the family or clan. Ludicrous as
this may seem to us now, this was the prevailing consciousness
dominating not only the common man but also more or less the scientific
community. The notion of healthy elderly, especially healthy 70 year
olds or older, was an oxymoron in the late 1800's.
Pro- and anti-longevity genes hypothesis
What have we gained since the dawn of this century, then? We have
eradicated most of the large epidemics (with the exception of AIDS,
malaria, and tuberculosis), significantly reduced infant mortality,
improved nutrition and health care, and gained 20 years of average
human lifespan. In most developed countries, the average lifespan has
increased from approximately 55 to 77 years of age. This tremendous
gain in longevity tempts us, perhaps unconsciously, to ask the daring
question: can one survive to the maximal human lifespan, and can one do
so disease-free? The life of 120-year-old Madame J. Calment of Arles,
France attests that the answer to this question is a resounding
"yes." However, can everyone experience what she did? Logically, we
turn to scientific advances for the answer, as we have previously done
for eradication of infectious diseases. We now ask, are there such
things as longevity assurance genes? Are they responsible for the gain
of lifespan seen in centenarians? If so, what are they, and what are
the counteracting genes for not living as long? Do these anti-longevity
genes determine the incidence of cancer and cardiovascular and neuronal
degeneration in old age? The search for pro- and anti-longevity genes,
and characterizing them, may then be the penultimate goal for every
student of the human genome mystery.
Recent scientific insights into replicative senescence
Scientists have evolved the strategy of attacking complex
problems by reducing them to a more simply analyzed model. How can a
reductionist telescope the quest for the identification and functional
characterization of human longevity and the genes determining it? The
answer is the use of animal model and culture systems. The flourishing
and exciting developments in scientific findings from the use of yeast,
worms, fruit flies, and aged rodents and primates, as well as the human
fibroblast culture model (1)
, are a testimony to the
success of this approach. From studies on senescent human fibroblasts,
milestone findings have contributed not only to the general
understanding of replicative senescence (the fact that many types of
cells survive long after they lose the capacity to reproduce), but also
to other areas in terms of regulation of cell-cycle traverse,
apoptosis, neoplastic transformation, and terminal differentiation. I
list here just a few of these findings: 1) replicative
senescence is a genetically dominant trait (2)
, and may be
in essence a tumor-suppressing mechanism (3)
;
2) the dominance resides in human chromosomes 1, 4, and/or 6
(4-6)
; 3) telomere shortening is a clocking
mechanism for cellular age, the number of serial passages needed to
reach replicative senescence (7
, 8
);
4) the expression of a gene called c-fos is
repressed and a protein named RB is not phosphorylated in senescent
cells (9-11)
; 5) p21 (or Sdi1) is a candidate
gene halting senescent cells from replicating (12)
[p16
was recently identified as important in regulating replicative
senescence (13-18)
]; and 6) senescent human
fibroblasts do not readily die but are resistant to apoptosis (the
internally programmed natural process of cellular death)
(19)
.
Polygenic regulation of the aging process and signal transduction
Emerging from these breakthroughs is the realization that the
determination of both the normal aging process, and aberrancies from
it, may be by complex genetic traits with polygenic regulation. As one
considers signal transduction pathways, the molecular control
mechanisms of most cellular phenomena, one is impressed by the
interlocking networking of all the genes involved in the success of
implementing a mitogenic stimulus leading to cell division. So far,
there are four different known pathways of signaling events: the PI3
kinase, RAS/MAP kinase, NF-
B, and JNK-STAT pathways
(20
, 21
). Each has its respective signals to
initiate its cascade of events, with their respective series of
cytoplasmic and nuclear targets. Of course, there are cross-bridges
among these four pathways, MAP kinase being the most famous one
(22-28)
. Moreover, future findings may reveal that the
boundaries between these four pathways are not clear-cut. A humbling
lesson for us is the realization that our candidate gene of interest
may be one of the many genes whose levels of expression orchestrate the
establishment of signaling orders for intra- as well as intercellular
tasks.
Stochastic versus programmed theories of regulating the aging
process
In the 70's, biogerontologists loved to debate whether the
aging process was controlled by random stochastic events or by
programmed regulation. Lifespan determination was thought to be due to
either the building up of a cascade of errors or the programmed onset
of expression of a group of master genes whose functions are
genetically implemented and regulated as a time clock. Evolutionary
selection for longevity was then viewed as favoring individuals that
are fittest, with the best genes, overcoming the stochastic errors or
the clock. Arguments as to the relative truth of these two theories,
stochastic versus programmed, plague many scientific gatherings of
gerontologists, although it now seems that neither camp embodies the
answers to all aspects of regulation of human and animal longevity. As
we discussed above for signal transduction pathways, the hundreds of
genes involved in the four known pathways may be exquisitely ordered,
but when a stimulus is implemented it may follow a program of
bifurcation until it reaches a state of chaos; order only becomes
obvious when the final decision of gene action is reached
(29)
. An analogy to this pattern of events is the
artificial intelligence embodied in the communication network via the
Internet system. Bird's-eye views of both the signal transduction
pathways and the e-mail Internet network might be quite similar, with
both stochastic appearance and programmed operation.
Cell cycle traverse and regulation of quiescence
We've known for some time that in general, dividing cells follow
a recognized pattern called the cell cycle: after the G0
quiescent phase comes G1, then DNA synthesis in the S
phase, followed by G2 and ultimately M (for mitosis, or
cell division). An explosion of literature in the last few years forces
us to appreciate that this traverse of the cell cycle does not operate
as a simple phenomenon, like a train traveling on a well-defined track.
New substages and functions within each phase are recognized by the
identification of new groups of genes. We will focus our discussion
only on the molecular happenings during the G1 phase. In
the last two decades, several classes of genes have been identified as
functionally necessary for this phase: 1) genes involved in
DNA replication, such as DNA polymerases, ribonuclear reductases,
thymidine kinases, histones, topoisomerases, helicases, etc.
(30
, 31
); 2) immediate early genes
such as c-fos, c-myc, c-jun, Ras, E2F,
etc. (32
, 33
); 3) the need for RB
phosphorylation led to the discovery of the classes of cyclins (cyclin
A, B, D, E, G, and H) and cyclin-dependent kinases such as
cdc2, cdk2, cdk4, cdk6,
cdk11, etc. (33-37)
. By no means is this list
exhaustive, nor is the functional identification of each member with
G1-phase traverse definitive. Adding to this complexity is
the other confounding class of gene expression, i.e. the growth factors
such as families of insulin-like growth factor, epidermal growth
factor, platelet-derived growth factor, transforming growth factor,
tumor necrosis factor, nuclear factor-B, and their respective
targets and associated kinases and phosphatases. Understanding the
transcriptional, translational, and posttranslational regulation of all
these genes' expressions and how they functionally regulate the
success of G1-phase is the formidable challenge set before
us as cell biologists seeking to unravel the mysteries of cell cycle
traverse.
Regulation of quiescence, replicative senescence, and terminal
differentiation
A popular model to explain the regulation of cell proliferation is
the yin-yang paradigm; here, a common hypothesis referring
to growth-arrest regulation is thought of as a gain of
nonproliferation-specific gene expressions and the loss of
proliferation-specific gene expressions. If one accepts this gain vs.
loss logic, what then regulates the difference in potential to
reawaken to divide between quiescent and senescent human fibroblasts,
or characterizes permanently post-replicative terminally differentiated
neurons? Would the differences be dictated more by gains or by losses?
Key to these questions may be the identification of the gains; the
discovery of cyclin-dependent kinase inhibitors p21, p27, p16, p18, and
p57, and their respective functions may open a new way to investigate
the different regulatory modes for quiescence vs. terminal
differentiation, and for quiescence vs. senescence. The recent finding
that p27 is specific to terminally differentiated (but not quiescent)
muscle (38)
, and p16 to senescent fibroblasts
(13-15)
, while both cell lines and stages are
p21-positive, may provide us a handle to study the molecular operation
of temporary vs. permanent growth-arrest states.
Replicative senescence, telomere shortening, immortality, and
oncogenesis
Similar to the above gain vs. loss argument, what then determines
the difference between young replicating fibroblasts and their rapidly
growing transformed counterparts? Do quantitative and qualitative gene
losses eventually produce a cascade driving fibroblasts to metaplasia?
The fact that we can generate a failure to induce DNA synthesis in
senescent human fibroblasts simply by introducing c-fos or
antisense p21 (3)
clearly reveals to us that for a cell to
leave replicative senescence may require several stages of
intervention, defined here as sequential steps toward neoplastic
transformation: 1) escape from replicative senescence, and
become immortal; 2) gain replicative ability at a rate
beyond that of young fibroblasts; 3) gain replicative
ability to grow in low serum concentration conditions; 4)
outgrow anchorage-dependence; and 5) acquire the invasive
mode to become malignant. Obviously the first stage, i.e. the escape
from senescence, is the key that has received intense attention,
including restoring telomere length via telomerase as an added
dimension in the effort to re-stimulate DNA synthesis in permanently
growth-arrested human senescent fibroblasts.
Balancing molecular operations at the G1/S border and
organismic longevity
Investigations by our lab and others have suggested that there are
three options for a cell when it reaches the G1/S border:
it can enter the S-phase for DNA replication; it can be triaged to the
death route, to commit apoptotic suicide; or it can do neither, and
remain dormant (3
, 38-64
). Obviously,
senescent human fibroblasts have chosen the latter option. What
then determines the molecular decision among these three choices? The
answer may lie in the controlled regulation of families of genes
involved in signal transduction, cell cycle traverse, killer and
survival gene expressions, etc. What is even more obvious is that
preventing a cell from entering the G1 phase in the first
place constitutes a cellular strategy avoiding both cell replication
and apoptotic death, a necessary mode for most of the functioning,
growth-arrested cells in our body.
|
APOPTOSIS, AGE-DEPENDENT MUSCLE ATROPHY, AND MICROGRAVITY TRAVEL
|
|---|
Aging is associated with a significant decrease in muscle mass,
considered as age-dependent muscle degeneration. The growth of human
muscle peaks at about the age of 30–35, followed by decline; the
ultimate muscle mass in the elderly depends on the height of the peak
around age 35 and the slope of decline. A higher peak and gradual
sloping contribute to increased muscle mass in advanced age. Decreased
muscle mass is not only the main reason for diminished muscle strength,
but may also provide a hostile environment for muscle repair and
regeneration. Results of grafting experiments have shown that old
muscle fibrils grafted into a young muscle environment survive, whereas
grafting in the opposite direction leads the young muscle to die,
supporting the hypothesis that the old muscle environment is
unfavorable to muscular homeostasis (65
, 66
).
In humans, a significant fraction of muscle fibers are denervated in
the elderly (67
, 68
) and our results have
shown that intact innervation may be the key to maintaining regulated
translational control for protein synthesis. This loss of innervation,
along with other changes, including decreased myofiber size, reduced
metabolic energy and blood circulation, repressed response to injury
and regenerative ability, and alterations in overall tissue composition
such as isoform types and the extracellular matrix milieu, may be
involved in producing the muscle wasting observed in the elderly.
We have recently identified a novel translational elongation
factor, S1, a sister gene to the well-known EF-1
(69-72)
. In muscle, EF-1 is the embryonic form and S1
is the adult form of the elongation factor required for all protein
synthesis. The ratio of EF-1/S1 is extremely low in healthy adult
muscle. During injury with intact innervation, the EF-1/S1 ratio
shifts to high but returns to low when muscle repair is completed;
however, in conditions of injury with denervation, the EF-1/S1 ratio
does not return to the low level. Furthermore, this high EF-1 level
tends to drive the cell toward apoptosis, or programmed cell death. In
extremely old rats, the EF-1/S1 ratio reverts to the embryonic high
ratio. These results lead us to suggest that significantly high levels
of denervation in old muscles may contribute to the high EF-1 level,
producing a tissue environment unfavorable for newly regenerated muscle
to survive. We hypothesize that the dying myotubes may eventually
create a hostile microenvironment, causing neighboring cells to die as
well. We further hypothesize that the presence of these apoptotic foci
causes the death of not only existing myotubes, but also regenerated
muscle fibers, thus rendering the old or long-term-denervated muscle
tissues hostile to regeneration. Investigation of age-dependent muscle
atrophy may open the way to study microgravity-associated muscle
debility. Because our work on age-dependent muscle atrophy suggests
that neuronal survival is essential to healthy muscle status, we here
suggest that prolonged microgravity travel may compromise neuronal
survivability and thus cause muscle atrophy, producing degeneration in
muscle in the short period of a few months. A possible parallel
phenotypic presentation of muscle debility between the elderly and
those who undergo prolonged microgravity travel may derive from the
same molecular mechanisms, i.e. the loss of denervation leading to
neuronal cell death, and subsequent loss of muscle fibers through
apoptotic death and failure to regenerate. Future research on
inhibitors to apoptosis and protection of neurons from the same
suicidal program should open therapeutic means not only to prevent or
retard age-dependent muscle loss but also to protect astronauts from
losing muscle mass after prolonged microgravity travel.
|
DOES RESEARCH IN SPACE LEAD TO A BETTER UNDERSTANDING OF AGING?
|
|---|
One of the most difficult tasks in studying the aging process is
the limitation of time. Most, if not all, aging changes are based on
continuous cellular or tissue events that occur over long time periods,
i.e. from birth to death. Classically, in an organism, the aging
process is defined as beginning at the start of the post-replicative
period. For some animals such as Pacific Salmon, the reproductive
lifespan and the maximal lifespan are the same. For mammals, maximal
lifespan includes a significantly prolonged period of post-reproductive
life. This extended post-reproductive lifespan is suggested as a means
to insure that the skills of nurturing the young are passed on from
generation to generation. However, with the advent of improved
medicine, nutrition, and public health, human lifespan is increasing
beyond the needs of post-reproductive lifespan to pass nurturing skills
to the young. A centenarian matriarch's post-reproductive lifespan can
be more than 40 years, two-fifths of her lifespan. How can one begin to
investigate prospectively the aging process occurring in her? Worst of
all, there is no simple biological model available for us to study the
aging process, which would require observing individuals over close to
half of their lifetime, during the post-reproductive period. Even
models such as the standard rodent systems, rats and mice, would
require a period of 3 years to provide the entire picture of
physiological changes over the lifespan. The primate models would
require even longer, 15–30 years, to complete a thorough
characterization of the aging process. Therefore, if research
proves that thechanges that happen during microgravity travel
may be a telescopic compression of changes that take a lifetime, the
immediate gain from space study is to provide experimental model
systems that are otherwise unavailable. Once this is proven to be true,
any therapeutic treatment to combat
microgravity-induced degeneration could be easily adapted to
the attempt to deter, delay, or reduce the burden of age-dependent
debility, the ultimate goal of every biologist who studies the etiology
of aging-dependent diseases. We do not imply that the astronauts are
human guinea-pigs for aging studies but rather explorers of the
frontiers of the unknown in the sphere of biology as well as astronomy.
|
NONLINEAR DYNAMICS AND COMPLEX SYSTEMS
|
|---|
The success of the molecular revolution in identifying key
genetic factors associated with many familial diseases has unearthed
many shortcomings in the recently prevailing philosophy regarding how
the many biological processes operate. A common mistake is the
inability to comprehend that our human body is composed of tissues
whose cells are not configured as in two-dimensional culture
plates, with the selected and cloned progeny of a single cell strain.
The success of a molecular manipulation such as antisense transfection
to knock out the function of a single gene is the beginning millimeter
of advance in a mile-long quest for the eventual understanding of how
that single gene functions in a cell in an organ of an individual who
is of a defined subset of a population (Fig. 1
). It is important to realize that none of the genetic traits we
inherit functions in isolation, independent of the environment to which
they are subject (Fig. 2
). Therefore, in order to understand the complexities that govern
the outcome of our physiological actions, we must entertain a shift of
rationale and experimental design from the reductionist's point of
view to a system analysis. We may have to shift conceptual gears to
analyze not only how a single gene functions, but also how it
coordinates with hundreds of other genes in the cellular milieu
(Fig. 3
). As we contemplate how each of hundreds of genes contributes to
controlling the fundamental mechanisms dictating the proliferation and
differentiation programs of individual cells, we must realize that
these processes are keyed in the multilayers of superimposed
orchestration of operation that eventually precipitate an action to
drive the cells to proliferate or differentiate (Fig. 4
).
View larger version (24K):
[in this window]
[in a new window]
|
Figure 1. Diagrammatic illustration of how genes, cells, organs, individuals, and
populations operate in a series of concentric spheres of functional
working order.
|
|
View larger version (34K):
[in this window]
[in a new window]
|
Figure 2. Diagrammatic illustration of the hypothesis that lifespan determination
is governed by the interaction of genetic and epigenetic factors, and
how different molecular processes and other factors influence the
outcome of this interaction.
|
|
View larger version (25K):
[in this window]
[in a new window]
|
Figure 4. Diagrammatic illustration of the interlocking orchestration of various
molecular processes involved in the functional gene expression leading
to the eventual precipitation of biological states such as apoptosis,
proliferation, or differentiation.
|
|
|
CONCLUSION: NEED FOR A NEW APPROACH
|
|---|
Clearly, we are confronted with problems as to how to begin to set
up experiments that require the analysis of a genetic framework
composed of hundreds of genes' actions. The recent emergence of
high-throughput technology in the micro-array approach provides the
technical capability to trace hundreds of parallel analyses of gene
expressions at the levels of DNA, RNA, and protein specimens, through
transcriptional, translational, and posttranslational regulation. One
byproduct of the current Human Genome Project is the establishment of
high-speed automatic DNA sequencing, affording us the previously
unimaginable speed of identifying a million base pairs of information
daily in the genetic make-up of Homo sapiens. This type of
technological advance, marrying the molecular approach with
computerized automatic systems, will certainly position us in the next
century with the technology and tools needed to dissect complex changes
such as age-dependent atrophy and microgravity effects on human
physiology, and what is common between them. Advances in this direction
will surely demonstrate that bioinformatics with a computational
biology approach is a necessary tool for data analysis. The outcry for
experimental design in future information gathering, in advance of
understanding travel either in space or on Earth, will certainly be
questions such as: what are the controls? who is being compared with
whom? the newborn? those with perfect health? those with accumulated
stress? Moreover, with the advances of technology and explosion of
genetic information, we will need a translation from millions of data
points to an understandable lexicon, usable and applicable to the next
level of experimental design to extract new information. Thus, the
hunger for advances as to how to diminish age-dependent or
microgravity-travel atrophy will only be satisfied by the integration
of diverse disciplinary approaches from mathematics to genes, from
engineering to proteins. The ultimate goal is then how to use the
present advances in the information highway to pave another set of
highways leading us to understand how our human body works, and how we
can orchestrate to maximize its functionality, in space or on
Earth.
|
ACKNOWLEDGMENTS
|
|---|
This work was supported by an operating grant (R01 AG09278) from
the National Institute on Aging of the National Institutes of Health
and from the Defense Advance Research Project Agency of the U.S.
Department of Defense. The author is deeply indebted to Mr. Alan N.
Bloch for many contributory discussions and editorial comments, as well
as proofreading the text.
|
REFERENCES
|
|---|
-
Jazwinski, S. M. (1996) Longevity, genes, and aging. Science 273,54-59[Abstract]
-
Lumpkin, C. K., Jr, McClung, J. K., Pereira-Smith, O. M., Smith, J. R. (1986) Existence of high abundance antiproliferative MRNA's in senescent human diploid fibroblasts. Science 232,393-395[Abstract/Free Full Text]
-
Campisi, J. (1996) Replicative senescence: an old lives' tale. Cell 84,497-500[Medline]
-
Annab, L. A., Dong, J. T., Futreal, P. A., Satoh, H., et al (1992) Growth and transformation suppressor genes for BHK Syrian hamster cells on human chromosomes 1 and 11. Mol. Carcinogen. 6,280-288[Medline]
-
Hensler, P. J., Annab, L. A., Barrett, J. C., Pereira-Smith, O. M. (1994) A gene involved in control of human cellular senescence on human chromosome 1q. Mol. Cell Biol. 14,2291-2297[Abstract/Free Full Text]
-
Ning, Y., Weber, J. L., Killary, A. M., Ledbetter, D. H., et al (1991) Genetic analysis of indefinite division in human cells: evidence for a cell senescence-related gene(s) on human chromosome 4. Proc. Natl. Acad. Sci. USA 88,5635-5639[Abstract/Free Full Text]
-
Harley, C. B., Futcher, A. B., Greider, C. W. (1990) Telomeres shorten during ageing of human fibroblasts. Nature (London) 345,458-460[Medline]
-
Guarente, L. (1996) Do changes in chromosomes cause aging?. Cell 86,9-12[Medline]
-
Seshadri, T., Campisi, J. (1990) Repression of c-fos transcription and altered genetic program in senescent human fibroblasts. Science 247,205-209[Abstract/Free Full Text]
-
Dulic, V., Drullinger, L. F., Lees, E., Reed, S. I., Stein, G. H. (1993) Altered regulation of G1 in senescent human diploid fibroblasts: accumulation of inactive cyclin E-Cdks and cyclin D1-Cdk2 complexes. Proc. Natl. Acad. Sci. USA 90,11034-11038[Abstract/Free Full Text]
-
Stein, G. H., Beeson, M., Gordon, L. (1990) Failure to phosphorylate the retinoblastoma gene product in senescent human fibroblasts. Science 249,666-669[Abstract/Free Full Text]
-
Noda, A., Ning, Y., Venable, S. F., Pereira-Smith, O. M., Smith, J. R. (1994) Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. Exp. Cell Res. 211,90-98[Medline]
-
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., Lowe, S. W. (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88,593-602[Medline]
-
Afshari, C. A., Vojta, P. J., Annab, L. A., Futreal, P. A., Willard, T. B., Barrett, J. C. (1993) Investigation of the role of G1/S cell cycle mediators in cellular senescence. Exp. Cell Res. 209,231-237[Medline]
-
Alcorta, D. A., Xiong, Y., Phelps, D., Hannon, G., Beach, D., Barrett, J. C. (1996) Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Proc. Natl. Acad. Sci. USA 93,13742-13747[Abstract/Free Full Text]
-
Atadja, P., Wong, H., Garkavisev, I., Veillette, C., Riabowol, K. (1995) Increased activity of p53 in senescent fibroblasts. Proc. Natl. Acad. Sci. USA 92,8346-8352
-
Reznikoff, C. A., Yeager, T. R., Belair, C. D., Savelieva, E., Puthenveet-til, J. A., Stadler, W. M. (1996) Elevated p16 at senescence and loss of p16 at immortalization in human papilloma virus 16 E6, but not E7, transformed human uroepithelial cells. Cancer Res 56,2886-2890[Abstract/Free Full Text]
-
Ogryzko, V. V., Hirai, T. H., Russanova, V. R., Barbie, D. A., Howard, B. H. (1996) Human fibroblast commitment to a senescence-like state in response to histone deacetylase inhibitors is cell cycle dependent. Mol. Cell. Biol. 16,5210-5218[Abstract]
-
Wang, E. (1995) Failure to undergo programmed cell death in senescent human fibroblasts is related to inability to down-regulate bcl 2 presence. Cancer Res 55,2284-2292[Abstract/Free Full Text]
-
Cahill, M. A., Janknecht, R., Nordheim, A. (1996) Signalling pathways: jack of all cascades. Curr. Biol. 6,16-19[Medline]
-
Cheatham, B., Kahn, C. R. (1995) Insulin action and the insulin signalling network. Endocr. Rev. 16,117-142[Medline]
-
Pumiglia, K. M., Decker, S. J. (1997) Cell cycle arrest mediated by the MEK/mitogen-activated protein kinase pathway. Proc. Natl. Acad. Sci. USA 94,448-452[Abstract/Free Full Text]
-
Perkins, N. D., Felzien, L. K., Betts, J. C., Leung, K., Beach, D. H., Nabel, G. J. (1997) Regulation of NF-B by cyclin-dependent kinases associated with the p300 coactivator. Science 275,523-527[Abstract/Free Full Text]
-
Lopez-Llasaca, M., Crespo, P., Giuseppe-Pellici, P., Gutkind, J. S., Wetzker, R. (1997) Linkage of G protein-coupled receptors to the MAPK signalling pathway through PI 3-kinase gamma. Science 275,394-397[Abstract/Free Full Text]
-
Lee, F. S., Hagler, J., Chen, Z. J., Maniatis, T. (1997) Activation of the IB kinase complex by MEKK1, a kinase of the JNK pathway. Cell 88,213-222[Medline]
-
Hughes, P. E., Renshaw, M. W., Pfaff, M., Forsyth, J., Keivens, V. M., Schwartz, M. A., Ginsberg, M. H. (1997) Suppression of integrin activation: a novel function of a Ras/Raf-initiated MAP kinase pathway. Cell 88,521-530[Medline]
-
Franke, T. F., Kaplan, D. R., Cantley, L. C. (1997) PI3K: Downstream AKTion blocks apoptosis. Cell 88,435-437[Medline]
-
Momand, J., Zambetti, G. P. (1997) Mdm2: "Big Brother of p53.". J. Cell. Biochem. 64,343-352[Medline]
-
McAdams, H. H., Arkin, A. (1997) Stochastic mechanism in gene expression. Proc. Natl. Acad. Sci. USA 94,814-819[Abstract/Free Full Text]
-
Stillman, B. (1996) Cell cycle control of DNA replication. Science 274,1659-1664[Abstract/Free Full Text]
-
Elledge, S. J. (1996) Cell cycle checkpoints: preventing an identity crisis. Science 274,1664-1672[Abstract/Free Full Text]
-
Sherr, C. J. (1996) Cancer cell cycles. Science 274,1672-1677[Abstract/Free Full Text]
-
Hunter, T. (1993) Braking the cycle. Cell 75,839-841[Medline]
-
Paulovich, A. G., Toczyski, D. P., Hartwell, L. H. (1997) When checkpoints fail. Cell 88,315-322[Medline]
-
Levine, A. J. (1997) p53, the cellular gatekeeper for the growth and division. Cell 88,323-332[Medline]
-
Hunter, T. (1997) Oncoprotein networks. Cell 88,333-346[Medline]
-
Follette, P. J., O'Farrell, P. H. (1997) Connecting cell behavior to patterning, lessons from the cell cycle. Cell 88,309-314[Medline]
-
Franklin, D. S., Xiong, Y. (1996) Induction of p18INK4c and its predominant association with CDK4 and CDK6 during myogenic differentiation. Mol. Biol. Cell 10,1587-1599
-
Vaux, D. L. (1993) Toward an understanding of the molecular mechanisms of physiological cell death. Proc. Natl. Acad. Sci. USA 90,786-789[Abstract/Free Full Text]
-
Wyllie, A. H., Kerr, J. F. R., Currie, A. R. (1980) Cell death: the significance of apoptosis. Int. Rev. Cytol. 68,251-307[Medline]
-
Ucker, D. S. (1991) Death by suicide—one way to go in mammalian cellular development. New Biologist 3,103-109[Medline]
-
Wyllie, A. H., Morris, R. G., Smith, A. L., Dunlop, D. (1984) Chromatin cleavage in apoptosis: Association with condensed chromatin morphology and dependence on macromolecular synthesis. J. Pathol. 142,67-77[Medline]
-
White, E. (1996) Life, death, and the pursuit of apoptosis. Genes Dev 10,1-15[Free Full Text]
-
Glucksmann, A. (1951) Cell deaths in normal vertebrate ontogeny. Biol. Rev. 26,59-86
-
Wyllie, A. H. (1980) Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 284,555-556[Medline]
-
Ellis, R. E., Horvitz, H. R. (1986) Genetic control of programmed cell death in the nematode C. elegans. Cell 44,817-829[Medline]
-
Martin, S. J., Green, D. R. (1995) Protease activation during apoptosis: Death by a thousand cuts?. Cell 82,349-352[Medline]
-
Evan, G. I., Wyllie, A. H., Gilbert, C. S., Littlewood, T. D., Land, H., Brooks, M., Waters, C. M., Penn, L. Z., Hancock, D. C. (1992) Induction of apoptosis in fibroblasts by c-myc protein. Cell 69,119-128[Medline]
-
Smeyne, R. J., Vendrell, M., Hayward, M., Baker, S. J., Miao, G. G., Schilling, K., Robertson, L. M., Curran, T., Morgan, J. I. (1993) Continuous c-fos expression precedes programmed cell death in vivo. Nature 363,166-169[Medline]
-
Chen, Y.-Y., Rosenberg, N. (1992) Lymphoid cells transformed by Abelson virus require the v-abl protein-tyrosine kinase only during early G1. Proc. Natl. Acad. Sci. USA 89,6683-6687[Abstract/Free Full Text]
-
Colombel, M., Olsson, C. A., Ng, P. Y., Buttyan, R. (1992) Hormone regulated apoptosis results from reentry of differentiated prostate cells into a defective cell cycle. Cancer Res 50,4313-4319
-
Pandey, S., Wang, E. (1995) Cells en route to apoptosis are characterized by the up-regulation of c-fos, c-myc, c-jun, cdc-2, and RB phosphorylation, resembling events of early cell-cycle traverse. J. Cell. Biochem. 58,135-150[Medline]
-
Meikrantz, W., Schlegel, R. (1995) Apoptosis and the cell cycle. J. Cell. Biochem. 58,160-174[Medline]
-
King, K. L., Cidlowski, J. A. (1995) Cell cycle and apoptosis: common pathways to life and death. J. Cell. Biochem. 58,175-180[Medline]
-
Cyrus, V., Yuan, J. (1998) Proteases to die for. Genes Dev 12,1551-1570[Free Full Text]
-
Houweling, A., He, X., and Wang, E. (1995) An
apoptosis pathway regulated by the potential for proliferation rather
than dependence on p53 gene expression. 35th Annual Meeting of the
American Society for Cell Biology, Washington, DC
-
Symonds, H., Krall, L., Remington, L., Saenz-Robeles, M., Lowe, S., Jacks, T., Van Dyke, T. (1994) p53-dependent apoptosis suppresses tumor growth and progression in vivo. Cell 73,703-711
-
Vogelstein, B., Kinzier, K. W. (1992) p53 function and dysfunction. Cell 70,523-526[Medline]
-
Yonish-Rouach, E., Grunwald, D., Wilder, S., Kimchi, A., May, E., Lawrence, J-J., May, P., Oren, M. (1993) p53-mediated cell death: Relationship to cell cycle control. Mol. Cell Biol. 13,1415-1423[Abstract/Free Full Text]
-
Clarke, A. R., Pordie, C. A., Harrison, D. J., Morris, R. G., Bird, C. C., Hooper, M. L., Wyllie, A. H. (1993) Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature 362,849-852[Medline]
-
Gottlieb, E., Haffner, R., von Ruden, T., Wagner, E. F., Oren, M. (1994) Down-regulation of wild-type p53 activity interferes with apoptosis of IL-3 dependent haematopoietic cells following IL-3 withdrawal. EMBO J 13,1368-1374[Medline]
-
Harris, A. L. (1992) p53 expression in human breast cancer. Adv. Cancer Res. 59,69-88[Medline]
-
Hollstein, M., Sidransky, D., Vogelstein, B., Harris, C. C. (1991) p53 mutations in human cancer. Science 253,49-53[Abstract/Free Full Text]
-
Kastan, M. B., Onyekwere, O., Sidransky, D., Vogelstein, B., Craig, R. (1991) Participation of p53 in the cellular response to DNA damage. Cancer Res 51,6034-6311
-
Carlson, B. M., Faulner, J. A. (1989) Muscle transplantation between young and old rats: age of host determines recovery. Am. J. Physiol. 256,1262-1266
-
Carlson, B. M. (1995) Factors influencing the repair and adaptation of muscles in aged individuals: Satellite cells and innervation. J. Gerontol. 56A(Suppl.),96-100
-
Faulkner, J. A., Brook, S. V., Zerba, E. (1990) Skeletal muscle weakness and fatigue in old age: Underlying mechanisms. Annu. Rev. Geront. Geriat. 10,147-166
-
Brooks, S. V., Faulkner, J. A. (1993) Skeletal muscle weakness in old age: underlying mechanisms. Med. Sci. Sports Exer. 26,432-439
-
Lee, S., Francoeur, A. M., Liu, S., Wang, E. (1992) Tissue-specific expression in mammalian brain, heart, and muscle of S1, a member of the EF-1 gene family. J. Biol. Chem. 267,24064-24068[Abstract/Free Full Text]
-
Lee, S., Stollar, E., Wang, E. (1993) Localization of S1 and elongation factor-1 MRNA in rat brain and liver by non-radioactive in situ hybridization. J. Histochem. Cytochem. 41,1093-1098[Abstract]
-
Lee, S., Wolfraim, L. A., Wang, E. (1993) Characterization of the differential expression of S1 and Elongation factor-1 alpha during rat development. J. Biol. Chem. 268,24453-24459[Abstract/Free Full Text]
-
Lee, S., Ann, D, Wang, E. (1994) Cloning of human and mouse CDNAs for S1, the second member of the mammalian elongation factor-1 alpha gene family: analysis of a possible evolution pathway. Biochem. Biophys. Res. Commun. 203,1371-1377[Medline]
This article has been cited by other articles:
|
|
|
|
 
M. Maccarrone, N. Battista, M. Meloni, M. Bari, G. Galleri, P. Pippia, A. Cogoli, and A. Finazzi-Agro
Creating conditions similar to those that occur during exposure of cells to microgravity induces apoptosis in human lymphocytes by 5-lipoxygenase-mediated mitochondrial uncoupling and cytochrome c release
J. Leukoc. Biol.,
April 1, 2003;
73(4):
472 - 481.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. A. Ray
Interaction between vestibulosympathetic and skeletal muscle reflexes on sympathetic activity in humans
J Appl Physiol,
January 1, 2001;
90(1):
242 - 247.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Papaseit, N. Pochon, and J. Tabony
Microtubule self-organization is gravity-dependent
PNAS,
July 18, 2000;
97(15):
8364 - 8368.
[Abstract]
[Full Text]
[PDF]
|
|
|
TOP
ABSTRACT
INTRODUCTION
