Newly Developed Biological ‘Clocks’ Reveal Immunological Signs of Aging, and How to Slow Down This Ticking

We know that our immune system plays an essential role in our health. From protecting us from harmful invaders to helping us heal from both the minor (like paper cuts) and the major (like surgeries), a healthy immune system keeps us safe and functioning well. But what’s lesser-known is that we have an “immune age” that can differ from the age our birth certificates say, and this immunological age is tightly linked to inflammation. Although acute inflammation is necessary and helpful — without it, that minor paper cut could turn into a deadly infection — the more malicious kind is chronic, systemic inflammation. 

In a study published this month in Nature Aging, Sayed and colleagues develop a novel biological clock that assesses how quickly our immune systems are aging based on biomarkers of chronic inflammation. Based out of Stanford University and the Buck Institute of Aging, the research team identifies the proteins and patterns that accelerate our immune and inflammatory age, coining the clock as iAge. (No, it’s not the newest product from Apple, although it does utilize just as much algorithm-based artificial intelligence!) 

How Our Immunological Clock Ticks and Tocks

Inflammation plays a key role in the development and progression of aging in our cells, tissues, and organs. Although we know that body-wide inflammation is detrimental to health and accelerates aging, there is no standardized biomarker to characterize this inflammatory age — until now, with the iAge clock. 

In this study, Sayed and colleagues looked at 50 immune and inflammatory markers from blood samples of 1,001 people between the broad age range of 8 and 96. Using deep learning algorithms, the team constructed a metric to measure chronic inflammation and immune functioning and how these biomarkers change with age in healthy versus unhealthy people. 

One of the leading priorities in health research is multimorbidity — the coexistence of multiple health conditions in one person, reflecting an increased accumulation of cell- and organ-based damage. In this model, there was a strong correlation between higher iAge and multimorbidity in adults over age 60, underlying the influence of immunological age on adverse health conditions. In a smaller subgroup of older adults, the research team found that the iAge measured at baseline was highly predictive of frailty and all-cause mortality seven years later — even more predictive than calendar age. 

Plus, a higher iAge score was linked to increased markers of immune cell senescence — a state of irreversible cell growth arrest that leaves cells in a zombie-like state. This causes cells to remain dysfunctional in the body but leave a trail of collateral damage behind, further increasing inflammation.

Inflammatory Biomarker Predicts Heart Damage

The researchers found one immune biomarker to be most significantly related to both iAge and multimorbidity — CXCL9. This small protein is a chemokine, a specific type of cytokine (signaling molecule) that attracts cells to sites of infection and increases the activity of pro-inflammatory genes. Higher levels of CXCL9 strongly correlated with a greater iAge and increased markers of aging in the cardiovascular system. 

CXCL9 levels began to increase around age 60, even in some older adults classified as ‘extremely healthy.’ Higher CXCL9 levels were linked to adverse heart-related biomarkers in these older adults, including increased cardiac remodeling — changes to the heart's size and shape in response to damage. 

They also exhibited higher pulse-wave velocity in their hearts, reflecting arterial thickness and organ damage. These biomarkers tend to be better predictors of future cardiovascular-related events than conventional risk factors (like cholesterol), indicating that CXCL9 may be a potential therapeutic marker for assessing early cardiovascular risk in otherwise healthy adults. 

CXCL9 Curbs Cardiovascular Health

Additionally, CXCL9 was found in higher amounts in aged endothelial cells — the single layer of cells lining blood vessels and the heart — cultured in a lab. Damage to the endothelium plays a critical role in the development of age-related heart conditions. As this damage may precede other signs of cardiovascular aging, targeting it as early as possible could delay these conditions and potentially provide clinically meaningful impact. 

The team also finds that inhibiting CXCL9 in the cell cultures rescued and reversed the arterial dysfunction, indicating that targeting this molecule could prove beneficial to heart health for those with a high iAge. Lastly, Sayed and colleagues looked at CXCL9 levels in young versus aged mice, finding that the older animals had significantly higher levels of this chemokine, in tandem with impaired endothelial function.

As the authors state in their published paper, “We demonstrate that CXCL9 is a master regulator of vascular function and cellular senescence, which indicates that therapies targeting CXCL9 could be used to prevent age-related deterioration of the vascular system and other physiological systems as well.”

Watching the Clock As We Age 

With the iAge results — and a simple blood test — it may soon be easier to tell who is at risk for increased immunological aging, which strongly correlates with endothelial damage and subsequent cardiovascular-related disorders. Compared to other biological clocks, the information from this immune- and inflammation-based clock may be more feasible to provide actionable results, which could extend older adults’ healthspan — the number of years lived without developing chronic conditions. For example, it’s likely simpler to target lowering CXCL9 levels than it is to alter chemical modifications to DNA patterns (as with epigenetic clocks)

Dr. Furman summarizes their work, stating, "Bringing biology to our completely unbiased approach allowed us to identify several metrics, including a small immune protein which is involved in age-related systemic chronic inflammation and cardiac aging. We now have means of detecting dysfunction and a pathway to intervention before full-blown pathology occurs."

References: 

Sayed, N., Huang, Y., Nguyen, K. et al. An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty, and cardiovascular aging. Nat Aging 1, 598–615 (2021). https://doi.org/10.1038/s43587-021-00082-y