Brain serotonin circuit reverses decline in physical activity with age

Physical inactivity increases with age and is the fourth leading risk factor for mortality. Establishing the mechanisms underpinning declining activity with age has remained both elusive and difficult to overcome. Older (50-70 years old) compared with younger (17-30 years old) United Kingdom participants showed reduced physical activity, and this profile was effectively modelled in mice. Analysis of brain serotonin neurons in the dorsal raphe (5-HT^DR) revealed altered firing activity in older mice. Chemogenetically mimicking this 5-HT^DR tone in young adult mice produced an older adult physical activity profile. Genetically blocking 5-HT activity at 5-HT_2C receptors prevented the decline in physical activity with age. Importantly, barring 5-HT action at 5-HT_2C receptors specifically within the ventral tegmental area restored youthful physical activity levels and strength in older mice. These data fill a longstanding knowledge gap by defining brain circuitry programming the decline in physical activity with age, and importantly, a means to reverse it.