The mammalian circadian clock governs physiological, endocrine, and metabolic responses coordinated in a 24-h rhythmic pattern by the suprachiasmatic nucleus (SCN) of the anterior hypothalamus. The SCN also dictates circadian rhythms in peripheral tissues like the kidney. The kidney has several important physiological functions, including removing waste and filtering the blood and regulating fluid volume, blood osmolarity, blood pressure, and Ca2+ metabolism, all of which are under tight control of the molecular/circadian clock. Normal aging has a profound influence on renal function, central and peripheral circadian rhythms, and the sleep-wake cycle. Disrupted circadian rhythms in the kidney as a result of increased age likely contribute to adverse health outcomes such as nocturia, hypertension, and increased risk for stroke, cardiovascular disease, and end organ failure. Regular physical activity improves circadian misalignment in both young and old mammals, although the precise mechanisms for this protection remain poorly described. Recent advances in the heart and skeletal muscle literature suggest that regular endurance exercise entrains peripheral clocks, and we propose that similar beneficial adaptations occur in the kidney through regulation of renal blood flow and fluid balance.

Critical biological processes are under control of the circadian clock. Disruption of this clock, e.g. during aging, results in increased risk for development of chronic disease. Exercise is a protective intervention that elicits changes in both age and circadian pathologies, yet its role in regulating circadian gene expression in peripheral tissues is unknown. We hypothesized that voluntary wheel running would restore disrupted circadian rhythm in aged mice. We analyzed wheel running patterns and expression of circadian regulators in male and female C57Bl/6J mice in adult (~4 months) and old (~18 months) ages. As expected, young female mice ran further than male mice, and old mice ran significantly less than young mice. Older mice of both sexes had a delayed start time in activity which likely points to a disrupted diurnal running pattern and circadian disruption. Voluntary wheel running rescued some circadian dysfunction in older females. This effect was not present in older males, and whether this was due to low wheel running distance or circadian output is not clear and warrants a future study. Overall, we show that voluntary wheel running can rescue some circadian dysfunction in older female but not male mice; and these changes are tissue dependent. While voluntary running was not sufficient to fully rescue age-related changes in circadian rhythm, ongoing studies will determine if forced exercise (e.g. treadmill) and/or chrono-timed exercise can improve age-related cardiovascular, skeletal muscle, and circadian dysfunction.

Circadian misalignment occurs with age, jet lag, and shift work, leading to maladaptive health outcomes including cardiovascular diseases. Despite the strong link between circadian disruption and heart disease, the cardiac circadian clock is poorly understood, prohibiting identification of therapies to restore the broken clock. Exercise is the most cardioprotective intervention identified to date and has been suggested to reset the circadian clock in other peripheral tissues. Here, we tested the hypothesis that conditional deletion of core circadian gene Bmal1 would disrupt cardiac circadian rhythm and function and that this disruption would be ameliorated by exercise. To test this hypothesis, we generated a transgenic mouse with spatial and temporal deletion of Bmal1 only in adult cardiac myocytes (Bmal1 cardiac knockout [cKO]). Bmal1 cKO mice demonstrated cardiac hypertrophy and fibrosis concomitant with impaired systolic function. This pathological cardiac remodeling was not rescued by wheel running. While the molecular mechanisms responsible for the profound cardiac remodeling are unclear, it does not appear to involve activation of the mammalian target of rapamycin (mTOR) signaling or changes in metabolic gene expression. Interestingly, cardiac deletion of Bmal1 disrupted systemic rhythms as evidenced by changes in the onset and phasing of activity in relationship to the light/dark cycle and by decreased periodogram power as measured by core temperature, suggesting cardiac clocks can regulate systemic circadian output. Together, we suggest a critical role for cardiac Bmal1 in regulating both cardiac and systemic circadian rhythm and function. Ongoing experiments will determine how disruption of the circadian clock causes cardiac remodeling in an effort to identify therapeutics to attenuate the maladaptive outcomes of a broken cardiac circadian clock.

The mammalian circadian clock operates on a 24-hour cycle and regulates physiological, endocrine, and metabolic responses to changes in the environment. Aging disrupts this circadian process, increasing risk for development of age-associated diseases. Free-wheel running is not only an indicator of circadian rhythm, but also a strong predictor of survival from age-related diseases (i.e. cardiovascular disease). Thus, understanding the impact of age on free-wheel running can lead to a better understanding of disease progression. We analyzed free wheel running in both male and female C57BL/6J mice at young (3-6 months) and old (18-21 months) ages exposed to standard 12h light/dark cycle. Running wheel data was recorded hourly for 10 days. As expected, young female mice ran more than male mice, and old mice ran less than young mice. Regulation of wheel running demonstrated that older mice of both sexes had a delayed start time in activity patterns. Young mice began running immediately at lights off (signaling the start of their active period) and ran consistently throughout the dark phase with peak activity in the first 2 hours. In contrast, older mice had a delayed response to light with peak activity not occurring until hours 4-6 of the dark cycle and nightly activity ending 2 hours before lights on. Ongoing work will assess the central (brain) and peripheral (muscle, cardiac) regulation of free-wheel running in aging. Together, we demonstrate the importance of studying molecular mechanisms underlying circadian misalignment in older individuals to identify ways to combat age-associated disease with circadian misalignment.

Critical cardiovascular processes are under control of the central circadian clock. Disruption of this clock (i.e. during aging) results in increased risk for development of chronic disease such as cardiovascular disease. Exercise is a protective intervention implicit in both age and circadian related pathologies, yet its role in regulating circadian gene expression in the heart remains untested. We hypothesized that circadian rhythm would be disrupted in aged mice and rescued by free‐wheel running. We analyzed wheel running patterns in male and female C57BL/6J mice at young (3–6 months) and old (18–20 months) ages exposed to standard 12h light/dark cycle. As expected, young female mice ran further than male mice, and old mice ran significantly less than young mice. Older mice of both sexes had a delayed start time in activity and early cessation of free‐wheel running, which likely contributes to shorter total diurnal running distances. Free‐wheel running resulted in an expected left ventricular (LV) hypertrophy in young animals, however older animals demonstrated a regression of LV mass. Old mice demonstrated dysregulated cardiac circadian clock expression (BMAL, Per2) compared to young animals, an effect which was not rescued by free‐wheel running. Together our data suggest that the aged heart undergoes a unique adaptation to running compared to the young heart. While voluntary running was not sufficient to rescue age‐related changes in circadian rhythm, ongoing studies will determine if forced exercise and/or chronotimed exercise can improve age‐related cardiac and circadian dysfunction.