## 1 Introduction  
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with 38 (PACAP38) or 27 (PACAP27) amino acid residues [1]. PACAP acts through specific PAC1 receptors and VPAC1, and VPAC2 receptors which also bind a related peptide, vasoactive intestinal peptide (VIP), with equal affinity. In addition to the receptorial mechanisms of action, PACAP is able to traverse biological barriers and act directly intracellularly, and it also transactivates other receptors [1, 2]. The eight splice variants of the PAC1 receptor activate different signal transduction pathways. The most common pathway through which PACAP exerts its actions is the cAMP/protein kinase A pathway. The expression of the PACAP receptors has been described to show changes according to developmental stage and other environmental conditions [3, 4, 5]. The splice variants of the receptor, the different signaling pathways, and the other routes of action are responsible for the very diverse actions of the peptide. Among others, PACAP has been shown to play a role in several physiological processes, such as micturition [6], cardiac excitability [7], control of body weight [8], respiration [9], pain processes [10], cartilage metabolism [11] as well as addiction and stress-related behaviors [12]. PACAP acts as a growth factor and influences the development of the nervous system as well as peripheral organs. These effects include actions on neuronal mitosis, migration, myelination, and tissue differentiation [13; 14; 15; 16; 17]. In the periphery, PACAP plays a role in haemopoetic stem cell proliferation [18], and skeletal and immune development [19; 20]. Similar to developmental effects, PACAP plays a role in restorative processes in various injuries. This has been reviewed several times [21; 22; 23; 24; 25; 26; 27]. The main protective mechanisms include strong antiapoptotic and anti-inflammatory effects as well as antioxidant capacity of the peptide [22; 25]. Previously, we hypothesized that the effects of PACAP against increased apoptosis, and that inflammation and oxidative stress could also be an important protective factor in aging. Indeed, we have found that mice lacking endogenous PACAP display an early onset systemic amyloidosis present in most organs [28]. Based on these observations, we proposed that PACAP gene-deficient animals could serve as a model of accelerated aging [29]. Much less is known about mice lacking the specific receptor of PACAP (PAC1 receptor). Some studies have been published on altered physiological and pathological reactions of these mice, but it is not known whether they show any aging-related signs [30; 31]. The clinical importance of PACAP has been highlighted in several studies [32]. PACAP is upregulated in different injuries and diseases; furthermore, PACAP gene polymorphism has been associated with altered stress response [33; 34]. Homozygous PACAP gene-deficient mice are well known to react with increased injuries to harmful stimuli. This has been proven in dozens of pathological conditions [22; 35; 36]. However, complete PACAP deficiency has not been described in humans and is not likely to occur. Nevertheless, partial deficiency or decreased levels have already been described in humans. For example, decreased PACAP levels have been shown in posttraumatic stress disorder in female patients [33], and in the cerebrospinal fluid of multiple sclerosis patients [37]. Furthermore, [PERSON] and coworkers have measured significantly decreased PACAP levels in the cerebrospinal fluid and decreased peptide expression in the brains of Alzheimer's disease patients, correlating with the decline of cognitive performance [38; 39]. Thus, as partial deficiency of PACAP is a more likely clinical scenario, studying heterozygous PACAP-deficient mice could give a valuable insight into possible clinical correlations. Only scarce data are available about heterozygous mice and aging.