Office workers aged 40–59 are at a critical stage in which accelerated physiological ageing overlaps with workplace stress. Their health risks are multisystemic, insidious in progression, and partially reversible. This article integrates existing evidence from cell biology, pathophysiology, epidemiology, and clinical research to systematically review the whole-system pathogenic mechanisms underlying the midlife health crisis among office workers. The literature indicates that telomere shortening, mitochondrial functional decline, accumulation of oxidative stress, and diminished autophagic function constitute the four fundamental mechanisms of cellular ageing. Sedentary behaviour, shift work, overtime work, and chronic psychological stress in the workplace accelerate these degenerative processes by elevating cortisol, disrupting metabolic rhythms, and inducing systemic low-grade inflammation. This pathogenic chain is centred on insulin resistance and, through intermediary links such as metabolic syndrome, gut microbiota dysbiosis, endocrine disorders, and sleep apnoea, ultimately drives the development of cardiovascular disease, non-alcoholic fatty liver disease, chronic kidney disease, and sensory degeneration. This article further identifies major blind spots in contemporary health knowledge and proposes reversibility-oriented integrated intervention strategies at both the individual health-management level and the workplace-institutional level. Combining the holistic perspective and principle of balance inherent in holistic health, this article argues that midlife health management should shift from a “treat disease when it arises” model to an upstream, risk-interruption model, achieving multisystem coordinated intervention within the reversible window.