Hormetic Triggers for Intervention in Aging, Disease and Trauma

Abstract

Hormesis refers to the ability of a chemical or physical agent to condition the physiological state of an organism to tolerate stress with low doses of otherwise harmful agents. Evolutionary evidence shows that the survival and longevity of species hinge on their optimal ability to resist stress challenge. Hormesis is a potent strategy to stimulate latent repair processes to tolerate a specific challenge. Examples of hormetic agent-mimetics, which induce at least partial physiological conditioning, activate known pathways of longevity determinants, i.e., genetic stability, altered metabolism, immunoregulation and stress resistance. Despite the diversity of age-related diseases, glucose and oxidation-mediated protein and DNA damage are common denominators. The associated physiological conditioning-benefits may trigger: 1) activation of latent stress resistance pathways of youthful DNA repair; 2) increased resistance to oxidizing pollutants; 3) improved protein structure and function; 4) improved immunity; 5) damaged tissue remodeling; 6) adjustments in central and peripheral nervous systems; 7) altered metabolism; and 8) delay or breaking of inappropriate protein cross-links. Hormetic mimetics have intervention potential in cancer, diabetes, age-related diseases, infectious diseases, heart and kidney failure, cardiovascular diseases and Alzheimer's disease. Small nucleotide SOS signals, dipeptides, ethanol, thiols, and metals and conserved peptide sequences found in sharks, frogs, woodchucks, and bears, can regulate cytokines, cellular immunity, and central and peripheral neuronal regulatory pathways to promote healthy blood pressure maintenance, heart rate, and metabolic pathways. disease sensitivity. Conserved stress mimetics are highlighted here that rejuvenate DNA and proteins repair and thus may intervene in aging, disease, and trauma. Hibernation Induction Trigger mimetics, Deltorphins, emerge as novel hormetic agents, effective both as pre and post exposure to physiological conditioners to tolerate stress, and prevent damage, and delay possibly aging. Hormesis mimetics offer powerful survival strategies, with better control over the beneficial dose response. Combinations of several mimetics may more closely mimic environmental challenges, which stimulate multiple stress responses.

Hormesis is central to toxicology, pharmacology and risk assessment

“…It is expected that these agents will be translated into life-enhancing pharmaceuticals. 83 In short, hormetic effects are a central feature of the modern and future pharmacy.…”

Alternative Strategy for Alzheimer’s Disease: Stress Response Triggers

“…Since the appropriate threshold of low-dose beneficial versus toxic dose of environmental and chemical stress is difficult to assess, the use of mimetic agents of these stresses offers better dosage control to avoid high-dose stress damage [ 2 ]. Mimetics can trigger stress-related transcriptomes, expression of families of genes activated by a common transcription factor, that provide benefit not only the targeted beneficial response, but also youthful rejuvenation, and improvement of multiple avenues to stress resistance to intervene in multiple age-related disease [ 5 – 7 ]. These fundamental survival pathways, lifespan assurance loci, master regulators, also called vitagenes, confer plasticity to species longevity, lifespan extension, rejuvenation, and repair [ 2 , 5 – 12 ].…”

“…Mimetics can trigger stress-related transcriptomes, expression of families of genes activated by a common transcription factor, that provide benefit not only the targeted beneficial response, but also youthful rejuvenation, and improvement of multiple avenues to stress resistance to intervene in multiple age-related disease [ 5 – 7 ]. These fundamental survival pathways, lifespan assurance loci, master regulators, also called vitagenes, confer plasticity to species longevity, lifespan extension, rejuvenation, and repair [ 2 , 5 – 12 ]. As the molecular roles of aging, stress and neurodegenerative disease are elucidated, oxidative stress emerges as a common damage denominator and activation of pathways used in early development; that is, FOXO and IGF-1, also serve roles in mitigation of stress resistance and disease [ 13 – 15 ].…”

Hormesis: Calabrese Responds

“…Third, Mushak’s inflexibility concerning hormesis is reflected in his comments that minimize the impact of hormesis and its growing applications. Despite the significant biomedical impact of hormesis, Mushak fails to acknowledge the reality that hormetic effects are the basis for how most anxiolytic ( Calabrese 2008a ), antiseizure ( Calabrese 2008b ), memory ( Calabrese 2008c ; Zoladz and Diamond 2009 ), Alzeheimer disease ( Calabrese 2008c ; Congdon et al 2009 ), and numerous other classes of drugs work ( Kastin and Pan 2008 ; Mattson 2008 ; Sonneborn 2008 ; Thong and Maibach 2008 ), with all such drugs having to pass the regulatory oversight of the Food and Drug Administration for efficacy and safety. On the environmental side, Mushak—in both his letter and his commentary ( Mushak 2009 )—did not acknowledge that the largest-ever rodent cancer bioassay (24,000 mice) that was designed to determine the nature of the dose response in the low-dose zone for carcinogens revealed hormetic responses for acetyl aminofluorene- induced bladder cancer and that this was affirmed by the 14-member Society of Toxicology expert panel convened to assess these findings ( Society of Toxicology ED 01 Task Force 1981 ).…”