Abolishing the 24-hour clock by knocking out a key gene during development accelerates aging and shortens lifespan by two thirds in mice, but this effect is absent if the gene deletion is delayed until after birth, according to a new study published this week inScience Translational Medicine.
As humans age, biological rhythms flatten, slow down, and eventually stop. Whether this relationship between aging and the molecular clock that drives such rhythms reflects cause or effect is unknown. To assess the role of the molecular clock in aging, Penn researchers made conditional Bmal1 knockout mice missing the BMAL1 protein only during adult life and compared them with conventional knockouts in which the gene is absent during development.
In both cases, the clock was paralyzed. Cyclical variation in gene expression, behavior, and blood pressure was abolished. However, while some effects suggestive of aging were common to both strains of mice - cataracts and signs of neurodegeneration - others, including lifespan, fertility, and signs of arthritis were absent when Bmal1 deletion was delayed until after birth. Indeed, in some cases - such as the capacity for hair regrowth after shaving - the impact of the knockout was reversed.
Analysis of gene expression showed that while both knockouts stopped genes oscillating in a circadian rhythm, the conventional knockouts also changed the overall expression of many non-cycling genes, which functionally may explain the divergent findings.
The conventional knock out of Bmal1 has been used extensively to implicate the molecular clock in body functions and disease. The findings prompt reconsideration of these assumptions and highlight the need to understand the role of clock genes during development.
"Indeed, the importance of Bmal1 expression during development in the determination of lifespan is reminiscent of the Barker hypothesis, which postulates that the fetal environment influences disease expression and lifespan in humans after birth," senior author suggested. "The Barker hypothesis has been thought to reflect the epigenetic impact of maternal exposures, such as to cigarettes, alcohol, or toxins in the environment. Given the anticipatory role of the clock, an intriguing possibility raised by these findings is that the timing of such exposures might modulate their impact on postnatal life."