Chronobiological Modulation of Mitochondrial Bioenergetics and Cellular Senescence: A Dual-Phase Systems-Level Strategy for Proteostatic and Bioenergetic Resilience in Aging

Biological aging is closely associated with progressive mitochondrial dysfunction(definition) and the accumulation of systemic cellular damage. Conventional antioxidant-based interventions are increasingly regarded as insufficient, as they predominantly target reactive oxygen species (ROS) as downstream manifestations rather than addressing upstream determinants of mitochondrial decline. Here, a dual-phase, chronobiologically structured intervention is proposed, designed to align with endogenous circadian metabolic rhythms. By partitioning intervention into an activation phase and a restoration phase, this framework is intended to engage complementary processes governing bioenergetic flux and cellular quality control. Morning administration is designed to provide metabolic substrates and transport facilitators to support diurnal mitochondrial activity, whereas evening administration is hypothesized to favor pathways associated with macromolecular repair, redox homeostasis, and the modulation of senescent cell burden. Temporal orchestration of these agents may engage coordinated mechanisms, including NAD⁺-dependent signaling networks and context-dependent interactions between autophagic processes and senomorphic or senolytic pathways. While circadian regulation of mitochondrial function is well established and individual components of this framework are supported by preclinical and emerging clinical data, direct evidence demonstrating that temporally structured, multi-compound interventions improve clinically meaningful aging endpoints in humans remains limited. Accordingly, this work does not assert clinical efficacy but instead presents a mechanistically grounded, hypothesis-generating framework for systems-level intervention design.