Journal of Internal Medicine最新文献

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive decline. Although amyloid-β and tau pathologies remain central to our understanding of AD, growing evidence suggests that disrupted lipid metabolism and impaired bioenergetics are closely linked to these hallmark features. Genetic, lipidomic and functional studies point to alterations in cholesterol, phospholipids and polyunsaturated fatty acids, which can influence mitochondrial function, organelle communication and glial responses. These processes are further modulated by apolipoprotein E (APOE) genotype, sex differences and systemic metabolic states such as obesity and diabetes, contributing to neuroinflammation and cognitive decline. Although findings are sometimes conflicting, an emerging theme is that lipid and energy metabolisms are central to how genetic and environmental risk factors shape AD pathogenesis. This integrated perspective highlights lipid and bioenergetic pathways as promising therapeutic targets, where metabolic modulators, lipid-directed interventions and lifestyle strategies may complement amyloid-based therapies and offer opportunities for precision approaches, particularly in women and APOE ε4 carriers.

Metabolic diseases, including obesity, Type 2 diabetes (T2D), and metabolic syndrome, are increasingly prevalent worldwide, driven by sedentary lifestyles, aging populations, and complex genetic and environmental factors. Traditionally understood as disorders of glucose and lipid metabolism, a growing body of evidence now implicates cellular senescence as a central, age-related contributor to metabolic dysfunction. Senescent cells (SCs) accumulate in key metabolic tissues where they disrupt tissue function through the senescence-associated secretory phenotype (SASP), a pro-inflammatory and fibrogenic secretome. SASP factors exacerbate insulin resistance, chronic inflammation, and tissue remodeling, advancing the progression and complications of metabolic diseases. These insights have catalyzed the development of senotherapeutics, a class of interventions that includes senolytics (to eliminate SCs), senomorphics (to suppress SASP), and senosensitizers (to render resistant SCs more vulnerable to clearance). Although preclinical studies show promise, translation into clinical practice faces significant challenges, including identifying reliable biomarkers, understanding SC heterogeneity, and optimizing treatment timing and safety. As research advances, senotherapeutics may offer a transformative approach not only to managing metabolic diseases but also to mitigating associated comorbidities. The recognition that antidiabetic agents already in clinical use can modulate key features of senescence highlights a unique translational opportunity, suggesting that prevention of age-related metabolic disorders may be achievable with therapies already available in routine clinical practice. Medicine is poised to enter a new era in which targeting cellular senescence could fundamentally reshape the prevention and treatment of age-related metabolic disorders, offering the potential for improved healthspan and reduced disease burden across the lifespan.

The exponential rise in plastic production has driven widespread contamination by micro- and nanoplastics (MNPs) in the environment. These plastic particles and their chemical additives have been detected in water sources, human bodily fluids, and reproductive tissues. With global fertility rates declining, their role as potential contributors is under investigation. This scoping review compares findings from in vitro experiments, in vivo studies across animal models, and epidemiological data to assess potential reproductive hazards associated with MNP exposure. Forty original studies published within the last decade were identified. MNPs have been detected in human breast milk, placenta, endometrium, ovaries, testis, semen, follicular fluid, blood, and urine samples. Humans are estimated to absorb 74,000–121,000 particles annually through inhalation, ingestion, skin contact, and use of plastic materials, including medical devices. Experimental evidence demonstrates that MNPs can cross biological barriers, interact with cells, and disrupt cellular pathways, including steroidogenesis, energy metabolism, inflammatory pathways, and oxidative stress. Thirty in vivo animal studies have associated MNPs with altered reproductive endpoints in both males (i.e., altered semen quality and spermatogenesis) and females (i.e., altered folliculogenesis, depleted ovarian reserve, and reduced litter sizes), with possible transgenerational effects. In conclusion, current evidence suggests MNPs may represent a reproductive health hazard to humans and animals. The relative contributions of particle toxicity and their chemical additives remain difficult to disentangle. Overall, plastics and their associated chemicals represent a serious health and environmental concern, which continues to grow in the absence of restrictions and international agreements.

Although research on ageing has largely concentrated on understanding the fundamental biology of the ageing process and devising pharmaceutical interventions in order to slow it down, increasing evidence has underscored the crucial role of environmental inputs across the life course and across generations, in shaping both individual and intergenerational trajectories of age-related health. These include nutrition, air pollution, social deprivation, lifestyle factors, climate change and exposure to environmental toxins, including microplastics and nanoplastics. The development of the concept of the exposome of ageing and the emergence of the new field of ‘exposomics’ have identified a blind spot, in particular, for geroscience. The impact of the exposome affecting human ‘healthspan’ (i.e., years lived in good health), extending across generations, is significant and yet under-explored in research. As such, it is under-appreciated that the declining health of the planet will have intergenerational ripple effects, epigenetically priming adverse health in future generations. We discuss the capacity to manipulate our exposome to mitigate against such effects, by addressing root causes, rather than symptoms, of both physiological and planetary dysregulation, dysfunction and decay. We propose a systems-based framework that reconnects research on ageing with exposomics and planetary ecology, creating a new field of ‘ecological or exposome pharmacology’, harnessing the activity of Nrf2 as a senotherapeutic intervention to improve trans- and intergenerational physiology in the face of declining planetary health.

Background: Elevated low-density lipoprotein (LDL) cholesterol causes atherosclerotic cardiovascular diseases. Variables of whole-body cholesterol metabolism, for example, high cholesterol absorption efficiency, might also be atherogenic, whereas the role of bile acids is controversial.

Objectives: This post hoc study concerns the impact of cholesterol absorption on bile acid metabolism. The hypothesis was that cholesterol absorption efficiency interferes with bile acid metabolism.

Methods: Cholesterol metabolism was studied using absolute and relative methods. Elimination of cholesterol from the body as bile acids and neutral sterols was assessed from 24-h faecal collections and analysed by gas-liquid chromatography. Cholesterol absorption efficiency was evaluated by a peroral continuous dual-isotope feeding method, and cholesterol synthesis by a sterol-balance technique. The relative methods included analyses of serum biomarkers of cholesterol absorption efficiency and cholesterol synthesis by gas-liquid chromatography.

Results: Faecal bile acids, neutral sterols and cholesterol synthesis were lower in high- versus low-cholesterol absorbers. Elimination of cholesterol from the body as bile acids and neutral sterols was reduced in high- versus low-cholesterol absorbers. Serum and LDL cholesterol levels did not differ in low- versus high-cholesterol absorbers. Absolute and relative methods of cholesterol metabolism correlated with each other, suggesting that the results can be considered valid.

Conclusion: In high-cholesterol absorbers, poor elimination of cholesterol from the body as bile acids and neutral sterols may indicate an increased risk of atherosclerosis. It can be prevented by decreasing cholesterol absorption and increasing reverse cholesterol transport by dietary means combined with ezetimibe and statin treatment, when needed.