Re-Visiting a Post by Lou Pagnucco
pagnucco at oeonline.com
Sat Oct 24 23:37:11 EST 1998
Thanks for reopening the issue.
I hope it turns out to be an important one.
Excelife <excelife at earthlink.net> wrote in article
<70p2ad$2qp$1 at ash.prod.itd.earthlink.net>...
> Senescent cells appear to accumulate in tissues with age. Furthermore at
> least some of these cells, like fibroblasts, can be identified by their
> profile of enzymatic activity and stained so that they are clearly
> under the microscope.
> ( See the description of Judith Capisi's work at the
> Now, senescent fibroblast produce many times the amount of collagenases
> - possibly the most important family of enzymes responsible for the
> degradation of the extracellular matrix. Are these senescent fibroblasts
> responsible for some of the features of aging like lax skin, overly
> capillaries, breakdown of the blood-brain-barrier, some arthritic
> If so, since they can be identified by staining, can they also be
> by smart drugs which have special affinity for these cells and
> toxic to them? directly toxic, phototoxic, or apotosis inducing ?
> L. Pagnucco
> I'm reposting a post of yours from a while back. At that time I
> that I didn't think this approach would be beneficial since the remaining
> cells would reproduce and just generate more senescent cells.
> After reviewing the research of Dr. Effros at U.C.L.A. in regards to
> immunosenescence it appears that the strategy you suggested may be of
> From Dr. Effros work including, (Am J Hum Genet 1998 May;62(5):1003-7
> "Replicative senescence in the immune system: impact of the Hayflick
> T-cell function in the elderly."), it appears that one of the negative
> effects of senescent cells, at least in T-cells, is that they inhibit the
> production of more functional cells. Elimination of these senescent
> may allow for the production of other more productive cells.
> Additionally, even if the remaining cells did progress more rapidly
> senescence, due to this increased cellular production, the majority of
> would initiate apoptosis rather than becoming senescent. Thus the
> effect may very well be improved functioning of the system(s) in which
> strategy of eliminating senescent cells were employed.
> Thomas Mahoney, Pres.
> Lifeline Laboratories, Inc.
I thought I might supply a few citations and abstracts (below) on the
Notice that in the first abstract below, the authors
state that the NIA is funding research looking into
whether increasing apoptosis in senescent or damaged
cells may be beneficial.
J Am Geriatr Soc 1997 Sep;45(9):1140-6
What does cell death have to do with aging?
Warner HR, Hodes RJ, Pocinki K
Public Information Office, National Institute on
Aging, NIH, Bethesda, MD 20892, USA.
When Lockshin and Zakeri discussed the relevance
of apoptosis to aging 7 years ago, the common view
was that apoptosis would have primarily a negative
impact on aging by destroying essential and often
irreplaceable cells. That view has now changed to
one that acknowledges that there are two general ways
in which apoptosis can play a role in aging:
(1) elimination of damaged and presumably dysfunctional
cells (e.g., fibroblasts, hepatocytes), which can then
be replaced by cell proliferation, thereby maintaining
(2) elimination of essential post-mitotic cells
(e.g., neurons, cardiac myocytes), which cannot
be replaced, thereby leading to pathology.
Evidence exists in two systems (fibroblasts and
thymocytes/lymphocytes) that there are age-related
decreases in the potential for apoptosis, although
the molecular bases for the decreases in these
two systems appear to differ. Upon becoming senescent,
fibroblasts lose the ability to down-regulate
expression of the bcl-2 gene in response to an
apoptotic signal; thus, apoptosis is blocked even
though an initiating signal has been received. In
contrast, thymocytes/lymphocytes lack the ability to
initiate the signal because of down-regulation of the
cell surface receptor Fas.
There is limited information available for other
tissue types, and nothing is known about why and
how age-related changes occur. An interesting observation
is that the frequency of up-regulation of the bcl-2
gene as a result of chromosome translocation in otherwise
normal B cells increases with age; the functional
consequences of this phenomenon during aging are not
known. The role of apoptosis in regulating cell number
is also a promising area of research. The studies on liver
damage and neoplastic lesions suggest an extremely
important role for apoptosis in controlling cancer. This
may be particularly important in the prostate where
hypertrophy and/or cancer are a virtual certainty with
ever-increasing age. It is not known whether the ability
to undergo apoptosis declines in the prostate with
increasing age, but it appears possible that it may,
thus explaining the loss of control over cell number in
this tissue. A particularly important area of research
is whether apoptosis plays a role in the changing balance
between bone formation and resorption observed during
osteoporosis. Monica Driscoll has already pointed out
that, "regulation and execution of cell death is an
absolutely critical process that interfaces with nearly
every aspect of life. Future investigation of the links
of cell death to cellular aging and the aging of organisms
should be an exciting enterprise." The results currently
available do suggest that apoptosis is a process that may
be important in aging, at least in some tissues, and the
mechanism of its regulation, in particular, needs to be
understood. Several tumor suppressor gene and oncogene
products are involved in signal transduction associated
with apoptosis, but it remains to be shown which of these,
if any, are actually involved in "on-off" switches for
apoptosis. Where great progress has been made is in
understanding the events occurring after binding of either
Fas ligand or tumor necrosis factor to their respective
receptors. However, one area about which little is known
is the identity of the signals that initiate this process
in response to intracellular damage. Through continuing
research on cell death mechanisms, funded by the NIA, we
hope to provide answers to such fundamental questions as:
1. Are there age-related changes in apoptosis, and what
role, if any, do these have in the aging process?
2. If age-related changes in apoptosis do occur, what
molecular mechanisms are altered to produce these
3. Can approaches be developed to improve the detection
and elimination of damaged cells in vivo in tissues
where cell replacement is possible?
4. Can death of damaged cells be attenuated or delayed
in nonrenewable tissues, and, if so, is it advantageous
to the org
Upregulation of Apoptosis with Dietary Restriction:
Implications for Carcinogenesis and Aging
S. Jill James,1 Levan Muskhelishvili,1 David W. Gaylor,
2 Angelo Turturro,2 and Ronald Hart2
1Division of Biochemical Toxicology, 2Division of Biometry
and Risk Assessment, U.S. Food and Drug Administration,
National Center for Toxicological Research, Jefferson, Arkansas
The maintenance of cell number homeostasis in normal
tissues reflects a highly regulated balance between the
rates of cell proliferation and cell death. Under
pathologic conditions such as exposure to cytotoxic,
genotoxic, or nongenotoxic agents, an imbalance in these
rates may indicate subsequent risk of carcinogenesis.
Apoptotic cell death, as opposed to necrotic cell death,
provides a protective mechanism by selective elimination
of senescent, preneoplastic, or superfluous cells that
could negatively affect normal function and/or promote
cell transformation. The relative efficiency or dysfunction
of the cell death program could therefore have a direct
impact on the risk of degenerative or neoplastic disease.
Dietary restriction of rodents is a noninvasive intervention
that has been reproducibly shown to retard tumor development
and most physiologic indices of aging relative to ad
libitum-fed animals. As such, it provides a powerful
model in which to study common mechanistic processes
associated with both aging and cancer. In a recent study
we established that chronic dietary restriction (DR)
induces an increase in spontaneous apoptotic rate and a
decrease in cell proliferation rate in hepatocytes of
12-month-old B6C3F1 DR mice relative to ad libitum
(AL)-fed mice. This diet-induced shift in cell
death/proliferation rates was associated with a marked
reduction in subsequent development of spontaneous hepatoma
and a marked increase in disease-free life span in
DR relative to AL-fed mice. These results suggest that
total caloric intake may modulate the rates of cell death
and proliferation in a direction consistent with a cancer-
protective effect in DR mice and a cancer-promoting effect
in AL mice. To determine whether the increase in spontaneous
apoptotic rate was maintained over the life span of DR mice,
apoptotic rates were quantified in 12-, 18-, 24- and
30-month-old DR and AL mice. The rate of apoptosis was
elevated with age in both diet groups; however, the rate
of apoptosis was significantly and consistently higher in
DR mice regardless of age. In double-labeling experiments,
an age-associated increase in the glutathione S-transferase-II
expression in putative preneoplastic hepatocytes in AL mice
was rapidly reduced by apoptosis upon initiation of DR.
Thus, interventions that promote a low-level increase in
apoptotic cell death may be expected to protect genotypic
and phenotypic stability with age. If during tumor promotion
an adaptive increase in apoptosis effectively balances the
dysregulated increase proliferation, the risk of permanent
genetic error and carcinogenesis would be minimized.
-- Environ Health Perspect 106(Suppl 1):307-312 (1998).
Neurol Clin 1998 Aug;16(3):735-45
Aging and apoptosis control.
Tomei LD, Umansky SR
LXR Biotechnology Incorporated, Richmond,
California 94804, USA.
The phenomenon of aging is distinct from processes
associated with advanced age known to increase risk of
diseases, such as cancer. Furthermore, the process of aging
is not necessarily related to phenomena such as in vitro
replicative senescence; however, any unifying hypothesis of
aging must account for all age-dependent phenomena,
including senescence. It is proposed that apoptosis forms
the ultimate protective process for preservation of
phenotypic fidelity in multicellular organisms since it
is the process by which the organism detects damage and
replaces the defective cell. Time-dependent degeneration
of apoptosis control is the rate-limiting step in the
process of aging.
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