MOLECULAR ATLAS OF AGING. META-GROUP 8. NEUROTROPHINS: THE ARCHITECTS OF THE BRAIN THAT LEAVE US WITH AGE. INTEGRATIVE APPROACH IN THE CONTEXT OF META-MEDIUM THEORY AND META-REGULATORS

Relevance. Neurotrophins are a family of small proteins critical for the survival, development, differentiation, and maintenance of neuronal function. They provide synaptic plasticity, learning, memory, and neuroprotection. Without them, the brain cannot renew, adapt, and recover. As we age, their levels drop, and this decline is directly linked to cognitive decline, neurodegeneration, and loss of mental health. The four main members of this family—BDNF, NGF, NT-3, and NT-4/5—work as a single neurotrophic network that supports the brain from early development to old age. Aim. To present age-related degradation of the neurotrophin system as the eighth level of molecular aging — the loss of brain architects, turning physical aging into a cognitive catastrophe. To substantiate the need for systemic restoration of neurotrophic signaling through the tuning of meta-regulators. Results. It was shown that with age, there is a systemic decrease in the levels of all four neurotrophins, disruption of their processing (accumulation of pro forms), depletion of Trk receptors, and imbalance in favor of pro-apoptotic p75NTR. BDNF, the level of which decreases in Alzheimer's disease, is critical for synaptic plasticity and neuroprotection, and its signaling through TrkB inhibits GSK-3β, a key enzyme involved in tau phosphorylation and amyloid-β production. NGF demonstrates age-related dysmetabole: the maturation of proNGF to mature NGF is impaired in the preclinical and clinical stages of Alzheimer's disease, while the degradation of mature NGF is enhanced. The accumulation of proNGF in the cortex causes retrograde degeneration of basal cholinergic neurons through the activation of p75NTR. NT-3, critical for maintaining the integrity of the neuromuscular junction, prevents age-related sarcopenia through activation of the Akt/mTOR pathway. p75NTR, a common neurotrophin receptor, plays a key role in maintaining the stability of the neuromuscular junction and muscle strength during aging. A multimodal approach (Quatotron technique) to the physiological restoration of the neurotrophin network through stimulation of endogenous production and normalization of receptor balance has been proposed. Conclusion. Neurotrophins are the eighth level of molecular aging, the system that determines whether the brain will be able to maintain plasticity and cognitive functions. Their recovery through the systemic management of meta-regulators opens up new opportunities for the prevention of neurodegenerative diseases and the preservation of cognitive health.