Crabtree, D. R. | Search bioRxiv

bioRxiv2025

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 physical activity (PA) with age has remained both elusive and difficult to overcome. Older (50-70 years old) compared with younger (17-30 years old) UK participants showed reduced PA, and this profile was effectively modelled in mice. Analysis of brain serotonin (5-HT) neurons in the dorsal raphe (DR) revealed altered firing activity in older mice. Chemogenetically mimicking this 5-HTDR tone in young adult mice produced an older adult PA profile. Genetically blocking 5-HT activity at 5-HT2C receptors (5-HT2CRs) prevented the decline in PA with age. Importantly, barring 5-HT action at 5-HT2CRs specifically within the ventral tegmental area restored youthful PA levels and strength in older mice. These data fill a longstanding knowledge gap by defining brain circuitry programming the decline in PA with age, and importantly, a means to reverse it.

neuroscience↗

bioRxiv2023

Augmented gut hormone response to feeding in older adults exhibiting low appetite.

Age-related changes in gut hormones may play a role in anorexia of ageing. The aim of this study was to determine concentrations of ghrelin, PYY, and GLP-1 in older adults exhibiting an anorexia of ageing phenotype. Thirteen older adults with healthy appetite (OA-HA; 8f, 75{+/-}7 years, 26.0{+/-}3.2 kg{middle dot}m-2), fifteen older adults with low appetite (OA-LA; 10f, 72{+/-}7 years, 23.6{+/-}3.1 kg{middle dot}m-2), and twelve young adults (YA; 6f, 22{+/-}2 years, 24.4{+/-}2.0 kg{middle dot}m-2) completed the study. Healthy appetite and low appetite were determined based on BMI, habitual energy intake, self-reported appetite, and laboratory-assessed ad libitum lunch intake. Participants provided a fasted measure of subjective appetite and blood sample (0 minutes) before consuming a standardised breakfast (450 kcal). Appetite was measured every 30 minutes for 240 minutes and blood was sampled at 30, 60, 90, 120, 180 and 240 minutes. At 240 minutes, an ad libitum lunch meal was consumed. Relative energy intake at lunch (expressed as percentage of estimated total energy requirement) was lower for OA-LA (19.8{+/-}7.7%) compared with YA (41.5{+/-}9.2%, p<0.001) and OA-HA (37.3{+/-}10.0%, p<0.001). Ghrelin suppression was greater for OA-LA than YA at 90 minutes (-512{+/-}477 pg{middle dot}mL-1 vs. 174{+/-}182 pg{middle dot}mL-1, p=0.045) and 180 minutes (-502{+/-}147 pg{middle dot}mL-1 vs. -208{+/-}202 pg{middle dot}mL-1, p=0.049), and lower than OA-HA at 60 minutes (-447{+/-}447 pg{middle dot}mL-1 vs. -125{+/-}169 pg{middle dot}mL-1, p=0.039). GLP-1 concentration was higher for OA-LA compared with YA at 180 minutes (5.00{+/-}4.71 pM vs. 1.07{+/-}2.83 pM, p=0.040). Net AUC for PYY response to feeding was greater for OA-LA compared with OA-HA (p=0.052). No differences were seen in subjective appetite. These observations in older adults exhibiting an anorexia of ageing phenotype suggest augmented anorexigenic responses of gut hormones to feeding may be causal mechanisms of anorexia of ageing.

physiology↗