Stem cell aging: what bleach can teach

Jie Liu & Toren Finkel

Intracellular oxidants may contribute to overall lifespan, in part by affecting stem cells. The connection between
oxidants and aging now gains strength in a study of hematopoietic stem cells, which respond to oxidants by
activating a pathway leading to stem cell exhaustion (pages 446451).
Late-night infomercials are filled with advertisements for dietary supplements that claim
to be rich in natural antioxidants. Often,
a well-tanned announcer encourages the
viewer to purchasein three easy installmentsan all-natural way to live longer by
fighting the bodys harmful free radicals. The
scientific basis for these suspect claims can be
traced back to a theoretical study published by
Denham Harman in the 1950s, which is now
often referred to as the free radical theory of
aging1. This theory, both supported and challenged by a wealth of experimental evidence,
hypothesizes that the cumulative effects of
reactive oxygen species (ROS) on our DNA,
proteins and membranes ultimately determines our lifespan2.
If ROS do in fact cause us to age, they probably dont uniformly affect all the cells in
our body. Particularly at risk might be cells
that persist throughout an organisms lifespan, such as cardiac myocytes, neurons and
other postmitotic cells. Also at risk seem to be
endogenous adult stem cells, cells that have the
capacity to both self-renew and give rise to differentiated progenitor cells. Among the most
active stem cells in the body are hematopoietic
stem cells (HSCs), which give rise to all the
cells in the blood.
In this issue, Ito and colleagues significantly
advance our understanding of how ROS
might affect the aging of HSCs3. They find
that a rise in hydrogen peroxidethe active
ingredient in household bleachstimulates
a pathway that causes stem cells to exit from
their normal quiescent state. This oxidantinduced proliferation eventually induces HSC
exhaustion.
The authors are in the Cardiology Branch, National
Heart, Lung, and Blood Institute, Bethesda,
Maryland 20892, USA.
E-mail: finkelt@nih.gov

Atm/

Environmental or
genetic stressor

Aging

ROS
p38 MAPK
Quiescence,
normal
hematopoiesis

Proliferation
stem cell exhaustion,
bone marrow failure

Katie Ris

2006 Nature Publishing Group http://www.nature.com/naturemedicine

NEWS AND VIEWS

Figure 1 Reactive oxygen species modulate stem cell proliferation. Deficiency in the Atm gene or
normal aging results in an increase in ROS levels within hematopoietic stem cells (HSCs). This increase
in oxidants may also occur with the other genetic and environmental conditions associated with
premature bone marrow failure (for example, Fanconi anemia and acquired aplastic anemia). The rise in
ROS levels selectively activates the p38 MAPK pathway, which appears to coax HSCs from a quiescent
to a proliferative state. Over time, this increased proliferation results in the exhaustion of the HSC pool
and the clinical appearance of bone marrow failure.

The new findings emerge from observations

made by the same group a few years ago when
they were studying Atm (ataxia telangiectasia
mutated), a protein aberrant in a debilitating
childhood disease characterized by neurodegeneration, immune dysfunction and a predisposition to lymphoid malignancies4. Atm
is a cell cyclecheckpoint regulator that is activated after DNA damage, and it is also thought
to be involved in regulating oxidant levels; in
the absence of Atm, oxidant levels rise5.
Ito and collagues found that mice deficient
in the gene encoding Atm developed earlyonset bone marrow failure and that HSCs
obtained from these mice exhibited elevated
levels of ROS. Whats more, treatment with
the hydrogen peroxide scavenger N-acetylcysteine rescued these mice from bone marrow failure.
These observations were consistent with
other data showing that antioxidant treatment
can rescue the increase in malignancies seen in
Atm-deficient mice6. Such findings suggested
that a rise in intracellular ROS levels mediates

NATURE MEDICINE VOLUME 12 | NUMBER 4 | APRIL 2006

many of pathological effects of Atm, although

how a deficiency in Atm leads to increased
ROS levels remained obscure.
In their present study, Ito and colleagues
provide further insight into the link between
oxidant levels and HSC biology3. In particular,
they show that HSCs from mice are exquisitely
sensitive to oxidative stress induced by buthionine sulfoximine (BSO), an agent that depletes
intracellular glutathione and thereby raises
intracellular hydrogen peroxide. Treatment
of HSCs with BSO abolished the ability of
these cells to contribute to hematopoiesis
when transplanted into an irradiated host.
Such findings were expected from the authors
previous studies, but they next delved into the
molecular mechanism.
They found that oxidative stress within the
HSC appears to specifically activate the p38
MAPK pathway, a signaling pathway that
seems to respond to diverse cellular stresses.
This redox-dependent activation was selective
for HSCs and was not observed in the more
differentiated hematopoietic progenitors.

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 2006 Nature Publishing Group http://www.nature.com/naturemedicine

NEWS AND VIEWS

The investigators went on to show that the
p38 MAPK pathway was constitutively activated in HSCs obtained from Atm-deficient
mice and that inhibition of the p38 MAPK
pathway rescued the bone marrow defect
in these animals. In normal HSCs, examination of the bone marrow revealed that a
significant fraction of stem cells were quiescent and in the G0 phase of the cell cycle.
Deletion of Atm, or a rise in ROS, appears to
stimulate the p38 MAPK pathway in HSCs,
leading this normally quiescent stem cell
population to begin actively dividing.
Finally, the authors attempted to relate
these observations to normal aging by examining wild-type HSCs in serial transplantation experiments. In this strategy, a small
number of donor HSCs are infused into a
recipient irradiated host. After four months,
the donor HSCs are extracted, purified and
used again as donor cells for another irradiated host. This procedure is repeated in a
serial fashion, and thereby provides a useful measure of long-term HSC repopulating
activity.
The authors showed that with each successive transplantation of HSCs, levels of
ROS and p38 MAPK activity rose. Similarly,
serial transplantation led to fewer and fewer
HSCs that could maintain quiescence and
contribute to subsequent hematopoiesis.
Again, treatment with an antioxidant or
p38 MAPK inhibitor reversed these aging
effects.
Together, these results suggest that
increases in ROS within HSCscaused by

genetic defects such as Atm deficiency or by

natural agingresult in activation of the
p38 MAPK pathway. Once activated, p38
MAPK appears to coax the HSCs from a quiescent state into active cell-cycle progression
(Fig. 1). Over time, this lack of quiescence
appears to ultimately contribute to stem cell
exhaustion and bone marrow failure. This
finding is also consistent with other studies suggesting that the inability to maintain
quiescence can lead to HSC exhaustion7.
The mechanism for the redox activation
of p38 MAPK is unclear, but may involve
oxidant-induced inactivation of specific
phosphatases8. Whatever the exact sequence
of events, it appears that oxidants may contribute to the aging of adult HSCs not as
random and nonspecific damaging agents as
was originally hypothesized in the free radical theorybut instead, through the redoxdependent activation of a specific MAPK
pathway. That finding dovetails with more
than a decade of data suggesting that ROS
can contribute to normal mitogenic pathways as specific signaling molecules9.
It is presently unclear how this newly
described ROS-dependent pathway limiting
stem self-renewal fits into other established
pathways of stem cell aging. For instance,
the polycomb gene Pcgf4 (also known as
Bmi-1) also appears to be required for neural
stem cell and HSC self-renewal10. Could the
polycomb gene family be a potential target
of the ROS-activated p38 MAPK pathway?
Interestingly, a recent study suggests that
Bmi-1 can directly bind to an upstream acti-

vator of p38 MAPK11. It is also unclear why

HSCs, as compared to their more differentiated progenitors, are so sensitive to oxidantinduced p38 MAPK activation. These and
other questions must await future studies.
For now, we are left with a set of observations suggesting that in HSCs, and perhaps
other adult stem cells, the level of intracellular ROS determines the balance between
quiescence and proliferation. Increased oxidants can presumably push normally quiescent stem cells to divide and, in doing so,
presumably shorten their functional lifespan. Such a mechanism may be important
in normal aging, but perhaps even more
important in a variety of premature bone
marrow failure syndromes such as Fanconi
anemia. In line with that idea, these conditions are often characterized by augmented
levels of oxidative stress12. In the end, perhaps those late-night infomercials are on to
something.
1. Harman, D. J. Gerontol. 11, 298300 (1956).
2. Balaban, R.S., Nemoto, S. & Finkel, T. Cell 120,
483495 (2005).
3. Ito, K et al. Nat. Med. 12, 446451 (2006).
4. Ito, K. et al. Nature 431, 9971002 (2004).
5. Rotman, G. & Shiloh, Y. Bioessays 19, 911917
(1997).
6. Schubert, R. et al. Hum. Mol. Genet. 13, 1793
1802 (2004).
7. Cheng, T. et al. Science 287, 18041808 (2000).
8. Tonks, N.K. Cell 121, 667670 (2005).
9. Sundaresan, M., Yu, Z.X., Ferrans, V.J., Irani, K. &
Finkel, T. Science 270, 2969 (1995).
10. Park, I.K. et al. Nature 423, 302305 (2003).
11. Voncken, J.W. et al. J. Biol. Chem. 280, 51785187
(2005).
12. Pagano, G. et al. Eur. J. Haematol. 75, 93100
(2005).

Streptococcus moves inward

P Patrick Cleary
A common bacterium, group A Streptococcus, mysteriously causes a range of diseases from benign strep throat to
flesh-eating wounds. The difference between pharyngeal and invasive disease is now traced to mutations in two
regulatory genes.
The wide spectrum of group A streptococcal (GAS) disease spans uncomplicated strep
throat to flesh-eating wound infections. A
genome-wide analysis of streptococcal gene
expression by Sumby et al. in PLoS Pathogens
offers a new molecular explanation for the

The author is in the Department of Microbiology,

University of Minnesota, Minneapolis, Minnesota
55455, USA.
E-mail: clear001@umn.edu

384

capacity of GAS to turn an irritable brush

fire in the throat into a raging inferno
throughout the body1. A single mutation
in a global two-component signaling locus,
CovRS, alters expression of 1015% of genes
and equips the organism with the ability to
cause invasive disease.
Historically, complications of GAS infections such as scarlet fever, rheumatic fever
(ARF) and acute glomerulonephritis fluctuated, both temporally and geographically,
within a constant background of pharyngitis

and impetigo. The incidence of these afflictions varies widely; individuals can harbor
bacteria in their tonsils for long periods without symptoms, whereas others develop sepsis
and life-threatening toxic shock. Although
rare in the US2, ARF continues to adversely
affect the health of resource-poor populations with prevalences as high as 3 per 1,000
(ref. 3).
GAS virulence depends on arrays of
secreted and surface proteins that retard
innate defenses, mimic host macromol-

VOLUME 12 | NUMBER 4 | APRIL 2006 NATURE MEDICINE