| Physical inactivity is one of the most serious public health challenges in the 21st century.Worldwide,approximately 7.2%of all-cause deaths and 7.6%of cardiovascular disease(CVD)deaths are estimated to be attributed to physical inactivity.The World Health Organization(WHO)recommends that adults should do at least 150 minutes/week of moderate physical activity(MPA),75 minutes/week of vigorous physical activity(VPA)or an equivalent combination of physical activity(PA)to keep healthy.However,whether the health benefits from an equivalent amount of MPA or VPA differ is still unknown.Current evidence indicated that compared with MPA,participation in VPA might be associated with lower risks of all-cause and CVD mortality;however,inconsistency still exists and evidence on associations of different PA intensities with mortality from the Asian population is scarce.The mechanism underlying the inverse association of PA with reduced mortality risk remains unclear.Inflammation and oxidative stress have been considered as potential mechanisms underlying the occurrence of death and CVD.Counts of peripheral blood white blood cell(WBC),as well as its major subtypes including lymphocytes,monocytes,neutrophils,eosinophils,and basophils,are important indicators to reflect inflammatory levels in clinical practice.Previous studies have shown that risks of all-cause and CVD mortality increased with the increasing of peripheral total WBC counts.Mitochondrial DNA copy number(mtDNAcn)is a key indicator of oxidative stress,the decrease of which was also closely associated with all-cause and CVD mortality.Emerging evidence has suggested that PA could mitigate the levels of inflammation and oxidative stress;however,whether peripheral total and differential WBC counts,and mtDNAcn mediate the associations of PA with all-cause and CVD mortality remain to be explored.To narrow the knowledge gap,based on the Dongfeng-Tongji Cohort(DFTJ)and the UK Biobank(UKB),we investigated the independent and combined associations of different intensities of PA with all-cause and CVD mortality in the first part of the study.We further explored the mediating effect of peripheral total and differential WBC counts on the associations of PA with risks of all-cause and CVD mortality in the second part of the study.Last,we explored the mediating effect of mtDNAcn on the associations of PA with risks of all-cause and CVD mortality in the third part of the study.Part 1 Associations of physical activity with all-cause and cardiovascular mortalityObjective:To investigate the associations of different intensities of PA with all-cause and CVD mortality among Chinese and UK middle-aged and old adults.Methods:This study included 26 584 participants from the DFTJ and 329 296 participants from the UKB without CVD,cancer,abnormal electrocardiogram and with complete PA information at baseline,based on a prospective study design.According to the definition of different intensities of PA suggested by WHO,activities with a metabolic equivalent task(MET)coefficient of 3.0-5.9 were defined as MPA;activities with≥6 MET were defined as VPA.The total PA amount was calculated by a weighted summation of the corresponding MET,frequency/week,and duration/time of PA(MET-hours/week),the proportion of VPA to total PA was categorized into three groups(0%,0%-30%and>30%).To explore the joint effect of different intensities of PA on mortality,this study further combined MPA(<150,150-300,≥300 minutes/week)and VPA(<75,≥75 minutes/week)into a joint exposure variable according to WHO recommended value and took those with MPA<150 and VPA<75 minutes/week(the lowest PA group)as the reference group.The Cox proportional hazards regression model was used to calculate the hazard ratios(HRs)and 95%confidence intervals(CIs)for PA associated with all-cause and CVD mortality.Restricted cubic spline was used to explore the exposure-response relationship of the above associations.Results:After 5.7 and 11.9 years,respectively,of follow-up for DFTJ and UKB,17 113 deaths(DFTJ:1 402;UKB:15 711)and 3 345 CVD deaths(DFTJ:454;UKB:2 891)occurred.With the increasing of total PA,the risks of all-cause and CVD mortality decreased.Each log10(MET-hours/week)increment of total PA amount was associated with 22%(HR:0.78,95%CI:0.76-0.81)and 21%(HR:0.79,95%CI:0.73-0.85)lower all-cause and CVD mortality risks,respectively.Compared with MPA,0%-30%VPA to total PA was associated with lower risks of all-cause mortality(HR:0.81;95%CI:0.77-0.84)and CVD mortality(HR:0.73;95%CI:0.66-0.81).Joint analysis showed that compared with participants in the lowest PA group,those with 150-300 minutes/week of MPA and≥75 minutes/week of VPA were associated with lower all-cause mortality(HR:0.70,95%CI:0.64-0.77).Conclusions:In the Chinese and UK middle-aged and old adults,increasing PA levels were significantly associated with lower risks of all-cause and CVD mortality.Compared with those only participating in MPA,0%-30%of VPA to total PA was associated with lower risks of all-cause and CVD mortality.Middle-aged and old adults might gain most health benefit when performing 150-300 minutes of MPA and at least 75 minutes of VPA per week.Part 2 The mediating role of peripheral total and differential white blood cell count underlying the associations of physical activity with all-cause and cardiovascular mortalityObjective:To investigate the mediation effects of peripheral total and differential WBC counts on the associations of PA with all-cause and CVD mortality among Chinese and UK middle-aged and old adults.Methods:This part of study included 23 945 participants from the DFTJ and 313 600 participants from the UKB without CVD,cancer,abnormal electrocardiogram and with complete information on PA and peripheral total WBC counts at baseline,based on a prospective study design.Generalized linear model was used to calculate the associations of PA with peripheral total and differential WBC counts.Cox regression model was used to assess the associations of peripheral total and differential WBC counts with all-cause and CVD mortality."Mediate" macro was used to explore the mediation effects of peripheral WBC and subtypes on the associations of PA with all-cause and CVD mortality.Results:In the DFTJ and UKB,PA was inversely associated with peripheral total WBC,neutrophil,neutrophil-to-lymphocyte ratio(NLR;P<0.05).Each 1×109 cells/L increment of peripheral total WBC counts was associated with 5%(HR:1.05;95%CI:1.00-1.09)and 9%(HR:1.09;95%CI:1.08-1.10)higher risks of all-cause mortality;10%(HR:1.10;95%CI:1.02-1.19)and 11%(HR:1.11;95%CI:1.08-1.14)higher risks of CVD mortality,respectively.In the DFTJ,there was no significant mediation effect of peripheral total WBC and subtypes on the associations of PA with all-cause and CVD mortality.In the UKB,the association of PA with all-cause mortality was mediated by the peripheral total WBC(mediated proportion:5.2%;95%CI:3.8%-7.2%)and neutrophils counts(mediated proportion:6.7%;95%CI:4.7%-9.5%);the association of PA with CVD mortality was mediated by the peripheral total WBC(mediated proportion:18.6%;95%CI:2.8%-64.2%)and neutrophils counts(mediated proportion:27.6%;95%CI:3.5%-80.2%),respectively.Conclusions:In Chinese and UK middle-aged and old adults,increasing peripheral total WBC counts were positively associated with the risks of all-cause and CVD mortality.Peripheral total WBC and neutrophil counts significantly mediated the associations of PA with all-cause and CVD mortality in UK participants.Part 3 The mediating role of mitochondrial DNA copy number underlying the associations of physical activity with all-cause and cardiovascular mortalityObjective:To investigate the mediation effects of mtDNAcn on the associations of PA with all-cause and CVD mortality in Chinese middle-aged and old adults.Methods:This part of study included 673 participants measured mtDNAcn and with cycle threshold(Ct)≤0.3 from the 2008 survey of DFTJ,based on a prospective study design.Regular PA was defined as regularly participating in PA for at least 30 min for at least 5 times per week,those performed regular PA was further categorized to<5 years and≥5 years groups.Generalized linear model was used to examine the associations of regular PA and years with mtDNAcn.Cox regression model was used to assess the associations of mtDNAcn with all-cause and CVD mortality."Mediate" macro was used to explore the mediation effects of mtDNAcn on the associations of regular PA with all-cause and CVD mortality.Stratified analyses were used to explore the potential modified effects by age(<65 years,≥65 years),gender(men,women),body mass index(BMI;<24 kg/m2,≥24 kg/m2),smoking(yes,no),drinking(yes,no),hypertension(yes,no),hyperlipidemia(yes,no),diabetes(yes,no)on associations of regular PA and years with mtDNAcn.Results:Compared with those without regular PA,regular PA(β:0.173;95%CI:0.0440.302)and at least 5 years of regular PA(β:0.152;95%CI:0.032-0.272)were both positively associated with mtDNAcn.No significant association of mtDNAcn with all-cause and CVD mortality was observed,the multivariate adjusted HRs(95%CIs)of each log2(mtDNAcn)was 0.97(0.72-1.30)for all-cause mortality and 0.99(0.58-1.69)for CVD mortality.There was no significant mediation effect of mtDNAcn on the associations of regular PA with all-cause and CVD mortality.Stratified analyses showed that age modified the association of regular PA with mtDNAcn(Pinteraction=0.010);diabetes status modified the association of at least 5 years of regular PA with mtDNAcn(Pinteraction=0.014).Conclusions:In Chinese middle-aged and old adults,regular PA was positively associated with mtDNAcn.No significant mediation effect of mtDNAcn on associations of regular PA with all-cause and CVD mortality was observed.In addition,age and diabetes status significantly modified the association of regular PA with mtDNAcn. |
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