Resilience signaling and hormesis in brain health and disease

Abstract Acquired resilience in response to stress caused by environmental adverse changes and its role in medicine and public health is a central topic for the immediate e future. Along with nitric oxide (NO) and carbon monoxide (CO), hydrogen sulfide (H2S) is regarded as the third gasotransmitter and endogenous neuromodulator and plays multiple roles in the central nervous system under physiological and pathological states, especially in secondary neuronal injury. The endogenous level of H2S in the brain is significantly higher than that in peripheral tissues, and is mainly formed by cystathionine β-synthase in astrocytes and released in response to neuronal excitation. Mild stress can be beneficial, upregulating adaptive responses which enhance biological performance and protect against subsequent toxic challenges, through mechanisms that conform hormesis principles. In contrast, during toxic stress conditions the underlying inability to cope causes dysregulation of stress adaptive response mechanisms with low resilience status that increases vulnerability to disease. Detailed evaluations of biological systems showing acquired resilience reveal a hormetic biphasic dose-response relationship, being reported as the result of either a direct low dose stimulation or within the context of a preconditioning experimental protocol. The hormetic dose response defines the expression, amplitude, duration, and limitations of the acquired resilience in all biological systems. These acquired resilience-hormetic dose responses are widely reported in the pharmacology and nutritional literature with considerable information now clarifying underlying mechanisms at the level of receptor and cell signaling pathways. Aging is one of the most challenging public health and it is considered as a “cellular danger response” to environmental stressors or injury leading to development of neurodegenerative disorders. Therefore identifying personalized biomarker signatures of resilience can help us characterize biologically vulnerable individuals and on the other end, resilient individuals, such as centenarians, that represent the best model of longevity and healthy aging.