Restoring Neuroimmune Resilience: Chronokine Modulation of Microglia and Intercellular Communication During Aging

Aging profoundly affects brain function by promoting cellular senescence, chronic low-grade inflammation (inflammaging), and disruption of the communication networks that integrate neurons, microglia and astrocytes. Microglia, as central orchestrators of neuroimmune homeostasis, progressively acquire senescence and pro-inflammatory phenotypes with age, altering, not only their functions, but also their interactions with surrounding cells and contributing to neurodegenerative processes, such as Alzheimer's disease. However, the mechanisms by which aging disturbs microglia-cell communication, and whether these dysfunctions can be reversed, remain poorly understood. Our previous work demonstrate that the chronokine klotho extends lifespan, rejuvenates neuronal epigenetic profiles, and improves cognition in vivo. In this way, we recently engineered HEBE, a next-generation chimeric chronokine designed to potentiate the anti-aging actions of klotho, by adding sTREM2 subunit (to enhance microglial regulation) and TIMP2 to support vascular function. First results show that HEBE ameliorates memory deficits in an Alzheimer's disease model, supporting its therapeutic potential. The principal goal of this project is to elucidate the cellular and molecular mechanisms through which klotho and HEBE modulate senescence, neuroinflammation, and intercellular commmunication in human and animal models of aging and neurodegeneration. Using human iPSC-derived brain cells, aged mice with controlled microglia depletion/repopulation, and two pathological aging models (SAMP8 and AAP/Tau), we will (i) characterize chronokine-induced changes in senescence and microglial metabolism, (ii) define microglia-dependent versus microglia-independent mechanisms during physiological aging and (iii) determine how microgla shape chronokine efficacy in pathological aging. This project will advance fundamental knowledge on neuroimmune resilience and identify novel intervention points to restore microglial homeostasis, ultimately contributing to the development of innovative strategies for healthy brain aging.