THE FEMALE VARIABLE

Estrogen protects the brain, heart, and bones—but its power remains overlooked in aging research

By Hannah Ongley

It’s 2016: The US and UK have, respectively, voted for Donald Trump and Brexit. “Post-truth” is named Oxford’s word of the year; Zika virus is declared a public health emergency. David Bowie and Prince have just died, and purely by coincidence, longevity science—the study of the biological mechanisms of aging—is shifting from fringe interest to a well-funded field. In fact, the FDA has finally mandated that women be included in clinical trials.

The mandate—a bright spot that flew under the radar in a dark and eventful year—represented a turning point in biomedical research. But requiring scientists to account for sex as a biological variable was only the first step in dismantling decades of male-centric study design. The inertia of entrenched practices meant that many labs still ignored female subjects. Women’s fluctuating hormones simply introduced too many confounding variables. Wondering how to circumvent the estrous cycle, some longevity researchers even considered an experimental surgical procedure to remove the ovaries entirely. It would have been a disturbing way to treat women—luckily, the women in question were mice—but that rationale has been used for decades to justify the near-total exclusion of female subjects from biomedical research.

Across nearly every culture, time period, and socioeconomic class, women outlive men—sometimes by just a few years, sometimes by a decade or more. Today, thanks to the medical advances that have increased life expectancy over the past century, we have supercentenarians: Roughly, 90 to 95 percent of these individuals aged 110 or older are women. But in the lab, this incredible survival edge has rarely been studied on its own terms. While men chase longevity through peptides, protein powders, and cold plunges, they continue to burn out like overclocked processors. Yet science keeps insisting on their biology as the default.

The early decision to treat female biology as a confounder has shaped what we think aging looks like. It’s no coincidence that major research initiatives have treated women’s health as an exception to the rule. When the Women’s Health Initiative released its first results in 2002, it reflected that same impulse to flatten complexity in the name of clarity. Alarmist headlines about hormone replacement therapy (HRT) causing breast cancer spread across the country, and the fallout was pretty much immediate. The WHI, a $625 million NIH-backed trial, had been designed to evaluate whether HRT could protect postmenopausal women from heart disease, osteoporosis, and cognitive decline. Instead, it triggered panic. Millions of women stopped HRT overnight. Doctors, fearing liability, stopped prescribing it.

The WHI was one of the most expensive public health experiments in history. It was supposed to correct decades of gender bias in medicine, but it became a cautionary tale of bad headlines and overcorrections, and left a generation of women abandoned by science—collateral damage from the “X Causes Y, Science Says” genre of public health panic. In many ways, it feels like we’re still living in that aftermath.

The gap is wider still for marginalized groups, creating a profound multi-tiered system of care. Black women are disproportionately given hysterectomies and denied hormone therapy. Trans men on long-term estrogen suppression face unknown risks to brain, bone, and cardiovascular health. And women with early menopause from surgery or chemo often receive no long-term care, despite heightened risks for dementia and heart disease. Women with enough money, however, can buy access to hormones on demand. Even before Ozempic was the injectable du jour in Hollywood, according to a 2012 report in Vanity Fair, human growth hormone was being normalized not as therapy but as elective enhancement, the same way one might approach rhinoplasty or a boob job. Is this scientific advancement? Or just market logic in a lab coat?

Later analyses from the WHI trial found that the risk of breast cancer depended heavily on age, time since menopause, and the type of hormone used. For many women, the protective effects of HRT on the heart, brain, and bones outweighed the risks. But the damage was done.

In 2025, the WHI was quietly defunded under the Trump administration, closing the door on one of the few federal efforts dedicated to women’s aging and further entrenching gaps in medical research. This is emblematic of a broader failure. If we want meaningful breakthroughs in longevity, we need to stop treating female biology as an afterthought. Women’s resilience—a result of hormones, genetics, and social dynamics—might actually be the key to better aging for everyone.

Estrogen doesn’t just fade. It drops out like a keystone pulled from an arch. This sudden shift sets off a slow structural collapse that starts in the brain. A 2020 Journal of Neuroinflammation review identifies this shift as a systemic pro-inflammatory trigger. Estrogen acts like a thermostat for the body’s inflammatory response. As it drops, the system overheats, helping explain the elevated risk of stroke and Alzheimer’s in postmenopausal women. Its broader neuroprotective role—supporting glucose metabolism, mitochondrial function, and beta-amyloid clearance—remains underrecognized. Medical science has effectively spent decades studying a single-speed bike, while leaving half the population to navigate a complex, multi-geared machine without training wheels.

If a drug demonstrated such critical neuroprotective effects, it would be a breakthrough. When a hormone is responsible, it’s a glitch, shrugged off by the medical establishment even in the face of mounting data. A 2024 review of 33 randomized trials found hormone therapy did not raise overall mortality or cardiovascular risk, though it did increase clot and stroke risk. Benefits were greatest for women who began treatment within 10 years of menopause, showing that timing, not just treatment, matters. Yet despite decades of evidence, many women reporting cognitive symptoms are still misdiagnosed or ignored. Medical training devotes more hours to erectile dysfunction than menopause. There are no long-term human trials on mitochondrial aging with and without HRT, and few clinicians are trained to see menopause as anything other than a reproductive endpoint.

Now, take hormones out of the picture. Women are still outpacing their male counterparts. The female body builds in redundancy thanks to the unique mosaicism of female cells: Women have two X chromosomes, one a backup in case of damage, acting like a built-in biological buffer against mutations. Men simply don’t have this protection. The male Y—referred to as “the toxic Y” in a 2018 Biology of Sex Differences review—degrades with age and takes resilience with it. In mice, an XX chromosome pattern has been shown to extend lifespan. A 2018 Aging Cell study found that it conferred a genetic advantage regardless of gonadal sex, but especially when paired with ovaries. In humans, the advantage has been hiding in plain sight.

There’s no real mystery; we’re just ignoring the data. Ethical constraints demand that only animal studies can isolate chromosomes, but human clues still exist. Turner syndrome (XO), for example, increases mortality, while Klinefelter syndrome (XXY) still tracks male patterns, likely due to hormonal dominance. Yet few aging studies investigate XX-linked resilience.

While popular media occasionally picks up the “second X” story, the science hasn’t caught up. We still lack long-term studies on how menopause affects brain and cellular health. Most trials don’t distinguish between types of estrogen or how they’re delivered. And even though animal studies suggest women’s genetic makeup offers an edge, we have no way to measure that advantage in humans.

Women face a growing mismatch between health span, brain health span, and life span. Neglecting perimenopausal health means symptoms go untreated, driving up healthcare use, reducing productivity, and pushing many women into early retirement. Women make up two-thirds of Alzheimer’s patients, but receive only a fraction of the research funding. We are more likely to seek care, but are forced to navigate a system built around male biology. Meanwhile, biohacking—tinkering with off-label drugs like metformin or rapamycin—remains a boys’ club. If medicine keeps sidelining female biology, women may be forced to play lab rat too. Though with stronger health literacy, more experience managing hormones, and a collective approach to problem-solving, we may be the best candidates for self-experimentation anyway.

Maddy Dychtwald, a longevity expert and author, agrees that our healthcare system was built by men, for men, and that bias still shapes how treatments are developed and prescribed. In her book Ageless Aging, she recalls asking her doctor to try metformin, a diabetes drug increasingly used off-label by biohackers for its potential anti-aging effects. Her doctor reluctantly agreed, on the condition that they closely monitor side effects. But within days, Dychtwald became so ill she had to stop. The gut issues lingered for weeks. It was a visceral reminder that many common drugs, including those hailed as safe, have not been adequately tested on women. In longevity circles, metformin is practically a vitamin. For women, it might as well be roulette.

In the year 2000, before metformin, curcumin, or intermittent fasting took r/Biohackers by storm, researchers were exploring a different kind of anti-aging fix: pond scum. Nobel laureate Elizabeth Blackburn was studying a freshwater organism called Tetrahymena, which, she discovered, produced an enzyme that could rebuild telomeres, the protective caps on our chromosomes that wear down as we age. One day, the psychologist Elissa Epel walked into Blackburn’s lab and posed what Blackburn calls a life or death question: “What happens to telomeres in people who are chronically stressed?”

Caregiving wears women down—visibly. But Blackburn and Epel’s research showed that women who responded to stress as a challenge rather than a threat maintained longer telomeres. In her 2015 book with Epel, The Telomere Effect, Blackburn emphasizes that if we leave women out, we’re missing half the data: Women’s longer telomeres suggest a natural experiment in resilience we’ve barely begun to understand.

The same buffering effects that protect telomeres may also come from social environments. Women consistently maintain larger and more intimate social networks, which are associated with longer life. Men, by contrast, often rely on a spouse for social connections and face greater risk from isolation. These gendered patterns are cultural, but they have real biological consequences.

A 2021 study using the Midlife in the United States cohort found that, while social support lowered mortality for everyone, strain in close relationships raised mortality risk only for women. According to a landmark paper in Psychological Review, this sensitivity may reflect an evolved “tend and befriend” response: Under stress, women are more likely to nurture and seek connection. These support-seeking behaviors, driven by oxytocin and estrogen, are typically thought of as social habits, but additional studies suggest they’re biologically encoded. This is one of the most robust gender differences in psychology. Animal models, from rats to prairie voles, show similar stress-buffering effects from female social bonds.

Other research supports the idea that looking after others can be protective. A 2018 study found that caregivers, 60 percent of which are women, had a 16.5 percent lower mortality risk than non-caregivers, despite their higher stress. Psychological distress predicted mortality only in non-caregivers, suggesting that having a sense of purpose may mitigate the negative health effects of stress.

So why is female biology still missing from studies that claim to define human health? A 2023 Harvard report found that 99 percent of aging research overlooks menopause. Perimenopausal symptoms like depression, anxiety, and brain fog remain poorly understood. Structural barriers—limited training, insurance issues, and medical bias—further restrict care. Even when gender is acknowledged, biological sex is often treated as a social variable and left unexamined.

Evidence suggests that mandates and editorial policy can reshape the scientific landscape. A 2024 Scientific Reports study analyzed how sex/gender-specific funding and editorial guidelines from the NIH, Canadian GBA+, UKRI, and top journals like Nature and The Lancet have influenced research. Countries with progressive policies saw increases in sex- and gender-integrated research. Even in countries without formal policies, like Japan and China, editorial standards alone have led to measurable shifts in publication practices. The impact of journal editorial policy across countries shows that scientific norms and standards can shift practice even where formal policy lags behind, offering a model for how women’s biology can finally be taken seriously.

Fast-forward to the imagined future of 2035. The most advanced longevity lab in the country is studying, instead of trying to eliminate, the hormonal variability of its female subjects. This research feeds into advanced AI models that predict individual aging trajectories based on hormone cycles and genetic data. Wearable biosensors continuously monitor hormone fluctuations and mitochondrial health in real time. Experimental therapies precisely tune estrogen pathways to delay cognitive decline and prevent stroke. Gene-editing tools test the limits of XX chromosome resilience. Longevity clinics offer personalized protocols calibrated from decades of female-specific data.

Women’s bodies aren’t outliers; they’re blueprints. Studying women’s longer lifespans could be the frontier of biomedical innovation, unlocking radical new possibilities for extending healthy life for everyone. Instead of a medical system that’s willfully blind to half the data, we could build a fully predictive model of human aging—one that treats hormonal cycles, chromosome patterns, and sex-specific risks as the foundation for new longevity protocols, not complications to work around. The future of longevity research needs to start with the biology we’ve spent decades ignoring.