Abstract
BackgroundThe potential of anti-aging effect of DPP-4 inhibitors is unknown. This study was performed to determine whether linagliptin, a DPP-4 inhibitor, could protect against premature aging in klotho−/− mice.MethodsKlotho−/− mice exhibit multiple phenotypes resembling human premature aging, including extremely shortened life span, cognitive impairment, hippocampal neurodegeneration, hair loss, muscle atrophy, hypoglycemia, etc. To investigate the effect of linagliptin on these aging-related phenotypes, male klotho−/− mice were divided into two groups: (1) control group fed the standard diet, and (2) linagliptin group fed the standard diet containing linagliptin. Treatment with linagliptin was performed for 4 weeks. The effect of linagliptin on the above mentioned aging-related phenotypes was examined.ResultsBody weight of klotho−/− mice was greater in linagliptin group than in control group (11.1 ± 0.3 vs 9.9 ± 0.3 g; P < 0.01), which was associated with greater gastrocnemius muscle weight (P < 0.01) and greater kidney weight (P < 0.05) in linagliptin group. Thus, linagliptin significantly prevented body weight loss in klotho−/− mice. Survival rate of klotho−/− mice was greater in linagliptin group (93%) compared to control group (67%), although the difference did not reach statistical significance (P = 0.08). None of linagliptin-treated klotho−/− mice had alopecia during the treatment (P < 0.05 vs control klotho−/− mice). Latency of klotho−/− mice in passive avoidance test was larger in linagliptin group than in control group (P < 0.05), indicating the amelioration of cognitive impairment by linagliptin. Cerebral blood flow of klotho−/− mice was larger in linagliptin group than in control group (P < 0.01), being associated with greater cerebral phospho-eNOS levels (P < 0.05) in linagliptin group. Neuronal cell number in hippocampal CA1 region was greater in linagliptin group than in control group (P < 0.05). Linagliptin group had greater cerebral phospho-Akt (P < 0.05) and phospho-CREB (P < 0.05) than control group. Thus, linagliptin ameliorated brain aging in klotho−/− mice. The degree of hypoglycemia in klotho−/− mice was less in linagliptin group than in control group, as estimated by the findings of OGTT.ConclusionsOut work provided the evidence that DPP-4 inhibition with linagliptin slowed the progression of premature aging in klotho−/− mice, and provided a novel insight into the potential role of DPP-4 in the mechanism of premature aging.
Highlights
Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used blood glucose-lowering drug for treatment of type 2 diabetes [1, 2]
To address the potential role of DPP-4 in premature aging, we examined the effect of linagliptin on premature aging phenotypes in klotho−/− mice
Effects of linagliptin on cognitive function, cerebral blood flow, hippocampal neuronal cell, and brain Akt, eNOS, and cAMP response element binding protein (CREB) of klotho−/− mice As shown in Fig. 3a, latency of klotho−/− mice in passive avoidance test was significantly larger in linagliptin group than in control group (P < 0.05)
Summary
The following primary antibodies were used: anti-phosphorylated Akt and anti-Akt (1:2000, Cell Signaling Technology, Danvers, MA, USA), anti-phosphorylated eNOS (1:1000, BD Transduction Laboratories, Tokyo, Japan), anti-eNOS (1:2000, Cell Signaling Technology), anti-phosphorylated cAMP response element binding protein (CREB) (1:1000, Cell Signaling Technology), and anti-CREB (1:300, Cell signaling Technology) antibodies The intensity of those bands was quantified using Image J software (National Institutes of Health, Bethesda, MD, USA). To evaluate the muscle fiber size, thirty muscle fibers were measured by Image J software (National Institutes of Health) using the method of minimum Feret diameter and the mean diameter were compared between the groups as previously described by Briguet et al [26].
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