Women characteristically live significantly longer than men, and it is thought that this increased longevity is facilitated by longer telomeres present in womens’ DNA. Oestrogen is suggested to play a key role in maintaining these lengthened telomeres. However, testing this theory in mice has proven difficult due to several confounding factors, including an increased prevalence of breast cancer resulting from oestrogen exposure. In recent research published in Frontiers in Zoology, Doris Au and colleagues from the City University of Hong Kong present Japanese medaka fish as a new model species for studying this sex-dependent longevity. They find that sex dependent telomere length and longevity are also present in these teleosts, and moreover represent the first non-mammalian species to exhibit an age-related drop in oestrogen levels that is comparable to human menopause. Au discusses their findings, and how these can be used to further our knowledge of the aging process in humans.
What is sex-dependent longevity?
This is often referred to as the ‘longevity gender gap’ (LGG), which is the longevity difference between the two sexes. When males and females exhibit different lifespans, where one sex lives longer than the other, it results in this longevity gap.
What do we currently know about the mechanisms underlying cellular aging? How do these relate to sex-dependent longevity?
Aging is driven by the lifelong accumulation of molecular damage inside cells. Cellular molecular damage includes DNA damage (e.g. telomere shortening), RNA damage, protein damage and oxidative membrane damage. This will eventually trigger cell senescence and cell death by apoptosis, necrosis and autophagy (self-destruction of debris by lysosomes). How the above cellular aging mechanisms relate to sex-dependent longevity still remains unclear and demands further investigation.
Why can’t the standard animal models, such as mice, be used to investigate the effects of oestrogen and telomere length on senescence?
Rodents are not desirable for telomere- and oestrogen-related aging studies because the telomeres of inbred rodents are extraordinarily long, making it difficult to study the effects of critical telomere shortening on aging and sex-dependent longevity in either short-term experiments or within a single generation. Moreover, experiments in which oestrogen was fed to rodents increased the risk of breast and ovarian cancers in females, thus complicating studies on the direct effects of oestrogen on telomere and longevity in vivo.
Regarding the biology of sex differences, what similarities do female medaka fish and women share? Is this surprising?
Our continued monitoring of over 3000 male and female medaka reared under optimal laboratory conditions for over three years produced sufficient and reliable data to substantiate the notion that female medaka have a longer lifespan and telomeres than males. Interestingly, we also notice a natural decline of plasma oestrogen in female medaka during aging, which corresponded to ages in women between 46 – 60 years old (the menopause age range). These phenomena are very interesting. We did not expect the observed similarities in the LGG, oestrogen profile and age conversion between female medaka and women.
Moreover, as in humans, Japanese medaka exhibit a XX/XY sex-determination system and phenotypic sex dimorphism (male medaka have an open and wide caudal fin). Also, the Y-linked gene, DMY , in medaka is the only sex-determining gene identified in non-mammalian vertebrates.
Your study shows female medaka fish undergo a natural reduction in oestrogen production, which is comparable with the mammalian menopause. Why do you think teleosts exhibit this hitherto mammalian trait?
The term ‘menopause’ in this paper is used to describe the decline in oestrogen levels in aged female medaka. Different from menopausal women, aged female medaka, if they eat well (in terms of food quality as well as quantity), they can still produce eggs (though to a lesser extent). I don’t know the exact reasons why fish exhibit this typically mammalian trait. However given that the quality of eggs produced from aged females are generally poorer in quality, one could postulate that it is unwise to ‘encourage’ aged female medaka to produce too many low quality eggs/offspring, which may result in increasing competition for limited space and resources.
How can this new model in teleosts be used to further our understanding of the effects of oestrogen on female longevity?
Earlier studies using mammalian cells showed that oestrogen could reduce telomere shortening by: (a) increasing telomerase activity (the enzyme that replenishes telomere loss) via estrogen receptor-α- (ERα)- mediated transcription and post-translational activation of TERT (telomerase reverse transcriptase; the catalytic unit of telomerase), or (b) reducing oxidative telomeric DNA damage via ERα-mediated upregulation of mitochondrial antioxidant enzymes MnSOD and GPx.
Despite the fact that oestrogen has been proposed as the key factor contributing to the observed sex differences in telomere length and life expectancy in mammals, there is no direct evidence supporting the view that oestrogen reduces telomere loss and enhances longevity in vivo. The above postulations, however, have never been validated using a suitable animal system. Medaka fish are advantageous in the study of the direct effect of increased oestrogen on telemore length and longevity as they do not present the complication of breast cancer as reported in rodents. Moreover, they enable the study of oestrogen treatment on ‘postmenopausal’ females without the need for invasive ovariectomy as required in rodents.
What constraints need to be considered when using this new model?
I see more advantages than disadvantages when using this small fish model, which is easy to maintain, has a short generation time (2-3 months), produces many eggs for experiments, and is space saving and cost effective. Also, genome information is available for Japanese medaka. The major constraint is that some people maintain the stereotype that medaka as a fish, cannot be representative of mammals/humans.
What’s next for your research?
To continue research on using the medaka model to unravel the direct involvement of oestrogen on telomere maintenance and longevity in vivo. We also will continue our ongoing aging research on bone metabolism/osteoporosis and immune function using the medaka model.