Psycho-biological resilience is considered one of the most important factors in the epigenetics of aging. Cell senescence exhibits a series of possible biochemical derangements concerning mitochondria, proteasome, genome and membranes. Research has shown that resilience can be acquired through hormesis, a set of conservative and adaptive processes based on biphasic dose-response to specific mild stressors, such as fasting, intake of polyphenols, exercising, physical and chemical stress and mental engagement. These stimuli were shown to elicit beneficial cellular metabolic pathways, such as sirtuin activation, mechanistic target of rapamycin and insulin growth factor-1 downregulation, nuclear related factor 2 upregulation and autophagy. The complex of these resilience-building processes plays a documented role in longevity. Mitochondria are regarded as one of the core actors of aging processes and represent the main target of hormetic approaches [mitohormesis]; furthermore, the influence of the mind on mitochondria, and thus on the balance of health and disease has been recently established , leading to the so-called mitochondria psychobiology. Hence, psychologic and physical stress that reflects on these organelles may be regarded as a relevant factor in cell senescence and thus the proposed “mitoresilience“ denomination may be pertinent within the biomedical science of aging. Finally, the quantification of individual resilience is becoming increasingly important in aging science and the investigation of the autonomic nervous system through heart rate variability [HRV] proved to be a valid method to quantify this parameter. In conclusion, an integrated approach targeting hormetic pathways to improve psycho-physical resilience [namely mitoresilience], supported by the monitoring of HRV may represent a valuable option in longevity medicine.