| ObjectivesTo explore whether and how the pattern(timing and duration)of parent-child separation is associated with accelerated cellular aging,particularly with respect to functional aging and replicative senescence,indexed by telomere length(TL)attrition and mitochondrial DNA copy number(mtDNAcn)change,among adolescents aged 8-15 years during a two-year follow-up and to examine the interaction between different dimensions.MethodsThis cohort study was conducted in Chizhou,Anhui Province,one of the major rural migrant-sending regions,and 20%of participants in grades 4 to 8 without severe physical and mental disorders were randomly selected.In November 2019(baseline,T1),a total of 252 participants(8-15 years old;114 girls[45.2%]and 138 boys[54.8%])from two local primary and secondary schools were invited to participate in the study.Information on parent-child separation were reported by both adolescents and their primary caregivers.According to the timing and duration of parent-child separation,the participants were divided into three groups:no parent-child separation group(n=154),childhood(0-6 years of age)parent-child separation group(n=55),and prolonged(birth to present)parent-child separation group(n=43).All participants completed questionnaire surveys,physical examination,and oral swab sample collection in November 2019(baseline,T1),November 2020(one-year follow-up,T2),and October 2021(two-year follow-up,T3).At each wave,depressive symptoms were assessed using the Chinese version of the self-reported Mood and Feelings Questionnaire(MFQ),and self-harm behaviors were assessed using the non-suicidal self-injury(NSSI)questionnaire.Variables of psychological and behavioral problems were transformed into binary variables for all analyses.At the same time,oral swabs were collected from the adolescents,and TL and mtDNAcn were quantified using monochromatic multiple quantitative PCR(MMqPCR).One-way ANOVA and χ2 test were used to compare the differences in age,gender,BMI,family adversity events,family economic status,baseline psychological and behavioral problems,lifestyle,health status,TL,and mtDNAcn among adolescents with different parent-child separation experiences.The fixed effects logistic regression model was used to explore the association between parent-child separation experience,cellular aging groups,and psychological and behavioral problems during the two-year follow-up period.The fixed effects linear regression model was used to evaluate the association between different parent-child separation experiences and cellular aging biomarkers.Fixed-effects multiple logistics regression was used to explore the combined effect of replicative and functional cellular aging in adolescents with persistent parent-child separation.ResultsThe mean age was 11.85(SD:1.45)years old,including 138 males(54.76%)and 114 females(45.24%).Among the 252 adolescents,38.9%(98/252)of them separated from their parents during childhood.Among the adolescents with early-life parent-child separation,55(56.1%)of whom regained parental care during the transition period of adolescence,and the remaining 43(43.9%)of whom experienced prolonged parent-child separation till now.In the total sample,68(28.5%)had depressive symptoms and 79(29.9%)had NSSI behaviors.In the total sample,there was a downward trend in TL.After the 2-year follow-up,adolescents with childhood and prolonged parent-child separation had 11%and 44%shorter telomeres than baseline.For mitochondrial DNA copy number,mtDNAcn change in the following 2 years showed an opposite trend among adolescents with prolonged parent-child separation and those without or only childhood separation.Specifically,after the 2-year follow-up,adolescents with prolonged parent-child separation had a decrease of 73%in mtDNAcn,and in contrast,there was an increase of 32%and 13%in adolescents with childhood or without parent-child separation.Further comparison of the change rates between groups found that adolescents with prolonged parental separation had 32.4%(95%CI:12.1%,52.8%)and 34.9%(95%CI:16.5%,53.3%)higher in TL attrition and 94.0%(95%CI:71.5%,116.5%)and 70.9%(95%CI:48.5%,93.3%)in mtDNAcn decrease than those without parental separation during one-year and two-year follow-up,respectively.Notably,in mutually adjusted models of the two biomarkers,mtDNAcn decrease remained strongly associated with prolonged parent-child separation after adjusting for TL attrition,while the association between TL attrition and prolonged parent-child separation diminished after adjustment for mtDNAcn.Interestingly,adolescents separated from their parents in childhood but reunited with them during the transition to adolescence showed similar rates of cellular aging with counterparts who never separated from parents.When further exploring the independent and combined effects of parent-child separation experience on the two cellular aging markers,the results showed that prolonged parent-child separation experience was associated with an 8.76-time increased risk of accelerated cellular aging indicated by TL only(95%CI:1.82,43.08)and 5.82-time(95%CI:1.03,13.82)indicated by mtDNAcn only,and the risk of accelerated aging in both dimensions increased by 13.85 times(95%CI:2.62,73.15),suggesting that there may be an additive effect of prolonged parent-child separation on cellular aging.Of note,in this analysis,we still have not found an association between childhood parent-child separation and accelerated aging,no matter independently or in combination.Compared with adolescents who never separated from parents,those with prolonged parent-child separation had 2.65(95%CI:1.43,4.92)times and 2.59(95%CI:1.31,5.12)times higher risk of depression than those without parent-child separation at 1-year and 2-year follow-up,respectively.For NSSI,adolescents with prolonged parent-child separation had 2.8 times(95%CI:1.10,7.14)higher risk after one-year follow-up than those without parent-child separation.Notably,the risk of depressive symptoms and NSSI in the two-year follow-up in adolescents who separated from their parents during childhood but reunited with them during the transition to adolescence were similar to those without parent-child separation.The occurrence of replicative and functional cell aging additively contributes to the risk of NSSI.In comparison with individuals with low TL attrition and low mtDNAcn change as a reference group,the risk of NSSI was stepwise increased across groups by high TL attrition(OR=1.02,P>0.05)or high mtDNAcn change(OR=1.98,P>0.05)or both.The group with high TL and high mtDNAcn exhibited a 2.43-time increase in the risk of self-harm(95%CI:1.09,5.39).ConclusionThe present study suggests that the combined use of replicative and functional cell senescence is more effective in identifying adolescents at risk for cellular aging and psychological behavior problems;biomarkers regarding dysfunction may be more likely to reflect biological erosion beyond the established biomarker TL.Similar rates of cellular aging between adolescents reunited with parents during adolescence and those who have never experienced separation indicate that adolescence may confer a window of opportunity to buffer the biological effects of early parent-child separation.Taken together,this study demonstrates the effectiveness of functional markers in identifying cellular senescence and that the period of adolescence has the potential to reverse or remediate biological damage through interventions that target caregiving. |
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