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Stress is closely linked by its biological mechanisms to inflammation and by its consequences to accelerated aging. Stress triggers a hormonal response along the hypothalamus-pituitary-adrenal (HPA) axis, which can disrupt the ortho/parasympathetic balance essential for a harmonious life. Proper nutrition, adequate physical activity, and limiting the harmful influence of stress play important roles in avoiding the development of disease and promoting healthy aging. d-Limonene, a monoterpene shown to reduce inflammatory parameters in several pre-clinical and clinical models, could also produce an anti-stress action by altering ortho/parasympathetic parameters as well as central neurotransmitter functions. Here we report on a rat model, where a functional observational battery (FOB) was performed by submitting animals to non-pathological stress. d-Limonene or its metabolite perillyl alcohol (POH) were administered per os at a dose of 10 mg/kg. FOB tests were performed 1 hr before gavage and then at 60, 120, and 180 min. These tests confirmed the stressed status of control rats fed vehicle. Conversely, a series of parameters were significantly less disturbed in treated rats, who retained a better activity and displayed less signs of stress. These effects were more pronounced and sustained after ingestion of d-limonene than POH, suggesting the role of endogeneous metabolization of the terpene. These studies show that d-limonene exerts, through its metabolite POH, a significant anti-stress action measurable by behavioral and physiologic parameters under the influence of the nervous system. In addition to its anti-inflammatory effects, a beneficial role as an anti-stress substance could thus be claimed for d-limonene used as a dietary supplement.

The aging process depends on genetic stability, metabolic control, and resistance to stress; longevity in particular seems related to resistance to stress. Responses to stress anticipate adaptation to an unacceptable disparity between real or imagined personal experience and expectation, including adaptive stress, anxiety, and depression. However, if stress persists, it may lead to chronic diseases, ranging from inflammation and cancer to degenerative diseases. For some time, only remarkable stress was acknowledged to induce immune and vascular alterations, such as infection or hypertension. Now it is known that moderate stress independent of conventional risk factors can induce a potent alteration of health conditions and consequently shorten life quality and lifespan. Inflammation is a critical defense mechanism, that, uncontrolled, contributes to chronic conditions with inflammatory pathogenesis. Stressful life conditions turn out to induce a diffuse (systemic) pro-inflammatory status. Subclinical chronic inflammation is an important pathogenic factor in the development of metabolic syndrome, a cluster of common pathologies, including cardiovascular disease. Markers include mediators associated with endothelial activation and dysfunction. This work reports the in vitro and in vivo effects of the monoterpene AISA 5203-L on human vascular endothelial cells in reversing replicative senescence in preventing and alleviating nonpathological stress, as assessed by a functional observational battery (FOB) of 44 tests, addressing behavioral, neurological, and physiological criteria.