Re-Visiting a Post by Lou Pagnucco

Lou Pagnucco pagnucco at oeonline.com
Sat Oct 24 23:37:11 EST 1998


Hello Michael,

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
visible 
> under the microscope.
> 
> ( See the description of Judith Capisi's work at the 
>
URL:http://www.lbl.gov/LBL-Publications/Currents/Archive/Oct-6-1995.html#RTF
T
> oC2)
> 
> 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
permeable 
> capillaries, breakdown of the blood-brain-barrier, some arthritic
conditions, 
> etc.?
> 
> If so, since they can be identified by staining, can they also be
targeted
> by smart drugs which have special affinity for these cells and
selectively
> toxic to them?  directly toxic, phototoxic, or apotosis inducing ?
> 
> -- 
> Regards,
> L. Pagnucco
> 
> 
> Lou,
> 
> I'm reposting a post of yours from a while back.  At that time I
indicated 
> 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
some 
> benefit.
> 
> 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
limit on 
> 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
cells 
> may allow for the production of other more productive cells.
> 
> Additionally, even if the remaining cells did progress more rapidly
toward 
> senescence, due to this increased cellular production, the majority of
them 
> would initiate apoptosis rather than becoming senescent.  Thus the
overall 
> effect may very well be improved functioning of the system(s) in which
this 
> strategy of eliminating senescent cells were employed.
> 
>  
> 
> 
> Thomas Mahoney, Pres.
> Lifeline Laboratories, Inc.
> http://home.earthlink.net/~excelife/index.html
> 
> 

I thought I might supply a few citations and abstracts (below) on the
subject.

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.

Cheers,
Lou Pagnucco
----------------------------------------------------------------------------
--
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 
 homeostasis, and 

 (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 
    changes? 

 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 



Abstract

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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