MIT study finds that a gene associated with longevity also regulates the body’s circadian clock.
Human sleep and wake cycles are governed by an internal circadian clock that keeps time with the 24-hour light–dark cycle. This central clock also coordinates numerous physiological processes, including metabolism, body temperature, and hormone release. Disruption of this rhythm is linked to metabolic problems such as obesity and diabetes, and epidemiological studies show that people who work night shifts have a higher risk of metabolic disease.
A new study from MIT identifies SIRT1 — a gene previously linked to longevity and cellular stress resistance — as a key regulator of the brain’s central circadian clock. The research shows that circadian function in normal mice declines with age and that increasing SIRT1 levels in the brain prevents this deterioration. Conversely, removing SIRT1 in young mice impairs circadian control and produces patterns similar to those seen in aged animals.
Because SIRT1 protein levels also decline with age in normal mice, the investigators propose that enhancing SIRT1 activity in the human brain could protect circadian function and offer broad health benefits. Leonard Guarente, the Novartis Professor of Biology at MIT and senior author of the study, reports these findings in the June 20 issue of Cell.
Staying on schedule
The brain’s circadian center, the suprachiasmatic nucleus (SCN) within the hypothalamus, organizes most physiological events on a roughly 24-hour timetable. “Almost everything that happens physiologically is staged along the circadian cycle,” says Guarente. Emerging evidence suggests that preserving a strong circadian rhythm supports overall health, and that breakdowns in this timing system carry consequences for metabolism and possibly aging.
Previous work by Guarente linked a robust circadian pattern to increased lifespan in mice, prompting investigation into SIRT1’s role. SIRT1 is a master regulator of cellular responses to stress, coordinating hormone networks, proteins and genes that maintain cellular health. To test its function in the brain’s clock, the team engineered mice with different SIRT1 levels specifically in the brain: normal expression, complete loss, and two overexpression groups (roughly twofold and tenfold increases).
Results showed that mice without SIRT1 exhibited slightly longer circadian periods (approximately 23.9 hours) compared with normal mice (about 23.6 hours), while mice with tenfold SIRT1 overexpression had shorter cycles (about 23.1 hours). When the light–dark schedule was shifted, young mice adjusted their rhythms more readily than older mice, confirming earlier observations. Importantly, mice with elevated SIRT1 maintained circadian resilience with age and did not show the same age-related decline in clock function.
The molecular mechanism appears to involve SIRT1 regulation of BMAL1 and CLOCK, the core transcriptional drivers of the central circadian clock. By modulating these clock genes, SIRT1 helps preserve proper timing signals in the SCN.
Enhancing circadian function
Maintaining the ability to adapt to daily and seasonal fluctuations in light is essential for metabolic health, Guarente notes. “We experience a kind of mini jet lag every day as light cues change; the critical requirement is the ability to adapt smoothly to those jolts,” he says. Laboratory studies indicate young animals adapt quickly, while older animals lose that flexibility — a pattern that may apply to humans.
These findings raise the possibility of preventing or treating age-related metabolic and physiological decline by enhancing circadian function. Potential approaches include delivering SIRT1 activators that can cross the blood–brain barrier or targeting other components of the circadian machinery to preserve function in the aging brain. Some SIRT1-activating compounds are already under study for conditions like diabetes and inflammation, but most are not designed to reach the SCN. Designing brain-penetrant SIRT1 activators could provide a therapeutic avenue to sustain circadian health with age.
Roman Kondratov, an associate professor of biology at Cleveland State University, highlights the study’s translational promise: pharmacological modulators of SIRT1 are actively being developed, and if SIRT1 enhancement can rejuvenate the central clock, it may help delay or reverse age-associated changes in brain function.
Guarente’s laboratory is now exploring how diet interacts with circadian function and SIRT1 activity. They hypothesize that high-fat diets may disrupt circadian timing and that boosting SIRT1 signaling could counteract diet-induced clock dysfunction, potentially improving metabolic outcomes.
Notes about this aging and circadian rhythm research
The work was supported by the National Institutes of Health and the Glenn Foundation for Medical Research.
Contact: Anne Trafton — MIT
Source: MIT press release describing the study
Image Source: The brain image is available in the public domain.
Original Research: Abstract for “SIRT1 Mediates Central Circadian Control in the SCN by a Mechanism that Decays with Aging” by Hung-Chun Chang and Leonard Guarente, published in Cell, June 20, 2013.