Sci. Aging Knowl. Environ., 8 June 2005
Vol. 2005, Issue 23, p. pe17
[DOI: 10.1126/sageke.2005.23.pe17]

PERSPECTIVES

Why Females Live Longer Than Males: Control of Longevity by Sex Hormones

Jose Viña, Consuelo Borrás, Juan Gambini, Juan Sastre, and Federico V. Pallardó

The authors are at the Departamento de Fisiología, Facultad de Medicina, Avenida Blasco Ibáñez 17, 46010 Valencia, Spain. E-mail: jose.vina{at}uv.es(J.V.)

http://sageke.sciencemag.org/cgi/content/full/2005/23/pe17

Key Words: antioxidant enzymes • estrogen • free radicals • mitochondria • phytoestrogens • reactive oxygen species

Introduction

In the Western world, the average life span is 73.7 years for men and 83.8 years for women (1). Females also live longer than males in many other species (see Burger Perspective); for instance, in the laboratory, female Wistar rats live on average 14% longer than males. The fact that this phenomenon also occurs in animals other than humans indicates that it cannot be attributed to sociological factors but rather reflects specific biological characteristics of both genders.

Oxidants, Mitochondria, and Aging

Many theories have been postulated to explain aging (2), one of the most prominent being the free-radical theory of aging proposed by Harman in 1956 [see Harman Classic Paper; (3)]. In this view, oxygen-derived free radicals are responsible for age-associated damage to and dysfunction of cells and tissues (see "The Two Faces of Oxygen").

The free-radical theory of aging is supported by various lines of experimental evidence. For example, life span has been found to be extended by increasing antioxidant defenses, and an inverse relation has been observed between the rate of production of reactive oxygen species (ROS) and species' maximum life span (4-6). Administration of antioxidants can increase the mean life span of Drosophila (7, 8) (see also "Wrinkle Treatment for Worms"); Orr and Sohal have reported that simultaneous overexpression of the antioxidant enzymes copper/zinc superoxide dismutase (Cu/ZnSOD) and catalase in transgenic Drosophila extends mean and maximum life span (9). (For further discussion of antioxidant enzymes and aging, see Tower Perspective, Sampayo Perspective, Schriner et al. Science paper, and "Catalase and Mouse"). The fact that mitochondria are damaged inside intact cells as a function of aging was almost simultaneously reported by ourselves (10) and by Hagen and co-workers (11).

Mitochondria are an important source of free radicals, and mitochondrial components are also major targets for the free-radical damage associated with aging (see Nicholls Perspective) (10, 12, 13). More than 90% of the oxygen used by aerobic cells is consumed in mitochondria, and some 1 to 2% of this oxygen forms not water, as in normal respiration, but the superoxide anion O2- (14, 15). Superoxide is then converted into hydrogen peroxide (H2O2) within mitochondria, either spontaneously or through the action of manganese superoxide dismutase (MnSOD). The continuous generation of ROS by mitochondria throughout the life of a cell leads to "chronic" oxidative stress that plays a key role in cellular aging, and it is now well established that this involves oxidative damage to mitochondrial DNA, proteins, and lipids (10, 12, 16-18).

Oxidant production by mitochondria from females is significantly lower than that from males. We have measured the rate of H2O2 production and found that "female" mitochondria produce approximately half the amount of H2O2 generated by "male" mitochondria (19), as tested in hepatic and brain mitochondria from mice or rats. Moreover, neuronal mitochondria produce much greater quantities of oxidants than do glial mitochondria--a finding that agrees with the idea that postmitotic, nondividing cells suffer much more age-associated damage than do cells that divide normally.

To determine whether ovarian hormones such as estrogen are involved in the marked differences in oxidant production between mitochondria from male and female rats, we have tested the effects of ovariectomy and of estrogen replacement therapy on mitochondrial hydrogen peroxide production. Ovariectomy caused an increase in hydrogen peroxide production by liver and brain mitochondria, yielding values similar to those observed with mitochondria from males (that is, an increase of more than 60% from the values found normally with mitochondria from females). Estrogen replacement therapy completely abolished the observed increase in hydrogen peroxide production owing to ovariectomy (19).

Damage to Cell Components Is Greater in Males

As compared with males, females suffer considerably less oxidative damage to critical molecules such as mitochondrial DNA or glutathione (19, 20). Glutathione is a major intracellular antioxidant whose effective concentration is similar to that of glucose (21), and it is the major low-molecular-weight thiol in cells (22). The abundance of intracellular glutathione has been considered to be a biological marker of aging (23), and we have found that mitochondrial glutathione is related to the damage associated with aging (24). The mitochondrial concentration of glutathione in males is approximately half that seen in females.

DNA is a key component of the mitochondrial machinery (25), and its degree of oxidation increases with aging (12, 26). The observed abundance of 8-oxodeoxyguanosine, an excellent indicator of oxidative damage to DNA (see Skinner Review), is four times as great in males as in females (19, 20). This is the most pronounced oxidative change we have observed in mitochondrial DNA in any physiological situation, and it shows that chronic, continuous free-radical production in males results in marked oxidative and mutagenic lesions in mitochondrial DNA (27).

Let's Talk About Sex

A role for the sex hormones--testosterone in males and estrogen in females--in the gender differences in life span seen in mammals is widely accepted (28).

The role of testosterone in decreasing males' life span has been attributed to the link between this hormone and the male characteristics of aggression and competitiveness, as well as libido, which is known as "testosterone toxicity" (29). Testosterone also increases blood concentrations of low-density lipoprotein (LDL) cholesterol and decreases concentrations of high-density lipoprotein (HDL) cholesterol, so that males are more prone to cardiovascular diseases and stroke (30).

Estrogens, on the other hand, have beneficial effects on the cardiovascular system, because they reduce LDL cholesterol and increase HDL cholesterol (see "Greasing Aging's Downward Slide") (31). Estrogens also exhibit antioxidant properties in vitro, serving as chemical antioxidants owing to their phenolic structure (32). The estrogen concentrations needed for these chemical antioxidant properties to be important, however, exceed those observed in normal blood by more than an order of magnitude (33). More notably, in living cells estrogens exert their action indirectly by up-regulating the expression of the genes encoding antioxidant enzymes.

The amounts of exogenous estrogen that are used in estrogen replacement therapy are very unlikely to act directly as chemical antioxidants in vivo. In humans, for example, a daily dose of 50 µg of estrogen is typically used in the course of estrogen replacement therapy, whereas 400 mg--a dose some 8000 times as high--of the dietary supplement vitamin E are recommended for it to be effective as an antioxidant (34). Thus, the antioxidant action of estrogen is most likely exerted through the estrogen receptor and associated cell signaling pathways (see Pardee Review).

Females Overexpress Longevity-Related Genes

To try to explain the lower oxidative stress observed in mitochondria from females compared with mitochondria from males, we have studied the differences in expression and activity of mitochondrial antioxidant enzymes as a function of gender. The activity of both glutathione peroxidase and MnSOD was more than double in hepatic mitochondria from female rats as compared with that in mitochondria from males of the same age. Changes in expression of the genes encoding these enzymes followed a similar pattern. The fact that glutathione peroxidase activity in females is higher than in males was observed some time ago (35), but these changes were not related to gender differences in longevity.

By what mechanism does estrogen up-regulate those enzymes? We have found that physiological concentrations of estradiol (the primary estrogen produced by the ovaries) act through estrogen receptors to reduce hydrogen peroxide concentrations in MCF-7 cells (a mammary gland tumor cell line). Moreover, estradiol activates mitogen-activated protein kinases (MAPKs), specifically the enzymes ERK1 and ERK2, which in turn activate the signaling pathway involving the transcription factor nuclear factor kappa B (NF{kappa}B), as indicated by an increase in abundance of the p50 subunit of NF{kappa}B in nuclear extracts. Experimental blockade of MAPK and NF{kappa}B signaling prevents the antioxidant effect elicited by estradiol treatment. Activation of MAPK and NF{kappa}B by estrogens also drives the expression of longevity-related genes such as those encoding MnSOD, glutathione peroxidase, and cytochrome c oxidase (19, 20, 33). Hence, after binding to the estrogen receptor, estradiol activates MAPK and NF{kappa}B signaling events leading to increased expression of antioxidant enzymes (Fig. 1), providing a cogent explanation for the antioxidant properties of estrogen and its effects on longevity-related genes (19, 20, 33).



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Fig. 1. Molecular events that may explain why females live longer than males.

 
The Case for Phytoestrogens

The ability of estradiol to up-regulate genes encoding antioxidant enzymes suggests that its administration might be beneficial, particularly for males, perhaps allowing them to reach a life span similar to that of females. However, there is now considerable evidence garnered from estrogen replacement therapy in postmenopausal females to the effect that estrogen treatment can have major disadvantages [(36); see "Weathering the HRT Storm"].

It is possible that phytoestrogens--natural products that exert estrogen-like effects--could mimic the favorable effects of estrogens without their substantial drawbacks. The beneficial effects of phytoestrogens have been reported in the literature (37), and to our knowledge very few, if any, scholarly reports have shown detrimental effects. Genistein is one of the major phytoestrogens present in soy (38) and is able to decrease oxidative stress at concentrations that can be considered nutritionally relevant (that is, at concentrations normally found in the blood of people in the Far East, who eat relatively large quantities of soy in their normal diets). These concentrations of genistein are, however, significantly higher than those found in people living in the West, who are much less likely to eat soy. Just as with estradiol, the beneficial effects of genistein are mediated by its interaction with estrogen receptors, and the cell signaling pathways involved (MAPKs and NF{kappa}B) are the same as with estradiol (unpublished results from our laboratory).

Concluding Remarks

We have studied the reasons for the difference in life span between males and females and described experiments showing that estrogens are responsible for the lower mitochondrial free-radical production observed in females as compared with males. Estrogens elicit this effect by up-regulating expression of the genes encoding antioxidant enzymes such as MnSOD and glutathione peroxidase, both mitochondrial enzymes. Estradiol acts through its interaction with estrogen receptors, culminating in the activation of MAPK signaling and transcriptional stimulation involving NF{kappa}B.

Phytoestrogens decrease free-radical production by mitochondria and thus might be suitable agents with which to attempt to increase the life span of males. We have recently shown in vitro that phytoestrogens bind to estrogen receptors and activate the same signaling pathways as estradiol. The effect of dietary supplementation with phytoestrogens on longevity, particularly with a view to elucidating whether male life span can be increased to a similar level as that of females, remains to be studied in the future.

The importance of these studies lies in the fact that half of the population (males) live approximately 10% shorter lives than the other half (females). An understanding of the reasons for this difference in longevity may help us to understand the basic phenomenon of aging better and allow us to search for safe ways to increase male life span.


June 8, 2005
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Citation: J. Viña, C. Borrás, J. Gambini, J. Sastre, F. V. Pallardó, Why Females Live Longer Than Males: Control of Longevity by Sex Hormones. Sci. Aging Knowl. Environ. 2005 (23), pe17 (2005).




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