The Peripheral Vicious Cycle Hypothesis: An Upstream Physiological Driver of Aging Supported by Somato-Autonomic and Myofascial Evidence

Aging is widely regarded as a multifactorial process driven primarily by cell-intrinsic molecular damage, as formalized in the 12 hallmarks of aging (Lopez-Otin et al., 2023). Here it is proposed that many of these hallmarks are secondary consequences of a self- perpetuating upstream Peripheral Vicious Cycle (PVC) originating in the peripheral musculoskeletal system. Repeated sympathetic activation leads to incomplete resolution of muscle and fascial tone after the fight-or-flight response, resulting in persistent taut bands, local ischemia, and release of pro-inflammatory mediators. This sensitizes group III/IV afferents, whose ascending signals to the spinal cord and limbic structures (including the amygdala) trigger a reflexive increase in sympathetic outflow. The resulting feedback loop sustains peripheral ischemia and fibrosis, generating chronic low-grade inflammation that propagates systemically and accelerates multiple downstream molecular hallmarks. This paper synthesizes evidence from somato-autonomic reflex studies, myofascial trigger point research, age-related attenuation of the exercise pressor reflex, and mortality plateaus in extreme old age. The 12 hallmarks of aging are mapped onto the PVC, and seven testable predictions are outlined that can be examined with existing physiological techniques. If confirmed, the model suggests that a substantial fraction of age-related decline may be preventable by targeting the cycle at its peripheral origin through interventions acting selectively on skeletal muscle and fascia, without disrupting central autonomic or hormonal balance. This framework reframes geroscience by emphasizing prevention of the upstream physiological driver in addition to downstream molecular repair.