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Stem cell aging: what bleach can teachJie Liu & Toren Finkel

Intracellular oxidants may contribute to overall lifespan, in part by affecting stem cells. The connection betweenoxidants and aging now gains strength in a study of hematopoietic stem cells, which respond to oxidants byactivating a pathway leading to stem cell exhaustion (pages 446451).

Late-night infomercials are filled with adver-tisements for dietary supplements that claimto be rich in natural antioxidants. Often,a well-tanned announcer encourages theviewer to purchasein three easy install-mentsan all-natural way to live longer byfighting the bodys harmful free radicals. Thescientific basis for these suspect claims can betraced back to a theoretical study published byDenham Harman in the 1950s, which is nowoften referred to as the free radical theory ofaging1. This theory, both supported and chal-lenged by a wealth of experimental evidence,hypothesizes that the cumulative effects ofreactive oxygen species (ROS) on our DNA,proteins and membranes ultimately deter-

mines our lifespan2

.If ROS do in fact cause us to age, they prob-ably dont uniformly affect all the cells inour body. Particularly at risk might be cellsthat persist throughout an organisms lifes-pan, such as cardiac myocytes, neurons andother postmitotic cells. Also at risk seem to beendogenous adult stem cells, cells that have thecapacity to both self-renew and give rise to dif-ferentiated progenitor cells. Among the mostactive stem cells in the body are hematopoieticstem cells (HSCs), which give rise to all thecells in the blood.

In this issue, Ito and colleagues significantlyadvance our understanding of how ROSmight affect the aging of HSCs 3. They findthat a rise in hydrogen peroxidethe activeingredient in household bleachstimulatesa pathway that causes stem cells to exit fromtheir normal quiescent state. This oxidant-induced proliferation eventually induces HSCexhaustion.

The new findings emerge from observationsmade by the same group a few years ago whenthey were studying Atm (ataxia telangiectasiamutated), a protein aberrant in a debilitatingchildhood disease characterized by neurode-generation, immune dysfunction and a pre-disposition to lymphoid malignancies 4. Atmis a cell cyclecheckpoint regulator that is acti-vated after DNA damage, and it is also thoughtto be involved in regulating oxidant levels; inthe absence of Atm, oxidant levels rise 5.

Ito and collagues found that mice deficientin the gene encoding Atm developed early-onset bone marrow failure and that HSCsobtained from these mice exhibited elevatedlevels of ROS. Whats more, treatment withthe hydrogen peroxide scavenger N -acetyl-cysteine rescued these mice from bone mar-row failure.

These observations were consistent withother data showing that antioxidant treatmentcan rescue the increase in malignancies seen in Atm-deficient mice 6. Such findings suggestedthat a rise in intracellular ROS levels mediates

many of pathological effects of Atm, althoughhow a deficiency in Atm leads to increasedROS levels remained obscure.

In their present study, Ito and colleaguesprovide further insight into the link betweenoxidant levels and HSC biology 3. In particular,they show that HSCs from mice are exquisitelysensitive to oxidative stress induced by buthio-nine sulfoximine (BSO), an agent that depletesintracellular glutathione and thereby raisesintracellular hydrogen peroxide. Treatmentof HSCs with BSO abolished the ability ofthese cells to contribute to hematopoiesiswhen transplanted into an irradiated host.Such findings were expected from the authorsprevious studies, but they next delved into themolecular mechanism.

They found that oxidative stress within theHSC appears to specifically activate the p38MAPK pathway, a signaling pathway thatseems to respond to diverse cellular stresses.This redox-dependent activation was selectivefor HSCs and was not observed in the moredifferentiated hematopoietic progenitors.

The authors are in the Cardiology Branch, NationalHeart, Lung, and Blood Institute, Bethesda,Maryland 20892, USA.E-mail: finkelt@nih.gov

Atm /

Quiescence,normal

hematopoiesis

Proliferationstem cell exhaustion,bone marrow failure

Environmental orgenetic stressor

ROS

Aging

p38 MAPK

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

and the clinical appearance of bone marrow failure.

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The investigators went on to show that thep38 MAPK pathway was constitutively acti-vated in HSCs obtained from Atm-deficientmice and that inhibition of the p38 MAPKpathway rescued the bone marrow defectin these animals. In normal HSCs, exami-nation of the bone marrow revealed that asignificant fraction of stem cells were qui-escent and in the G0 phase of the cell cycle.Deletion of Atm, or a rise in ROS, appears tostimulate the p38 MAPK pathway in HSCs,leading this normally quiescent stem cellpopulation to begin actively dividing.

Finally, the authors attempted to relatethese observations to normal aging by exam-ining wild-type HSCs in serial transplanta-tion experiments. In this strategy, a smallnumber of donor HSCs are infused into arecipient irradiated host. After four months,the donor HSCs are extracted, purified andused again as donor cells for another irradi-

ated host. This procedure is repeated in aserial fashion, and thereby provides a use-ful measure of long-term HSC repopulatingactivity.

The authors showed that with each suc-cessive transplantation of HSCs, levels ofROS and p38 MAPK act ivity rose. Similarly,serial transplantation led to fewer and fewerHSCs that could maintain quiescence andcontribute to subsequent hematopoiesis.Again, treatment with an antioxidant orp38 MAPK inhibitor reversed these agingeffects.

Together, these results suggest thatincreases in ROS within HSCscaused by

genetic defects such as Atm deficiency or bynatural agingresult in activation of thep38 MAPK pathway. Once activated, p38MAPK appears to coax the HSCs from a qui-escent state into active cell-cycle progression(Fig. 1 ). Over time, this lack of quiescenceappears to ultimately contribute to stem cellexhaustion and bone marrow failure. Thisfinding is also consistent with other stud-ies suggesting that the inability to maintainquiescence can lead to HSC exhaustion 7.

The mechanism for the redox activationof p38 MAPK is unclear, but may involveoxidant-induced inactivation of specificphosphatases 8. Whatever the exact sequenceof events, it appears that oxidants may con-tribute to the aging of adult HSCs not asrandom and nonspecific damaging agents aswas originally hypothesized in the free radi-cal theorybut instead, through the redox-dependent activation of a specific MAPK

pathway. That finding dovetails with morethan a decade of data suggesting that ROScan contribute to normal mitogenic path-ways as specific signaling molecules9.

It is presently unclear how this newlydescribed ROS-dependent pathway limitingstem self-renewal fits into other establishedpathways of stem cell aging. For instance,the polycomb gene Pcgf4 (also known asBmi-1) also appears to be required for neuralstem cell and HSC self-renewal 10. Could thepolycomb gene family be a potential targetof the ROS-activated p38 MAPK pathway?

Interestingly, a recent study suggests thatBmi-1 can directly bind to an upstream acti-

vator of p38 MAPK 11. It is also unclear whyHSCs, as compared to their more differenti-ated progenitors, are so sensitive to oxidant-induced p38 MAPK activation. These andother questions must await future studies.

For now, we are left with a set of observa-tions suggesting that in HSCs, and perhapsother adult stem cells, the level of intracel-lular ROS determines the balance betweenquiescence and proliferation. Increased oxi-dants can presumably push normally qui-escent stem cells to divide and, in doing so,presumably shorten their functional lifes-pan. Such a mechanism may be importantin normal aging, but perhaps even moreimportant in a variety of premature bonemarrow failure syndromes such as Fanconianemia. In line with that idea, these condi-tions are often characterized by augmentedlevels of oxidative stress12. In the end, per-haps 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 inwardP Patrick Cleary

A common bacterium, group A Streptococcus , mysteriously causes a range of diseases from benign strep throat toflesh-eating wounds. The difference between pharyngeal and invasive disease is now traced to mutations in tworegulatory genes.

The author is in the Department of Microbiology,University of Minnesota, Minneapolis, Minnesota55455, USA.E-mail: clear001@umn.edu

The wide spectrum of group A streptococ-cal (GAS) disease spans uncomplicated strepthroat to flesh-eating wound infections. Agenome-wide analysis of streptococcal geneexpression by Sumby et al . in PLoS Pathogensoffers a new molecular explanation for the

capacity of GAS to turn an irritable brushfire in the throat into a raging infernothroughout the body 1. A single mutationin a global two-component signaling locus,CovRS, alters expression of 1015% of genesand equips the organism with the ability tocause invasive disease.

Historically, complications of GAS infec-tions such as scarlet fever, rheumatic fever(ARF) and acute glomerulonephritis fluc-tuated, both temporally and geographically,within a constant background of pharyngitis

and impetigo. The incidence of these afflic-tions varies widely; individuals can harborbacteria in their tonsils for long periods with-out symptoms, whereas others develop sepsisand life-threatening toxic shock. Althoughrare in the US 2, ARF continues to adverselyaffect the health of resource-poor popula-tions with prevalences as high as 3 per 1,000(ref. 3).

GAS virulence depends on arrays ofsecreted and surface proteins that retardinnate defenses, mimic host macromol-

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