Highlights: 

  • Resveratrol treatment restores the live offspring rate of middle-aged mice. 
  • Treatment with resveratrol restores the mitochondrial health of aged oocytes.
  • Increased live offspring rate correlates with increased activation of sirtuins — longevity-associated enzymes that modulate cell survival processes.

The female reproductive system ages faster than any other system in the body. Meanwhile, due to social, cultural, and economic factors, many women in developed countries are delaying motherhood, prompting scientists to search for a compound capable of deferring age-related infertility. A new study from the International University of Health and Welfare School of Medicine in Japan suggests that resveratrol may be that compound. 

Okamoto and colleagues report in Aging that short-term resveratrol treatment restores the quality of oocytes. They show that 22 weeks of resveratrol treatment increases the live offspring rate of middle-aged mice. Additionally, just one week of resveratrol treatment restores mitochondrial health and boosts sirtuin gene activation. The findings suggest that resveratrol can prevent the aging of the female reproductive system and promote fertility. 

Resveratrol Improves Age-Associated Infertility 

A previous study showed that resveratrol protects against age-associated infertility in mice. However, supplementation began at an age equivalent to about 15 human years, which may not be ideal. Therefore, Okamoto and colleagues began resveratrol supplementation in female mice at the human age equivalents of 58, 48, or 34, corresponding to 1, 12, or 22 weeks of treatment, respectively. 

After resveratrol treatment, the researchers fertilized the oocytes of the middle-aged mice with young mouse sperm, transplanted them into young surrogate mothers, and removed the offspring by Cesarean section. While the untreated mice had fewer live offspring than young mice, all durations of resveratrol treatment tended to increase the number of live offspring. The longest duration tested (22 weeks) reached statistical significance by raising the live offspring rate to the same level as young mice.  

(Okamoto et al., 2022 | Aging) Resveratrol Restores Live Offspring Rate. Aging (black) leads to significantly (a) lower live offspring. Resveratrol (white) increases the live offspring rate after 1 and 12 weeks of treatment, but not to statistical significance. Twenty-two weeks of treatment significantly (b) increases the live offspring rate to youthful levels. 

An oocyte is a relatively gigantic cell, about 10,000 times larger than a sperm cell. Like most cells, oocytes accumulate damage caused by excessive reactive oxygen species during aging. And like most aging cells, the mitochondria of oocytes become impaired and produce less cellular energy, called ATP. Consequently, oocyte quality declines with aging, leading to infertility.  

Okamoto and colleagues assessed the health of oocyte mitochondria by measuring a critical electrical property of mitochondria called the membrane potential. They found a reduction in the membrane potential of oocyte mitochondria from untreated middle-aged mice, indicative of impaired function. However, resveratrol treatment restored the mitochondrial membrane potential. Furthermore, oocyte ATP levels were increased by resveratrol treatment. 

(Okamoto et al., 2022 | Aging) Resveratrol Restores Mitochondrial Health. Compared to oocytes from young mice (gray), the mitochondrial membrane potential (Fluorescence intensity, left) and ATP levels (right) of oocytes from aged mice (black) were significantly (a) reduced. One week of resveratrol (Res) treatment significantly (b) increased the mitochondrial membrane potential and ATP levels, indicating improved mitochondrial health.

Resveratrol is a plant polyphenol with antioxidant and anti-inflammatory properties that activates sirtuins. Sirtuins are a family of enzymes with diverse functions, including the modulation of DNA repair and mitochondrial health. Okamoto and colleagues measured the gene activity of sirtuins and found that they correlated with the increased live offspring rates associated with resveratrol treatment. It is possible, then, that resveratrol slows or prevents oocyte decline by restoring mitochondrial health with sirtuin activation. 

Can Oocyte Decline be Delayed to Promote Fertility in Older Age?

The findings of this study suggest that resveratrol treatment can prevent oocyte aging as long as supplementation begins around the age of 34. At least two other mouse studies (referenced in the source article) have shown that resveratrol and a resveratrol derivative improve aged oocytes. Still, human studies are necessary to determine the effects of resveratrol on fertility. 

In addition to resveratrol, other molecules that improve mitochondrial health reduce oocyte and ovarian aging in mice. Obese mice fed the NAD+ precursor nicotinic acid exhibit reduced features of oocyte aging. Another NAD+ precursor, NMN, improves oocyte quality and the health of offspring from obese mice. Furthermore, several compounds that enhance mitochondrial health restore age-related infertility. These studies support that mitochondria-enhancing compounds, like resveratrol, can improve oocyte quality and promote fertility, at least in rodents.