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Prolonged sitting has emerged as a risk factor for early mortality, but the extent of benefit realized by replacing sitting time with exercise or activities of everyday living (i.e., nonexercise activities) is not known.We prospectively followed 154,614 older adults (59–82 yr) in the National Institutes of Health-AARP Diet and Health Study who reported no major chronic diseases at baseline and reported detailed information about sitting time, exercise, and nonexercise activities. Proportional hazard models were used to estimate adjusted hazard ratios and 95% confidence intervals (HR (95% confidence interval)) for mortality. An isotemporal modeling approach was used to estimate associations for replacing sitting time with specific types of physical activity, with separate models fit for less active and more active participants to account for nonlinear associations.During 6.8 yr (SD, 1.0) of follow-up, 12,201 deaths occurred. Greater sitting time (≥12 vs < 5 h·d−1) was associated with increased risk for all-cause and cardiovascular mortality. In less active adults (<2 h·d−1 total activity), replacing 1 h·d−1 of sitting with an equal amount of activity was associated with lower all-cause mortality for both exercise (HR, 0.58 (0.54–0.63)) and nonexercise activities (HR, 0.70 (0.66–0.74)), including household chores, lawn and garden work, and daily walking. Among more active participants (2+ h·d−1 total activity), replacement of sitting time with purposeful exercise was associated with lower mortality (HR, 0.91 (0.88–0.94)) but not with nonexercise activity (HR, 1.00 (0.98–1.02)). Similar results were noted for cardiovascular mortality.Physical activity intervention strategies for older adults often focus on aerobic exercise, but our findings suggest that reducing sitting time and engaging in a variety of activities is also important, particularly for inactive adults.