Sci. Aging Knowl. Environ., 30 July 2003
Vol. 2003, Issue 30, p. pe21
[DOI: 10.1126/sageke.2003.30.pe21]


Mouse and Human Cells Versus Oxygen

Peter J. Hornsby

The author is with the Sam and Ann Barshop Center for Longevity and Aging Studies at the University of Texas Health Science Center, San Antonio, TX 78245, USA. E-mail: hornsby{at};2003/30/pe21

Key Words: cancer • cultured cells • replicative senescence • reactive oxygen species • oxidative damage


Maximal life span varies dramatically depending on the species. One of the great puzzles in the biology of aging is the scaling of physiological declines and disease susceptibility with maximal life span in mammals. A recent publication from Judith Campisi's lab (1) offers new insight into differences between cultured mouse and human cells, which might also be relevant to understanding differences in aging and cancer rates between the two species.

Humans can live for over 100 years, and the average member of the species can expect to live to 60 or more years without major (life-threatening) health problems. Beyond that period, the incidence of the major diseases that limit life span increases enormously. Notably, the prevalence of cancer, a major cause of mortality, increases at the same period of life as do other major causes of death (heart disease, stroke, and so on) (2). Mice, which can live to over 3 years of age, also die of cancer or from diseases related to major organ systems, and they begin to succumb to these diseases at about 18 months of age (see "Dangerous Liaisons" for a comparison of cancer and aging in mice and humans). How this scaling occurs is not at all clear. In some ways, it is obvious that it must occur: If the average member of a species is to live to 75 years, then there can be no major cause of death that eliminates most members before age 25, for example. In other words, all causes of death must be delayed in a coordinated fashion if the maximal life span of a species is increased over evolutionary time periods.

How does this scaling occur? More specifically, with respect to cancer, how do humans generally avoid cancer until 60 or more years of age, whereas mice are likely to die of cancer at 2 years of age? This question becomes even more problematic when one considers the relative sizes of the species. A human being is about 3000 times heavier than a 25-g mouse and lives about 30 times as long. Consider also that cells are about the same size in mice and humans and that cell turnover occurs at about the same rate. Finally, if we assume that mice and humans have the same risk of dying of cancer over their life spans, then human cells must be approximately 90,000 times more resistant to tumorigenic conversion per unit of time than are mouse cells. (This assumption might not be entirely correct, but that does not substantially affect the basic validity of this argument.) Presumably, as part of the evolution of the life history of the human species, anticancer mechanisms evolved that were not present in short-lived ancestors (2).

Therefore, a major question about the cancer/aging relationship is why mouse cells are so much more susceptible to tumorigenic conversion than human cells. And then the related $64,000 question is: Could the differences underlying the tumorigenic conversion potential also be responsible for the overall difference in life span between mice and humans?

Replicative Senescence in Human and Mouse Cells

The significance of replicative senescence (a phenomenon in which cells enter a state of permanent growth arrest) for aging remains controversial (see "More Than a Sum of Our Cells"). The finding that telomere shortening (a process that occurs as a result of DNA replication) is the main cause of replicative senescence in cultured human fibroblasts, together with the observation that telomere shortening occurs in many human tissues during aging, did much to bring the significance of human fibroblast senescence into focus and clarified the potential significance for human aging [see (3) for a review of this area]. However, many scientists questioned the broad significance of these findings, because mouse cells have much longer telomeres than do human cells and, in contrast to human fibroblasts, often have telomerase activity (which serves to maintain telomere length) yet usually senesce rapidly in culture. Mice engineered to lack telomerase activity by inactivation of the telomerase RNA component gene (Terc) show a generation-dependent shortening of telomeres and usually cannot be bred beyond the sixth generation (4). However, when cells from the first three generations of Terc-/- mice (with telomeres of varying length) are placed in culture, the number of times they divide until they become senescent does not depend on telomere length, although telomere length becomes the dominant factor in cells from fourth-generation animals (5). These observations rule out telomere length as the factor that causes replicative senescence in cells from genetically normal mice.

The work of Parrinello et al. (1) sheds new light on the question of why mouse cells become senescent, by showing that this phenomenon is a reaction to oxidative stress resulting from the exposure of cells to an unphysiologically high concentration of oxygen. The importance of these findings is not so much for understanding replicative senescence, but for what they tell us about critical differences between mouse and human cells. Human cells avoid the causes of senescence suffered by mouse cells under the same environment (20% oxygen and the usual components of culture medium). Parrinello et al. end their discussion with the provocative suggestion that the superior ability of human cells to prevent or repair oxidative DNA damage contributes to the major differences in cancer incidence and aging rate between mice and humans.

Damaging Effects of Oxygen

How does oxygen damage cells? The well-known oxygen radical theory of aging is based on the knowledge that oxygen is damaging because it is the source of short-lived intermediates, generally termed reactive oxygen species (ROS), comprising superoxide, hydrogen peroxide, and the hydroxyl radical (see "The Two Faces of Oxygen"). ROS can be formed by purely chemical means (for example, by interactions of oxygen with transition metal ions), but it is usually assumed that in cells this process requires the interaction of oxygen with various proteins that produce ROS as a side effect of their enzymatic activity (6) (see Nicholls Perspective and Kristal Perspective).

Behavior of Human and Mouse Cells in Culture

It has been known for many years that there are substantial differences in the behavior of primary mouse and human fibroblasts under the conditions in which the cells are usually cultured (a medium containing salts, energy sources, amino acids, and vitamins, together with 10% serum, in a gas phase based on air mixed with CO2). Human cells proliferate for 50 or more population doublings, then stop dividing. Although karyotypic abnormalities can be found in human cells nearing senescence (7), most cells appear to stop dividing with a normal karyotype (8). Like human cells, bovine cells senesce as a result of telomere shortening; the fact that animals can be cloned from nuclei of bovine cells close to senescence also shows that replicative senescence is not associated with chromosomal abnormalities, at least not those that would prevent the formation of a viable organism (9).

In contrast, despite having long telomeres and telomerase activity, mouse cells rapidly enter a period of declining growth rate, variably termed senescence or crisis [note that the term "crisis" refers to a different phenomenon in human cells--specifically, a state reached after normal senescence is bypassed, in which very short telomeres cause chromosome fusion and breakage (3)]. This period of slowed growth is then often followed by a second period of accelerated growth that represents the emergence of a stably immortalized cell line. It has long been known that these lines usually show chromosomal abnormalities (10); presumably they derive from variants that arise during the period when most cells undergo irreversible growth arrest by senescence. These immortalized lines are readily transformed to a tumorigenic state by a variety of chemical, physical, and genetic agents (11). On the other hand, human fibroblasts never undergo spontaneous immortalization. Although they can be transformed to a fully tumorigenic state by appropriate combinations of genes (oncogenes and the gene encoding the telomerase catalytic subunit) introduced into the cells by retroviral transduction (12), they can be transformed by chemical and physical agents only by repeated applications of such agents over long periods (13). From these observations, one may conclude that under "standard" culture conditions, mouse cells, but not human cells, suffer damage that causes chromosomal aberrations and contributes to transformation to a tumorigenic state.

So what is this molecular basis for these differences? Parrinello et al. (1) show that a major difference is that mouse fibroblasts are damaged by the air-based oxygen concentration under which cells are usually cultured. When the concentration of O2 was lowered to 3% from 20%, mouse fibroblasts did not show a phase of slow growth but grew indefinitely at a more or less constant rate (Fig. 1). Lowering the concentration of O2 from 20% to 3% reduced the level of oxidative DNA lesions, principally 8-oxo-2'-deoxyguanosine (8-oxodG), which are mutagenic and cause chromosomal breaks. Human fibroblasts cultured in 20% O2 displayed a level of oxidative lesions similar to that of mouse cells at 3% O2 (1). One should not get the impression that human fibroblasts are unaffected by 20% oxygen. Lowering the oxygen to 3% extends the proliferative potential of human cells and lowers the concentration of the protein p21WAF1, a cell cycle inhibitor (14).

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Fig. 1. Mouse cells in culture undergo replicative senescence, a temporary slowing of the rate of growth of the cell population, in 20% oxygen but not in 3% oxygen. In 3% oxygen, the population grows continuously. In (A), the cumulative increases in the population size of mouse fibroblasts cultured at 20% oxygen and 3% oxygen are shown. In (B), the labeling index (the percentage of cells undergoing DNA synthesis) in 20% oxygen is shown. This reveals the point at which the rate of cell division is lowest; that is, the point of replicative senescence. [Adapted from (1) with permission from Nature Cell Biology]

These results imply that mouse cells have an excessive burden of oxidative lesions in DNA under standard culture conditions and that some of this DNA damage is unrepaired or misrepaired. The initial consequence is replicative senescence. Some cells escape permanent growth arrest and grow indefinitely with mutated DNA and stable chromosome abnormalities that predispose the cells to further genetic changes.

There are several ways in which human and mouse cells might differ, including (i) the rate at which oxidative lesions occur in DNA; (ii) the rate at which the lesions are repaired; (iii) the fidelity of repair; or (iv) the late-stage consequences of unrepaired or misrepaired DNA damage. Below I review some of the evidence for each of these possibilities.

Do Human and Mouse Cells Differ in the Rate at Which Oxidative Lesions Occur in DNA?

Using a form of the comet assay (a gel electrophoresis assay that detects fragmented DNA) adapted to detect oxidative lesions in DNA, Parrinello et al. revealed differences in the amount of DNA damage in human and mouse fibroblasts cultured under 20% O2 (1). Mouse cells had about three times more damage than human cells. However, the available evidence in the literature is inconclusive as to whether this apparent resistance of human cells to oxygen is a specific property of cultured human fibroblasts or applies generally to cultured human cells of other types and to human cells in the body. Moreover, if there is a general resistance of human cells to oxygen, it is not known what the mechanism might be.

A well-established idea is that the main site of the generation of ROS in cells is the mitochondrion (see "The Two Faces of Oxygen"), and furthermore that mitochondria from long-lived mammals such as humans generate fewer ROS from oxygen than do short-lived species such as mice (15) (see Praticò Review). The steady-state levels of 8-oxodG in mitochondrial DNA are higher in short-lived mammals (15), perhaps indicating higher levels of ROS generation. However, we do not know what fraction of the ROS generated by mitochondria reaches the nucleus and thereby contributes to oxidative damage of nuclear DNA, and we do not know whether most oxygen-dependent DNA damage originates from this source. Recent careful measurements show that ROS generation by mitochondria is very low under physiological conditions, except when mitochondria are utilizing fatty acids for respiration (16).

Some evidence suggests that the way in which oxygen damages cellular DNA might not involve cellular metabolism. Human volunteers breathing oxygen at pressures higher than normal show DNA damage (detected by the comet assay) in lymphocytes from blood sampled immediately after the oxygen exposure. Yet lymphocytes exposed in culture to similar oxygen conditions do not show damage (17). Oxidative damage might be mediated by the interaction of oxygen with extracellular constituents of the body or of the culture medium, such as lipoproteins (18). Because components of culture medium can vary widely, damage by oxygen might become apparent only when certain extracellular mediators are present. Varying experimental conditions might also explain some of the inconsistencies in the literature. For example, when human testis cells were exposed to differing oxygen concentrations in culture, there was more DNA damage at 20% and less at 5% and below (19). But an extensive trial of 20% versus 5% oxygen during the culture of human embryos after in vitro fertilization showed a slight increase in the number of embryos that reach the blastocyst stage when 5% oxygen was used, but there was no difference in the overall success rate, as judged by the number of embryos that maintained a viability sufficient to sustain a pregnancy (20). Yet for most other mammalian species, culturing embryos at 5% versus 20% oxygen produces less DNA damage (as detected by the comet assay) and yields an increased rate of successful embryo development (21). To summarize, some data in the literature suggest that human cells are more resistant than cells from other species to the damaging effects of oxygen. However, the generality of these conclusions is doubtful, in view of the variety of experimental systems and assays that have been used. It is also noteworthy that human and mouse fibroblasts are similarly sensitive to hydrogen peroxide (22).

The state of the field leaves many questions for future study. We need to understand the relative contributions of extracellular mediators and mitochondrial ROS when cells are exposed to oxygen. Mouse mitochondria might produce more ROS than human mitochondria, but this question requires more careful study. If extracellular mediators are of more importance, it is possible that, for unknown reasons, mouse cells are more sensitive to such mediators of damage.

One cannot assume, therefore, that the initial amount of DNA damage (that is, the amount of damage before repair takes place) caused by oxygen exposure is the same in the two species. Agents that create oxidative damage, such as hydrogen peroxide and organic hydroperoxides, interact with cellular and extracellular proteins and lipids, thereby forming more reactive molecules and radicals that damage DNA. Therefore, differences in the effects of any of these agents on mouse and human cells can result from quantitative and qualitative differences in these events. For experimental purposes, it would be useful to have an agent that damages DNA directly, yet yields the same lesions as oxygen exposure. As discussed below, to some extent ionizing radiation is such an agent. If the experimenter is able to inflict a defined amount of damage to cellular DNA, differences in survival and later events must result from differences in the amount and nature of repair.

Do Human and Mouse Cells Differ in the Rate at Which Oxidative Lesions Are Repaired?

To measure the rate of repair of lesions, one must create a known level of oxidative damage to DNA--a difficult task. However, ionizing radiation can be delivered in precise doses, and it causes both potentially mutagenic lesions and double-strand breaks in DNA, as does oxidative damage. In the older literature, there were reports that human cells are more efficient than mouse cells at repairing potentially lethal radiation damage (23). Most recent studies suggest that although cells from a few mammalian species, such as the Mongolian gerbil, are more radioresistant, cells from most species, including humans and mice, are broadly similar in their sensitivity to ionizing radiation (24). Sensitivity here is usually defined by clonogenic assays, so that a cell that either senesces or dies by apoptosis is counted as "dead" with respect to the ability to continue to divide. Despite whatever repair has occurred, such cells have accumulated a burden of DNA damage that is incompatible with continued normal cell division. The type of DNA damage that best correlates with the extent of killing is the double-strand break; mouse and human cells acquire similar numbers of double-strand breaks when irradiated (25). Depending on the cell type and the amount of damage, the cell becomes commited either to die by apoptosis or to enter irreversible growth arrest (that is, senescence) (26). However, cells that survive the insult and grow into a colony are not necessarily undamaged. Like ionizing radiation, ultraviolet (UV) light also kills cells as determined by clonogenic assays. Here there is a paradox, because human and mouse cells are similarly sensitive to UV light, but rodent cells remove some types of DNA lesions produced by exposure to UV much more slowly than do human cells (27). The greater sensitivity of mouse cells to 20% oxygen, therefore, contrasts with the similar sensitivity to ionizing radiation and UV light, despite differences in repair rates. So either the possibility raised earlier is correct (that mouse cells suffer more damage when exposed to 20% oxygen before any repair takes place) or the response of cells to oxygen (the series of events encompassing repair/survival or apoptosis/senescence) differs substantially from the responses to ionizing radiation and UV light.

Do Human and Mouse Cells Differ in the Damage That Becomes Fixed by Formation of Mutations or Chromosome Aberrations?

If human and mouse cells do not differ greatly in their initial responses to ionizing radiation, could they differ in the quality of repair in those cells that do not immediately die or senesce? There is no strong evidence for large differences in the rate of formation of chromosome aberrations. The rate of formation of micronuclei (small nuclei separate from the primary nucleus) in response to ionizing radiation is slightly higher in mouse as compared to human cells (28-30). Micronuclei are used as a measure of the presence of chromosome aberrations, because they contain acentric chromosome fragments and chromosomes that lag behind at anaphase. Although the types of radiation-induced chromosome aberrations acquired by mouse and human cells differ, in general, the incidence of chromosome abnormalities after exposure to radiation agrees with predictions based purely on the geometry of chromosomes in the nucleus (31). This implies that any mouse/human differences in the types of chromosome aberrations formed after radiation result from the spatial distribution of double-strand breaks in the nucleus, rather than differences in the ability of the cells to prevent such damage from becoming fixed in the form of chromosome aberrations.

Do Human and Mouse Cells Differ in the Late-Stage Consequences of Unrepaired or Misrepaired DNA Damage?

Differences in the behavior of human and mouse cells become evident when the late consequences of DNA damage are examined. In cells that survive the insult, damage may become fixed in the form of mutations and chromosome aberrations. In a population of irradiated human cells, many clones with chromosome aberrations disappear in the first few divisions after radiation exposure (32). Of course, when cells with chromosome damage continue clonal expansion, there has been a failure of the checkpoints that would normally eliminate such cells by apoptosis or senescence. This escape may occur more frequently in mouse cells than in human cells. There is clearly a close relationship between the checkpoints that operate to eliminate cells with chromosome damage and the replicative senescence checkpoint, in the form in which it operates in human cells (33). Some forms of these checkpoints might not operate in mouse cells, or might operate less efficiently. In late-generation Terc-/- mice with short telomeres, regeneration of the liver is impaired, but cells do not arrest at the G1/S phase of the cell cycle, as expected if the short telomeres trigger replicative senescence of the human cell type, but instead they arrest in mitosis (34). Terc-/- mouse embryonic stem cells show progressive telomere shortening in culture that eventually results in growth arrest (35). As telomeres shorten in these cells, there is an increasing frequency of chromosome aberrations. Although human fibroblast cultures do sometimes accumulate clones with chromosome aberrations, most pre-senescent cells in metaphase have an essentially normal karyotype (8). It is possible that the last cell division that takes place before one or both daughter cells become irreversibly senescent creates a chromosome fusion or break that triggers irreversible growth arrest (33). If so, arrest would appear to occur efficiently in human cells, whereas in mouse cells chromosome aberrations that should cause growth arrest often fail to do so and become stably propagated in descendant cells. The basis for these differences requires more study [see also (36) for a discussion of important differences between mouse and human chromosome biology].


There is no doubt that there are fundamental differences in human and mouse cell biology that could be responsible for the huge differences in cancer susceptibility (per cell per unit of time) and in aging rates between the species. So much still needs to be done to understand those differences. The important new findings by Parrinello et al. clearly indicate some new directions for those future studies.

July 30, 2003
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Citation: P. J. Hornsby, Mouse and Human Cells Versus Oxygen. Sci. SAGE KE 2003, pe21 (30 July 2003);2003/30/pe21

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