Obesity and aging are two important epidemic factors for metabolic syndrome and many other health issues, which contribute to devastating diseases such as cardiovascular diseases, stroke and cancers. The brain plays a central role in controlling metabolic physiology in that it integrates information from other metabolic organs, sends regulatory projections and orchestrates the whole-body function. Emerging studies suggest that brain dysfunction in sensing various internal cues or processing external cues may have profound effects on metabolic and other physiological functions. This review highlights brain dysfunction linked to genetic mutations, sex, brain inflammation, microbiota, stress as causes for whole-body pathophysiology, arguing brain dysfunction as a root cause for the epidemic of aging and obesity-related disorders. We also speculate key issues that need to be addressed on how to reveal relevant brain dysfunction that underlines the development of these disorders and diseases in order to develop new treatment strategies against these health problems.

Non‐alcoholic fatty liver disease (NAFLD), characterized by an increase in hepatic triglyceride (TG) content, is the most common liver disease worldwide. Aging has been shown to increase susceptibility to NAFLD; however, the underlying molecular mechanism remains poorly understood. In the present study, we examined hepatic TG content and gene expression profiles in body weight‐matched young (3 months old), middle‐aged (10 months old), and old (20 months old) C57BL/6 mice and found that TGs were markedly accumulated while mitochondrial β‐oxidation‐related genes, including PPARα, were downregulated in the liver of old mice. In addition, advanced glycation end product receptor (RAGE), a key regulator of glucose metabolism, was upregulated in the old mice. Mechanistically, suppression of RAGE upregulated PPARα and its downstream target genes, which in turn led to reduced TG retention. Finally, we found that hepatic RAGE expression was increased in aging patients, a finding that correlated with decreased PPARα levels. Taken together, our findings demonstrate that the upregulation of RAGE may play a critical role in aging‐associated liver steatosis.

By testing pseudotyped SARS-CoV-2 and HIV-based lentivirus, this study reports that exosomes/microvesicles (Ex/Mv) isolated from murine hypothalamic neural stem/progenitor cells (htNSC) or subtype htNSCPGHM as well as hippocampal NSC have innate immunity-like actions against these RNA viruses. These extracellular vesicles also have a cell-free innate antiviral action by attacking and degrading viruses. We further generated the induced versions of Ex/Mv through prior viral exposure to NSCs and found that these induced Ex/Mv were stronger than basal Ex/Mv in reducing the infection of these viruses, suggesting the involvement of an adaptive immunity-like antiviral function. These NSC Ex/Mv were found to be characterized by producing large libraries of P element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) against genomes of various viruses, and some of these piRNAs were enriched during the adaptive immunity-like reaction, possibly contributing to the antiviral effects of these Ex/Mv. In conclusion, NSC Ex/Mv have antiviral immunity and could potentially be developed to combat against various viruses.

We report a comparative analysis of the effects of immune activation in the fly nervous system using genetic activation models to target Drosophila NF-κB within Toll versus Imd pathways. Genetic gain-of-function models for either pathway pan-neuronally as well as in discrete subsets of neural cells including neuroendocrine insulin-producing cells (IPCs) or neuroblasts reduce fly lifespan, however, these phenotypes in IPCs and neuroblasts are stronger with Toll activation than Imd activation. Of note, while aging is influenced more by Toll/NF-κB activation in IPCs during adulthood, neuroblasts influence aging more substantially during development. The study then focused on Toll/NF-κB inhibition, revealing that IPCs or neuroblasts are important for the effects of lifespan and healthspan extension but in a life stage-dependent manner while some of these effects display sexual dimorphism. Importantly, co-inhibition of Toll/NF-κB pathway in IPCs and neuroblasts increased fly lifespan greater than either cell population, suggesting that independent mechanisms might exist. Toll/NF-κB inhibition in IPCs was also sufficient to enhance survival under various fatal stresses, supporting the additional benefits to fly healthspan. In conclusion, IPCs and neuroblasts are important for Drosophila NF-κB for controlling lifespan.

The hypothalamus plays an important role in aging, but it remains unclear regarding the underlying epigenetics and whether this hypothalamic basis can help address aging-related diseases. Here, by comparing mouse hypothalamus with two other limbic system components, we show that the hypothalamus is characterized by distinctively high-level DNA methylation during young age and by the distinct dynamics of DNA methylation and demethylation when approaching middle age. On the other hand, age-related DNA methylation in these limbic system components commonly and sensitively applies to genes in hypothalamic regulatory pathways, notably oxytocin (OXT) and gonadotropin-releasing hormone (GnRH) pathways. Middle age is associated with transcriptional declines of genes which encode OXT, GnRH and signaling components, which similarly occur in an Alzheimer’s disease (AD)-like model. Therapeutically, OXT-GnRH combination is substantially more effective than individual peptides in treating AD-like disorders in male 5×FAD model. In conclusion, the hypothalamus is important for modeling age-related DNA methylation and developing hypothalamic strategies to combat AD.