Despite the fact that trans-meridian travel and shift work are commonplace in our 24/7 society, few controlled studies have addressed the health effects of repeated phase shifts of the biological clock. Shift work [ 1] and chronic jet-lag [ 2] reduce mental acuity and increase the risk of a number of medical problems, including cancer, peptic ulcers and sleep disorders. Some of these problems become more severe with the number of years on the job, the result either of cumulative damage or the increased age of the subjects [ 3]. In general, morbidity associated with many organic disorders is increased in the aged; however, the role played by age-associated alterations in the circadian clock is poorly understood. In particular the effect of repeated schedule changes is largely unaddressed. Here we report evidence that chronic jeg-lag increases mortality rates in aged mice. We were led to the current experiment by an observation in an unrelated study where we found that three of eight aged transgenic rats exposed to a 6 hour advance of the light cycle died following the light schedule change. In contrast, no deaths were observed if the light cycle was delayed. In order to explore whether the effects of light schedule changes on longevity were reproducible in a larger study and observable in another rodent species, we placed young (8–12 month old) and aged (27–31 month old) C57BL/6 male mice on one of three lighting regimens for eight weeks. Nine young and 30 aged mice were maintained on a normal 12: 12 light–dark cycle. A second group of young (n= 9) and old (n= 30) mice was exposed to a 6 hour advance of the light-cycle once every seven days. The third group of young (n= 9) and old (n= 28) mice was phase-delayed by 6 hours once every 7 days. The rotating light schedules were chosen to effect large phase adjustments of the circadian system each week, such as would be expected to occur during flight across time zones or in some situations during rotating shift work cycles. While younger mice fared well on this 8 week schedule (only one death occurred), we found that aged mice were significantly affected by light schedule changes (Figure 1A, B). At the end of the 8 week period of light schedule rotations there was 47% survival in animals whose light cycle was advanced each week, 68% in those experiencing delays of the light cycle and 83% in unshifted aged mice (chi square, all groups, p< 0.05 on Day 54). Importantly, chronic stress was not implicated in this phenomenon as total daily fecal corticosterone levels did not increase in aged mice undergoing phase advances or phase delays (see Figure S1 in the Supplemental data published with this article online). To determine whether the effects of phase advances on mortality might be related to the duration between schedule changes, mice were shifted more rapidly, every 4 days. On this schedule, we found that advancers died more quickly than with weekly shifts ( Figure 1C; 60% survival on Day 24). Delayers fared much better than advancers (chi square p< 0.05 on Day 32). The data suggest that the asymmetry in mortality rates between animals exposed to light schedule advances and delays persists and is possibly enhanced with the shorter inter-shift interval of 4 days. Our data show that phase-advancing the light cycle hastens the death of aged mice. The mechanism underlying the