A mitochondria-targeting drug improved egg quality in older mice

Female fertility falls with age, and the main reason is the quality of the eggs (oocytes). Before an egg can be fertilized it has to mature: it must split its chromosomes correctly using a structure called the spindle, and fill its interior with the right supplies and working organelles. Both steps go wrong more often in older eggs. Mitochondria, the cell's power plants, are a prime suspect: in older eggs they work less well and leak more reactive oxygen species, damaging molecules that harm DNA and proteins.

Elamipretide is a small synthetic peptide (a chain of four amino acids) that settles on the inner membrane of mitochondria and helps keep it intact. It has been tested in people for other conditions, including, as the paper notes, a study in which it improved physical performance in older men. A team at Nanjing Agricultural University in China asked whether it could help older eggs.

What they did

• Mice: female mice aged 8, 10 and 12 months, which the team used as reproductively aged, received daily injections of elamipretide (doses of 3, 5 or 10 mg per kg of body weight were compared) for 3, 7 or 10 days. They were compared with untreated mice of the same age and with young mice. The best regimen, 5 mg/kg for 7 days, was used for the detailed experiments in 10-month-old mice.
• Measurements: litter size, the number and quality of eggs, fertilization and early embryo growth in a dish, and a close look inside the eggs: spindles, mitochondria, other organelles, and which genes and metabolites changed.
• Human eggs: at a hospital in Guangxi, China, immature eggs left over from IVF treatment (129 eggs in total) were randomly assigned to mature in a dish with or without the drug, then fertilized for research only; no embryos were transferred.
• Pig eggs: to test whether the effect holds across species, pig eggs were damaged with hydrogen peroxide and treated with the drug.

What they found

• Bigger litters, for a while. A week of treatment improved fertility in all three ages of mice, most clearly at 10 months. The benefit was short-lived, lasting only about a month.
• Better eggs. Treated older mice had more healthy follicles (the sacs in which eggs grow), and their eggs were fertilized more often and developed further as early embryos.
• Tidier insides. In older eggs, the spindles were often abnormal and chromosomes misaligned; the drug reduced these defects. It also restored the placement of mitochondria around the spindle, lowered reactive oxygen species, and brought other organelles and the cell's recycling system (autophagy) closer to the young pattern. It did not significantly reduce the number of dying eggs.
• A possible pathway. The drug shifted vitamin B6 metabolism in the ovary, and adding vitamin B6 to older mouse eggs in a dish improved their maturation. Older eggs showed raised activity of the VEGF growth-signal pathway; the drug brought it back to normal, and a VEGF-blocking compound had similar benefits on its own.
• Human eggs in a dish. Eggs from women aged 35 or older matured more often with the drug and showed higher fertilization and cell-division rates; eggs from younger women also matured better. The exact rates are in the figures.

What to keep in mind

• Mostly mice. The fertility results come from mice. Mouse reproduction differs from ours, and the benefit faded within about a month.
• Very small human test. The human eggs came from a handful of patients (the older group's 54 eggs came from three women), and the eggs were matured in a dish, not in the body. The paper's patient counts are also not fully consistent with each other. No pregnancies were attempted.
• Mechanism not settled. The abstract describes the drug as activating the VEGF pathway, while the results show it bringing raised VEGF activity back down. The vitamin B6 and VEGF links come from lab experiments and need confirmation.
• A drug, not a supplement. Elamipretide is an experimental injectable medicine. Doses that work in mice don't translate directly to people, and this study does not show it is safe or useful for fertility in women.

Why it matters

Older eggs are the main reason fertility falls with age, and there is no proven way to reverse their decline. This study suggests that protecting mitochondria can make older mouse eggs behave more like young ones, at least for a while, and gives a first, very small hint that human eggs respond in a dish. It is a lead for researchers, worth testing carefully in larger studies.