Sleep deterioration as a systems-level readout of aging biology: integrating metabolic, inflammatory and circadian mechanisms

Sleep architecture and continuity deteriorate markedly with aging, yet these changes are frequently approached as isolated sleep disorders rather than as manifestations of systemic biological dysregulation. Accumulating evidence indicates that age-related sleep fragmentation reflects the progressive disruption of interconnected metabolic, inflammatory and circadian networks that are central to the biology of aging. In this context, sleep can be more accurately interpreted as a functional readout of systemic biological coherence and resilience in later life. In this integrative mechanistic review, we synthesize current evidence linking metabolic dysregulation, inflammaging and circadian desynchronization to sleep deterioration in older adults, and propose an integrative conceptual framework structured around three interdependent functional domains: Temporal (circadian organization), Energetic (metabolic flexibility and bioenergetics), and Redox-Neuroimmune (chronic low-grade inflammation and oxidative stress). These domains converge on the AMPK-mTOR-SIRT1 axis, which acts as a central mechanistic hub coordinating energy sensing, inflammatory tone and molecular clock regulation. Within this framework, sleep deterioration is conceptualized not as a primary pathological entity, but as the downstream functional expression of impaired nocturnal cellular maintenance driven by reduced AMPK activity, persistent mTOR signalling and declining SIRT1-dependent regulation. Bidirectional feedback loops are considered, whereby sleep fragmentation may further exacerbate metabolic and inflammatory dysregulation, reinforcing loss of biological coherence with aging. Importantly, we explicitly address current methodological limitations, particularly the challenges of assessing AMPK-mTOR-SIRT1 activity in humans using non-invasive approaches. Rather than offering prescriptive therapeutic recommendations, this framework is intended as a mechanistic, hypothesis-generating model to guide future research, biomarker development and translational studies focused on metabolic-circadian resilience and biological aging.