All-cause mortality effects of replacing sedentary time with physical activity and sleeping using an isotemporal substitution model: a prospective study of 201,129 mid-aged and older adults

The health benefits of moderate-to-vigorous physical activity (MVPA) are well-established [1]. Large volumes of sedentary behaviour (SB), characterized by a low energy expenditure (≤1.5 metabolic equivalents) in a sitting or reclining posture [2], are thought to increase mortality risk independently of MVPA [3, 4]. The evidence is particularly strong for specific types of SB, such as television viewing [5, 6], which show consistent associations with health outcomes. The associations between sleep duration and health outcomes are complex, as both low and high durations are associated with mortality risk [7].

Although physical activity (PA), SB, and sleeping are behaviours that occupy a 24-hour day, investigators have typically examined each behaviour without considering what time-dependent behaviours are being displaced [4, 7–9]. For example, a 60-minute block of low-intensity walking will have different health effects depending on whether it displaces an equal amount of sitting, vigorous exercise, or brisk walking. This limitation can be overcome by statistical modeling that specifically estimates the effects of replacing one behaviour with another, the isotemporal substitution modeling [ISM] approach [10]. ISM, which is based on nutritional epidemiology methods analyzing the effects of substituting nutritional components [10], models simultaneously the effect of a given activity being performed and another activity being displaced in an equal time-exchange manner. ISM not only controls for confounding by other time-dependent behaviours, it also captures the effect of time substitution [10]. Very few studies to date have examined the replacement associations of SB, physical activity and other time-dependent behaviours with health outcomes in general [10–12] and no such study has had mortality as an outcome. The only study that has specifically considered the replacement associations of MVPA, SB, and sleeping was a cross-sectional study that found beneficial associations of replacing sedentary time with sleeping and MVPA and a number of cardiometabolic risk markers [12]. However, “sedentary time” in this study [12] did not distinguish between sitting and standing. Another recent cross-sectional ISM study [11] found that replacing sedentary time with MVPA, but not with light-intensity activity, was linked to beneficial associations with a range of cardiometabolic markers. Such information has both clinical and public health relevance and may be valuable in developing more accurate and specific public health recommendations, clinical guidelines, and preventative or therapeutic interventions.

In this study, we examined the estimated replacement effects of SB and other time-dependent behaviours on all-cause mortality in a large population-based cohort of Australians aged 45 years and over using isotemporal substitution modelling.

This is the first large-scale epidemiological study examining the replacement effects of sedentary time and other time-dependent behaviours on all-cause mortality using statistical modelling. Both screen time and total sitting time were independently associated with increased mortality risk, while standing, walking, and MVPA were associated with decreased mortality risk. We found beneficial associations for replacing sedentary time with equal amounts of sleeping (in participants who sleep < 7 h/day), standing, walking, and MVPA. Our results were robust to multiple measures that we took to minimize the chances of reverse causality.

Public health physical activity recommendations [21] are largely based on epidemiological evidence of non-substitution models. Our analyses suggest that the ISM [10] offers richer and more specific information than previous “static” methods. Because there seems to be a variation in the associations of most behaviours with mortality depending on the displaced activity, existing epidemiological evidence may underestimate the benefits of physical activity and the harms of sedentary behaviour. For example, the partition models showed that each hour/day of sitting is linked to an increased mortality risk of 3 % (2–4 %), but once the displaced activity is taken into account, this increased to 5 % (4–6 %) and 17 % (11–23 %) for displacing equal amounts of standing and MVPA, respectively.

For interventional targets, the most common scenario is that programs seek to reduce sitting and screen time and promote MVPA [22]. Interventions aimed at specifically replacing sitting with standing are less common and are mostly restricted to the occupational office-based environment [23]. Our results suggest that standing time also may be an additional promising interventional target. Given the evident difficulties in promoting MVPA at a population level, this approach might be promising for certain situations and populations/clinical groups where physical activity messages are difficult to disseminate. The only epidemiological study, to our knowledge, that specifically examined the associations of standing time with mortality [24] used a non-substitutional approach and found that the proportion of daily time spent on standing is associated with all-cause and CVD mortality in nearly inverse dose–response manner among the physically inactive participants only [24]. Our partition models suggested an independent beneficial effect of standing on mortality (3 % decrease in risk per hour of standing in the whole sample), and this association was present in both those who met and did not meet the physical activity recommendations. These beneficial associations of standing with mortality were even more substantial when standing time displaced SB. The cardiometabolic properties of standing have not been studied extensively, perhaps due to the absence of an established mechanism through which it may benefit health. A rodent model-based hypothesis put forward over a decade ago suggested that prolonged sitting causes dramatic reductions of lipoprotein lipase activity compared to standing up or ambulating [25], although human studies that manipulated experimentally sitting refute this hypothesis as there appears to be no benefit from replacing sitting with standing on blood lipid variables [26–28]. Instead, replacing sitting with standing [26, 29] or light-intensity walking [30] may improve postprandial blood glucose responses and energy expenditure [29].

Assuming that our findings represent causal effects, substituting sitting with standing or other light-intensity PA  may have considerable public health and clinical care implications, e.g. replacing three hours of sitting per day with standing may be associated with a cumulative decrease of 12–18 % in all-cause mortality risk. Working hours account for over half of total waking time [31] and workers in many professions spend on average more than 70 % of their work time sitting [32]. Unlike promoting physical activity, substitution of desk-based sitting for standing is a relatively straightforward intervention that has no additional time and location requirements. Objective British [33] and US data [34] indicate that on average people aged 70 years and older spent approximately 65–80 % of their waking time being sedentary. Substituting sedentary time with standing and light-intensity activity in this challenging age group may be promising.

The strengths of our study are the large population-based sample, the availability of data on a broad range of PA-related behaviours and sleep that collectively account for the majority of the 24-hour daily cycle, the novel statistical approach that allows examination of replacement effects, and the multiple measures we took to reduce the chances of reverse causation and confounding. While the relatively low 45 and Up response rate (19 % [13]) may be seen as a threat to the generalizability of our findings, it is unlikely that our results were materially compromised as relative risks based on internal comparisons are not dependent on the representativeness of the cohort. A previous analysis that compared a broad range of exposure-outcome associations in the 45 and Up cohort with another New South Wales population study with much higher response rate (~60 %) found that the relative risk estimates in the two studies were almost identical in both magnitude and direction [35]. A limitation of our work was that the exposures were only measured at baseline and our data did not reflect complete time-use as we lacked information on other light-intensity physical activity (non-walking/non-standing activities <1 · 5 MET). Our measure of screen time did not differentiate between recreational and occupational screen time, as the health effects of TV and other recreational screen [5, 6] may be different to those of e.g. occupational computer use. Our study is based on statistical modeling and not on actual replacements of one activity with another. Our time-dependent variables were all self-reported although many have been previously validated and our results further support their convergent validity. Standing, sitting, and sleeping were measured on a different scale to walking and MVPA and this may have affected comparability of the responses to some extent. Physical activity may have been over-reported and sitting time under-reported due to social desirability bias. There was no information on walking pace so it is not possible to make inferences about its intensity.

Sedentary time was associated with increased risk and physical activity with decreased risk for all-cause mortality in adults aged ≥45 years. The magnitude of these effects varied broadly according to the behaviour displaced and there was evidence of an activity intensity-graded response. Isotemporal substitution modelling offers richer and more specific insights into the associations of each time-dependent activity class with mortality compared to traditional non-substitutional approaches.