Sedentary Behavior Interrupted - A Pilot Study of Acute Interventions on Prolonged Sitting

Sedentary behavior, characterized by excess sitting time during waking hours, is detrimental
to health and increases cardiometabolic disease (e.g., type 2 diabetes) risk, independent of
moderate-to-vigorous physical activity. The mechanisms that mediate this are unknown and
there are no evidence-based methods known for effectively intervening on sedentary behavior.
The consequences of prolonged sitting time are of particular interest in older adults as
sedentary behavior and cardiometabolic disease risk both increase with aging and
moderate-to-vigorous physical activity may not be feasible. The investigators propose pilot
and feasibility testing of interventions for sedentary older adults that are designed to
interrupt prolonged sitting time. Interrupting sitting time through sit-to-stand
transitions, and standing and walking breaks increases muscle use and blood flow in the
lower parts of the body. Thus, the investigators believe that frequent sit-to-stand
interruptions of sitting time are the most efficacious sedentary behavior interventions,
compared to simply reducing sitting time or less frequent walking breaks, for improving
health outcomes and healthy aging. The investigators hypothesize that frequent sit-to-stands
during a 5-hour sitting period will result in health benefits that can be observed with a
simple 2-minute standing interruption, and that this will be associated with improvements in
metabolism and endothelial function. This pilot, 10-participant study will 1) generate
preliminary data for a revised Program Project Grant application to the National Institute
of Aging (NIA) that focuses on postmenopausal women, the fastest growing aged population
with high life-time risk of cardiometabolic risk. This pilot study will inform sitting
interruption modality design for two projects in the investigators' Program Project Grant
application: "Project 1: Sedentary Behavior Interrupted: A randomized crossover treatment
trial of acute effects on biomarkers of healthy aging in the laboratory (86 participants)"
and "Project 2: Sedentary Behavior Interrupted: A randomized trial of 6 month effects on
biomarkers of healthy aging and physical functioning in the real world (660 participants)."
The current design of this pilot study is enhanced by and responsive to feedback from our
initial NIA submission. This pilot study will increase our knowledge about how sedentary
behavior and sitting interruption interventions influence healthy aging in postmenopausal
women.

SPECIFIC AIM The deleterious health consequences of too much sitting are independent of
moderate-to-vigorous physical activity. Understanding the health consequences of sitting
time is particularly relevant for older adults who are extremely sedentary and at high risk
of several chronic diseases that have been linked with sitting time, including type 2
diabetes. Interestingly, sedentary behavior is least studied among older adults who may
benefit the most from reducing sitting time. Reducing uninterrupted sitting time in older
adults is a research priority because the pervasiveness of sitting time, typically >8 hours
per day, provides many opportunities for intervention. Specific interventions are required
to reduce sitting because it is such a habitual behavior and is reinforced by social norms
and chair-dominant contexts.

In this pilot study, the investigators focus on three different types of prolonged sitting
interruptions as variables. Studies have shown that frequent breaks in sitting may reduce
risk for cardiometabolic disease. In older adults, the investigators anticipate that
frequent sit-to-stand transitions will impact metabolic, inflammatory and other biomarkers,
in particular those related to mitochondrial and endothelial function. A key limitation of
previous sedentary intervention studies is that they have not impacted frequency of
sit-to-stand transitions; rather, they decreased total sitting and increased standing time.
Further, previous sedentary intervention studies have not directly compared frequent
sit-to-stand transition interruptions with other interruption modalities associated with
less frequent sit-to-stand transitions, for example, reduced overall sitting time (standing
more) or with occasional walking breaks. The investigators propose to test these sedentary
behavior interruptions modalities to disrupt prolonged sitting and explore mitochondrial-
and endothelial function-based mechanisms of action. Biologic theories suggest that
interrupting sitting via sit-to-stand muscle contraction and increased blood flow to
extremities is key to improving in healthy aging outcomes.

In a controlled laboratory study of prolonged sitting, 3 different interruption break types
will be utilized. Ten sedentary, postmenopausal participants 55+ years of age and body mass
index (BMI) of 27-45 will be enrolled. After screening and enrollment, participants will
visit the clinic on 4 occasions for a 6-hour monitoring period and, following a 1-hour
sitting run-in period, complete each of 4 5-hour sitting protocols. The 3 sitting
interruption protocols will each include sitting interruptions of different break frequency
and type and will allow evaluation of the effect of sit-to-stand transitions and
interruption type on acute metabolism and health outcomes. All study protocols include
baseline, mid-point, and end-of-study bathroom breaks for urine sample collection with
additional bathroom breaks allowed as needed. During each protocol at multiple time points,
blood samples will be collected to assess changes in biomarkers of glycemic regulation
(glucose and insulin areas under the curve) and mitochondrial function over the course of
the sitting protocols. During each protocol at multiple time points, changes in endothelial
function, specifically, blood pressure (indirect measure) and femoral flow-mediated dilation
(direct measure), will be assessed. Changes in these measures will be compared between
protocols. A small aliquot (0.5mL) of plasma samples and urine samples collected during the
protocol will be banked for possible ancillary, exploratory studies. This study is a
crossover design and each participant will be her own control. The investigators hypothesize
that frequent sit-to-stands during a 5-hour sitting period will result in health benefits
that can be observed with a simple 2-minute standing interruption, and that this will be
associated with improvements in metabolism and endothelial function. The investigators will
test this hypothesis in the following aim:

Study Aim: Using a randomized, controlled crossover study design, assess the feasibility and
metabolic and endothelial function outcomes of an acute bout of prolonged sitting ± standing
or walking interruptions using targeted metabolic and endothelial function biomarker
analyses.

Inclusion Criteria:

1. Postmenopausal woman, any ethnicity/race, 55+ years of age.

2. Ambulatory, medically stable, able to give informed consent, and safely complete the
protocols.

3. Fluent in the English language.

4. Body Mass Index range of 27-45kg/m2.

5. Sedentary: Average ≥6hr sitting time, and <20min physical activity on 3 or more days
per week, as assessed by self report.

Exclusion Criteria:

1. Mental states that would preclude complete understanding of the protocol and
compliance.

2. Chronic illness that may be associated with weight change (HIV/AIDS, active cancer,
or uncontrolled thyroid disease).

3. Body Mass Index <27 or >45kg/m2.

4. Anemia (hemoglobin ≤11g/dL) - determined by CBC test done at screening.

5. Arthritis or degenerative joint disease affecting knees where repeated
sitting/standing interruptions might cause pain.

6. Personal or family history of venous thrombosis.

7. Type 1 diabetes mellitus

8. Poorly controlled hypertension (SBP ≥165 or DBP ≥100).

9. Weight instability in past 3 months (no more than 5% up or down).

10. Participants <65 years of age with HbA1c ≥53 mmol/mol (7%) and participants ≥65 years
of age with HbA1c ≥58mmol/mol (7.5%) will be excluded for uncontrolled diabetes.34,35

11. Use of insulin medications.

12. Regular use of vasodilator medication AND high risk of stroke and/or heart attack
(i.e., history of multiple hospitalizations (>2X in the last 6 months), congestive
heart failure, atrial fibrillation, and/or stroke).

13. Use of any immunosuppressant or corticosteroid medication.

14. Use of medications that might cause weight change (e.g., second generation
anti-psychotics).

15. < 6hr average daily sitting time.

17) ≥20min physical activity average on 3 or more days per week 18) Participating in
another clinical trial. 19) Blood donation less than 56 days prior to screening visit. 20)
Smoking cigarettes or anything, and other use of tobacco products.