AMPK and mTOR play principal roles in governing metabolic programs; however, mechanisms underlying the coordination of the two inversely regulated kinases remain unclear. In this study we found, most surprisingly, that the late endosomal/lysosomal protein complex v-ATPase-Ragulator, essential for activation of mTORC1, is also required for AMPK activation. We also uncovered that AMPK is a residential protein of late endosome/lysosome. Under glucose starvation, the v-ATPase-Ragulator complex is accessible to AXIN/LKB1 for AMPK activation. Concurrently, the guanine nucleotide exchange factor (GEF) activity of Ragulator toward RAG is inhibited by AXIN, causing dissociation from endosome and inactivation of mTORC1. We have thus revealed that the v-ATPase-Ragulator complex is also an initiating sensor for energy stress and meanwhile serves as an endosomal docking site for LKB1-mediated AMPK activation by forming the v-ATPase-Ragulator-AXIN/LKB1-AMPK complex, thereby providing a switch between catabolism and anabolism. Our current study also emphasizes a general role of late endosome/lysosome in controlling metabolic programs.

SUMMARY Hypothalamic control of aging was recently proposed, but the responsible mechanisms still remain unclear. Here, following the observation that aging of mice started with a substantial loss of hypothalamic stem/progenitor cells that co-express Sox2 and Bmi1, we developed several mouse models with ablation of these hypothalamic cells, each of them consistently displaying an acceleration in aging-like physiological changes or shortening in lifespan. Conversely, aging retardation and lifespan extension were achieved in mid-aged mice when locally implanted with healthy hypothalamic stem/progenitor cells that were genetically engineered to survive from aging-related hypothalamic inflammatory microenvironment. Mechanistically, hypothalamic stem/progenitor cells greatly contributed to exosomal miRNAs in the cerebrospinal fluid which declined over aging, while central treatment with healthy hypothalamic stem/progenitor cells-secreted exosomes led to slowdown of aging. In conclusion, aging speed is controlled significantly by hypothalamic stem cells partially through release of exosomal miRNAs.

Polybrominated diphenyl ethers (PBDEs) and 2,2',4,4',5,5'-hexabromobiphenyl (BB-153) are chemicals known as brominated flame retardants. We have assessed the exposure status of the United States population to PBDEs and BB-153 and explored associations with demographic information, including participants' age, sex, and race/ethnicity. A total of 2,062 serum samples, from participants in the National Health and Nutrition Examination Survey (NHANES) 2003-2004 aged 12 years and older, were analyzed for PBDEs and BB-153; stratified and regression analyses were used to examine levels among demographic groups. The congener with the highest serum concentration was 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) [geometric mean 20.5 ng/g lipid]; followed by 2,2',4,4',5,5'-hexaBDE (BDE-153) [5.7 ng/g lipid]; 2,2',4,4',5-pentaBDE (BDE-99) [5.0 ng/g lipid; a value equal to the highest limit of detection for an individual sample]; 2,2',4,4',6-pentaBDE (BDE-100) [3.9 ng/g lipid]; BB-153 [2.3 ng/g lipid]; and 2,4,4'-triBDE (BDE-28) [1.2 ng/g lipid]. For BDE-47, we observed no significant difference in the least-squares geometric mean (LSGM) by sex, but with age we found both a linear decrease (p = 0.01) and a positive quadratic trend (p = 0.01). Its LSGM, 27.9 ng/lipid, in the 12-19 year olds decreased to 17.2 ng/g lipid in the 40-49 year group, and then curved upward to 20.4 ng/g lipid in the > or =60 years olds. Mexican Americans had the highest LSGM of BDE-47 (24.5 ng/g lipid), which was significantly higher than that of non-Hispanic whites (19.7 ng/g lipid, p = 0.01). Adults 60 years and older were twice as likely as adults 20-59 years old to have a serum BDE-47 concentration above the 95th percentile (p = 0.02). These data provide needed exposure assessment data for public health decisions.

The PHQ-9 and the PHQ-2 are valid and reliable tools to screen depression in Chinese college students. For screening purposes, cutoff scores of 11 and 3 are recommended for PHQ-9 and PHQ-2, respectively.