MOLECULAR ATLAS OF AGING. META-GROUP 16. HORMONES AND NEUROENDOCRINE REGULATION: A CONDUCTOR WHO LOSES CONTROL. INTEGRATIVE APPROACH IN THE CONTEXT OF THE THEORY OF META-ENVIRONMENTS AND META-REGULATORS

Relevance. The hormonal system is the main regulator of metabolism, growth, reproduction, stress response, and homeostasis. In youth, it works as a well-coordinated ensemble: cortisol and insulin accurately dose energy, leptin and adiponectin regulate appetite and fat metabolism, sex hormones and growth hormone support tissues. However, with age, this ensemble becomes upset: cortisol becomes chronically elevated, insulin becomes resistant, leptin loses sensitivity, adiponectin paradoxically increases against the background of developing resistance, sex hormones and growth hormone fade away, and thyroid function in brain tissues decreases locally. A neuroendocrine imbalance occurs, which turns the precise regulatory system into a chaotic noise that accelerates all age-related diseases. Aim. To present age-related dysregulation of the hormonal system and neuroendocrine axes as the sixteenth level of molecular aging — the loss of conducting control, which makes all other breakdowns uncontrollable. To substantiate the need for systemic restoration of neuroendocrine balance through the tuning of meta-regulators. Results. It was shown that with age, systemic dysregulation of all major hormonal axes occurs. The HPA axis becomes hyperactive: basal cortisol levels increase with age, predicting hippocampal atrophy and cognitive impairment; In the largest longitudinal study (n=1814, 31 years of follow-up), cortisol levels follow a U-shaped trajectory: they decrease at 20–30 years of age, are stable at 40–50 years, and increase after 60 years. Insulin resistance develops against the background of chronic inflaming, cellular aging, and mitochondrial dysfunction, and the mechanism is related to the distal stages of the insulin signaling cascade. Leptin resistance also progresses with age, mediated by neuroinflammation in the brainstem. Adiponectin shows a paradoxical age-related dynamics: its level is positively correlated with age after BMI correction (r=0.281; p=0.001), but this does not reflect a protective effect, but the development of adiponectin resistance with the suppression of AdipoR2, leading to oxidative stress and senescent-like phenotype in muscles. The GH/IGF-1 axis steadily declines with age, with weakened GH/IGF-1 signaling associated with healthy aging and protection against age-related diseases. DHEA drops sharply: peak at 20 years, by 80-90 years of age, only 10-20% of the level of young adults remain. Sex hormones decrease in a sex-specific way: a decrease in estradiol in women increases biological age by 0.18–0.29 years, while a decrease in testosterone in men increases by 0.07–0.71 years. In the aging brain, local hypothyroidism develops due to a decrease in the expression of thyroid hormone transporters (MCT8, OATP1C1) and impaired conversion of T4 to T3 in astrocytes. A multimodal approach (the Quatotron method) to the physiological restoration of neuroendocrine balance through the tuning of neurovegetative, metabolome- and immuno-inflammatory meta-regulators has been proposed. Conclusion. The hormonal system is the sixteenth level of molecular aging – the main regulatory circuit, whose failure makes all other breakdowns uncontrollable. Its systemic recovery through the control of meta-regulators opens up new opportunities for the prevention of age-associated diseases and healthy longevity.