John R Speakman , Sharon E Mitchell·18 Mar 2026
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Calorie restriction (CR) is a nutritional intervention known to delay aging and extend lifespan across a wide range of species, raising the possibility of similar benefits in humans. This apparent universality has been questioned by studies reporting shortened lifespan under CR in certain mouse strains. Here, we provide a short perspective on these conflicting findings. Using simple simulation analyses, we explored the apparent strain-specific effects on CR outcomes. Our results illustrate how experimental factors have confounded previous interpretations and led to overemphasis on genotype effects. Reproducible CR studies are crucial for understanding the true potential of CR as a broadly applicable intervention in aging.
Zhihui Zhang , John A Hawley , Min-Dian Li·28 Mar 2026
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Exercise performance in endurance- and power-based events is time-of-day dependent in both humans and rodents. Accordingly, there has been growing interest in determining whether there is an optimal time of day for physical activity that can amplify the well-known benefits of exercise on metabolic health in humans. Here, we discuss critical features of circadian biology that underpin many of the physiological responses to the timing of exercise. Recent studies indicate that the circadian clock regulates exercise capacity through the coordination of tissue-specific physiological responses, including fuel metabolism and mitochondrial biogenesis. Synchronized actions between circadian clocks and clock-output pathways residing in the skeletal muscle and other tissues are likely to explain how external time-of-day cues influence exercise performance and physiological responses to exercise. Understanding the circadian biology of exercise will provide the foundation on which future individualized exercise protocols are prescribed to improve metabolic health outcomes at both individual and population levels.
Shuting Yu , Lele Song , Wunier Wunier , Shuyu Ouyang , Youpeng Ding , Lixing Zhan , Yi Arial Zeng , Yingying Le·24 Dec 2025
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Intestinal stem cells (ISCs) play critical roles in the self-renewal and regeneration of the intestinal epithelium under physiological conditions and after injury, respectively. However, the underlying mechanisms are not fully understood. In this study, we investigate the role of the G protein-coupled receptor formyl peptide receptor 2 (FPR2) in intestinal epithelium homeostasis and regeneration. In mice, knocking out Fpr2 in either intestinal epithelial cells (IECs) or ISCs significantly reduces villus height and crypt depth by impairing ISC and transit-amplifying (TA) cell proliferation and differentiation, primarily TA cell differentiation. Mechanistic studies using intestinal organoid culture and bulk and single-cell RNA sequencing revealed that activation of FPR2 promotes proliferation and differentiation of ISCs and TA cells by activating the wingless/integrated (Wnt), Notch, and Hippo signaling pathways via protein kinase C (PKC)−extracellular signal-regulated kinase (ERK). Under physiological conditions, the Wnt and Notch signaling pathways mediate the regulation of ISC proliferation and differentiation by FPR2. Fpr2 deficiency in mouse IECs exacerbates X-ray- and 5-fluorouracil-induced villus and crypt injury, and delays intestinal epithelium regeneration by reducing ISC and TA cell proliferation. Administering an FPR2 agonist to mice significantly increases survival rates and accelerates intestinal epithelium regeneration after irradiation. Taken together, these results demonstrate that intestinal epithelial FPR2 plays a key role in intestinal epithelium homeostasis and regeneration by promoting ISC and TA cell proliferation and differentiation. FPR2 is a potential therapeutic target against chemotherapy- and radiotherapy-induced intestinal injury.
Weiming Gong , Ping Guo , Lu Liu , Xiubin Sun , Shukang Wang , Fuzhong Xue , Lujia Shen , Zhongshang Yuan·07 Jan 2026
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Despite advances in traditional risk factors for cardiovascular diseases (CVDs), significant residual risk of CVDs remains incompletely captured. Integrative analysis incorporating cardiovascular magnetic resonance imaging (CMR) could facilitate to discover novel therapeutic targets. This study aims to identify potentially druggable plasma proteins for CVDs by incorporating CMR traits with integrative omics analysis. By integrating protein quantitative trait loci (pQTL) datasets of plasma proteins from Atherosclerosis Risk in Communities (ARIC) study with genome-wide association studies of 19 CVDs and 82 CMR traits, we sequentially used proteome-wide association study (PWAS), Mendelian randomization (MR), and colocalization analysis to identify putatively causal proteins. Replication MR was conducted using deCODE pQTL data, followed by observational association analysis using UK Biobank individual-level data, and multidimensional downstream analyses, as well as Phenome-wide MR. In total, we identified 342 protein-CVD pairs and 115 protein-CMR pairs through PWAS. MR and colocalization analyses revealed 66 protein-CVD and 39 protein-CMR pairs with potential causal relationships, of which 51 protein-CVD and 33 protein-CMR pairs were replicated. Additionally, 26 protein-CVD and 6 protein-CMR pairs showed significantly observational associations. Multidimensional downstream analysis highlighted potential biological pathways and druggability insights. Notably, AGER, CCN3, FER, and SPON1 were identified as proteins associated with both CVDs and CMR traits. Phenome-wide MR (Phe-MR) analysis suggests potential beneficial effects of these proteins on other diseases. Our findings highlight potentially druggable plasma proteins for CVDs by incorporating CMR traits, providing novel insights into CVD pathogenesis and therapeutic drug development.
Qiwen Yang , Na Kong , Jing Wu , Yan Yang , Xinge Zhang , Yuan Lin , Zhibin Hu , Guijun Yan , Haixiang Sun , Chaojun Li·02 Feb 2026
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Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age, typically characterized by irregular menstrual cycles. Our study found that postpartum menstrual cycles were largely restored in PCOS patients following assisted reproductive technology (ART) therapy. However, this recovery in menstrual cycles was not associated with any specific ART procedures. Using a PCOS mouse model, we demonstrated that elevated progesterone levels during pregnancy were responsible for normalizing estrous cyclicity. Elevated levels of progesterone induce granulosa cell apoptosis and deplete large follicles, which potentially contribute to ovarian function suppression during pregnancy. Mechanistic studies indicated that progesterone decreased follicle-stimulating hormone receptor (FSHR) expression in a GATA binding protein 2 (GATA2)-dependent manner. Interestingly, the capacity of granulosa cells to convert androgens to estrogens significantly increased after progesterone withdrawal, as evidenced by elevated cytochrome P450 family 19 subfamily A member 1 (Cyp19a1) expression in granulosa cells when stimulated with FSH. Additionally, we found that progesterone administration reduced the thickness of the uterine endometrium in PCOS mice. Our findings suggest that sustained high levels of progesterone during pregnancy can enhance ovarian reproductive endocrine capacity and improve endometrial function, thereby facilitating the recovery of postpartum menstrual cycles.
Liangliang Kong , Hongying Tan , Xiaoting Zhu , Yiqing Wen , Yang Li·19 Feb 2026
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The central nervous system is highly sensitive to energy supply, and the hippocampus operates under sustained metabolic load due to continuous synaptic activity and information processing. Lysosomes couple nutrient status to cellular energetics through the mechanistic target of rapamycin complex 1 (mTORC1) and the autophagy–lysosome pathway, yet their subcellular contribution to neuronal metabolic profiles remains unclear. To address this, we established an in vivo AAV-LysoTag/Lyso-IP workflow combined with metabolomics to quantify metabolites within mouse hippocampal lysosomes. An in vitro Lyso-IP platform and immunofluorescence provided cell-based validation. Under every-other-day fasting, hippocampal lysosomes exhibited reprogramming: small-molecule substrates derived from amino acids and fatty acids accumulated; bis(monoacylglycero)phosphate (BMP) was upregulated, indicating enhanced intraluminal vesicle formation and lipid degradation/sorting; sphingolipids and cardiolipin increased, consistent with selective mitophagy. Notably, high basal lysosomal levels of malic acid and α-ketoglutarate (α-KG) suggested additional sources beyond mitochondria. Immunofluorescence further showed lysosomal localization of isocitrate dehydrogenase and fumarate hydratase, suggesting partial residency of these enzymes. The oxoglutarate carrier (OGC, SLC25A11) signals were observed in LAMP1+ compartments, suggesting potential transmembrane exchange of α-KG and malic acid. Together, our data indicate that lysosomal TCA-related metabolites are maintained by three parallel routes: mitochondrial delivery to lysosomes, local production by resident enzymes, and transporter-mediated exchange. These metabolites supplement and reshape neuronal carbon flux and metabolic resilience at the subcellular level. Our findings elevate lysosomes from degradative endpoints to mobilizable metabolic hubs in the brain and provide both methodological and conceptual frameworks for neurometabolic adaptation under energy scarcity.
Yue Yin , Xiaojing Jia , Shengli Wu , Hong Qiao , Guijun Qin , Tiange Wang , Chunyan Hu , Hong Lin , Shuangyuan Wang , Yu Xu , Mian Li , Min Xu , Jie Zheng , Xiadi He , Yingfen Qin , Xulei Tang , Zhen Ye , Ruying Hu , Lixin Shi , Qing Su , Xuefeng Yu , Li Yan , Qin Wan , Gang Chen , Zhengnan Gao , Guixia Wang , Feixia Shen , Xuejiang Gu , Zuojie Luo , Li Chen , Xinguo Hou , Yanan Huo , Qiang Li , Yinfei Zhang , Tianshu Zeng , Chao Liu , Youmin Wang , Tao Yang , Huacong Deng , Lulu Chen , Jiajun Zhao , Yiming Mu , Guang Ning , Yuhong Chen , Jieli Lu , Weiqing Wang , Yufang Bi , for the 4C Study Group·03 Apr 2026
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Optimal control of hemoglobin A1c (HbA1c), blood pressure, and cholesterol (ABC risk factors) is essential for reducing cardiovascular disease (CVD) risk in individuals with diabetes. However, age-specific contributions of these factors remain inadequately characterized. Using data from the China Cardiometabolic Disease and Cancer Cohort study, we assessed the associations between ABC risk factors and incident CVD among Chinese adults with diabetes, stratified by age groups of < 55, 55 to < 65, 65 to < 75, and ≥ 75 years. Cox proportional hazards models and population-attributable fractions (PAFs) were used to quantify the associations between ABC risk factors and incident CVD. During a median follow-up of 10.1 years, 4,707 incident cases of CVD were documented. Higher levels of baseline HbA1c, systolic blood pressure (SBP), and low-density lipoprotein cholesterol (LDL-C) were significantly associated with increased CVD risk. Age modified these associations (P interaction < 0.05), with progressively attenuated hazard ratios (HRs) observed in older age groups. Compared with HbA1c < 7.0%, HbA1c ≥ 9.0% showed stronger CVD associations in adults aged < 55 years (HR = 2.42; 95% confidence interval [CI]) 1.98 − 2.97) than aged ≥ 75 years (HR = 1.50; 95% CI: 1.12 − 2.02), and SBP ≥ 140 mmHg and LDL-C ≥ 4.1 mmol/L were significant only in younger groups. The leading contributor of PAFs for CVD was SBP (28.3%), followed by HbA1c (12.0%) and LDL-C (9.2%), with diminishing impacts across older groups. These results underscore the importance of age-specific management of ABC risk factors in diabetes care, with the benefit of stricter risk factor management in younger adults and the need for a more flexible approach in older populations.
