The complexity of inflammatory activity in caregivers: Commentary on “Associations of perceived stress, depressive symptoms, and caregiving with inflammation: A longitudinal study” by Elayoubi et al.

There has been noteworthy progress in the everevolving understanding of inflammatory pathways and the pathophysiological role they play – in the aging process as well as in chronic, noncommunicable diseases ranging from diabetes mellitus to depressive disorders (Hunter, 2012). With a focus on caregivers and in contribution to this body of literature, Elayoubi et al. in their longitudinal study, have examined the association of perceived stress and depressive symptoms upon inflammatory biomarkers in persons who transitioned to caregiving (in comparison to healthy controls), over a period of approximately 9.3 years (Elayoubi et al., 2022). The aging process has been recognized as a complex, universal phenomenon, influenced by the interaction of genetic, epigenetic, stochastic, and environmental factors (Franceschi and Campisi, 2014). Associated with aging is a chronic, low-grade, nonspecific, multisystemic inflammatory process – inflammaging. The possible origins of the inflammatory process include (i) damaged cells and macromolecular compounds that accumulate with aging, (ii) microbial flora, including the gut microbiome, (iii) cellular senescence and the release of pro-inflammatory cytokines, (iv) increased activation of coagulatory pathways, and (v) age-related changes to the immune system (immunosenescence). In line with the inflammaging hypothesis, studies have shown that older adults have elevated levels of pro-inflammatory cytokines, including C-reactive protein (CRP), interleukin-6 (IL-6) and IL-8, and tumor necrosis factor alpha, receptor 1 (TNFR1) (Franceschi and Campisi, 2014). Further, several chronic noncommunicable diseases associated with the aging process and metabolic syndrome appear associated with inflammaging and the persistent, low-grade elevation of inflammatory biomarkers (Furman et al., 2019; Hunter, 2012). While inflammation appears to coexist with aging, at the other end of the aging process, the experience of early life adversity (ELA) appears to be associated with dysregulation of the HPA axis, alteration in cortico-striatal-thalamic-cortical connectivity, autonomic dysfunction, and greater increase in pro-inflammatory cytokines in response to stress. ELA also predisposes those affected to increased inflammation in later life (Beurel et al., 2020; Furman et al., 2019). The experience of acute and chronic stress has been shown to be associated with an increase in the levels of pro-inflammatory cytokines. The experience of stress and affective disorders, particularly depressive disorders, have also been shown to have a fairly consistent association with a similar, chronic, low-grade, multisystemic inflammatory process (Maydych, 2019). Persons with depressive disorders also demonstrate a similar pro-inflammatory process, with higher levels of IL-1, IL-6, TNF-α, and CRP, when compared with controls without depressive disorders (Maydych, 2019). A synthesis of literature on inflammatory theories of disease may suggest an intuitive, deceptively simple, telescopic relationship between adversity, stress, depression, inflammation, metabolic syndrome, chronic disease, and aging (Furman et al., 2019). It has been postulated that chronic inflammation plays a role in the etiology of all diseases across the lifespan, suggesting a unified inflammatory theory of disease (Furman et al., 2019). The influence of chronic stress upon the metabolism and immune system of the individual is clear, leading to the question of whether it may be possible to extend the inflammatory hypothesis from the intrapersonal to the interpersonal domain. Thus, it may be possible to identify individuals who, by virtue of their interpersonal relationships and life experiences, are vulnerable to chronic stress, depressive disorders, chronic inflammation, metabolic disorders, and poorer health outcomes – inflammaging. Caregiving – the activity or profession of regularly looking after a child or a sick, elderly, or disabled person – is an interpersonal relationship usually associated with chronic stress and one that can predispose the older adult to poorer physical and mental health outcomes (Jeste et al., 2021). Elayoubi et al. have examined whether it would be possible to demonstrate an association between caregiver stress and inflammaging. This would render it possible to identify older adult caregivers vulnerable to inflammaging and develop International Psychogeriatrics (2023), 35:2, 63–66 © International Psychogeriatric Association 2022