The main purpose of this study is to illustrate how, within the nursing profession, work ability can be deteriorated by a job alienation mechanism which acts differently according to age. From the total number of nurses participating in the NEXT Study, a sample of 27,146 nurses was selected. In addition to age, “Job demands”, “Job control” and “Harassment at work” were considered as determinants of job alienation. “Overcommitment”, “Uncertainty about patients' treatment” and “Work meaning” were used as symptoms of job alienation. Finally, “Work Ability Index” (WAI) was employed as the outcome variable. A structural equation model was used to test the job alienation hypothesis. The model demonstrated a good fit with the data. Overcommitment, uncertainty about patients' treatment and work meaning had a direct effect on WAI. High job demands, high harassment at work, low job control and age had both direct and indirect effects (via overcommitment, uncertainty about patients' treatment and work meaning) on WAI. Low work ability in older nurses is due to ageing and to an increase in overcommitment yielded by perceived high demands, low job control and high harassment at work. On the contrary, among the nurses under 50 years old, decrease of WAI turned out to be more associated with higher uncertainty about patients' treatment and lower work meaning, which both affect the possibility to reach more professional competence and develop occupational expertise.