MOLECULAR ATLAS OF AGING. META-GROUP 6. NEUROTROPHINS (BDNF, NGF, NT-3, GDNF): COGNITIVE DEATH. WITHOUT THEM, DEMENTIA, DEPRESSION, LOSS OF PLASTICITY. INTEGRATIVE APPROACH IN THE CONTEXT OF META-MEDIUM THEORY AND META-REGULATORS

Abstract

Relevance. In the hierarchy of 22 groups of molecules affected by aging, neurotrophins occupy the sixth place — after gas transmitters (energy foundation), rejuvenation signaling proteins (regeneration architects), pro-inflammatory cytokines (chronic inflammatory fire), exogenous xenobiotics (toxic load), and coagulation factors (thrombotic readiness). While the previous groups create damage and turn it into fatal events, neurotrophins are the system that determines whether the brain will be able to adapt to these damages or begin to deteriorate irreversibly. Neurotrophins are "fertilizer for the brain": without them, neurons die, synapses disappear, plasticity is lost, and cognitive functions are irreversibly declined. Aim. To present age-related degradation of the neurotrophin system as the sixth level of molecular aging — "cognitive death", which turns accumulated damage into dementia, depression and loss of neuroplasticity. To substantiate the need to restore neurotrophin signaling through the systemic tuning of meta-regulators. Results. Four key neurotrophins—BDNF, NGF, NT-3, and GDNF—have been shown to form an integrative network that controls neuronal survival, synaptic plasticity, neurogenesis, and glial function. BDNF, which is reduced in Alzheimer's disease and mild cognitive impairment, is critical for the maintenance of pericytes and the brain's microvascular network. NGF, the "master regulator" of cholinergic neurons in the basal forebrain, demonstrates age-related dysmetabole: the maturation of proNGF to mature NGF is disrupted and its degradation is enhanced. NT-3, which is critical for maintaining neuromuscular junction integrity and axonal regeneration, prevents age-related sarcopenia through activation of the Akt/mTOR pathway. GDNF, interacting with GFRα1/RET receptor complexes, modulates redox homeostasis and provides trophic support for dopaminergic neurons. With age, the levels of all four neurotrophins decrease, signaling through Trk receptors is disrupted, and neurons remain without trophic support. A multimodal approach (Quatotron technique) to physiological restoration of the neurotrophin network through stimulation of endogenous production of BDNF, NGF, NT-3 and GDNF has been proposed. Conclusion. Neurotrophins are the sixth level of molecular aging, a system that determines whether the brain will be able to maintain plasticity and cognitive functions despite accumulated damage. 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.