Sehoon Park^1,2, Seong Geun Kim², Soojin Lee^3,4, Yaerim Kim⁵, Semin Cho⁶, Kwangsoo Kim⁷, Yong Chul Kim², Seung Seok Han^2,8, Hajeong Lee^2,4, Jung Pyo Lee^4,8,9, Kwon Wook Joo^2,4,8, Chun Soo Lim^4,8,9, Yon Su Kim^1,2,4,8 & Dong Ki Kim^2,4,8*

¹Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea;
²Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea;
³Department of Internal Medicine, Uijeongbu Eulji University Medical Center, Seoul, South Korea;
⁴Department of Internal Medicine, SeoulNational University College of Medicine, Seoul, South Korea;
⁵Department of Internal Medicine, Keimyung University School of Medicine, Daegu, South Korea;
⁶Departmentof Internal Medicine, Chung-Ang University Gwangmyeong Hospital, Gyeonggi-do, South Korea;
⁷Transdisciplinary Department of Medicine & Advanced Technology, SeoulNational University Hospital, Seoul, South Korea;
⁸Kidney Research Institute, Seoul National University, Seoul, South Korea;
⁹Department of Internal Medicine, Seoul NationalUniversity Boramae Medical Center, Seoul, South Korea

Correspondence to: Dong Ki Kim, MD, PhD

Background
Ageing traits and frailty are important health issues in modern medicine. Evidence supporting the causal effects of tobacco smoking on various ageing traits is required.

Methods
This study performed Mendelian randomization (MR) analysis instrumenting 377 genetic variants associated with being an ever-smoker at a genome-wide significance level to test the causal estimates from tobacco smoking. The outcome data were obtained from 337 138 white British ancestry participants from the UK Biobank. Leucocyte telomere length, appendicular lean mass index, subjective walking pace, handgrip strength, and wristband accelerometry-determined physical activity degree were collected as ageing-related outcomes. Summary-level MR analysis was performed using the inverse variance-weighted method and pleiotropy-robust MR methods, including weighted median and MR-Egger. Observational association between the outcome traits and phenotypically being an ever-smoker was also investigated.

Results
Summary-level MR analysis indicated that a higher genetic predisposition for tobacco smoking was significantly associated with shorter leucocyte telomere length (twofold increase in prevalence of smoking towards standardized Z-score, −0.041 [−0.054, −0.028]), lower appendicular lean mass index (−0.007 [−0.010, −0.005]), slower walking pace (ordinal category, −0.047 [−0.054, −0.033]) and lower time spent on moderate-to-vigorous physical activity (hours per week, −0.39 [−0.56, −0.23]). The causal estimates were non-significant towards handgrip strength phenotype (kg, 0.074 [−0.055, 0.204]). Pleiotropy-robust MR results generally supported the main causal estimates. The observational findings also showed significant association between being an ever-smoker and the ageing traits.

Conclusions
Genetically predicted and observational tobacco smoking status are significantly associated with poor ageing phenotypes. Healthcare providers may continue to reduce tobacco use, which may be helpful in reducing the burden of ageing and frailty.