Age-related decline in the efficacy of DNA repair may underlie reproductive aging, say researchers.
As reported in Science Translational Medicine, the team found that double-stranded DNA breaks accumulated over time in the oocytes of mice and of women.
The proportion of human primordial follicles with double-stranded breaks (DSBs) was 19%, on average, in four women aged 20 years or younger, compared with 64% in four older women. Likewise, the number of DSBs in germinal-vesicle-stage oocytes averaged 56 among five women aged 28 years or younger versus 594 in four women age 35 years or older.
In parallel, expression of key DNA repair genes, including the breast cancer risk gene BRCA1, declined with age in mice and women.
"Our findings may also shed light on why there is a significant compromise in reproductive function during the latter half of the third decade of life," say Kutluk Oktay (New York Medical College, USA) and team.
In oocytes from 24 women, expression of the DNA repair genes BRCA1, MRE11, Rad51, and ATM declined with age, and the rate of decline was higher for all genes bar BRCA1 in women older than 36 years, relative to younger women.
The researchers say that this will leave the oocyte reserve more vulnerable to genotoxicants, resulting in rapid accumulation of DBSs. This would trigger apoptosis, causing "the accelerated elimination of oocytes during later reproductive years."
They add: "Those oocytes that survive despite the accumulation of DNA damage may be functionally impaired, which would explain the decline in reproductive performance during the 10 to 15 years before menopause."
Oktay et al also show that BRCA1 mutations have reproductive consequences. Mice with such mutations produced fewer ooctyes under stimulation than wild-type mice (14 vs 33), indicating a smaller ovarian reserve, and they had smaller litters (5.6 vs 7.6 pups). Furthermore, 24 women with BRCA1 mutations had diminished ovarian reserve relative to 60 without, indicated by significantly reduced levels of anti-Müllerian hormone (1.22 vs 2.23 ng/mL) despite being of a similar age.
"This state-of-the-art work sheds new light on the role of DSBs in mediating the effects of aging and, possibly, genotoxic stress and chemotherapy on the ovarian reserve," say Joshua Johnson (Yale University School of Medicine, New Haven, Connecticut, USA) and David Keefe (New York University Langone Medical Center, USA) in a commentary accompanying the study.
They note that chemotherapy reportedly causes DSBs. "Keeping this in mind, the new information suggests that patient age at chemotherapeutic treatment may be even more important than previously appreciated when considering fertility preservation strategies."
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