Molecular Atlas of Aging. Meta-group 4. Exogenous Xenobiotics: an Anthropogenic Shock Accumulating Over Decades. Integrative Approach in the Context of Meta-medium Theory and Meta-regulators

Relevance. In the hierarchy of 22 groups of molecules affected by aging, exogenous xenobiotics occupy the fourth place — after gas transmitters (energy foundation), rejuvenation signaling proteins (architects of regeneration) and pro-inflammatory cytokines (chronic inflammatory fire). Unlike the three previous groups, which are endogenous systems that malfunction with age, exogenous xenobiotics are an external anthropogenic cargo that the body is forced to carry within itself for decades. A modern person is exposed to thousands of foreign chemical compounds — heavy metals, persistent organic pollutants, plasticizers, pesticides, and microplastics — every day, many of which have half-lives ranging from several years to decades and accumulate in adipose tissue, bones, liver, kidneys, and brain. Aim. To present exogenous xenobiotics as the fourth level of molecular aging — an anthropogenic toxic cargo that exacerbates all three previous breakdowns and requires a separate detoxification strategy. To substantiate the need for a systematic approach to reducing the burden of xenobiotics through the restoration of the body's own detoxification mechanisms. Results. Heavy metals (lead, cadmium, mercury, arsenic) have been shown to accumulate in tissues with half-lives of up to 10–30 years, disrupt the autophagosomal-lysosomal pathway, activate the NLRP3 inflammasome via mitochondrial oxidative stress, and induce neuronal senescence via the p53/p21/Rb pathway. Persistent organic pollutants (PCBs, dioxins, furans) modulate DNA methylation and epigenetic senescence. Endocrine disruptors (BPA, phthalates) accelerate reproductive senescence. Microplastics and nanoplastics penetrate the blood-brain barrier, accumulate in tissues, cause mitochondrial dysfunction, and induce cell senescence through autophagy suppression. With age, the activity of enzymes of phases I and II of detoxification decreases, the glomerular filtration rate decreases, the intestinal barrier is disrupted, which creates a "perfect storm" for accelerated biological aging. A multimodal approach (Quatotron technique) to systemic detoxification through activation of the NRF2 pathway, enhancement of phase II enzymes, mobilization of tissue depots, and stimulation of excretion has been proposed. Conclusion. Exogenous xenobiotics are the fourth level of molecular aging. Without their systemic elimination, any efforts at rejuvenation are compensated by the toxic effect of these compounds. Restoration of one's own detoxification mechanisms through the systematic management of meta-regulators opens up new opportunities for the prevention of age-associated diseases and healthy longevity.