Compound D159687, a phosphodiesterase 4D inhibitor, induces weight and fat mass loss in aged mice without changing lean mass, physical and cognitive function.

AIMS: Therapies that recapitulate the health benefits of caloric restriction in older adults are needed. Phosphodiesterase 4 inhibitors demonstrate such promise. We examined their effects on body weight and composition, physical and cognitive function in aged mice using Compound D159687 (D159687). METHODS: Nineteen 18-months old mice were randomized to receive either control (DMSO) or D159687 for seven weeks. We assessed food intake, body weight and body composition over time and performed once the following tests: treadmill, inverted grip strength, rotarod, spontaneous Y maze tests and skeletal muscle mitochondrial biogenesis. RESULTS: Four of the D159687 treated mice died in the first week. Necropsy suggests acute lung injury. D159687 treated mice weighed more than control mice at baseline. After controlling for baseline weight, D159687 treated mice lost 4.2 grams(g) more weight than control mice, mainly from fat mass loss (p value < 0.001). Muscle mass was unchanged between the two mice groups. D159587 mice ate significantly more food than the control mice. We found no difference between the two groups in the results of treadmill, rotarod and spontaneous Y maze tests and in mitochondrial biogenesis. CONCLUSION: Compound D159687 induced weight loss, predominantly fat mass loss and increased food intake in aged mice. The caloric restriction and lean mass preservation potential of PDE4D inhibitors deserve further verification. Findings may have major therapeutic implications when translated to the older adult population. Although physical and cognitive parameters were unchanged in this study, further studies would be needed to verify these results. The high death rate in the D159687 treated mice may have been due to the technical aspects of oral gavage.

Suboptimal hydration remodels metabolism, promotes degenerative diseases, and shortens life.

With increased life expectancy worldwide, there is an urgent need for improving preventive measures that delay the development of age-related degenerative diseases. Here, we report evidence from mouse and human studies that this goal can be achieved by maintaining optimal hydration throughout life. We demonstrate that restricting the amount of drinking water shortens mouse lifespan with no major warning signs up to 14 months of life, followed by sharp deterioration. Mechanistically, water restriction yields stable metabolism remodeling toward metabolic water production with greater food intake and energy expenditure, an elevation of markers of inflammation and coagulation, accelerated decline of neuromuscular coordination, renal glomerular injury, and the development of cardiac fibrosis. In humans, analysis of data from the Atherosclerosis Risk in Communities (ARIC) study revealed that hydration level, assessed at middle age by serum sodium concentration, is associated with markers of coagulation and inflammation and predicts the development of many age-related degenerative diseases 24 years later. The analysis estimates that improving hydration throughout life may greatly decrease the prevalence of degenerative diseases, with the most profound effect on dementia, heart failure (HF), and chronic lung disease (CLD), translating to the development of these diseases in 3 million fewer people in the United States alone.

Low ambient oxygen prevents atherosclerosis.

Large population studies have shown that living at higher altitudes, which lowers ambient oxygen exposure, is associated with reduced cardiovascular disease mortality. However, hypoxia has also been reported to promote atherosclerosis by worsening lipid metabolism and inflammation. We sought to address these disparate reports by reducing the ambient oxygen exposure of ApoE-/- mice. We observed that long-term adaptation to 10% O2 (equivalent to oxygen content at ∼5000 m), compared to 21% O2 (room air at sea level), resulted in a marked decrease in aortic atherosclerosis in ApoE-/- mice. This effect was associated with increased expression of the anti-inflammatory cytokine interleukin-10 (IL-10), known to be anti-atherogenic and regulated by hypoxia-inducible transcription factor-1α (HIF-1α). Supporting these observations, ApoE-/- mice that were deficient in IL-10 (IL10-/- ApoE-/- double knockout) failed to show reduced atherosclerosis in 10% oxygen. Our study reveals a specific mechanism that can help explain the decreased prevalence of ischemic heart disease in populations living at high altitudes and identifies ambient oxygen exposure as a potential factor that could be modulated to alter pathogenesis. Key messages: Chronic low ambient oxygen exposure decreases atherosclerosis in mice. Anti-inflammatory cytokine IL-10 levels are increased by low ambient O2. This is consistent with the established role of HIF-1α in IL10 transactivation. Absence of IL-10 results in the loss of the anti-atherosclerosis effect of low O2. This mechanism may contribute to decreased atherosclerosis at high altitudes.

Genetic deficiency of the mitochondrial protein PGAM5 causes a Parkinson's-like movement disorder.

Mitophagy is a specialized form of autophagy that selectively disposes of dysfunctional mitochondria. Delineating the molecular regulation of mitophagy is of great importance because defects in this process lead to a variety of mitochondrial diseases. Here we report that mice deficient for the mitochondrial protein, phosphoglycerate mutase family member 5 (PGAM5), displayed a Parkinson's-like movement phenotype. We determined biochemically that PGAM5 is required for the stabilization of the mitophagy-inducing protein PINK1 on damaged mitochondria. Loss of PGAM5 disables PINK1-mediated mitophagy in vitro and leads to dopaminergic neurodegeneration and mild dopamine loss in vivo. Our data indicate that PGAM5 is a regulator of mitophagy essential for mitochondrial turnover and serves a cytoprotective function in dopaminergic neurons in vivo. Moreover, PGAM5 may provide a molecular link to study mitochondrial homeostasis and the pathogenesis of a movement disorder similar to Parkinson's disease.