A new type of age ‘clock’ can assess chronic inflammation to predict whether someone is at risk of developing age-related disorders such as cardiovascular and neurodegenerative disease. The clock measures ‘biological age’, which takes health into consideration and can be higher or lower than a person’s chronological age.
The inflammatory ageing clock (iAge), reported on 12 July in Nature Aging1, is one of the first tools of its kind to use inflammation to assess health. Other age clocks have used epigenetic markers, chemical groups that tag a person’s DNA as they age and are passed along as cells divide. The researchers who developed iAge hope that, because inflammation is treatable, the tool could help doctors determine who would benefit from intervention — potentially extending the number of years a person lives in good health.
The study “is a further reinforcement of the fact that the immune system is critical, not only for predicting unhealthy ageing, but also as a mechanism driving it”, says Vishwa Deep Dixit, an immunobiologist at Yale School of Medicine in New Haven, Connecticut, who was not involved in the work.
iAge is based on the idea that as a person ages, their body experiences chronic, systemic inflammation because their cells become damaged and emit inflammation-causing molecules. This ultimately leads to wear and tear on their tissues and organs. People who have a healthy immune system will be able to neutralize this inflammation to some extent, whereas others will age faster.
To develop iAge, a team including systems biologist David Furman and vascular specialist Nazish Sayed at Stanford University in California analysed blood samples from 1,001 people aged 8–96 who are part of the 1000 Immunomes Project, which aims to investigate how signatures of chronic, systemic inflammation change as people age. The researchers used the participants’ chronological ages and health information, combined with a machine-learning algorithm, to identify the protein markers in blood that most clearly signal systemic inflammation. In particular, they pinpointed the immune-signalling protein, or cytokine, CXCL9 as a top contributor; it is mainly produced by the inner lining of blood vessels and has been associated with the development of heart disease.
Sayed says that CXCL9 being a key component of iAge gives new credence to the adage that “you’re only as old as your arteries”.
After developing it, the researchers tested iAge by collecting the blood of 19 people who had lived to at least 99 years old, and using the tool to calculate their biological age. On average, the centenarians had an iAge 40 years lower than their actual age, according to a press release — aligning with the idea that people with healthier immune systems tend to live longer.
Scientists have long explored the idea of age clocks as a predictor of how healthy a person currently is. Epigenetics-based research in this area has shown some promise2, but María Mittelbrunn, a molecular biologist at the Autonomous University of Madrid, says that evaluating a person’s biological age by measuring epigenetic changes to their DNA can be complicated. Measuring inflammation with a blood test would be easier, making a tool such as iAge more practical for a clinical setting.
Furman hopes that iAge and other age clocks based on inflammation might enable personalized treatments, too.
When examining CXCL9 as a biomarker of systemic inflammation, Furman and his colleagues grew human endothelial cells, which make up the walls of blood vessels, in a dish and artificially aged them by letting them divide repeatedly. The researchers saw that high levels of the protein drove the cells into a dysfunctional state. When the team silenced expression of the gene that encodes CXCL9, the cells regained some function, suggesting that the protein’s harmful effects might be reversible.
If caught early, “inflammation is one of the best things we can treat”, says Mittelbrunn. “We have developed amazing anti-inflammatory tools, so I think it’s a biological process that we have a lot of knowledge about and can target easily.” For instance, researchers have long known about salicylic acid (a starting material for making aspirin), and have more recently developed JAK/STAT inhibitors for inflammatory conditions such as rheumatoid arthritis .
Sayed envisions a future in which anyone can undergo inflammatory-biomarker profiling on a regular basis to keep tabs on their risk of developing age-related disease. “If we can control ageing in a more impactful way,” he says, “I think we can have a more graceful ageing process.”
Sayed, N. et al. Nature Aging https://doi.org/10.1038/s43587-021-00082-y (2021).
Fahy, G. M. et al. Aging Cell 18, e13028 (2019).