Sayed N, Huang Y, Nguyen K, Krejciova-Rajaniemi Z, Grawe AP, Gao T, Tibshirani R, Hastie T, Alpert A, Cui L, Kuznetsova T, Rosenberg-Hasson Y, Ostan R, Monti D, Lehallier B, Shen-Orr SS, Maecker HT, Dekker CL, Wyss-Coray T, Franceschi C, Jojic V, Haddad F, Montoya JG, Wu JC, Davis MM, Furman D. An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging. Nat Aging. 2021 Jul;1:598-615. Epub 2021 Jul 12 PubMed.
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University of Texas Health Science Center at Houston
An objective way to quantify aging is a prerequisite to designing targeted interventions for the doomed biological process, which invariably leads to the end of life. In this new study, Sayed et al. devised an inflammatory aging clock, properly named iAge, to track human multimorbidity, immunosenescence, etc. In particular, they identified chemokine CXCL9 as the most significantly increased marker in aging blood and provided evidence for its critical involvement in cardiovascular aging. These findings compliment the IMM-AGE score established by the same group earlier, which was based on high-dimensional blood immune cell trajectory (Alpert et al., 2019). Together with other recent large-scale proteomic studies of wide age-spectrum cohorts (Lehallier et al., 2019; Tanaka et al., 2018), it becomes increasingly evident that blood-based proteomic signature of aging does exist and has the power of calibrating a meaningful clock to track normal aging.
Interestingly, CXCL9 is shown to increase with age in human blood endothelial cells (EC), govern inflammation and proliferation in aged EC, impair vascular function, and drive EC senescence. We all hear the saying—what is good for your heart is good for your brain. What’s bad for the heart might be bad for the brain, also. Aging adults frequently suffer declining memory and cognitive functions, together with cardiovascular comorbidity. Although CXCL9 impacts on CNS function was not investigated in the current study, other immune factors enriched in aged plasma, such as CCL11 and B2M, have been shown to negatively affect neurogenesis and memory experimentally (Villeda et al., 2011; Smith et al., 2015).
The relevance of elevated peripheral CXCL9 to Alzheimer’s disease is difficult to gauge at this time. Previously, a multifactorial, data-driven analysis pinpointed an early role of vascular dysregulation on late-onset AD (Iturria-Medina et al., 2016). In that study, the circulating factor most elevated in AD blood was the chemokine CXCL10, rather than CXCL9. Interestingly, both CXCL9 and CXCL10 are known to be readily induced by interferons—cytokines involved in anti-viral and various inflammatory responses. Given the presence of systemic alterations reportedly associated with AD, such as dysregulation of microbiota and peripheral immune cells, an inflammatory blood signature distinct from normal aging may be present in AD. Comprehensive studies are needed to shed light on whether an “iAD” clock exists or AD patients can be subtyped based on their peripheral inflammatory profiles.
References:
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