· u l a v P ) 8 1 6 9 = n ( ) 6 8 9 8 7 1 = n ( · u l a v P ) 9 3 2 4 2 = n ( ) 3 0 5 9 2 3 = n ( c i t s i r e t c a r a h C ) 4 . 2 2 ( 3 7 2 3 ) 8 . 9 1 ( 8 6 7 9 2 ) 1 . 2 2 ( 3 2 1 2 ) 9 . 9 1 ( 5 8 5 5 3 ) 3 . 2 2 ( 6 9 3 5 ) 8 . 9 1 ( 3 5 3 5 6 t r o h S ) 5 . 3 4 ( 6 6 3 6 ) 7 . 1 4 ( 7 0 7 2 6 ) 6 . 3 4 ( 3 9 1 4 ) 7 . 1 4 ( 2 5 6 4 7 ) 6 . 3 4 ( 9 5 5 0 1 ) 7 . 1 4 ( 9 5 3 7 3 1 r e i r r a c 4 E O P A . g n d n u o r i f o e s u a c e b 0 0 1 o t m u s t o n y a m s e g a t n e c r e P * . x e d n I y t i d b r o m o C n o s l r a h C i . g n i s u o h d n a , y t i l i b a l i a v a r a c , t n e m y o p m e , s s a l c l a i c o s n o n o i t a m r o f n l i s e n b m o c h c i h w i , x e d n

2 m / g k 0 3 5 . 8 1 : x e d n i s s a m y d o b s a d e n i f e d s a w e p a h s y d o b y h t l a e H . s e r o c s k s i r c i n e g y l o p o t g n d r o c c a ) e l i t n u q t s e h g h > ( i i i t r o h s d n a , ) s e l i t n u q 4 2 ( e t a i d e m r e t n i i , ) e l i t n u q t s e w o l < ( g n o i l s a d e i f i s s a l c e r e w s e i r o g e t a c k s i r c i t e n e G

Original research life lost regardless of which lifespan group an individual is at, and the subgroup of long lifespan and unfavourable lifestyle has the most years of life lost (figure 2). Among individuals with a genetic propensity for short lifespan (high PRS), those with a favourable lifestyle (high HLS) would have 5.22 (95% CI 5.18 to 5.24) years longer of lifespan than those with an unfavourable lifestyle (low HLS) (online supplemental table 13). Given that the largest proportion of participants had four healthy lifestyle factors (28.91%), the optimal lifestyle combination for a prolonged lifespan were derived to be never smoking, regular physical activity, adequate sleep duration, and healthy diet, according to the rank of the size of the effect estimates (online supplemental table 14).

Discussion In this study, we comprehensively investigated the associations between genetic risk and lifestyle risk factors regressed against lifespan in 353 742 participants of the UK Biobank cohort. Our results indicated that a high genetic risk was associated with a 21% increased risk of death compared with a low genetic risk, independent of lifestyle factors. In contrast, an unfavourable lifestyle was associated with an approximately 78% increased risk of death compared with a favourable lifestyle within and across genetic risk categories. Furthermore, the genetic risk of a shorter lifespan or premature death might be offset by a favourable lifestyle by approximately 62%. Participants with a genetic predisposition to a short lifespan and an unfavourable lifestyle had a 2.04 times higher death risk compared with those with a genetic predisposition to a long lifespan and a favourable lifestyle. Our study also indicated that adherence to healthy lifestyles could substantially att