Centenarians Reveal Clues to Healthy Brain Aging
Epigenetic clocks and biomarkers reveal why some centenarians maintain brain health and survive longer.
As populations age globally, one of the most pressing scientific questions is no longer how long we live, but how well.
While Alzheimer’s disease and cognitive decline are often viewed as inevitable consequences of extreme old age, a small but growing body of evidence challenges this assumption. Centenarians who remain cognitively healthy into their tenth decade offer a rare and powerful window into biological resilience.
Prof. Henne Holstege, full professor at the Vlaams Instituut voor Biotechnologie/KU Leuven and associate professor at Amsterdam University Medical Center, has studied these exceptional individuals through the lens of genetics, neuropathology, and biological aging. Her recent work explores whether peripheral measures of aging, such as epigenetic clocks derived from blood, can predict survival independently of brain pathology or cognition.
In this interview, Holstege explained why centenarians are nature’s experiment in healthy aging, how different aging systems contribute independently to mortality, and what this means for the future of dementia research.
Epigenetic clocks reveal biological age beyond the calendar
What are epigenetic clocks, and why are they useful for studying aging in centenarians?
Epigenetic clocks are molecular tools that estimate biological age by analyzing DNA methylation patterns that change predictably over time. Unlike chronological age, these measures capture how quickly or slowly the body appears to be aging at a systemic level.
“The clocks are interesting because they can give us an indication of whether somebody is biologically younger or older than their chronological age,” said Holstege.
Holstege and her colleagues, including first author Yaran Zhang, wanted to determine whether epigenetic clocks remain meaningful even at extreme ages and whether they still associate with outcomes such as mortality.
“Of all clocks, the GrimAge clock seems to be pretty robust, even at that high age,” she said.
While not developed specifically for centenarians, Holstege emphasized that “they can be applied to anyone”, making them useful for studying why some individuals maintain better health and survive longer than others.
Unlike earlier clocks, which were mainly trained to estimate chronological age, GrimAge was developed to capture mortality-related biological aging. In the study, GrimAge was linked to age-related myeloid shift, in which the proportion of myeloid cells in the peripheral blood increases with age relative to lymphoid cells.
As Holstege explained, “Apparently, myeloid shift still takes place even at these extreme ages, and it appears to contribute to the mortality-related signal captured by GrimAge.”
How epigenetic clocks inform aging research:
- Epigenetic clocks estimate biological age using DNA methylation patterns
- GrimAge remains predictive of mortality even in centenarians
- Immune-related aging processes continue to shape survival at extreme ages
Cognitively healthy centenarians as a model of Alzheimer’s resilience
What makes cognitively healthy centenarians a particularly valuable group for understanding resilience to Alzheimer’s disease?
Extreme phenotypes often provide the clearest biological insights, and cognitively healthy centenarians represent exactly that. While most individuals eventually show signs of cognitive decline if they live long enough, this subgroup appears to defy that trajectory altogether.
“There's this odd subgroup that just doesn't. How do they do that? Why are they like that?” said Holstege.
For Holstege and her team, this makes them uniquely informative.
“They prove that maintaining brain health for humans is possible.” — Prof. Henne Holstege
These individuals function as a natural experiment in disease resistance, and genetics plays a large role in this resilience. Holstege described centenarians as “genetically protected,” emphasizing that nature has already solved many of the problems researchers are trying to address.
“The only thing now we need to do is to decode that and understand which genetic elements are involved in maintaining that brain health, and specifically, how these elements regulate brain cells to uphold brain health despite the effects of aging,” she said.
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The hope is that if researchers can begin to recognize how this process is mechanistically controlled, it will provide information for those who have an increased risk of developing Alzheimer's disease.
Why centenarians matter for Alzheimer’s research:
- They demonstrate that cognitive health is possible at extreme age
- Genetic protection offers clues to disease resistance mechanisms
Peripheral aging, cognition, and biomarkers contribute independently to survival
Did you observe large variability in epigenetic aging among centenarians, and how did this relate to their cognitive status or biomarker profiles?
Holstege’s team observed substantial variability in epigenetic aging among centenarians, and this variability also predicted mortality. However, they wanted to know whether this effect overlapped with other known predictors of survival, such as cognitive performance or neurodegeneration markers, including plasma neurofilament light chain (NfL) levels.
Neurofilament light chain (NfL)
NfL is a structural protein found in the axons of neurons and is released into cerebrospinal fluid and blood when neurons are damaged or degenerating. As a result, NfL is widely used as a biomarker of neuroaxonal injury and neurodegeneration.
They found that epigenetic age, cognitive scores measured by the Mini-Mental State Examination (MMSE), and plasma NfL levels each predicted mortality—but for different reasons. “The reason why the clocks predict mortality is a different reason than why plasma NfL predicts it or why MMSE predicts it,” Holstege explained.
This independence means that combining these measures improves survival prediction.
Their findings underscore that aging is not a single process but a collection of parallel systems that decline at different rates. Peripheral aging, brain integrity, and cognitive function each tell a distinct part of the aging story.
“There are different parts of our physiques that are differentially contributing or independently contributing to decline, and all of them deserve to be researched or explored more deeply.” — Prof. Henne Holstege
Independent aging systems shape survival:
- Epigenetic age predicts mortality independently of cognition
- Plasma NfL and MMSE capture different biological risks
- Combining measures improves survival prediction accuracy
Targeting biological aging to support cognitive resilience
Do you think interventions targeting biological aging processes could help promote cognitive resilience later in life?
Holstege emphasized the importance of early detection and prevention. Advances in plasma proteomics now allow researchers to estimate biological age at the level of individual organs, potentially identifying disease processes before symptoms emerge. Intervening at this stage could preserve overall physiological health—and by extension, brain function.
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“If you can treat a problem before you have symptoms, you can prevent a lot of issues,” she said.
Cognitive performance also depends heavily on systemic health, particularly energy metabolism and cardiovascular function. “What’s good for your heart is also good for your brain,” Holstege said.
Preventing or treating peripheral disease may therefore reduce cognitive vulnerability, even if it does not directly target brain pathology.
However, she also cautioned that not all processes are interconnected. Some brain-specific diseases may progress independently of peripheral health. The challenge lies in distinguishing which pathways can be modified systemically and which require targeted neurological intervention.
“Treating issues before they become an actual problem will, in the end, always contribute to a healthier life, and that will also include your brain.” — Prof. Henne Holstege
Can aging interventions protect cognition?
- Early detection enables preventative intervention
- Systemic health strongly influences brain function
- Some brain diseases may remain independent of peripheral aging
Multiomics technologies driving the next phase of aging research
What are the next steps for this research?
For Holstege, longevity without cognitive health holds little appeal. Her primary goal is preventing dementia, not merely extending lifespan.
“I think it doesn't really make any sense to reach 100 years if you develop dementia—in my opinion, we have to solve that problem first,” she explained.
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This focus has driven a research program centered on brain donation from cognitively healthy centenarians.
“These brains that have aged without dementia are a goldmine for neurodegeneration research; we know exactly how the centenarian donors functioned right before death, which means that we can now ask; which molecular changes do we see in the brain that associate with the very first steps in the trajectory of cognitive decline,” said Holstege.
“These first steps are important because if we recognize those, we may still be able to put a halt to further progress. Once too much brain damage has occurred, we will hit a point of no return,” she added.
Technological advances are making this possible. Long-read sequencing allows detailed analysis of genomic structure, while single-cell transcriptomics, proteomics, and metabolomics reveal how genetic differences translate into cellular function. Holstege is particularly interested in causality—tracing resilience back to its genetic origins.
By integrating multiomics data across brain regions and cell types, her team aims to identify the molecular pathways that preserve cognition despite age and pathology.
Technologies shaping resilience research:
- Brain donation enables pathology–cognition comparisons
- Long-read sequencing reveals genetic structure and regulation
- Multiomics approaches link genes to cellular resilience
Cognitively healthy centenarians challenge long-held assumptions about aging, dementia, and biological decline. Holstege’s work shows that peripheral epigenetic aging predicts survival, highlighting aging as a multi-system process. By combining molecular clocks, brain biomarkers, and cognitive measures, researchers can better understand the mechanisms that preserve brain health.
Key takeaways
- Epigenetic clocks remain predictive of mortality even in centenarians
- Peripheral aging, cognition, and neurodegeneration contribute independently to survival
- Genetic and molecular resilience mechanisms are central to healthy brain aging
- Multiomics technologies are accelerating the search for dementia prevention strategies
This content includes text that has been created with the assistance of generative AI and has undergone editorial review before publishing. Technology Networks' AI policy can be found here.
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