Xi Gu, M Mong-Wei Lin, Yiming Xia, Xiangyu Cheng, Hongke Pan, Min Cai, Maorong Jiang, Dengbing Yao
Background: Population aging is significantly altering the clinical conditions of peripheral nerve injury (PNI); however, the age-specific mechanisms that affect nerve regeneration remain unclear. Although the peripheral nervous system has the potential for regeneration, functional recovery after peripheral nerve injury is unsatisfactory in elderly people. The current research mainly focuses on young organisms, leaving a crucial gap in our understanding of how aging fundamentally alters the regenerative microenvironment and affects final therapeutic outcome. This review aims to integrate the latest evidence on aging-related changes in peripheral nerve repair and clarify the underlying mechanism of failed nerve regeneration in elderly people. Summary: An increasing amount of data indicates that aging not only delays the regenerative process but also significantly affects the nervous system’s microenvironment. In an aging environment, chronic low-level inflammation (known as “inflammaging”) caused by mitochondrial dysfunction, Schwann cell senescence, and abnormal macrophages impedes axon regeneration. Moreover, aging cells secrete pro-inflammatory mediators such as interleukin-6 and tumor necrosis factor-α, strengthening the paracrine aging process and establishing a positive feedback inflammatory cycle. We therefore integrated a metabolic–immune-aging framework to explain age-related regenerative resistance and emphasize the transformation barriers limiting clinical applications. Conclusions: Understanding the systems-level interactions within the aging nerve microenvironment is essential for developing age-tailored therapeutic strategies. Targeting metabolic dysfunction, immune dysregulation, and cellular senescence may offer new avenues for improving functional recovery in elderly patients with PNI.