The increased risk in aging-related comorbidities associated with obesity is a significant public health concern. Weight loss via lifestyle intervention has been shown to improve negative health outcomes; however, the mechanistic pathway by which this occurs is unknown. One biomarker of importance is Klotho, with higher levels being associated with slower aging processes. Evidence has shown Klotho to be lower in obese adults compared to normal-weight adults. Exercise may independently increase levels of Klotho; however, whether the effects on Klotho are enhanced when exercise is included within the context of a weight loss intervention is not understood. Purpose: The primary aim was to examine changes in Klotho concentration in response to a behavioral weight loss intervention, by intervention condition, and weight loss response. Methods: Three hundred and eighty-three overweight and obese adults (age: 45.0+7.9 years; BMI: 32.4+3.8 kg/m2) were randomized to DIET, DIET+PA150, and DIET+PA250. One hundred fifty-two of 383 participants provided blood samples at all time points, and were classified as “responder” or “non-responder” for this study. The intervention contained a prescribed calorie restricted diet (1200-1800 kcal/day) and increased physical activity (0-, 150-, 250 min/week). Intervention groups attended weekly in-person group sessions for months 1-6, with combined in-person and telephonic sessions for months 7-12. Results: Participants had significant reductions in weight, BMI, and body composition, and increased cardiorespiratory fitness across the 12-month intervention. Klotho concentration also significantly, increased across the 12-month behavioral weight loss intervention (p=0.010); however, there was no difference by intervention group or weight loss response. Although non-significant, participants who performed physical activity had greater changes in Klotho concentration across the 12-month intervention. Further, Klotho concentration was found to be inversely associated with lean body mass (p=0.021). Conclusion: This study provides evidence within the context of a weight loss intervention, that Klotho concentration significantly, but modestly, increases with weight loss. However, despite sustained weight loss, this increase in Klotho was not sustained throughout the intervention. Results do not support weight loss drive Klotho response. However, non-significant results support physical activity to influence Klotho, within the context of obesity and weight loss. Further investigation to examine how weight loss and physical activity may alter biomarkers of aging in adults with obesity is warranted
