Telomeres are DNA‒protein complexes composed of base pairs of TTAGGG repeats at the end of linear chromosomal DNA [1
], which protect the DNA from damage [2
]. Telomeres shorten with cell replication and cell division [3
] and reflect cell turnover. In adults, shortened leukocyte telomere length reflecting the different lengths of telomeres at the ends of the 23 chromosomes [4
], has been suggested as a robust biomarker related to biological aging [5
]. Short telomere length has been associated with increased risks for morbidity and mortality [10
One of the major proposed factors for shortened telomere length is mental health, specifically the status of depression [11
], although mixed findings on the relationship between depression and telomere length have been reported in cross-sectional and prospective cohort studies [16
]. In a general Danish population study, short telomere length was not associated with an increased risk of depression [19
]. A large-scale population-based study demonstrated no association between telomere length and depression, whereas a relatively small sample-based study reported an inverse relationship between telomere length and depression. These inconsistent findings may be due to the presence of chronic inflammation, which influences both depression and telomere length.
Depression is commonly associated with suicidal behavior and medical illnesses related to a further enhanced suicide risk [20
]. In particular, medical disorders have been identified as a significant risk factor for both suicidal behavior and suicidal ideation, especially among depressed patients [20
]. Short telomere length may be involved not only in depression but also in determining the increased rate of both medical disorders and suicidality. Specifically, the existence of a previous mood disorder, prior and current history of medical disorders, and cognitive impairment were reported to be the most important risk factors for suicide.
Previous research on the mechanisms of telomere erosion identified inflammation as having an important influence on telomere length [21
]. In particular, chronic inflammation has been suggested to influence overall cell turnover and is associated with a shorter telomere length [23
] as well as an increased risk for depression [24
]. However, limited knowledge exists on the combined effects of inflammation and depression on telomere length in young adults.
Therefore, in the present study, we hypothesized that there are different combined effects of inflammation and depression status on telomere length in young adults in the USA. The aim of this study was to investigate the interrelationships among inflammation, depression, and telomere length using a nationally representative sample of adults in the USA.
In the present study, we observed a significant association between elevated levels of inflammation and shortened telomere length only in men without depression. We did not observe this relationship in men with major depression or depressed affect or in women regardless of the depression status. Consistent with our findings, Needham et al. [17
] reported a lack of association between depression, anxious symptomology, and telomere length in young adults across different racial and ethnic groups using the NHANES 1999–2002. The authors indicated that the lack of association might have been due to the fact that telomere length reflects biological aging in later life, rather than in the early stages of life. This explanation can be applied to our findings of a lack of associations between CRP and telomere length in both men and women with depression.
People become less resilient to stress because physiological aging may modify the responsivity to stress [32
]. Although the underlying mechanisms still need to be investigated, this might be partially explained by the kynurenine pathway, which is part of tryptophan catabolism [34
]. As the kynurenine pathway is activated, tryptophan levels decrease, which may lead to depression [35
] and age-related neurodegenerative diseases [36
]. This was also supported by a previous animal study using female Wistar rats that indicated significant changes in the kynurenine pathway with increasing age [37
]. Furthermore, higher accumulation levels of damaged tissues and cells were observed in advanced age. Such oxidized proteins are more likely to be attacked by free radicals, and this may contribute to oxidative stress [38
]. Therefore, participants aged 20–39 years may be resilient to stress, which was not indicated by shortened telomere length in our study.
In another study by Shaffer et al. [18
], the authors suggested that the absence of an association between concurrent depressive symptoms and telomere length may reflect the fact that leukocyte telomere length is influenced by cumulative environmental factors over time, whereas assessments of depressive symptoms generally focus on only the past 1–2 weeks. This explanation could also apply to our study findings, since telomere length reflects a long period of time, whereas the survey assessed depression status over the past 12 months.
In this study, a linear regression model revealed that telomere length decreased as CRP levels increased in men, regardless of the depression status, and in women with major depression or depressed affect, but not in women without depression. This illustrated an inverse linear relationship between telomere length and inflammation in young adults in the USA, except for women without depression. Similar results were observed for multivariable logistic analyses. Among men without depression, those with higher levels of inflammation (CRP > 0.2 mg/dL) had increased odds of having shortened telomere length compared to those in men with lower levels of inflammation (CRP ≤ 0.2 mg/dL). In contrast, there was no association between CRP, depression status, and telomere length in women.
Contrasting findings to those of the present study could be partially explained by sex differences due to hormonal responses, estrogen vs. testosterone, and antioxidant capacity [33
] between men and women. Testosterone increases susceptibility to oxidative stress [39
], whereas estrogen has been suggested to activate telomerase [40
] and might provide protection to telomeres [41
], antagonizing the effect of telomere shortening during early stages of life [42
]. In addition, previous studies reported significant associations between fluctuations in estrogen levels and the risk of depression [43
] and decreased estrogen level in women experiencing depression [45
]. While estrogen may have telomere protection activity among women without depression, this may not have been the case in the women with major depression or depressed affect in the current study. The present study has several strengths and limitations. Firstly, this study used a racially diverse and nationally representative sample of young adults in the USA; thus, the findings may be generalizable to the young adult population in the USA. Depression was assessed using the CIDI, a reliable and structured instrument [46
]. The study controlled for important confounders including age, family PIR, race/ethnicity, marital status, physical activity, and BMI. Despite the strengths of this study, there are also limitations. Telomere length was measured in leukocytes, which did not reflect telomere length in other cells or tissues. Furthermore, no measurement of telomerase activity was available in this study. High telomerase activity with short telomere length has been associated with distress in early life and impaired psychosocial resources [42
]. Lastly, this research was limited by its cross-sectional design and subsequent inability to address questions of causality regarding how the depression status influences the association between inflammation and telomere length. Future research is warranted to provide insights into the associations between depression, inflammation, and telomere shortening through prospective cohort studies.
In conclusion, there was a significant and inverse linear association between inflammation and telomere length in men with and without depression and women with depression. The associations of inflammation and depression with telomere length differed by sex in young adults in the USA. Among men without depression, those with an elevated CRP level had increased odds of having a shortened telomere length compared to men with low CRP levels after controlling for covariates. Finally, in women, there was no association between CRP and telomere length, regardless of the depression status. The present findings may be of clinical significance for the monitoring of inflammation levels and depression status as determinants of telomere length.