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An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging
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In conclusion, by applying artificial intelligence methods to deep immune monitoring of human blood we generate an inflammatory clock of aging, which can be used as a companion diagnostic to inform physicians about patient’s inflammatory burden and overall health status, especially in those with chronic diseases. Furthermore, our immune metric for human health can identify within healthy older adults with no clinical or laboratory evidence of cardiovascular disease, those at risk for early cardiovascular aging. Lastly, 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.
Nature Aging 2021
"we demonstrate that iAge predicts multimorbidity and mortality and therefore can be used as a biological surrogate of age-related health versus disease. iAge is directly associated with multiple disease phenotypes, including cardiovascular aging, frailty, immune decline and exceptional longevity. In our recent work16, we combined cellular phenotypes to describe subject- and population-level immune aging phenotypes (IMM-AGE), which correlated with iAge. This suggests that future research should leverage both immune-age scores to propose a unified metric that reflects multiple aspects of immune aging, thus potentially providing a better clinical predictive value.
silencing of CXCL9 in ECs resulted in a reversal of the high inflammation/low proliferation early senescence phenotype, which suggests by tackling CXCL9 it may be possible to delay onset of EC senescence…...CXCL9 has also been shown to be associated with falls in the older population101,102, which parallels our results predicting frailty.
At least two sources of CXCL9-mediated inflammation can ensue with aging based on our findings; one that is age-intrinsic and observed in aging ECs and one that is independent of age (likely as a response to cumulative exposure to environmental insults) and found in the validation cohort of 97 apparently healthy adults. Notably, we did not find any significant correlation between known disease risk factors reported in the study (BMI, smoking, dyslipidemia) and levels of CXCL9 gene or protein expression. We thus hypothesize that one root cause of CXCL9 overproduction is cellular aging per se, which can trigger metabolic dysfunction…..endothelium as a central player in cardiovascular aging, consistent with previous findings104 and they also suggest that ECs may be one source of inflammation, but it is also possible that cardiomyocytes play a role as in models of acute myocardial infarction there is activation of the inflammasome NLRP3 in these cells105,106. As ECs but not cardiomyocytes expressed the CXCL9 receptor, CXCR3 (Extended Data Fig. 9), we hypothesize that this chemokine acts both in a paracrine fashion (when it is produced by macrophages to attract T cells to the site of injury) and in an autocrine fashion (when it is produced by the endothelium) creating a positive feedback loop. In this model, increasing doses of CXCL9 and expression of its receptor in these cells leads to cumulative deterioration of endothelial function in aging. Moreover, silencing of CXCL9 in ECs resulted in a reversal of the high inflammation/low proliferation early senescence phenotype, which suggests by tackling CXCL9 it may be possible to delay onset of EC senescence."
Abstract
While many diseases of aging have been linked to the immunological system, immune metrics capable of identifying the most at-risk individuals are lacking. From the blood immunome of 1,001 individuals aged 8–96 years, we developed a deep-learning method based on patterns of systemic age-related inflammation. The resulting inflammatory clock of aging (iAge) tracked with multimorbidity, immunosenescence, frailty and cardiovascular aging, and is also associated with exceptional longevity in centenarians. The strongest contributor to iAge was the chemokine CXCL9, which was involved in cardiac aging, adverse cardiac remodeling and poor vascular function. Furthermore, aging endothelial cells in human and mice show loss of function, cellular senescence and hallmark phenotypes of arterial stiffness, all of which are reversed by silencing CXCL9. In conclusion, we identify a key role of CXCL9 in age-related chronic inflammation and derive a metric for multimorbidity that can be utilized for the early detection of age-related clinical phenotypes.
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