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2023-12-06news-articleNews<p>Fabrisia Ambrosio, PhD, MPT, director of the Discovery Center for Musculoskeletal Injury, discusses the need for better models of menopause and other female-specific traits.</p>

Q&A: Fabrisia Ambrosio: 99 Percent of Preclinical Aging Research Ignores Menopause

December 6,  2023

Menopause is a significant transition that comes with aging. This drastic change has health effects, but researchers don't properly consider it in 99 percent of preclinical aging studies, as highlighted in a new perspective piece, published in Nature Aging by Fabrisia Ambrosio, PhD, MPT and colleagues, with co-first authors Gabrielle Gilmer and Zachary Hettinger from the Ambrosio lab.

One of the issues in studying menopause's role in healthy aging is the lack of reliable animal models of menopause. This gap trickles up the clinic, impacting women's healthcare, according to Ambrosio, who is the director of the Discovery Center for Musculoskeletal Injury of the Schoen Adams Research Institute at Spaulding Rehabilitation. In her new paper, she discusses the need for better models of menopause and other female-specific traits.

Q: What do we know about the role menopause, pregnancy, breastfeeding and birthing play in aging?

Menopause is inextricably intertwined with aging in female individuals. On average, females will live about a third of their lives postmenopausal. We lack data to understand how menopause affects aging and how it might contribute to disease or age-related declines. In preclinical models, it's something that we just haven't effectively addressed, and so we haven't been able to study it well.

Similarly, when we think about pregnancy, about 86 percent of female individuals will give birth at some point. And in the clinic, pregnancy, childbirth and breastfeeding can have long-term health effects — in some cases, it is protective. In other cases, it may contribute to disease. Again, this is a variable prevalent in humans but largely ignored in animal studies — most of the animals we use have never given birth.

I feel an overwhelming sense of urgency when I think about this. The science has so much catching up to do. Hundreds of years of research studies have been dominated by male animal models and male humans.

Q: How does this gap impact healthcare outcomes?

Our healthcare system lacks data on how to treat age-related diseases in females. In the clinic, we're falling behind and can’t treat aging females as effectively as we would like. It represents a significant gap in clinical practice.

And the consequences are tangible. Females live longer, but they live with more physical declines, cognitive declines and cardiovascular issues. For example, we know that the number of misdiagnoses of a heart attack in females is higher than in males. And the same is true for a stroke.

In the example from our research, females get osteoarthritis more frequently than males, starting from around the time of menopause, which contributes to greater declines in physical mobility into older age. And yet, when we look at aging female rodent models, they display a relative protection against the loss of cartilage health with aging.

Alzheimer’s disease is another example. The incidence is higher in females than males. But it has been difficult to recapitulate this sex difference in our animal models.

Q: How often is menopause considered in studies of age-related health issues?

When we look at age-related diseases, over 75 percent of them are likely influenced by menopause in one way or another. But the great majority of preclinical aging biology research studies fail to consider menopause in their experimental setup. In our new paper, we found that less than 1 percent of published studies considered menopause. The fact that we’re not including menopause or other female-specific traits in preclinical models is a big, missed opportunity.

Q: Why is it important what animal models studies use?

There's no doubt that clinical (human) studies are critical for understanding disease. But much of our scientific understanding of the mechanisms by which diseases develop relies on animal models. Animal models let us understand the fundamentals of disease in a way that we can't with humans.

Q: Why don’t we have an animal model of menopause?

Unlike humans, female rodents do not always have a persistent menopause phase. For many rodents, their hormone levels stay constant or increase even into older age. In fact, humans are quite unique in this way. Some monkeys undergo menopause, but that's pretty much right at the end of their lifespan, though a new study indicates that some chimpanzees may undergo menopause in mid-life. Other than that new work, the literature has only found humans and some types of whales spend a good amount of their lifespan post-menopause.

Q: What's needed to address this gap?

There's been a lot of emphasis by the National Institutes of Health (NIH) for researchers to do better in considering sex as a biological variable in their studies. And that's based on the recognition that so much research to date has only been done in males.

Of course, aging is another crucial biological variable. So now we're thinking about the intersection of sex and aging and the need to ensure that our aging models are capturing human trajectories.

The first step is increased recognition of the limitations of the current models and consideration of the contribution of menopause on aging and disease. I hope we'll start seeing more studies take menopause and other female-specific traits into account, to better understand aging and disease in human females.

We need a mechanism to bring aging researchers together to share their ideas on understanding aging in the postmenopausal population. And then, we need additional funding for research that considers female-specific traits and uses some of these new models.

I hope in the coming years, we'll see some dedicated funds and resources for this type of work.