Mechanisms of Ageing and Development
122 (2001) 1537– 1553
www.elsevier.com/locate/mechagedev

Viewpoint

Does functional depletion of stem cells
drive aging?
David Schlessinger a,*, Gary Van Zant b
a

Laboratory of Genetics, Gerontology Research Center, National Institute on Aging, NIH-NIA,
5600 Nathan Shock Dri6e, Baltimore, MD 21218, USA
b
Di6ision of Hematology/Oncology, Markey Cancer Center, Uni6ersity of Kentucky Medical Center,
800 Rose St., Lexington, KY 40536 -0093, USA
Received 16 April 2001; received in revised form 17 May 2001; accepted 18 May 2001

Abstract
The regenerative power of stem cells has raised issues about their relation to aging. We
focus on the question of whether a decline in the function of stem cells may itself be a
signiﬁcant feature of aging. The question is implicitly two-fold: does functional depletion of
stem cells affect the accumulation of aging-related deﬁcits, and -- whether or not depletion
is signiﬁcant -- can activation of stem cells alleviate deﬁcits? Two types of system are
considered: 1) the exhaustible pool of ovarian follicles. The depletion of follicles leads to the
aging-related phenomenon of menopause; and 2) the reserve of hematopoietic stem cells.
Substantial numbers are sustained throughout life, but in mouse models, endogenous
replicative activity has been shown to decline sharply with age. We discuss the possible
implications of these observations for the rate of aging and the prospects for intervention.
© 2001 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Immortal cells; Ovarian follicles; Hematopoiesis; Lifespan

* Corresponding author. Tel.: +1-410-558-8337; fax: +1-410-558-8331.
E-mail address: schlessingerd@grc.nia.nih.gov (D. Schlessinger).
0047-6374/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 0 4 7 - 6 3 7 4 ( 0 1 ) 0 0 2 9 9 - 8

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1. The aging manifesto
We are born from immortal cells. Yet all of us are chained by aging and
mortality. How does this come about, and what can we do about it?
Restated in standard scientiﬁc terms, there has been a fundamental paradox in
biological thinking about aging and death compared with embryonic life. The
paradox has been mentioned as relevant to the evolution of aging (Kirkwood and
Austad, 2000), but recent discoveries about stem cells make it unavoidable to
confront it in detail. The confrontation, discussed here, questions traditional
assumptions about the nature of aging and the possibility of intervention in the
aging process.

2. Germ cells versus ‘disposable’ somatic cells
By deﬁnition, our hereditary potential is passed on by immortal, totipotent cells:
that is, cells that can reproduce and initiate full development of new individuals in
their progeny on an evolutionary time scale. An extra boost to survival is given by
the production of a vast excess of germ cells, both eggs and sperm, compared with
the number of progeny.
In contrast to the immortal, totipotent germ cells, the rest of the body consists
mainly of ‘mortal’, differentiated cells. This distinction has a special importance for
theories of the mechanism of aging-related processes, for the substratum of aging
has been taken to be the mortal cells and their integument products (Hayﬂick,
1994). Aging itself has often been ascribed to the accumulation of ‘damage’ of one
kind or another in mortal cells— poorly-repaired damage of chromosomal DNA,
stress-related mistakes in structural proteins or enzymes or turnover, deletions in
mitochondrial DNA, etc. Based in part on such thinking, important discussions
have ascribed aging to ‘disposable soma’ (Kirkwood, 1977; Kirkwood and Rose,
1991), with the notion that selection has chieﬂy operated to increase fertility, and
the cells and tissues of the body need have only enough oomph to maintain
function through child-bearing age. At that point the soma (that is, the individual)
becomes evolutionary dead meat, and, therefore, unsurprisingly subject to insults
that have no selective counterpressure to promote continued survival.
This formulation has shown remarkable staying power, with masterful presentations and repetitions (Medawar, 1952; Charlesworth, 1993; Rose, 1991 Westendorp
and Kirkwood, 1998; Kirkwood, 2001). But several considerations suggest that it
may require modiﬁcation.
First, the distinction begs the question of what constitutes the difference between
germ cells and ‘disposable’ cells. After all, germ cells should be subject to all the
stresses and environmental changes and stochastic errors in DNA replication and
deletion, etc. that are thought by various constituencies to result in aging. How do
germ cells escape that formal cause, and if there are escape mechanisms, why don’t
differentiated cells escape in a similar way? There has been some tendency to say
that comparable immortality of somatic cells is linked to uncontrolled growth in

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cancer (e.g. Kirkwood, 1977), but that assertion is controverted by recent research.
For example, oligodendrocyte cells (Tang et al., 2001), glial cells (Mathon et al.,
2001), and mammary epithelial cells (Romanov et al., 2001), which are clearly
‘disposable’, can apparently grow and divide indeﬁnitely in culture without ‘aging’.
So can a variety of stem cells (including embryonic stem cells, Suda et al., 1987), as
discussed further below.
The doctrine of disposable soma also assumes (or states as an inference) that
there is no signiﬁcant selection for ‘old age’ (or on the contrary, that there may be
selection for genes that are positive at younger ages but have negative effects in old
age, Williams, 1957). But within our own species, longevity has a clearly demonstrated genetic component, particularly for survival to ‘centenarian’ status (Perls et
al., 1998, 2000). Therefore, at the very least, some individuals have a more
disposable soma than others. The notion of disposability is further weakened if one
takes into account the possibility (Schlessinger and Ko, 1998), fostered by versions
of group selection, that there may be positive selection for only small numbers of
very old individuals, with driving forces that might be negative for the bulk of a
population.

3. Germ cells and soma, meet stem cells
The notion of disposable soma has also been sustained by the traditional
assumption that aging is a post-developmental process, occurring in a compartment
of life that starts in late maturity (Hayﬂick, 1994; Miller, 2001). But this view is
challenged by the ﬁndings with a third category of cells, ‘stem cells’, that retain
developmental potential.
Recent studies have sharply increased the repertoire of astonishing properties of
stem cells. These cells are not in themselves ‘germ cells’, and are clearly differentiated, but they have long been known to retain the possibility of self-renewal as well
as further differentiation into end-stage cells. Successive adoptive transfer experiments have demonstrated that mouse lympho-hematopoietic cells, for example, can
go through immense numbers of productive divisions to repopulate depleted
marrow (Harrison, 1972; Iscove and Nawa, 1997; Siminovitch et al., 1964). Furthermore, and more relevant to this discussion, it is now clear that the ‘differentiation’ of stem cells is not irreversible, and one kind of stem cells can substitute for
others to repopulate the reserves of many tissues (Bjornson et al., 1999; Brazelton
et al., 2000; Brustle et al., 1999; Ferrari et al., 1998; Gussoni et al., 1999; Jackson
et al., 1999; Kopen et al., 1999; Lagasse et al., 2000; Lavker and Sun, 2000; Mezey
et al., 2000; Orkin, 2000; Uchida et al., 2000; Watt and Hogan, 2000; Weissman,
2000). Thus, stem cells retain the capacity to grow and divide apparently without
limit, and they can ‘dedifferentiate’ and ‘redifferentiate’ (or transdifferentiate directly) to a new stem cell lineage (Weissman, 2000). In extreme tests of potential,
both stem cells and ‘ordinary’ somatic cells can contribute nuclei to enucleated eggs
to clone mammals (Wilmut et al., 1997; Wakayama et al., 1999, 2000). Such cloning
experiments demonstrate that the differentiation and limited potential of cells that

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has been linked to aging is contingent. Contrary to earlier thinking, ‘commitment’
is often intrinsically reversible.
The a priori and experimental weakening of the neat distinction between germ
cells and soma is not merely academic. There are deﬁnable differences between
these types of cells and stem cells, which are linked to genetic mechanisms of aging;
and depending on what those differences are, there may or may not be interventions that can change the rate of aging or make the survival of all individuals
approximate the longest lived in an extant population— or even augment survival
beyond current limits.
One can then ask, what special abilities or mechanisms of stem cells can be
regained by somatic cells?, to what extent can we capitalize on reversibility to
regenerate aging cells or tissues? and more generally, what is the relation of stem
cells to aging?

4. Embryonic life and stem cell dynamics
We have pointed out elsewhere (Schlessinger and Ko, 1998) that aging-related
phenomena have a profound dependence on earlier processes, many of them
initiated in utero. Although, no one would argue that the loss of cells and function
with age is in any way the reverse of development, it seems obvious that knowing
more about the process of formation of cells and tissues, and the factors required,
can help to prolong or even to regenerate failing components of the aging body.
One can then consider how, and how well the pool of stem cells is adapted to needs
at different ages; or whether damaged (or non-dividing ‘crisis’, Hayﬂick, 1994) cells
that are resistant to or not accessible to stem cell replacement contribute to the
fundamental course of aging. To answer such concerns we require information
about three features of stem cells throughout life: their numbers, their accessibility/
mobilizability, and their capacity to replace or supplement already existing mature
cells.
Fig. 1 contrasts two fundamental alternatives for cell dynamics, exempliﬁed by
mammalian ovarian follicles (Fig. 1a) and hematopoietic stem cells (Fig. 1b). In
both cases, the cells retain indeﬁnite capacity for growth and division. But they
differ in the extent to which they are called on or available to exercise that capacity.
Follicles are progressively depleted, whereas blood stem cells are repeatedly expanded in bursts of activity. (It is notable that evolution has no rigid, invariant
commitment to strategies. For example, the nematode has no ‘somatic’ stem cells;
and in Drosophila (Xie and Spradling, 2000), in contrast to mammals, ovarian
follicles are made continuously through life, much in the manner of Fig. 1b).

5. Menopause and ovarian follicle dynamics
At the moment of birth, a mammalian female infant has all the ovarian follicles
that she is destined to have (Fig. 1a, Fig. 2). Reproductive lifespan is then

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determined by the progressive depletion of that pool through successive menstrual
cycles (Faddy, 2000; Simpson and Rajkovic, 1999; Morita and Tilly, 1999). The
critical embryonic events that yield the ﬁnal pool are thus the balance of synthesis
and turnover of cells. The process is marked by the formation of a very large

Fig. 1. (a) Ovarian follicle dynamics. A ﬁxed pool of follicles available at birth is depleted by atresia, and
after puberty, by ovulation until the numbers fall too low and menopause ensues. (b) Hematopoietic
stem cell dynamics. Periodic bursts of production of mature cells occur from a self-renewing compartment of stem cells (it remains unclear whether there is clonal succession, with stem cells called upon one
or a few at a time, or if all stem cells contribute continuously to most or all bursts; contradictory data
(Harrison et al., 1987; Jordan and Lemischka, 1990) may result because the transplant model usually
studied deviates from the homeostatic condition in vivo).

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Fig. 2. Follicle dynamics during life. The production of high levels of germ cells in utero (yellow) is
accompanied by massive atresia; only about 10% of oocytes are protected by follicular cells (blue) by
birth. The ovarian follicles and their oocytes are then progressively depleted until menopause (see Faddy,
2000).

number of germ cells (of the order of 10 000 000) in fetal life. These are then largely
discarded during a phase of active atresia (apoptosis). At the same time, however,
about 600 000 are surrounded by follicular cells and largely preserved at birth and
until puberty initiates the cycles of ovulation (Fig. 1a, Fig. 2).
One might expect that a variety of transcription factors are involved in setting the
rate and extent of synthesis of follicles, and that correspondingly, a number of
genes would be involved in setting the rate of atresia. In fact, atresia seems to work
through the Bcl system, but with a number of specialized components that modify
the relative stability of follicles (Hsu and Hsueh, 2000; Morita and Tilly, 1999;
Morita et al., 1999a,b).
A clue to the regulation of the ﬁnal number of follicles at birth comes from recent
investigations of premature ovarian failure (POF; Tibiletti et al., 2000). In contrast
to the mean age of menopause of about 51 in all cultures and eras that have been
studied, about 1% of all women either never go through menarche or undergo
primary or secondary amenorrhea before age 40 (Coulam et al., 1986; Chang et al.,
1992). A fraction of these women are easily ascertained, because they are affected
by the linked, complex eyelid condition of Blepharophimosis, Epicanthus Inversus,
Ptosis Syndrome (BEPS, c 605597 in Mendelian inheritance in man, National
Center for Biotechnology Information).

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The gene responsible for BEPS has been cloned from its chromosome three locus
(Crisponi et al., 2001). It proves to be the FOXL2 gene, a winged-helix transcription factor. Consistent with the phenotypes of BEPS and premature ovarian failure,
the gene is expressed essentially only in developing eyelids and in ovarian follicles;
the loss of function of one of the chromosome three alleles leads to eyelid
overgrowth and ovarian follicle deﬁciency. It should now be possible to determine
whether the gene truly acts as a rheostat to determine follicle number, and whether
that effect is exerted at follicle synthesis or maintenance (in Turner syndrome,
another genetic source of POF, the sole X also is thought to be haploinsufﬁcient,
leading to streak gonads (Zinn et al., 1993). This has been related to excessive
atresia in at least some patients (Schlessinger et al., 2001; Simpson and Rajkovic,
1999)).
Certainly, once the pool of ovarian follicles is formed, the simplest ‘counting’
mechanism for depletion would be a ‘commuter ticket’ model, in which a repeated
event involves the ordered, sequential loss of a critical component-either as a
function of time or of cyclical activity. The depletion of follicles indeed generally
occurs for some follicles each ovulation cycle until a threshold value is reached
beyond which ovulation fails and menopause ensues. The cyclical needs of ovulation are met by periodic release of the cascade of hormones that pick out a follicle
and send it on its way from the ovarian pool. The detailed mechanism is unknown,
but we want to point out three vital features: (1) the starting size of the pool, (2)
the rate of depletion, and (3) the need for a ‘threshold’ level. As discussed above,
the initial number is set during early development. In normal biology, the rate of
turnover is then ﬁxed by the ovulation cycle. The third feature, the ‘threshold’,
remains mysterious. The remaining cells could have accumulated damage, like
DNA breaks or mitochondrial deletions, that prevents them from functioning—
that is, they could have damage equivalent to ‘aging’ (see below), essentially
eliminating them from the pool of stem cells. But there is also the alternative notion
of failure of ‘mobilizability’: even if competent stem cells (follicles) remain, they
may be in a location where stimulating hormones cannot reach them, or the
number of follicles may have fallen to a level where they cannot sustain an
adequate level of a paracrine hormone, or there may be a physical or cellular
interaction that prevents them from division (gap junctions with follicle cells,
stretching of ﬁbers from extracellular matrix, etc.).
Many of the parameters that support the possible existence of ‘immobilizable’
cells have been better assessed in other models, particularly for hematopoiesis.

6. Hematopoiesis and other stem cell systems: is functional depletion relevant?
In sofar as follicles represent (totipotent!) stem cells, they demonstrate that
depletion of a stem cell reserve can indeed lead to an irreversible age-related loss of
function, in the classic instance of menopause. But how relevant is this example to
other types of stem cells (hematopoietic, germ cell, neuronal, etc.)? The major
difference (Fig. 1b) is that cell dynamics do not yield a ﬁnal pool of ﬁxed size that

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is irreversibly depleted. Instead, an added degree of ﬂexibility is achieved in two
ways to modify the stem cell pool. In one, ongoing cell differentiation is required,
for example, to sustain the steady state of red cells in blood in the face of turnover
of end-stage mature cells. In the other process affecting the pool, stimuli like the
reduction of oxygen, with the red cell maturation response stimulated by erythropoietin, or blood loss from a wound, or challenge by an infectious agent, lead to
additional waves of differentiation (Fig. 1b).
The question then arises, is depletion of their numbers a signiﬁcant feature of the
fate of stem cells that follow the dynamics of Fig. 1b? Based on all we know, the
answer is ‘no’. For example, repetitive protocols in which a small number of mouse
stem cells are used to reconstitute the hematopoietic system of irradiated animals
can be successfully carried through multiple generations, and only extreme conditions, involving prior treatment of mice with cyclophosphamide and cytokines,
mimicking some treatment protocols for cancer, damages the capacity of marrow
cells to contribute to the serial transplants (Hornung and Longo, 1992). Also,
studies of aging in inbred strains show that the number of bone marrow stem cells
is not appreciably diminished in old age. In fact, numbers are increased in both of
two strains, DBA/2 and C57BL/6, studied in detail at middle-age (1 year) to
2–5-fold the level in 2-month-old animals (de Haan and Van Zant, 1999a). After 1
year, a strain-dependent difference in numbers is observed, but is less than 2-fold
over most of the lifespan (de Haan and Van Zant, 1999a; Morrison et al., 1996).
Thus, it is not surprising that clinical medicine rarely deﬁnes a syndrome caused by
loss of blood cell precursors (aplastic anemia and lymphopenia are exceptions,
though they are not generally thought to be strictly age-dependent).
On the other hand, although the numbers of stem cells tend to be maintained,
inter-strain variations in cell cycle kinetics of stem and progenitor cells of the
hematopoietic system of mice have been identiﬁed. To determine whether interstrain variations are cell-autonomous and thus under the control of ‘stem cell
genes’, or are extrinsically regulated by the environment, strains with large,
quantiﬁable variations were selected, and chimeric mice were constructed by
aggregating embryos of the strains and implanting them into foster mothers. The
resulting mice are cellular chimeras in which all tissues, including the hematopoietic
stem cell system, consist of a mixture of cells derived from the two embryos. Any
genotype-restricted differences in stromal and humoral milieu that may affect stem
cell function are thought to be obviated in the chimeras, with all stem cells exposed
to the same environment. This permits one to attribute observed differences to
cell-autonomous (genetic) causes. Fig. 3 shows the level of chimerism in the
peripheral blood leukocyte populations of mice generated by aggregating DBA/2
and C57BL/6 embryos (Van Zant et al., 1990). DBA/2 stem cell contributions to
lympho/hematopoiesis decline with age, and after about 2 years, blood cells are
entirely of C57BL/6 origin. The results demonstrate that the inter-strain differences
are cell autonomous. Furthermore, because cells of both the lymphoid and myeloid
compartments are affected, the effects probably take hold at the level of the stem
cell.

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Nevertheless, although, there is a growing numerical advantage of C57BL/6 stem
cells in old-aged chimeras, DBA/2 stem cells are not gone, large numbers of
potentially active DBA/2 stem cells are still present and competent (Van Zant et al.,
1992). This is demonstrated in Fig. 4, in which blood cell chimerism is shown in a
single chimeric animal. DBA/2 chimerism was about 15% early in life but by 2 years
of age had dropped to 0, and there was no longer any DBA/2 hematopoiesis
evident. At 31 months of age, after 9 months of only C57BL/6-derived hematopoiesis, the mouse was sacriﬁced and its marrow cells were transplanted into
lethally irradiated recipients. DBA/2 stem cells were reactivated and contributed
robustly to engraftment at a disproportionately high level (40%) relative to
chimerism in the early life of the donor chimera ( 15%). With time, however, the
stem cells again become quiescent. This cycle of activation and subsequent quiescence was repeated in another round of transplantation to secondary recipients
(Fig. 4). These data argue that during aging, DBA/2 stem cells do not disappear,
but become less sensitive or refractory to those environmental cues that foster
differentiation, and possibly stem cell replication, in young animals. In other words,
the curve of Fig. 3 superﬁcially resembles the decline phase of Fig. 2, but not
because stem cells are being ‘used up’ like ovarian follicles. Rather, DBA/2 stem
cells are tending to become quiescent.
Reactivation of DBA/2 stem cells somehow occurs during the transplantation
procedure, modifying the ‘mobilizability’ of stem cells. In other words, mobilizability declines during the aging of the mice, with functional but relatively mild
numerical depletion of stem cells.
The cell cycle kinetics in the hematopoietic compartments of DBA/2 and
C57BL/6 mice have been studied, and observed differences are consistent with the

Fig. 3. Quiescence of DBA/2 stem cells in C57BL/6l DBA/2 embryo-aggregated chimeric mice. Blood
cell chimerism was measured in a group of 6 – 8 chimeric animals over 3 years, using glucose phosphate
isomerase polymorphism as a genotype-speciﬁc marker. Note the complete quiescence of the DBA/2
stem cell pool after 30 months.

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Fig. 4. Quiescence and re-‘mobilization’ of DBA/2 stem cells through transplantation. Marrow was
harvested at 31 months from a chimera in which DBA/2 stem cells had ceased blood cell production, and
was transplanted into lethally irradiated recipients. Marrow was subsequently harvested from the group
of primary recipients at 37 months and transplanted into a second group of lethally irradiated recipients.
Note the repetitive cycles of ‘mobilization’ and quiescence of stem cells during transplantation and
engraftment.

results of transplantation of chimeric marrow (de Haan and Van Zant, 1999a,b).
Cell cycling of progenitor cells in young animals, measured by a standard assessment of the fraction of cells that survive hydroxyurea treatment, is much greater in
DBA/2 mice, but in both strains the replication rate drops dramatically with age
until it is barely detectable in old animals of either strain. The initial competitive
advantage of DBA/2 stem cells when transplanted may derive from the generally
higher rate of proliferation in their progenitor cell compartment. But what accounts
for the arousal and robust function of deeply quiescent DBA/2 stem cells transplanted from old chimeras? Indeed, what causes the deep quiescence of the DBA/2
stem cells at a time when in the same environment old C57BL/6 stem cells continue
to function normally and provide all of the requisite blood cells of all lineages?
What accounts for the loss of ‘mobilizability’?
Based on the probable importance of ‘other’ (extrinsic) features of stem cell
recruitment, there may be an age-related change in the environment of stem cells
that renders the cells less accessible or responsive to activation. Activation of stem
cells would be favored in transplantation experiments, either as a result of exposure
to the abnormal cytokine milieu found in lethally irradiated transplant recipients, of
dissociation from their native stroma in preparing a cell suspension, or of association with new stroma in the transplant recipient. These notions are not novel; the
work of Bissell’s group (Schmeichel et al., 1998) has established the determinative

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role that can be played by extracellular matrix in replication/differentiation
pathways.
Although, it has been argued that there is complete tolerance to cells from both
parents in chimeras (Mintz and Silvers, 1967; Mintz and Palm, 1969), it is difﬁcult
to exclude effects of natural killer cells or other immune phenomena on the relative
decline of stem cells from one parent (Fig. 3). However, in transplant experiments
using chimeric marrow, treatment of the recipients with anti-asialo GM1 antibody
to kill NK cells had no effect on either the quantitative or temporal contributions
of C57BL/6 and DBA/2 stem cells to engraftment (Van Zant et al., 1990). In both
the antibody-treated and control groups, DBA/2 stem cells made robust contributions to early engraftment but, as in the chimeras themselves, ultimately became
quiescent. In the same vein, the comparable, age-related decline of the fraction of
replicating stem cells in every strain examined (see below) is less likely to be
immune-modulated. Furthermore, there are fragmentary but suggestive indications
of similar progressive quiescence of other types of stem cells. In particular, there are
already several reports indicating that during brain aging, neural stem cells are
present at normal levels, but for some reason, stem cell proliferation declines (Kuhn
et al., 1996; Montaron et al., 1999). Again in this case, immune modulation would
be relatively unlikely, but remains conceivable.
Whatever the mechanism for quiescence and declining mobilizability of stem cells
during aging, a working hypothesis can be formulated from a look at the relationship between mouse longevity and cell cycle kinetics (Fig. 5). There is a strong
negative correlation between the mean lifespan of eight commonly used inbred
mouse lines and the fraction of hematopoietic progenitor cells in S-phase of the cell
cycle (de Haan and Van Zant, 1997). The natural lifespan of DBA/2 mice is very
nearly the time at which DBA/2 hematopoiesis ceased in the chimeras discussed
above, indicating either an intriguing coincidence or a causal relationship. In

Fig. 5. Negative correlation between hematopoietic progenitor cells in cell cycle and the mean lifespan
of eight inbred strains of mice. The strains (from lowest to highest cell cycle kinetics) were 129/J,
C57BL/6J, BALB/cJ, A/J, DBA/2J, C3H/HeJ, AKR/J, and CBA/J. Cell cycle activity was measured by
the fraction of progenitor cells (cobblestone area-forming cells counted at day 7) killed by a 1-h
incubation with hydroxyurea. The regression line has a correlation coefﬁcient of 0.55 that is statistically
signiﬁcant (PB 0.01).

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Fig. 6. Short- and long-term defenses against aging deﬁcits. Homeostasis is subject to various stresses
that deplete or damage function. The short-term (immediate) responses that help to maintain/restore
homeostasis include intracellular turnover and repair as well as stress responses to oxidation, heat, etc.
In addition, germ cells and stem cells can provide longer-term renewal that replaces or regenerates cells
and tissues.

provocative terms, these results suggest that functional depletion of stem cells not
only occurs, but may itself be a principal feature of aging, and possibly a driving
force.

7. The future of aging
In the life of a metazoon, as schematized in Fig. 6, the effects of stress and
wear-and-tear on homeostasis can be seen as counteracted by two types of
processes. One is immediate, based on constitutive repair and intracellular turnover
supplemented by other stress responses (including, e.g. heat shock, panic, acute
phase, and apoptotic responses). Other, longer-term responses to stress involve
critical interactions with embryonic processes. To recapitulate, they are based on
the regeneration and renewal of cells and tissues, which are dependent in turn on
the setting of stem cell pool size and rates of turnover in early development. As
reviewed here, functional depletion of ﬁxed numbers dominates the subsequent fate
of ovarian follicles, whereas turnover rates and mobilizability, with little drop in
numbers, may determine the fate of most stem cells. The underlying mechanisms
and genetic factors determining the numbers, turnover rate, and mobilizability of
stem cells remain to be elucidated, though they seem to be related to cell cycle
checkpoint controls that may be more or less stringent in different strains, but
always lead to increasing quiescence (cf. Martin and Oshima, 2000).

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One can explicitly note that the fundamental difference between germ cells and
somatic cells, the paradox stated at the start of this discussion, is not resolved here.
In fact, the formal cause of aging-oxidation, mitochondrial deletion, etc. remains
undetermined. In organisms like nematodes, which lack stem cells, aging acts on
somatic cells in an approximation of the ‘disposable soma’ formulation, and many
have argued plausibly that a universal mechanism underlies aging in all species (see
below). Furthermore, the insults that produce aging may occur in stem cells as well
as somatic cells. In fact, the correlation between lifespan and stem cell activity in
inbred mouse strains (Fig. 5) may be fortuitous. At present, mammalian lifespan is
usually limited by speciﬁc diseases (heart disease, end-stage renal failure, etc.) that
are not thought to involve a reduction in stem cell activity in their etiology. It is,
therefore, highly speculative to think that organ-speciﬁc depletion of stem cell
function could determine the fate of an organ, and thereby be involved in
determining lifespan, and in that sense, the title to this essay is truly a question to
be investigated, and not a claim. Nevertheless, regardless of the degree to which
stem cells may be involved in particular disease processes, the existence and
potential of stem cells make an important difference in discussing current prospects
for aging. To be more precise: stem cell-based intervention is foreseeable. The
ﬂexibility of possible intervention is increased by two ﬁndings. First, as reviewed
above, there is increasing evidence for the plasticity of stem cells: neuronal or other
stem cells can repopulate a number of stem cell compartments in the body,
apparently because their commitment is partial or reversible. Second, stem cell
manipulation in vitro may remedy problems of mobilizability. In many scenarios of
‘regeneration’ or ‘supplementation’, the endogenous numbers and milieu of stem
cells appear to be secondary. Instead, projections proceed on the basis of increasing
the numbers of functioning stem cells in models like marrow transplantation or
even egg transfer from donors. In other words, stem cells are in effect activated
(‘remobilized’) in vitro and then provided back to a host.
Such proposals are consistent with the general paradigm of a rate of aging that
can be shifted by intervention, as inferred from the studies of caloric restriction in
organisms ranging from yeast (Jazwinski, 2000) to nematode (Lakowski and
Hekimi, 1998) to rodents (Lee et al., 2000) to monkeys (Lane, 2000). Both longevity
and reserves against stress (Sohal and Weindruch, 1996; Mattson, 2000) are
increased by limitations in caloric intake. In an independent line of research in
humans, the work of Perls’ group (Hitt et al., 1999; Perls et al., 1998, 2000) has
suggested that a ‘rate of aging’, under genetic control, is modiﬁed in supercentenarians. It should soon be known whether caloric restriction and supercentenarian
advantage act on the same or different genetic substrata. In particular, it can be
asked whether mouse strains with differential longevity or differential responses to
caloric restriction have corresponding differences in stem cell kinetics and mobilizability. Already mouse studies show the inverse relation of longevity and stem cell
kinetics (Fig. 5), and in a ﬁrst hint about possible features of reserves in supercentenarians, Perls’ ﬁndings include the suggestive observation that supercentenarian
women have a recorded mean age of last childbirth of 46.2 years, considerably in
excess of peer female cohorts who survive menopause but die younger (Perls et al.,
1997).

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In conclusion, it is early times in the study of stem cells, and one can mainly raise
issues at this time. It seems increasingly likely, however, that an understanding of
the determination of numbers, rate of turnover, and mobilization/activation of
various types of stem cells will provide ways to prevent or alleviate many unwanted
age-related phenomena. Stem cells are suspended in a limbo between an immortal
state and irreversible, mortal commitment, and could in principle replace every
structure, including ‘poorly renewable’ collagen, etc. They may thus be superimposed on any detailed mechanism of aging to determine the fate of the aging body.
Returning to our initial statement,
We have nothing to lose but our chains. Can the regulation of functional
depletion of stem cells provide the key to unlock them?

Acknowledgements
This review and its formulation are dedicated to our teacher Gene Goldwasser,
in the context of our own developments (‘mobilization’?) at the University of
Chicago. We thank Dr Minoru Ko for drafting Fig. 1, Dr Antonino Forabosco for
the formulation of Fig. 2, and Dr Mark Mattson and Dr Dan Longo for helpful
suggestions.
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