Benayoun et al. collected heart, liver, olfactory bulb, and primary neural stem cells from mice at three different ages and simultaneously analyzed their epigenomes and transcriptomes (Benayoun et al., 2019). This comprehensive study identified recurrent age-related chromatin and transcriptional changes in the upregulation of immune system response pathways, particularly the interferon (IFN) response, in all mouse tissues. Intriguingly, the 16 genes upregulated with age across tissues are responsive to interferon, and the phenomenon of age-related innate immune activation is seemingly applicable to humans. Shavlakadze et al. compared liver, skeletal muscle, kidney, and the hippocampus at seven different age points of rats and, via gene expression profiling, discovered a progressive upregulation of innate immune responses, including IFN responses, in the tissues (Shavlakadze et al., 2019). Among the 11 annotated genes jointly upregulated in all four tissues, the majority are inducible by interferon. Angelidis et al. conducted concomitant transcriptome and proteome analysis and revealed a similar upregulation of immune activation, including the interferon response, focusing on cells isolated from young versus old mouse lungs (Angelidis et al., 2019). Moreover, Baruch et al. compared multiple aged tissues and identified the choroid plexus as a locus within the aging brain that expresses extraordinarily high IFN signature (Baruch et al., 2014). Despite pending confirmation in humans, these studies collectively highlight that progressive inflammation, in particular IFN response, constitutes a conserved core process related to tissue and organ aging, a term coined here as IFN-aging.

From these intriguing discoveries and other recent research development, a paradigm that blends the fundamental principles of molecular biology and immunology starts to emerge. The mammalian genome encodes three types of interferons–types I (primarily IFNα/β), II (IFNγ), and III (IFNλ), among which types I (IFN-I) and III IFN are induced via innate immune responses upon sensing of microbial nucleic acids by innate immune receptors, such as cGAS (Roers et al., 2016). In the absence of pathogen infection, host-derived nucleic acids may activate the IFN pathway aberrantly, a process now postulated to take place during aging.

Constituting >40% of the human and rodent genomes, transposable elements (TE), with viral reminiscence, are routinely repressed in somatic cells to prevent their mobilization (Bourque et al., 2018; Makałowski et al., 2019). The “transposon theory of aging” posits that the cellular control mechanism that keeps TEs in check declines with age and contributes to age-related tissue dysfunction (Murray 1990; De Cecco et al., 2013; Li et al., 2013; Gorbunova et al., 2014; Wood et al., 2016; Gorbunova et al., 2021). In vitro, primary cells under replicative or other stress can enter a state of growth arrest named senescence. While undergoing other cellular and molecular changes, these cells secrete proinflammatory factors, a feature termed senescence-associated secretive phenotype (SASP) (Coppé et al., 2008). At a late stage, senescent cells accumulate cytosolic DNA from activated LINE-1, a family of TEs, which activates the cGAS-STING innate signaling pathway to initiate IFN-I response as part of full SASP (Franceschi and Campisi 2014; De Cecco et al., 2019). TE derepression and cGAS-STING-IFN innate signaling is predominant in a group of diseases called laminopathy, including several conditions of accelerated aging (Graziano et al., 2018). Mechanical stress from defective nuclear lamina can disrupt the heterochromatin structure that normally silences LINE-1, which leads to its activation and subsequent immune response (Kreienkamp et al., 2018; Earle et al., 2020). Sirtuins are a class of nicotinamide adenine dinucleotide-consuming enzymes implicated in diverse biological pathways. In particular, SIRT3 and SIRT6 critically stabilize the nuclear lamina and maintain TE quiescence as the cells or animals lacking these genes undergo senescence or premature aging, respectively (Simon et al., 2019; Diao et al., 2021).

Genomic instability and epigenetic alterations are key hallmarks of aging (López-Otín et al., 2013). DNA damage affects many aspects of the aging phenotype, and genetic mutations affecting genome maintenance and repair promote the premature onset of age-related pathologies (Rieckher et al., 2021; Schumacher et al., 2021). Double-stranded DNA damage is sufficient to induce IFNβ production, which stimulates the p53 pathway and promotes senescence (Yu et al., 2015). While age-associated epigenetic alterations weaken the genome surveillance mechanism and increase TE transposition, manipulating genes known to affect heterochromatin structure mitigate the expression of TEs and extend life span (Wood et al., 2016). Not coincidentally, laminopathy often manifests with DNA damage, epigenome alteration, and loss of genomic integrity (Shumaker et al., 2006; Kreienkamp et al., 2018; Earle et al., 2020). In keeping with these mechanisms, Benayoun et al. detected TE activation in conjunction with epigenetic reprogramming in the aging tissues, a finding consistent with the profound upturn of IFN response (Benayoun et al., 2019).

Besides nuclear defects, aging cells accumulate mutations and deletions in the mitochondrial genome. The “mitochondrial theory of aging” denotes that accumulation of damage to mitochondria and mitochondria DNA (mtDNA) leads to aging of humans and animals, in line with the accelerated aging of mtDNA mutator mice (Trifunovic et al., 2004; Kujoth et al., 2005; Jang et al., 2018). mtDNA evolutionarily resembles bacterial DNA, an agonist for innate IFN response. mtDNA stress stimulates the escape of mtDNA into the cytosol, where it engages with the cGAS-STING pathway to initiate IFN response (West et al., 2015). Intriguingly, genetic ablation of the IFN-I receptor not only attenuates the hyperinflammatory phenotypes but also extends the life span of the mtDNA mutator mice (Lei et al., 2021). Altogether, these studies reveal a causal relationship between age-associated nuclear or mitochondrial dysregulation and innate IFN response (Figure 1).