Basic Research

New Study Shows Resveratrol Derivative Delays Ovarian Aging and Egg Cell Decline 

With a plant-based polyphenol called THSG, scientists delay ovarian aging and egg cell decline by boosting sex hormone activity in mice.

By Dylan G. Arrazati

Key Points: 

  • THSG treatment preserves the quantity and quality of egg cells (oocytes) in aging mice, suggesting that it delays the decline in reproductive potential. 
  • It is estimated that THSG delays oocyte decline by 8 years for women.
  • Aging mice treated with THSG exhibit increased activity of sex hormone-related proteins, which play a key role in mitigating oocyte decline upon ovarian aging.

Several critical processes during prenatal development must be executed to produce healthy offspring. However, these events require healthy, viable egg cells, which drastically decline in quality upon aging. Notably, current data indicate that women now have children at later stages of life, which has driven scientists to develop safe and effective therapeutics to delay ovarian aging and preserve oocyte health. 

In a new study published in the journal Frontiers in Cell and Developmental Biology, researchers from Taipei Medical University in Taiwan explore the effects of THSG (2,3,5,4’-tetrahydroxystilbene-2-O-β-D-glucoside) on ovarian aging in young and aged mice. Lin and colleagues found that young (4-weeks-old) and aged (24-weeks-old) mice treated with 10 mg/kg THSG twice a week had significantly healthier oocytes and greater oocyte numbers than untreated matched controls. Furthermore, THSG treatment increased the activity of hormone-related proteins in young and aged mice.  

THSG Attenuates Oocyte Degradation

Reproductive success gradually decreases with age, eventually coming to a complete halt (infertility). Aging infertility is heavily tied to the decline of oocytes, which are housed in the ovaries. Compromised oocyte quality drives ovarian aging by hampering critical growth and maturation processes. With this in mind, Lin and colleagues examined whether early or late THSG treatment could defer oocyte degradation and improve oocyte quality. 

The investigators first treated young mice with THSG for 32 weeks and aged mice with THSG for 16 weeks, monitoring oocyte decline every four weeks. Results showed that treated mice had significantly more oocytes than untreated mice, demonstrating that THSG retards the rate of oocyte decline. Furthermore, oocyte decline in aged mice began at 36 weeks (~45 human years) while untreated mice experienced decreased oocyte numbers at 28 weeks (~37 human years), further highlighting that THSG hinders oocyte degradation. 

Lin and colleagues proceeded to analyze ovarian follicle growth, which plays a vital role in nourishing egg cells to improve their quality before being fertilized. Young mice treated with THSG exhibited more mature follicles than untreated mice, indicating that THSG increases oocyte quality. The investigators then looked at the accumulation of a hormone (AMH) that contributes to follicle development and oocyte viability in the ovaries of aged mice. They found that AMH was drastically higher in treated aged mice than in untreated mice. Taken together, the findings suggest that early and late THSG treatment attenuates ovarian aging by deferring oocyte degradation and boosting oocyte quality.

THSG preserves number of oocytes in aged mice.
(Lin et al., 2022 | Front. Cell Dev. Biol.) THSG preserves the number of oocytes in aged mice. Although oocyte numbers significantly decline with age in untreated (#, white) and THSG-treated ($, gray) mice, THSG-treated mice have significantly (*) more oocytes from 28 to 40 weeks of age. 

THSG Increases Sex Hormone Important for Oocyte Health

Aging inevitably obstructs the reproductive cycle and oocyte health, both of which require sufficient amounts of estradiol, the primary form of the female sex hormone estrogen that also decreases with age. Accordingly, Lin and colleagues examined THSG’s effect on estrogen synthetase (cyp19a), the enzyme responsible for synthesizing estradiol, in young and aged mice. Furthermore, the investigators looked at the activity of an estrogen receptor (er-β) that is known to impact follicle maturation in oocytes.  

Although cyp19a activity declined with age in both young and aged mice, it remained significantly higher in treated mice compared to untreated mice. Young and aged mice also had more er-β activity than untreated mice by the end of treatment. Overall, the findings indicate that THSG stimulates estrogen synthesis and maintains higher sensitivity to estradiol, which may account for improved ovarian aging. 

THSG delays the decline of cyp19a and increases er-β in aged mice
(Lin et al., 2022 | Front. Cell Dev. Biol.) THSG delays the decline of cyp19a and increases er-β activity in aged mice.  While cyp19 activity (left) significantly declines and er-β significantly increases with age in untreated (#, white) and THSG-treated ($, gray) mice, THSG-treated mice have significantly (*) more of both with aging. 

Is THSG Safe in Humans? 

THSG is derived from resveratrol, a plant-based polyphenol with well-established anti-oxidative and anti-inflammatory properties that contribute to extended lifespan in worms and flies. Previous animal and human studies have demonstrated resveratrol’s ability to stimulate oocyte maturation and improve overall quality post-ovulation, the period after an ovary releases a mature egg. Current evidence suggests that resveratrol has therapeutic potential to attenuate ovarian aging, but more research is needed for scientists to rule out the possibility of resveratrol-induced fetal abnormalities. The same goes for THSG; however, a previous study found that THSG was safer and more effective than resveratrol at treating gum disease, another age-related condition. That being said, solidifying TSHG as a safer alternative to resveratrol requires more comparative studies evaluating the effects of resveratrol and THSG on ovarian aging.  

Model & Dosage

Model: Female C57BL/6J mice 

Dosage: 10 mg/kg by oral gavage twice weekly

Source

 Lin H-Y, Yang Y-N, Chen Y-F, Huang T-Y, Crawford DR, Chuang H-Y, Chin Y-T, Chu H-R, Li Z-L, Shih Y-J, Chen Y-R, Yang Y-CSH, Ho Y, Davis PJ, Whang-Peng J and Wang K (2022) 2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-Glucoside improves female ovarian aging. Front. Cell Dev. Biol. 10:862045. doi: 10.3389/fcell.2022.862045

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