A Potent PDK4 Inhibitor for Treatment of Heart Failure with Reduced Ejection Fraction.

Heart failure with reduced ejection fraction (HFrEF) is characterized not only by reduced left ventricular ejection fraction (EF) but is also combined with symptoms such as dyspnea, fatigue, and edema. Several pharmacological interventions have been established. However, a treatment targeting a novel pathophysiological mechanism is still needed. Evidence indicating that inhibition of pyruvate dehydrogenase kinase 4 (PDK4) may be cardioprotective has been accumulating. Thus, we focused on vitamin K3 and used its framework as a new PDK4 inhibitor skeleton to synthesize new PDK4 inhibitors that show higher activity than the existing PDK4 inhibitor, dichloroacetic acid, and tested their cardioprotective effects on a mouse heart failure model. Among these inhibitors, PDK4 inhibitor 8 improved EF the most, even though it did not reverse cardiac fibrosis or wall thickness. This novel, potent PDK4 inhibitor may improve EF of failing hearts by regulating bioenergetics via activation of the tricarboxylic acid cycle.

Inoculation of lymphocytes from young mice prevents progression of age-related hearing loss in a senescence-associated mouse model.

Despite the increase in age-related hearing loss (ARHL) prevalence owing to increased population aging, preventive measures against ARHL have not yet been established. The immune system becomes one of the most dysfunctional systems upon aging, and immunosenescence greatly affects homeostasis and promotes systemic aging along with chronic inflammation and oxidative stress. This study aimed to determine whether immuno-rejuvenation procedures can prevent ARHL and have clinical applications as well as to analyze the communication mechanisms between the systemic immune system and the cochlea using a murine model. Lymphocytes from young mice inhibited the progression of ARHL. The method of cryopreserving these lymphocytes and inoculating them at the onset of ARHL suggests their clinical application. Mice that were administered this treatment not only maintained auditory threshold but also avoided spinal ganglion degeneration, cellular immune aging, and nitric oxide production, which causes age-related tissue damage. These findings coincide with our previous strategies against immunosenescence and neuronal aging. Therefore, the manipulation of systemic immune function may contribute not only to the prevention of ARHL but also to the development of novel anti-aging clinical measures, paving the way to healthy longevity with preserved organ function.