Global studies on the transcriptional landscape of aged tissues have also emphasized the relevance of inflammatory pathways in aging (de Magalhães et al., 2009; Lee et al., 2012). Overactivation of the NF-κB pathway is one of these transcriptional signatures of aging, and conditional expression of an NF-κB inhibitor in the aged skin of transgenic mice causes the phenotypic rejuvenation of this tissue, as well as the restoration of the transcriptional signature corresponding to young age (Adler et al., 2007). Likewise, genetic and pharmacological inhibition of NF-κB signaling prevents age-associated features in different mouse models of accelerated aging (Osorio et al., 2012; Tilstra et al., 2012). A novel link between inflammation and aging derives from the recent finding that inflammatory and stress responses activate NF-κB in the hypothalamus and induce a signaling pathway that results in reduced production of gonadotropin-releasing hormone (GnRH) by neurons (Zhang et al., 2013). This GnRH decline can contribute to numerous aging-related changes such as bone fragility, muscle weakness, skin atrophy, and reduced neurogenesis. Consistently, GnRH treatment prevents aging-impaired neurogenesis and decelerates aging development in mice (Zhang et al., 2013). These findings suggest that the hypothalamus may modulate systemic aging by integrating NF-kB-driven inflammatory responses with GnRH-mediated neuroendocrine effects.
Further in vivo evidence linking inflammation and aging derives from work on the mRNA decay factor AUF1, which is implicated in the cessation of the inflammatory response by mediating cytokine mRNA degradation (Pont et al., 2012). AUF1-deficient mice exhibit a marked cellular senescence and premature aging phenotype that can be rescued by re-expression of this RNA-binding factor. Interestingly, in addition to directing inflammatory cytokine mRNA decay, AUF1 contributes to maintaining telomere length by activating the expression of the telomerase catalytic subunit TERT (Pont et al., 2012), again demonstrating that one single factor may have a strong impact on different aging hallmarks.
A similar situation occurs with sirtuins, which may also have an impact on inflammatory responses associated with aging. Several studies have revealed that, by deacetylating histones and components of inflammatory signaling pathways such as NF-κB, SIRT1 can downregulate inflammation-related genes (Xie et al., 2013). Consistent with these findings, reduction of SIRT1 levels correlates with the development and progression of many inflammatory diseases, and pharmacologic activation of SIRT1 may prevent inflammatory responses in mice (Gillum et al., 2011; Yao et al., 2012; Zhang et al., 2010). SIRT2 and SIRT6 may also downregulate the inflammatory response through deacetylation of NF-kB subunits and transcriptional repression of their target genes (Kawahara et al., 2009; Rothgiesser et al., 2010).

Other Types of Intercellular Communication

Beyond inflammation, accumulating evidence indicates that aging-related changes in one tissue can lead to aging-specific deterioration of other tissues, explaining the interorgan coordination of the aging phenotype. In addition to inflammatory cytokines, there are other examples of “contagious aging” or bystander effects in which senescent cells induce senescence in neighboring cells via gap-junction-mediated cell-cell contacts and processes involving ROS (Nelson et al., 2012). The microenvironment contributes to the age-related functional defects of CD4 T cells, as assessed by using an adoptive transfer model in mice (Lefebvre et al., 2012). Conversely, lifespan-extending manipulations targeting one single tissue can retard the aging process in other tissues (Durieux et al., 2011; Lavasani et al., 2012; Tomás-Loba et al., 2008).

Restoring Defective Intercellular Communication

There are several possibilities for restoring defective intercellular communication underlying aging processes, including genetic, nutritional, or pharmacological interventions that may improve the cell-cell communication properties that are lost with aging (Freije and López-Otín, 2012; Rando and Chang, 2012). Of special interest in this regard are the DR approaches to extend healthy lifespan (Piper et al., 2011; Sanchez-Roman et al., 2012) and the rejuvenation strategies based on the use of blood-borne systemic factors identified in parabiosis experiments (Conboy et al., 2005; Loffredo et al., 2013; Villeda et al., 2011). Moreover, the long-term administration of anti-inflammatory agents such as aspirin may increase longevity in mice and healthy aging in humans (Rothwell et al., 2011; Strong et al., 2008). Additionally, given that the gut microbiome shapes the function of the host immune system and exerts systemic metabolic effects, it appears possible to extend lifespan by manipulating the composition and functionality of the complex and dynamic intestinal bacterial ecosystem of the human body (Claesson et al., 2012; Ottaviani et al., 2011).

Overview

There is compelling evidence that aging is not an exclusively cell-biological phenomenon and that it is coupled to a general alteration in intercellular communication, offering opportunities to modulate aging at this level. Excitingly, proof of principle exists for rejuvenation through blood-borne systemic factors (Conboy et al., 2005; Loffredo et al., 2013; Villeda et al., 2011).