We usually know frailty when we see it… You see and hear various versions of it in my office every day. Someone who once moved through the world without thinking much about their physical abilities begins walking more slowly. Getting out of a chair requires more effort. Carrying groceries becomes challenging. A fall that once would have produced a bruise results in a fracture, or an infection that might have meant a few miserable days instead produces a hospitalization followed by weeks or months of recovery.
For most of my career, this is largely how we have thought about frailty: by what we can see and measure on the outside. Gait speed slows, grip strength declines, muscle disappears, balance worsens, and the physiological reserve that once allowed someone to absorb a setback is gone.
But an intriguing body of research is asking a different question… What if frailty isn’t simply something we can see? What if it also leaves a biological fingerprint inside the body?
That is the idea behind research efforts such as FRAILOMIC and BIOFRAIL. Instead of measuring a single biomarker, researchers have used omics technologies to look across enormous numbers of biological signals simultaneously, including gene expression, circulating proteins, metabolites, microRNAs, and other regulatory molecules.
When researchers compared robust older adults with those who were becoming frail, the biological patterns weren’t the same. Differences appeared across signals related to inflammation, cellular stress, gene regulation, metabolism, and other processes that maintain and repair the human organism.
That immediately makes frailty more interesting than simply saying someone is old and weak.
But it also raises a question we still cannot answer well.
Is the fingerprint causing frailty, or recording it?
Finding a molecular signature associated with frailty does not mean researchers have discovered the molecular cause of frailty.
Perhaps chronic inflammation, altered cellular stress responses, mitochondrial dysfunction, changes in gene regulation, and other biological processes contribute to the loss of muscle, strength, endurance, and resilience that eventually becomes recognizable as frailty.
Or perhaps…
Someone who becomes less active loses muscle, their metabolic health may deteriorate, and their cardiovascular fitness declines. They may accumulate more visceral fat, get sicker, sleep poorly, eat less protein, take more medications, and spend more time sedentary. Those changes themselves could alter inflammatory signaling, gene expression, metabolism, and many of the molecular signals we are measuring.
Most likely, the relationship isn’t a straight arrow in either direction; perhaps it’s more of a loop.
Biology influences behavior and physical capacity, while activity, muscle contraction, nutrition, disease, sleep, medications, environmental exposures, and physical capacity continually feed information back into the biology. Over decades, those interactions may gradually push someone toward robustness or toward frailty.
That is why I would resist calling any collection of these markers a “frailty test” today. We aren’t there yet. But something else makes these findings much more interesting.
What happens when you train an 80-year-old?
A recent study took older adults with a median age of approximately 79 and put them through 16 weeks of supervised, individualized, multicomponent exercise.
This wasn’t simply a recommendation to walk more. The participants trained strength, aerobic fitness, balance, and flexibility, with the program adjusted to their abilities.
Four months later, researchers looked at what had changed. These people became physically more capable.
Walking speed improved, grip strength increased, and performance on the Short Physical Performance Battery—which incorporates walking, balance, and the ability to rise from a chair —improved.
That shouldn’t surprise you… Their median age was approximately 79. That’s awesome. You’re never too old. These weren’t 40-year-olds trying to improve their 10K time. These were people approaching their ninth decade, demonstrating that the aging human body still responds when we ask something of it.
Then the researchers looked inside. They measured 13 molecular markers associated with frailty that had previously emerged from the FRAILOMIC and BIOFRAIL work. Ten changed significantly after the exercise intervention, generally shifting away from the frailty pattern and toward the pattern seen in more robust older adults.
These included signals related to inflammation, cellular stress, senescence, and gene regulation. CXCL8, for example, participates in inflammatory signaling. EGR1 is involved in cellular responses to stress and other stimuli, while several microRNAs that help regulate gene expression also changed. The investigators even identified combinations of molecular markers that differed between people classified as responders and non-responders.
We need to be careful, though. This does not mean exercise “reversed aging.” And it certainly doesn’t mean that lowering one of these molecules with a drug would reproduce the effects of exercise. I believe that it tells us something subtler and more interesting.
When physical capacity changed, some of the biology associated with frailty changed too. Thus, the phenotype and the molecular fingerprint were not completely fixed. But it’s still a chicken-and-egg problem. What initiated the frailty process… the function or the molecular structure?