Biomarkers of Oxidative and Mitochondrial Stress Are Associated With Accelerated Pace of Aging at Midlife in a Birth Cohort

Abstract

Oxidative stress and mitochondrial dysfunction are proposed to play prominent roles in the biology of aging. Human studies are limited and confounded by metabolic disturbances associated with age-related diseases. In this study, we have measured biomarkers of oxidative and mitochondrial stress in blood samples from up to 864 participants in the longitudinal Dunedin Multidisciplinary Health and Development Study at age 45. We then determined the correlation between these cross-sectional biomarkers and the longitudinal Pace of Aging, a composite score that represents whole-organism functional decline in each participant from 26 to 45 years old, and facial age at 45 years old. Protein carbonyls and allantoin were selected as biomarkers for oxidative stress, and GDF-15 as a marker of mitochondrial stress. Midlife levels of these biomarkers were low but varied across the population. GDF-15 showed the strongest associations with the Pace of Aging (β = 0.26, p < .0001) and facial age (β = 0.12, p = .001) in sex- and smoking-adjusted models. The Pace of Aging was also significantly associated with allantoin (β = 0.14, p < .0001) and protein carbonyls (β = 0.09, p = .005), and allantoin was associated with facial age (β = 0.08, p = .02). These associations remained when the limited number of participants with age-related disease were removed from the analyses. Our results provide evidence of increased oxidative stress and mitochondrial stress in faster-aging humans at midlife, well before the onset of age-related disease.

Keywords: Aging; Biomarkers; GDF-15; Mitochondria; Oxidative stress.

Figure 1.

Schematic representation of accelerated aging and mitochondrial/oxidative stress measures. (a) The 2 aging measures previously assessed in the Dunedin study: (a) Facial age at age 45, (b) Pace of Aging, a whole-body measure of the rate of aging, based on longitudinal assessment of 19 biomarkers across multiple organ systems measured in study members at 26, 32, 38, and 45 years old. (b) The 3 biomarkers relating to oxidative or mitochondrial stress assayed at age 45: allantoin and protein carbonyls in plasma, and GDF-15 in serum. Created in BioRender https://BioRender.com/a20a284.

Figure 2.

Distributions of oxidative stress and mitochondrial stress biomarkers at age 45. Distributions of each biomarker showing the mean (dashed line, Table 1) and box plots showing median and interquartile range (reported in Supplementary Table 3). (a) Protein carbonyls, N = 860. (b) Allantoin, N = 849 (excludes individuals with chronic kidney conditions), (c) GDF-15, N = 864.

Figure 3.

Associations between Pace of Aging and biomarkers of oxidative and mitochondrial stress by quintiles. (a) Protein carbonyl values plotted by Pace of Aging quintile (mean ± SE): Q1) 0.082 ± 0.0028 nmol/mg (n = 171), Q5) 0.085 ± 0.0016 nmol/mg (n = 172), Cohen’s d = 0.12 (95% CI: −0.09; 0.34). (b) Allantoin values plotted by Pace of Aging quintile, (mean ± SE): Q1) 2.0 ± 0.054 µM (n = 170), Q5) 2.4 ± 0.056 µM (n = 167), d = 0.51 [0.30; 0.73]. (c) GDF-15 values plotted by Pace of Aging quintile (mean ± SE): Q1) 434 ± 10 pg/mL (n = 173), Q5) 611 ± 21 pg/mL (n = 172), d = 0.82 [0.60; 1.0]. (d) Pace of Aging values plotted against protein carbonyl quintile (mean ± SE): Q1) 0.955 ± 0.020 (n = 171), Q5) 1.05 ± 0.024 (n = 171), d = 0.35 [0.13; 0.56]. (e) Pace of Aging values plotted against allantoin quintile (mean ± SE): Q1) 0.915 ± 0.023 (n = 169), Q5) 1.02 ± 0.023 (n = 168), d = 0.36 [0.14; 0.57]. (f) Pace of Aging values plotted against GDF-15 quintile (mean ± SE): Q1) 0.880 ± 0.018 (n = 173), Q5) 1.13 ± 0.025 (n = 172), d = 0.89 [0.66; 1.1]. Error bars are mean and standard error; t tests comparing the bottom and top quintile (2-tailed) were performed for each marker, *p = .05, **p = 0.01, ***p < .001, ****p < .0001. For full descriptive statistics per quintile, see Supplementary Table 4.