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From stem to stern

Nature volume 449, pages 288291 (20 September 2007) | Download Citation

Immortality is the stuff of myth and legend, but lifespan extension is the subject of serious scientific inquiry. Exploring the causes and effects of ageing in stem cells should aid this quest.

The explosion of research on stem cells has given the promise of treatments for degenerative diseases of ageing, enhancement of the repair of damaged tissues and possibly even slowing of decline-in-function that occurs with advancing age. But how stem cells are affected by the ageing process, and whether such changes are a cause or a consequence of organismal ageing, remain unclear1. Three research teams2,3,4 have recently reported their findings on how age-related accumulation of DNA damage and changes in global patterns of gene expression might lead to the decline of stem-cell function.

In mammals, stem cells reside in many adult tissues and either continually produce new cells for tissues with a high turnover (blood, skin and gut) or serve as a reservoir for gradual cellular replacement or repair in the more stable tissues (liver, muscle and brain)1. Stem-cell function, just like that of other cells, declines with age. However, to what extent age-related changes in stem-cell function are due to intrinsic ageing of the cells or due to changes in the environment in which they reside5 is still unclear.

Many theories have been put forth to explain the decline of cell and tissue function with age, but a main challenge for researchers who study ageing is to distinguish among potential causal influences, virtually all of which interact with one another and lead to organismal ageing (Fig. 1). The free-radical theory of ageing proposes that reactive oxygen species, which are by-products of normal metabolism, are responsible for damage to many cellular components, including DNA6.

Figure 1: Interplay between factors and networks influencing ageing.
Figure 1

As stem cells are essential for tissue homeostasis and repair throughout life, three groups2,3,4 have explored what factors influence alterations in their function with age. These studies, together with previous work, suggest that the story is complex, involving interactions between different networks and at several levels. At the genomic level, both internal and environmental factors cause alterations in individual genes, groups of genes through epigenetic changes, and chromosomes, at least some of which arise from direct damage to DNA. At the levels of cells and tissues, functional changes in stem cells and other cells in the tissue influence each other and are, in turn, influenced by systemic changes that may be conveyed from one tissue to another via the circulation. All of these may contribute to the possible development of cancer in tissues throughout the body. The ultimate outcome is organismal ageing.

Several mechanisms of DNA repair that are essential for healthy tissues and long life7 have evolved in cells of higher organisms. In humans or mice, mutations in genes encoding DNA-repair enzymes may lead to dramatic increases in the incidence of cancer and the shortening of lifespan. What has remained unclear is how susceptible adult stem cells are to the age-related accumulation of DNA damage, how effective DNA-repair activities are in these cells, and to what extent this balance contributes to the characteristics of tissue ageing.

Nijnik et al.2 and Rossi et al.3 tested the hypothesis that accumulation of DNA damage is an essential mechanism underlying age-related decline in the function of haematopoietic stem cells (HSCs). These cells reside in the bone marrow and give rise to all cellular components of blood — from red blood cells to cells of the immune system8. For this, Rossi et al. studied mice that carry mutations in various DNA-repair pathways and show signs of accelerated ageing, whereas Nijnik et al. discovered and studied a mouse strain with a mutation in a gene encoding a DNA-repair enzyme, which models a human syndrome characterized by immunodeficiency and developmental abnormalities.

Both teams found that HSC function was severely impaired in rapidly ageing mutant mice. Moreover, HSCs from the mutant mice had compromised ability to generate blood cells even when they were transplanted into normal mice, indicating that the defects were intrinsic to the stem cells. Intriguingly, although the types of DNA defects that would be expected to accumulate in the various mouse mutants studied are different, the altered HSC functions observed in all of these mutants were similar. This suggests that HSCs have a limited repertoire of potential responses to intrinsic damage.

Do these results pertain to HSC ageing and the age-related decline of immune responses in normal mice? That partially depends on how accurately biological processes in the genetic mutants studied reflect those of normal ageing. Clearly, there are limitations in extrapolating results from a mouse or human with a single gene mutation, even if the outcome of the mutation resembles normal ageing. Thus, it is crucial to investigate the relationship between accumulation of DNA damage and ageing in genetically normal HSCs and their progeny.

Rossi et al.3 did find that HSCs from normal old mice have more DNA damage than those from younger animals, hinting that increased DNA damage may be responsible for limited stem-cell function in aged organisms. However, these authors also found that, in old mice, the DNA of HSC progeny was less damaged than HSCs themselves. This could be either because the progeny with high levels of DNA damage are selectively eliminated, because only HSCs without DNA damage successfully divide, or because the committed progenitors that are derived from HSCs can repair the lesions more efficiently than can HSCs themselves.

Can mechanisms other than accumulation of damaged DNA underlie stem-cell ageing? Chambers et al.4 asked whether the overall pattern of cellular gene expression was altered in aged HSCs. Looking for changes across the whole genome, they found that, indeed, old HSCs show high-order changes in gene expression: groups of genes, or entire chromosomal regions, which were normally silenced in young HSCs, were now turned on, whereas other genes and genomic regions were expressed at lower levels than in young cells.

Among the genes with reduced expression were those involved in modulating chromatin, which is the complex formed by DNA and histone proteins. Epigenetic changes — changes in chromatin structure without mutations in the DNA sequence — influence gene expression. The authors4 suggest that such epigenetic changes may underlie altered HSC function in aged animals. In agreement with the observations of Nijnik et al.2 and Rossi et al.3, Chambers and colleagues also found that the expression of genes involved in DNA repair was reduced in aged HSCs. Intriguingly, studying a mutant mouse strain with features of premature ageing, they found that HSCs had a 'molecular signature', defined as a distinct pattern of gene expression, that was similar to that of HSCs from young animals4, even though there is a marked decline in HSC regenerative potential in this strain9. Although this finding is interesting as a possible example of how a molecular signature of ageing may be uncoupled from cellular function, it may also highlight how a rapidly ageing mouse mutant might not mimic the characteristics of normal ageing.

The work of Chambers et al.4 brings into perspective the complexities of the ageing process and how single-gene mutations or single biological processes are unlikely to account for the myriad of cellular, tissue and organismal changes associated with ageing. Even if epigenetic changes are a hallmark of ageing, what are the processes that initially lead to them in old cells? The juxtaposition of these studies raises a conundrum similar to that of 'chicken or egg': do age-related epigenetic changes render DNA more susceptible to damage, or does DNA damage underlie epigenetic changes? And how do general epigenetic modifications fit in with specific genes that have been shown to limit HSC function10 or maintain HSC potential11 during ageing? More importantly for regenerative medicine, are these epigenetic changes (and thus possibly ageing) reversible?

The authors2,3,4 converge in their general conclusions that, with age, adult HSCs decline in function but not number, and that DNA damage and epigenetic modifications may limit the regenerative potential of these cells. They also agree that HSCs are not protected from age-induced damage and, in fact, ageing may result in an accumulation of DNA mutations in these cells, thereby increasing the risk of cancer.

Their findings also raise further questions. Are these observations true for adult stem cells in other tissues, particularly tissues with much lower cellular turnover than the blood? Would stem-cell 'enhancement', whether genetic or epigenetic, delay the ageing characteristics of a particular tissue or even lead to an extension of lifespan? Understanding what limits stem-cell function during ageing will be essential for the field of regenerative therapeutics, which proffers the hope that the remarkable potential of stem cells will be harnessed for the repair of injury and the treatment of diseases.


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  1. Anne Brunet is in the Department of Genetics, and Thomas A. Rando is in the Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA.

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