How the Body Ages: Exploring Frailty, Menopause, and the Biology of Healthspan

At a recent ISB Research Roundtable, Assistant Professor Dr. Alice Kane shared new insights into one of the most fundamental questions in biology: why do some people age in good health while others experience earlier decline?

Drawing on research across molecular biology, human cohorts, and animal models, Kane outlined a growing body of evidence that aging is not simply the passage of time but a complex biological process that can vary dramatically from person to person.

At the center of her talk was the concept of frailty, a measure of accumulated health deficits that provides a more precise way to quantify aging than chronological age alone.

“Chronological age is not a good measure of health,” Kane said. “We see tremendous variability in how people age — even among individuals of the same age.”

A New Lens on Aging: Frailty as a Biological Signal

Kane’s work is grounded in the “geroscience” hypothesis — the idea that a small number of core biological mechanisms drive aging and, in turn, increase the risk of a wide range of diseases, from cancer and heart disease to Alzheimer’s and diabetes.

Rather than studying these diseases in isolation, researchers are increasingly focused on understanding — and potentially targeting — the underlying processes of aging itself.

Frailty offers a powerful way to do that.

Using a “frailty index,” researchers can assess dozens of health-related factors — from physical function and disease burden to laboratory values and self-reported health — to generate a score that reflects an individual’s biological aging trajectory.

This approach has proven to be a strong predictor of outcomes, including mortality, hospitalization, and overall health decline.

From Mice to Humans: Identifying Biomarkers of Aging

The Kane Lab is working to identify biological markers of frailty — measurable signals in the body that could help predict how someone will age.

In mouse studies, her team has identified metabolic pathways — particularly those related to amino acid metabolism — that are associated with frailty independent of chronological age.

They also identified specific molecules that may predict future frailty, including:

• alpha-ketoglutarate, a metabolite with antioxidant properties
• nicotinamide riboside (NR), a precursor to NAD⁺ often studied in aging research

These findings suggest that frailty is not simply a byproduct of aging, but a distinct biological state with its own underlying mechanisms.

To test whether these findings translate to humans, Kane and collaborators analyzed large datasets, including the UK Biobank and ISB’s Arivale cohort.

The results revealed:

• Strong links between frailty and inflammation (“inflammaging”)
• Associations with immune system dysfunction
• Connections to metabolic health and insulin signaling

Together, these findings point to a complex, systems-level view of aging — one that integrates molecular, physiological, and behavioral factors.

A Persistent Mystery: Why Women Are More Frail — but Live Longer

One of the most striking findings in aging research is a paradox: women consistently show higher frailty scores than men, yet have lower mortality rates.

Kane highlighted this phenomenon as a key open question in the field.

Possible explanations include:

• Differences in health behaviors and reporting
• Social and caregiving roles
• Biological factors, including sex chromosomes and hormones

Menopause, in particular, may play a critical role.

“The reproductive system in women appears to age faster than many other tissues,” Kane said, noting links between menopause, broader health outcomes, and lifespan.

A New Frontier: Studying Female Reproductive Aging

To better understand these dynamics, Kane’s lab is developing new approaches to study aging in the female reproductive system.

In a pilot study, researchers used at-home sampling kits to collect cervicovaginal fluid and blood samples from participants across different ages. The goal: to identify biological signals of aging in a tissue that is both accessible and understudied.

Early results suggest this tissue may show signs of accelerated biological aging compared to blood, offering a potential new window into how aging unfolds in women.

The team is now working to expand this research to larger, more diverse populations.

What Matters Most Today

While the science of aging is advancing rapidly, Kane emphasized that the most effective strategies for maintaining health are still familiar:

• Regular physical activity
• Healthy diet
• Good sleep
• Strong social connections

“These are the core things we know make a difference,” she said. “There’s exciting research underway, but we’re not yet at the point where new interventions are ready to replace them.”

Looking Ahead

Kane’s work reflects a broader shift in biomedical research — from treating individual diseases to understanding and targeting the aging process itself.

By combining systems biology with large-scale human data and controlled laboratory models, researchers are beginning to map the complex pathways that shape how we age.

The ultimate goal: not just to extend lifespan, but to expand healthspan — the years we live in good health, independence, and function.

Watch the full recording here.