Brain Inflamm-aging: Cytokine Clock Predicts Brain Atrophy

It has been demonstrated that the words in a language determine how we think, and this process is called “linguistic determinism.” For example, among English speakers, snow is simply white, and that is all. For people living in Nordic countries with 50 different words to describe the color of snow, the vast whiteness of the tundra is a complex world. They have words for white fluffy snow, white deep snow, and white frozen snow, making them understand snow differently. Similarly, in French, the word for getting old, “vieillir,” is not the same as the colloquial word for age. The term “Aging” that we use in English amalgamates the arrow of time that is a physical phenomenon ensuring, on the one hand, that the consequences cannot exist before their cause and, on the other hand, the push of entropy against the order during the passage of time.

In a recent study, researchers have discovered that humans lose an estimated 5% of their brain volume each decade after age 40. This decline in importance with advancing age has been found to lead to diminished cognitive performance and memory capacity, often seen in Alzheimer's Disease patients. While this strong association between aging and brain atrophy at the population level is evident, individual physiology may also play a role. Generalized assumptions about aging can obscure factors such as biological sex or inflammatory processes.

Scientists at the Buck Institute for Research on Aging and the University of California, San Francisco suggest mechanisms by which the brain ages and how time can contribute to this process, but it is among several drivers underlying the process of getting old.

These findings could potentially lead to therapies explicitly tailored to individuals — if not for the difficulty associated with isolating age from other physiological factors at work within an individual's body over time.

?The study led by Nikola T. Markov , Ph.D., and David Furman , Ph.D. at the Buck Institute for Research on Aging , analyzed 554 patients using volumetric MRIs and blood immune samples taken over a decade, breaking open the black box between physiological aging and the aging of the brain. The study appeared in The Proceedings of the National Academy of Sciences on Friday, Dec. 2nd.

To do so, the Buck and UCSF collaborators first looked at circulating blood proteins. They identified patterns of concentrations of inflammatory proteins that increase with age, a process called “Inflamm-aging” (More on inflamm-aging to come).

The measure is called CyClo or a “cytokine clock.” The authors also found that both the cytokine clock and brain shrinkage follow different trajectories depending on the biological sex of the participants, with females having a faster-ticking cytokine clock but overall being more protected from brain shrinkage (see Chronological vs Biological Age 1Pager )

As time marches on, the proteins that define aging experience a gradual but steady uptick. Scientists have found that these age-related protein increase in concentration over time, resulting in an inexorable rise of inflammation levels away from those seen in youthful individuals. Remarkably, researchers can predict someone’s calendar age with surprising accuracy just by studying the concentration profile of these same proteins. This discovery has significant implications for our understanding of aging, its effects on human health, and exposures and individual characteristics that may exacerbate or dampen these processes.

Altogether, statistically, the Buck/UCSF team utilized canonical correlation of large datasets to delineate the impact of chronological time, sex, and inflammatory markers on the atrophy of certain brain regions. Similar to our difficulties in describing the aging process independently from the passing of time linguistically, it is difficult to measure the aging of biological systems independent of age. However, the canonical correlation analysis utilized in this study allowed this delineation.

Senior author David Furman , Ph.D., sees two potential uses for the science. 1) an actionable diagnostic test to identify Alzheimer’s or Mild Cognitive Impairment earlier and 2) a personalized cocktail of cytokines to help individuals become more resilient to brain atrophy and cognitive decline.

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Authored with Nikola T. Markov Ph.D – Bioinformatician at the Buck Institute for Research on Aging ; and first author of Age-related brain atrophy is not a homogenous process: Different functional brain networks associate differentially with aging and blood factors. https://www.pnas.org/doi/10.1073/pnas.2207181119