Immunity

Anti-Diabetes Drug Metformin Protects Against Reproductive Aging in Latest Study

Ovarian fibrosis (scarring) – a hallmark of ovarian aging – is prevented when mice are given metformin, a common anti-diabetes medication.

By Yedida Bogachkov, Ph.D.

Key Points:

  • Metformin prevents the age-related progression of ovarian fibrosis in old mice.  
  • Fibrosis already present in older mice is not reversed by metformin treatment. 
  • The effects of metformin appear to be due to immune system rejuvenation. 

As we age, it becomes more difficult for our organs to regenerate new cells. Instead, our cells are replaced by structural proteins like collagen, manifesting in fibrosis. Fibrosis occurs in many organs, including the lungs, heart, and reproductive organs, like the ovaries. Aging-related ovarian fibrosis leads to an increased risk of cancer and tumor formation. If these changes can be prevented, cancer risk could drop. A new study seems to show that a common diabetes medication may be the answer.

The study, out of the University of Ottawa in Canada, published in Science Advances, focused on aged female mice given 350 mg/kg of metformin in their drinking water each day for six months. The scientists found that metformin treatment helped prevent age-related ovarian fibrosis through its effects on the immune system but did nothing to change fibrotic changes that were already present. The treatment also served to change the cells responsible for secreting collagen (fibroblasts) to a positive remodeling type.

“The results demonstrate that metformin can [affect] specific populations of immune cells… to prevent age-associated ovarian fibrosis and offers a new strategy to prevent ovarian fibrosis,” the researchers write.

Metformin Prevents Ovarian Fibrosis

Ovarian fibrosis begins in mice when they are about 14 months old (~ 47 human years), so mice were treated with metformin at this age to determine if metformin prevents fibrosis (prevention group). To determine if metformin reverses fibrosis, mice were treated at 18 months of age (~56 human years) when fibrosis has already built up (reversal group). To assess ovarian fibrosis levels, the investigators measured collagen. Collagen is the main structural protein within the skin and most other organs throughout the body; however, too much collagen causes fibrosis. 

The prevention group displayed no increase in collagen, as compared to young mice (3-6 months old, ~20-34 human years), indicating that metformin treatment may prevent collagen deposition. However, the reverse group saw no change in collagen. These findings demonstrate that providing metformin treatment during the time when age-associated ovarian fibrosis is normally established prevents collagen formation, but metformin does not help reverse ovarian fibrosis that is already present.

ovarian fibrosis
(Landry et al., 2022 | Science Advances) Metformin Reduces Ovarian Fibrosis in Old Mice. Untreated old mice (20 months) have more fibrosis (measured by collagen) than younger mice (3-6 months and 12-17 months) unless treated with metformin (Preventive metformin) starting at 14 months. However, for older mice (24 months), who started treatment at 18 months, metformin had no effect on collagen (Reverse metformin).

The researchers found that there are two types of fibroblasts – cells that secrete collagen – present in ovarian tissue: Negative remodeling fibroblasts, which promote collagen formation, ultimately leading to tissues becoming stagnant and resistant to change (remodeling), and positive remodeling fibroblasts, which degrade old tissue, and encourage new tissue growth.

Landry and colleagues found that in immunodeficient mice, fibrosis begins at an earlier age than in normal mice, suggesting that the immune system may play a role in ovarian fibrosis. Furthermore, they found that in mice treated with metformin, there was a shift in the fibroblast subtypes, with more positive remodeling fibroblasts present in the mice treated with metformin, supporting the role of these positive remodeling fibroblasts in maintaining healthy tissue and preventing fibrosis.

ovarian fibrosis
(Landry et al., 2022 | Science Advances) Increased Ovarian Fibrosis in Immunodeficient Mice. A commonly used immunodeficient mouse model (NSG) shows signs of increased ovarian fibrosis (collagen) beginning in middle age (12-17 months) and is sustained until old age (≥20 months), suggesting the role the immune system plays in ovarian fibrosis.

Metformin for Anti-Aging

Metformin is a commonly used anti-diabetes medication. This study shows that it may also have anti-aging effects, at least when it comes to ovarian fibrosis, serving to prevent age-related changes to the ovaries. Other studies have also shown that metformin may have anti-fibrotic, and thus anti-aging, effects in other organ systems, such as the liver and lung, although those studies were done in younger mice. 

Metformin’s ability to change the immune landscape helps prevent stagnant (senescent) fibroblasts from persisting, allowing for new fibroblasts to thrive. Pre-menopause ovarian tissue is constantly going through cycles of remodeling, but when stopped, there is limited pressure to promote remodeling, so fibrosis ensues. Preventing fibrosis and encouraging remodeling may be a valid anti-aging approach. More research is needed to uncover whether metformin has similar anti-aging and anti-fibrotic properties in other aged organs.

Model & Dosage

Model: female C57BL/6 mice

Dose: 350 mg/kg per day of metformin in drinking water

Source

Landry, D.A., Yakubovich, E., Cook, D.P., Fasih, S., Upham, J., Vanderhyden, B.C. Metformin prevents age-associated ovarian fibrosis by modulating the immune landscape in female mice. 2022. Science Advances doi:10.1126/sciadv.abq1475

References
  1. R. C. Shankaraiah, E. Callegari, P. Guerriero, A. Rimessi, P. Pinton, L. Gramantieri, E. M. Silini, S. Sabbioni, M. Negrini, Metformin prevents liver tumourigenesis by attenuating fibrosis in a transgenic mouse model of hepatocellular carcinoma. Oncogene 38, 7035–7045 (2019).
  2. S. Rangarajan, N. B. Bone, A. A. Zmijewska, S. Jiang, D. W. Park, K. Bernard, M. L. Locy, S. Ravi, J. Deshane, R. B. Mannon, E. Abraham, V. Darley-Usmar, V. J. Thannickal, J. W. Zmijewski, Metformin reverses established lung fibrosis in a bleomycin model. Nat. Med. 24, 1121–1127 (2018).
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