Reduced insulin/IGF1 signaling prevents immune aging via ZIP-10/bZIP–mediated feedforward loop

Abstract

A hallmark of aging is immunosenescence, a decline in immune functions, which appeared to be inevitable in living organisms, including Caenorhabditis elegans. Here, we show that genetic inhibition of the DAF-2/insulin/IGF-1 receptor drastically enhances immunocompetence in old age in C. elegans. We demonstrate that longevity-promoting DAF-16/FOXO and heat-shock transcription factor 1 (HSF-1) increase immunocompetence in old daf-2(−) animals. In contrast, p38 mitogen-activated protein kinase 1 (PMK-1), a key determinant of immunity, is only partially required for this rejuvenated immunity. The up-regulation of DAF-16/FOXO and HSF-1 decreases the expression of the zip-10/bZIP transcription factor, which in turn down-regulates INS-7, an agonistic insulin-like peptide, resulting in further reduction of insulin/IGF-1 signaling (IIS). Thus, reduced IIS prevents immune aging via the up-regulation of anti-aging transcription factors that modulate an endocrine insulin-like peptide through a feedforward mechanism. Because many functions of IIS are conserved across phyla, our study may lead to the development of strategies against immune aging in humans.

Immunosenescence, Inflammaging, and Frailty: Role of Myeloid Cells in Age-Related Diseases

“…Dietary restriction appears to effectively regulate innate immunity and to extend lifespan, by its impact on the immunometabolic sensors, leading to gene reprogramming, as demonstrated in pre-clinical models [ 236 , 237 ]. In particular, caloric restriction increases sirtuin expression and modulates mTOR and other immunometabolic sensor pathways, thus reducing pro-inflammatory molecule levels [ 238 , 239 ].…”

C. elegans: out on an evolutionary limb

“…ins-6 promotes learning by stopping the expression of ins-7, an inhibitory factor (Chen et al 2013). As worms grow old, a feed-forward mechanism modulates the expression of ins-7, thereby regulating immune ageing and behaviour (Lee et al 2021b). Others, such as ins-11, are only expressed in adult worms following infection, either in the epidermis or the intestine, depending on the pathogen and its route of infection (Lee et al 2018).…”

GPCR signaling promotes severe stress-induced organismic death inC. elegans

“…Our results suggest that the ISY-1/ mir-60 axis plays a gatekeeping role for ZIP-10 activation and phenoptosis, whereas the FLR-2/FSHR-1/GSA/KIN-2 axis is likely instructive by linking FTS stress to genes driving phenoptosis or promoting organismic sensitivity to lethal effects of FTS. FSHR-1 and ZIP-10 also mediate host cell responses to oxidative stress, various types of pathogens and immune aging (Kato et al, 2016; Lee et al, 2021; Miller et al, 2015; Powell et al, 2009). Indeed, we found that fshr-1 loss-of-function mutants, while being more FTS resistant than wild type, were less tolerant of cholesterol oxidative stress (Figure S4).…”