The study identified the negative consequences of disrupting meiosis.
A new study in an animal model of aging indicates a potential reason for why women who have early menopause or other genetic conditions affecting the reproductive system are more prone to develop cardiovascular disease, diabetes, and dementia.
The new study, led by researchers from the University of Pittsburgh and UPMC and published in the journal Aging Cell, found that disrupting a process called meiosis in C. elegans reproductive cells caused a decline in the worms’ health and triggered an accelerated aging gene signature similar to that of aging humans.
“This study is exciting because it’s the first direct evidence that manipulating the health of reproductive cells leads to premature aging and a decline in healthspan,” said senior author Arjumand Ghazi, Ph.D., associate professor of pediatrics, developmental biology, and cell biology and physiology at Pitt and UPMC Children’s Hospital of Pittsburgh. “The implications of this finding are profound: It suggests that the status of the reproductive system is important not simply to produce children, but also for overall health.”
While the consequences of aging on fertility are well known, research in the past two decades has started to show that reproductive fitness also has an impact on human aging and health. The issue is that it is difficult to directly examine this kind of cause and effect in humans. Ghazi and her colleagues then turned to the Caenorhabditis elegans, a microscopic nematode worm that is an ideal system for aging research due to its short lifetime (three weeks from birth to death) and shared genetic pathways with humans.
The researchers studied meiosis, a kind of cell division present in all animals from yeast to humans that happens exclusively in cells destined to produce sperm or eggs. They discovered that animals with mutations in meiosis genes had shorter lives than their non-mutated counterparts. The mutants also had worse overall health ratings, including premature reductions in mobility, muscular function, and memory.
“The exciting part of this healthspan work was that these animals also showed signs of disrupted protein homeostasis,” said Ghazi. “Disruption to the balance of proteins inside cells is at the heart of age-related neurodegenerative diseases, like Alzheimer’s disease.”
When the researchers improved protein homeostasis in the worms, some loss of lifespan was prevented. These findings point to disrupted proteostasis as a key mechanism linking reproductive health and aging.
Next, the team looked at gene expression changes in C. elegans. At day 1 of adulthood, meiosis mutants expressed genes that were remarkably similar to those normal worms wouldn’t express until day 10.
“In human terms, it’s like someone in their early 20s having the physical appearance, physiology, and gene signatures of a 70-year-old,” explained Ghazi. “Messing with meiosis has dramatic effects on healthspan and accelerates aging in C. elegans.”
Many of the same genes control aging in worms and humans. So the researchers asked if the meiosis mutants’ gene signature had any similarities with the genes of aging humans. They found that this was, indeed, the case — a notable finding as it suggests that disrupting the reproductive system may produce similar changes from worms to humans.
Since C. elegans can be used to make fundamental discoveries not possible in humans and more complex systems, this discovery opens up great possibilities for understanding how the reproductive system shapes aging, said Ghazi.
She is now planning to partner with UPMC Magee-Womens Hospital and Magee-Womens Research Institute to further probe this question in human patients who, due to genetic disease, undergo extremely premature menopause and exhibit complications such as heart disease, autoimmune disorders, and osteoporosis.
“Informed by our work in C. elegans, we want to develop a panel of age-related genes and use this to screen patients’ blood and saliva,” said Ghazi. “If we see evidence of the same genes being elevated in patients, it would be a major first step toward extending such studies to women who undergo early menopause and early infertility.”
Ghazi hopes that eventually this work could inform tests for early detection of health impairments triggered by reproductive abnormalities and new treatments or repurposing of existing drugs to treat such age-related diseases.
Reference: “Meiotic dysfunction accelerates somatic aging in Caenorhabditis elegans” by Julia A. Loose, Francis R. G. Amrit, Thayjas Patil, Judith L. Yanowitz and Arjumand Ghazi, 29 September 2022, Aging Cell.
The study was funded by the National Institutes of Health.