X-Message-Number: 25365
Date: Mon, 20 Dec 2004 11:03:33 -0800 (PST)
From: Doug Skrecky <>
Subject: telomeres may not be the key to aging

[Interesting that telomeres appear to play no role in either human skin
aging, or bone marrow aging.]

Br J Dermatol. 2004 Jan;150(1):56-63
Ageing of human epidermis: the role of apoptosis, Fas and telomerase.
  BACKGROUND: Aged human epidermis is characterized by morphological
changes including flattening of the dermal-epidermal junction and a
decrease in thickness. OBJECTIVES: To determine the roles of
proliferation, apoptosis, Fas (CD95), Fas ligand (FasL) and telomerase in
changes of human epidermis during ageing. METHODS: Human epidermis from
aged subjects (n = 14; mean age 70.7 years) and young subjects (n = 14;
mean age 23.4 years) was studied by histology, immunohistochemistry,
terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate
nick end labelling assay for apoptotic cells and reverse
transcription-polymerase chain reaction to determine epidermal thickness,
proliferation (Ki-67), apoptosis, expression of Fas and FasL, and
telomerase activity. RESULTS: Aged skin was associated with thinning of
the epidermis, decreased proliferation, and increased apoptosis below
the granular layer. This was associated with increased epidermal
expression of Fas and FasL. Telomerase activity was similar in aged and
young epidermis. CONCLUSIONS: Fas/FasL-mediated apoptosis, along with
decreased proliferation, may have a role in changes of human epidermis
during ageing. Telomerase activity did not appear to be limiting in young
vs. old human epidermis.

Bone. 2003 Dec;33(6):919-26.
Aging is associated with decreased maximal life span and accelerated
senescence of bone marrow stromal cells.
 Age-related decrease in bone formation is well described. However, the
cellular causes are not known. Thus, we have established cultures of bone
marrow stromal cells (MSC) from young (aged 18-29 years, n = 6) and old
(aged 68-81 years, n = 5) donors. MSC were serially passaged until
reaching maximal life span. Cell growth, markers of cellular senescence,
and osteogenic and adipogenic potential were determined in early-passage
and late-passage cells established from young and old donors. MSC from
old donors exhibited a decreased maximal life span compared with cells
from young donors (24 +/- 11 population doublings [PD] vs 41 +/- 10 PD, P
< 0.05) and mean PD rate was lower in old donor cells (0.05 +/- 0.02
PD/day) compared with young donor cells (0.09 +/- 0.02 PD/day) (P <
0.05). No differences were detected in number of senescence-associated
beta-galactosidase positive (SA beta-gal+) cells and mean telomere length
in early-passage cells obtained from young and old donors. However, MSC
from old donors exhibited accelerated senescence evidenced by increased
number of SA beta-gal+ cells per PD as compared with young (4% per PD vs
0.4% per PD, respectively). MSC from young and old donors were able to
form similar amounts of mineralized matrix in vitro and of normal
lamellar bone in vivo. In adipogenic medium similar numbers of adipocytes
formed in cultures of young and old donors. In conclusion, aging is
associated with decreased proliferative capacity of osteoprogenitor
cells, suggesting that decreased osteoblastic cell number, and not
function, leads to age-related decrease in bone formation.

[Skin aging is surprisingly easy to reverse, by changing the
microenvironment the skin is exposed to.]

J Gerontol A Biol Sci Med Sci. 2004 May;59(5):411-5
Aging of human epidermis: reversal of aging changes correlates with
reversal of keratinocyte fas expression and apoptosis.
 The goal of this study was to determine the role of Fas-mediated
apoptosis in human epidermal aging. Epidermal Fas expression and
apoptosis are increased in aged human skin. Aging changes of human
epidermis, including decreased epidermal thickness and proliferation, are
reversed following grafting of human skin to SCID (severe combined
immunodeficiency) mice. Skin from aged participants (n = 14; mean 70.7
years), and young participants (n = 14; mean 23.4 years) was grafted to
beige SCID mice, and epidermal thickness, proliferation (Ki-67
expression), apoptosis (TUNEL [Tdt-mediated dUTP nick end labeling]
reaction below granular layer), and expression of Fas and FasL were
determined by histology and immunochemical staining. Aged skin was
associated with thinning of the epidermis, decreased epidermal
proliferation, a significant increase in apoptosis below the granular
layer, and epidermal Fas expression. Engraftment significantly reversed
these aging changes, including apoptosis, and Fas expression. Correlation
of reversal of aging changes, with decreased epidermal Fas expression and
apoptosis, supports a role for Fas-mediated apoptosis in aging of human

[Could changes in bone marrow be responsible for a general "aging" of
this microenvironment?]

J Exp Med. 2004 Aug 16;200(4):411-23
Bone marrow microenvironmental changes underlie reduced RAG-mediated
recombination and B cell generation in aged mice.
  During aging, adaptive immunity is severely compromised, due in part to
decreased production of B lymphocytes and loss of immunoglobulin (Ig)
diversity. However, the molecular mechanisms that underlie age-associated
diminished B cell production remain unclear. Using in vivo labeling, we
find that this reduction in marrow pre-B cells reflects increased
attrition during passage from the pro-B to pre-B cell pool. Analyses of
reciprocal bone marrow chimeras reveal that the magnitude and production
rates of pre-B cells are controlled primarily by microenvironmental
factors, rather than intrinsic events. To understand changes in pro-B
cells that could diminish production of pre-B cells, we evaluated rag2
expression and V(D)J recombinase activity in pro-B cells at the single
cell level. The percentage of pro-B cells that express rag2 is reduced in
aged mice and is correlated with both a loss of V(D)J recombinase activity
in pro-B cells and reduced numbers of pre-B cells. Reciprocal bone marrow
chimeras revealed that the aged microenvironment also determines rag2
expression and recombinase activity in pro-B cells. Together, these
observations suggest that extrinsic factors in the bone marrow that
decline with age are largely responsible for less efficient V(D)J
recombination in pro-B cells and diminished progression to the pre-B cell

J Exp Med. 1976 Nov 2;144(5):1204-13
Decline in the growth potential of spleen-colonizing bone marrow stem
cells of long-lived aging mice.
  The growth capacity of femoral bone marrow stem cells from young and old
long-lived mice was assessed in the spleen of X-irradiated young and old
syngeneic recpients by determining: (a) the number of stem cells
colonizing the spleen, (b) the rate of incorporation of 125I-labeled
iododeoxyuridine by proliferating colony cells, and (c) the number of
cells present in the largest colonies at the end of the growth phase.We
found that the growth capacity of stem cells declined with age. We
further found that the spleen-seeking and spleen colony growth capacities
of old stem cells remained characteristically old even after they were
allowed to self-replicate in the bone marrow of young recipients for an
extended period of time. On the other hand, the spleen colony growth
capacity of young stem cells could be reduced by allowing them to
self-replicate in old recipients. These results suggest that the growth
capacity of old stem cells is an intrinsic characteristic which cannot be
readily altered, but that of young stem cells can be aged in an
accelerated manner by allowing them to self-replicate in old recipients.
An additional reduction was noted in the frequency of both young
and old stem cells colonizing the spleen of old recipients and in the
cell density of the largest colonies produced. These results indicate
that factors extrinsic to the stem cells are also responsible for the
decline with age in their spleen colony growth capacity. Thus, the growth
capacity of old stem cells in old recipients could be as low as 10% that
of young stem cells in young recipients.

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