Does Succinic Acid Treatment Improve Metabolic Health in a Murine Model of Early Aging?

Abstract

Aging is associated with a decline in metabolic health, specifically increased body weight, adiposity, mitochondrial dysfunction, and impaired insulin-stimulated glucose transport contributing to greater incidence of type II diabetes, even in early aging. Previously, we have documented that succinic acid (SA) improves mitochondrial function likely through increased mitochondrial biogenesis; however, the effects of SA on age-related metabolic health are unknown. Therefore, we sought to determine the effect of SA treatment on metabolic health in an early aging mouse model. Methods Metabolic health was measured in 43 mice (24 young (YG) vehicle, 19 aged (16 months); aged mice were randomized to vehicle (n=8) or succinic acid (n=11, 0.75 mg/ml in drinking water), respectively). After 6 weeks of treatment, insulin, glucose, and pyruvate tolerance tests were completed, and physical activity (PA), via spontaneous wheel running, was assessed for both the young and aged mice. Body weight (BW), epididymal white adipose tissue (EWAT) and heart mass measurements were obtained to assess possible effects on obesity, adiposity, and heart health. Results The aged mice had significantly increased BW (YG 27 ± 4 vs. Aged 38 ± 3g), heart weight (YG 0.13 ± 0.01 vs. Aged 0.17 ± 0.01 g), and EWAT mass (YG 0.51 ± 0.08 vs. Aged 1.4 ± 0.38 g) (all, p<0.05). Aged also had reduced pyruvate tolerance (YG 25470 ± 1206 vs. Aged 31883 ± 4348 area under the curve, AUC, p<0.05), though glucose (YG 47119 ± 3460 vs. Aged 43979 ± 8750 AUC) and insulin tolerance (YG 15425 ± 4364 vs. Aged 14928 ± 1762 AUC) were not affected by age (both, p>0.05). PA tended to be ~50% lower in the aged (YG 8778 ± 5774 vs. Aged 4132±1523 rev) mice, while aged mice treated with SA increased PA by 48% (6118 ± 2203 rev). SA treatment had no effect on BW (Aged 37.8 ± 2.7 vs. Aged-SA 37.7 ± 3.2 g), EWAT mass (Aged 1.4 ± 0.4 vs. Aged-SA 1.3 ± 0.4g), nor heart mass (Aged 0.17 ± 0.01 vs. Aged-SA 0.19 ± 0.04g) (all, p>0.05). Despite no significant age difference in glucose tolerance, SA treatment seemed to reduce the AUC in the aged animals (Aged 43979 ± 8750 vs. Age-SA 37181 ± 5383 AUC, p= 0.11); however, no such effect for SA was found with insulin or pyruvate tolerance. Conclusion In a murine model of early aging, despite elevated body weight, adiposity, and heart weight, we found no age-associated impact on glucose or insulin tolerance, though the impaired pyruvate tolerance is suggestive of greater gluconeogenesis in this model of early aging. Treatment with SA had no significant effect on body weight or adiposity, but we did find tendencies for improved glucose tolerance and physical activity. Further work is needed to determine if treatment with succinic acid, an FDA-approved compound, might improve metabolic health with aging.