In the July 12, 2021, issue of Nature Aging, researchers working at the Buck Institute for Research on Aging describe analysis from 1,001 immunomes of generally healthy patients correlating soluble immune biomarkers against measures of multimorbidity, immunosenescence, frailty and cardiovascular disease over 11 years of longitudinal study.

The researchers ultimately identified CXCL9 levels as most distinctly and most highly directly correlating with increased disease.

The approach specifically focused on age-related inflammatory aging (iAge), but not infectious or autoimmune disease.

The researchers showed that iAge measures could reliably predict multimorbidity or frailty 7 years in advance of clinical presentation better than calendar age.

Principal investigator Mark Furman, Associate Professor with the Buck Artificial Intelligence Platform, Buck Institute for Research on Aging, Novato, California and Director of the Stanford 1,000 Immunomes Project, explained to BioWorld Science, "I believe we have now for the first time an approach that reflects the inflammatory load that's triggered by what we call the exposome. This is not infectious; this is age-related mostly sterile inflammation. This is a very different type of inflammation from the one that everyone knows, that classically involves IL-6, TNF-alpha and IL-1beta. They are not coming up here. Our analysis reveals a different pathway."

It is crucial to understand the importance of multimorbidity as a measure because the healthcare system is configured for disease care based on treating each specific condition by indication and this ultimately has severe limitations. Furman explained that, "If you cured cancer for example, this would only increase lifespan of the population by a just 2.99 years. Moreover, in 2018 the Academy of Medical Sciences declared multimorbidity the number one top priority in healthcare research." The iAge approach could identify commonalities across diseases.

The population used in the latest study was a generally healthy ambulatory population, with no apparent infectious or autoimmune disease. They were tracked longitudinally for over 10 years. A more rigorous attempt at defining a healthy population was also examined by recruiting a "super healthy" population. This included 151 people aged 20-95 years with no single risk factor for disease. iAge was a good predictor of cardiovascular disease even in the super healthy individuals.

Most researchers have used C-reactive protein to study inflammation. But this is an acute-phase reactant, making it useful mainly for measuring acute inflammation. Vaccination will drive it up, but it is of no use for predicting cardiovascular disease, as correlation analysis indicates it is close to random.

The textbook canonical pathway describes interferon-gamma as stimulating increased high-level expression of CXCL9, but there are patients with no detectable interferon-gamma and yet they have high levels of CXCL9 boding a poor prognosis for no reason.

It is not known why some individuals have high CXCL9 levels and thus the question of what is causing CXCL9 to be elevated is currently unknown. As such, it is an active area of challenging investigation. As an example, Furman explained that his inflammatory age is a little higher than his calendar age, because his interferon levels are lower, but this is not because CXCL9 is high.

Furman explained, "Prior to this, if you were to go to the doctors and ask the question, 'How is my immune system?' They would have no clue. They might do something very general like a complete blood count or sedimentation rate, but nothing very specific. I think now we have an answer."

Currently Furman and his colleagues are performing research on five simultaneous programs including focus on Alzheimer's disease, frailty and fertility.

With infertility and neurodegenerative disorders they are involved in programs with NASA to measure whether there is accelerated aging phenotype in astronauts that are sent to the international space station.

For Alzheimer's disease, the team has 1,300 people followed for about 13 years with weighted diffusion imaging, functional MRIs and blood samples for performing untargeted analysis of 7,000 proteins and 5,200 metabolites, as well as the virome to analyze.

In terms of basic science, the researchers are working on identifying transcription factors controlling CXCL9 expression and from a translational aspect the company is focused on efforts to unbiasedly identify compounds that target these different proteins. Two double-blind, placebo-controlled clinical trials have been completed and now they're working on the third trial involving 1,000 people to test interventions designed to directly address 10 categorical immunotypes. They hope not only to demonstrate improvement of the inflammatory state in a relatively short time, but also to improve the aging phenotype.

They are now targeting CXCL9, searching for strategies that can boost interferon-gamma, which is very protective, but generally goes down with age, and developing treatments to address biomarker-driven categorical immunotypes.

Furman explained that while CXCL9 does appear to be the major player in most of the population, for some people may be something else. Thus, from a practical standpoint they want to offer the more comprehensive iAge test towards categorizing individuals by "immunotypes." They have now obtained 12 million funding for their company and are moving from academic research to industry standards with interventions that are tailored for different categorical immunotypes