In a groundbreaking study, scientists have mapped the most detailed genetic blueprint yet of frailty – the age-related decline in resilience that affects around 40% of people aged 65 and above, dramatically increasing the risk of hospitalization, disability and death. The findings offer new hope in the development of effective anti-aging therapies.
In the largest study of its kind, University of Colorado Boulder (CU Boulder) researchers led an international team that analyzed the DNA of more than 400,000 people, focusing on six key areas of frailty: physical strength, mobility, cognition, mood, cardiovascular health and nutritional status. Together, they paint a clear picture of how our bodies lose resilience over time – and some faster than others.
"Aging is not just one thing," said the study's co-author Dr. Kenneth Rockwood, a leading expert in frailty, based at Dalhousie University in Nova Scotia. "There are many ways to be frail. The question then becomes: What genes are involved?"
Using a combination of genetic tools – genome-wide association studies (GWAS) and genomic structural equation modeling (gSEM) – the team scanned millions of DNA markers to find variants linked not just to one symptom at a time, but to the overlapping biology that underlies multiple frailty traits. This approach uncovered 408 genetic loci (regions on the genome) associated with frailty – 371 of these had never before been linked to aging.
Many of the signals clustered in biological pathways are already suspected in contributing to advanced aging: chronic inflammation, metabolism, cardiovascular health and brain function. Others overlapped with known risk genes for Alzheimer’s disease, type 2 diabetes, depression and obesity, strengthening the idea that frailty is not a single condition but a web of interrelated processes.
An example the researchers give is the SP1 gene, which is associated with immune function and Alzheimer’s disease. They found it was strongly associated with the broad “poor cognition” subtype; while the FTO gene, associated with obesity, seemed to underlie several different subtypes. While it sounds a little confusing, that's because it is – it's a complex tangle of biological influences, which show that frailty is anything but a catch-all sign of aging.
"What this paper does is not only identify sub-facets of disordered aging but also demonstrate that there is very different biology underlying them," said senior author Andrew Grotzinger, assistant professor of psychology and neuroscience at CU Boulder. "The tangible next step is to figure out how to treat this underlying biology."
"It’s probably not going to be a single magic pill to address all the diseases that come with aging, but maybe it doesn’t need to be hundreds anymore," he added.
Currently, frailty is assessed with a 30-point index measuring known signs of aging – from walking speed to grip strength. Two people may share the same frailty score, but their genetic drivers – and thus their best treatment options – may be completely different.
In this study, the sheer number of loci uncovered has revealed that frailty is highly polygenic; no single "frailty gene" exists, but hundreds of small effects accumulate to speed up aging. This points to treatments that won’t be one-size-fits-all. Instead, interventions could target specific biological pathways depending on an individual’s genetic profile – whether with anti-inflammatories, metabolic drugs like rapamycin or NAD+ boosters, or senolytics – the experimental drugs that clear damaged "zombie" cells.
The findings back the geroscience hypothesis: To prevent or delay chronic disease, we must target the biology of aging itself. Measuring someone’s genetic risk profile for frailty could allow clinicians to predict not just if they’ll age faster, but how – and then tailor treatments accordingly.
"To be able to identify treatments to stop or reverse accelerated biological aging, you need to know what the underlying biology is," said first author Isabelle Foote, a postdoctoral associate at the Institute for Behavioral Genetics, CU Boulder. "This is the largest study yet to use genetics to try to do that."
The researchers have suggested that the clinical measurements of frailty should be broadened to factor in these six new subtypes. And the findings help reframe frailty not as an inevitable part of old age, but as a treatable, biological condition. It’s a shift that could one day see us able to actively manage how we age.
The study was published in the journal Nature Genetics.
Source: University of Colorado Boulder
