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Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide. It is associated with the ongoing degeneration of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies that contain α-synuclein. These pathological changes lead to abnormalities of motor symptoms (tremor, rigidity, bradykinesia) and non-motor symptoms (cognitive decline, sleep abnormalities, psychiatric abnormalities). The pathogenesis of PD is complex and multifactorial,...

Human-induced pluripotent stem cell-derived midbrain organoids offer a promising platform for modeling Parkinson's disease (PD). Yet, their utility has been limited by the absence of microglia and the development of a necrotic core during maturation. Here, we present an air-liquid interface (ALI) slice culture system for extended cultivation of midbrain organoids (mORGs), enabling efficient microglial integration, improved neuronal viability, and enhanced functional maturation. Compared with...

Cerebrovascular and neurodegenerative diseases rank among the leading causes of death worldwide and represent an increasing socioeconomic burden, particularly in aging populations. Pluripotent stem cell (PSC)-based therapies have emerged as promising strategies for replacing lost neurons and restoring neural circuits in disorders of the central nervous system (CNS). However, major barriers remain, including poor survival, limited integration, and variable functional maturation of transplanted...

Mechanisms linking CD33 variants to Alzheimer Disease (AD) are poorly defined. Here, we combine structural, cellular, and genetic analyses to delineate how the CD33^(M) splice isoform, upregulated in carriers of CD33 risk alleles, modulates microglial function. We show that CD33^(M) ectodomain dimerizes, enabling binding of large multi-sialylated molecules. We demonstrate that another AD risk protein - clusterin (CLU) ± Aβ oligomers (but not ApoE) binds with nanomolar avidity to CD33^(M), but...

Peripheral nerves regulate skin homeostasis by secreting neurotransmitters, but their role during skin aging remains incompletely understood. Here, we report that cutaneous denervation accelerates skin aging, as evidenced by collagen reduction. Neurofilament heavy chain (Nefh) is decreased in aged skin and is predominantly expressed in vesicular glutamate transporter 2-positive (Vglut2^(+)) skin-innervating glutamatergic neurons. Notably, dermal fibroblasts, the primary producers of collagen,...

The three-dimensional organization of chromatin into topologically associating domains (TADs) may impact gene regulation by bringing distant genes into contact. However, studies of TADs' function and their influence on transcription have been constrained by ambiguities in TAD boundary definitions and challenges in directly measuring their regulatory effects. We overcome these limitations by developing species-level consensus TAD maps for human and mouse by using a bag-of-genes approach that...

Cardiovascular aging is a major contributor to the development of cardiovascular diseases (CVDs), yet the mechanisms linking metabolic imbalance to age-related cardiovascular dysfunction remain unclear. Protein palmitoylation, a reversible lipid post-translational modification, regulates protein localization, stability, and signaling, but its role in cardiovascular aging has not been systematically defined. Importantly, protein palmitoylation appears to act as a double-edged sword: whereas its...

Cancer progression is shaped not only by tumor-intrinsic programs and the local microenvironment but also by profound metabolic rewiring of the host at the organismal scale. Tumors engage in dynamic cross-talk with distant organs, immune and neuroendocrine networks, and systemic nutrient pools, generating a metabolically permissive macroenvironment that fuels tumor growth, supports metastatic dissemination, and undermines therapeutic efficacy. In this review, we synthesize emerging evidence...

Human cytoplasmic leucyl-tRNA synthetase (LARS) is known to catalyze the ligation of leucine to tRNA^(Leu) during protein biosynthesis. However, LARS also acts as a nutrient sensor in a non-canonical activity to regulate cell growth. In this investigation, LARS was determined to be expressed at high levels in human liver cancer, which correlated with poor clinical outcomes in patients. Knockdown of LARS in HepG2 liver cancer cells suppressed cell proliferation and growth, yet promoted cell...

Cerebrovascular and neurodegenerative diseases rank among the leading causes of death worldwide and represent an increasing socioeconomic burden, particularly in aging populations. Pluripotent stem cell (PSC)-based therapies have emerged as promising strategies for replacing lost neurons and restoring neural circuits in disorders of the central nervous system (CNS). However, major barriers remain, including poor survival, limited integration, and variable functional maturation of transplanted...

In the mammalian host, Trypanosoma brucei proliferates as slender bloodstream forms before undergoing quorum-sensing (QS)-dependent differentiation into non-dividing transmissible stumpy-QS forms, a process that both controls parasitaemia and enables transmission to the tsetse fly. However, this model does not explain how transmission occurs in chronically infected patients and cattle, where parasite densities are often too low to trigger QS-mediated differentiation. We identify a relevant...

Sepsis triggers profound organism-wide disturbances, yet the cellular logic underlying its systemic impact remains poorly defined. By integrating single-cell transcriptomes from six septic tissues, we uncovered a conserved cross-tissue program characterized by inflammation-driven senescence, disrupted intercellular communication, and coordinated transcriptional reprogramming. Senescence signatures were broadly elevated across cell types and strongly coupled to altered communication networks,...

Regulation of insulin secretion by pancreatic β-cells is central to maintaining glucose homeostasis and overall metabolic health. Glucose is recognized as the major driver of insulin secretion; however, here, we highlight established and emerging evidence of important contributions of other nutrients, including amino acids, fatty acids and alternative fuels, as well as non-nutrient factors, in modulating both basal and postprandial insulin release. We discuss molecular mechanisms underlying...

CONCLUSION: Given the critical role of spiritual health, targeted strategies to promote PIL are needed to enhance healthy aging. The findings highlight PIL as the strongest predictor of capability well-being, alongside subjective health and financial factors within the Thai cultural context.

CONCLUSIONS: The life satisfaction rate of older adults in Hubei Province of China was relatively high, which was associated with both demographic factors and consumption-related factors. Consumption reflecting active social participation was positively associated with life satisfaction, while consumption reflecting obligatory or stressful activities was negatively associated. The study provided preliminary empirical evidence that may inform the development of aging policies and services.

Senescent cells accumulate following chemotherapy and during aging, where they contribute to dysfunction through the pro-inflammatory arm of the senescence-associated secretory phenotype (SASP), termed NF-κB-associated SASP (NASP). Here we show that short-term inhibition of CDK4/6 with abemaciclib suppresses established NASP in pre-existing senescent cells both in vitro and in vivo. This senomorphic effect reduces the pro-tumorigenic activity of chemotherapy-induced senescent cells and improves...

The RNA-binding protein Sex-lethal (Sxl) is classically known as a master regulator of sex determination and mRNA splicing in Drosophila melanogaster. However, this role is not conserved across species, and functions beyond the canonical pathway remain poorly understood. In this study, we uncover a splicing-independent role for Sxl at the chromatin level in the Drosophila brain. Using Targeted DamID (TaDa) profiling in neurons, we identify widespread binding of Sxl to promoter regions,...

Astrocytes play essential roles in neuropathology. Human astrocytes exhibit unique properties, highlighting the importance of studying astrocytic responses in human models. Varicose projection astrocytes, previously considered exclusive to hominoids and a physiological type of astrocytes, were suggested to reflect pathological burden, albeit direct evidence linking them to neurological diseases has been lacking. Here, we demonstrate that varicose projection astrocytes also appear in other...

CONCLUSION: Among the included studies, featuring a minimal outsole, a textured insole design, and a high collar design showed consistency to benefit older adults that provides textured feedback while offering foot protection, which may enhance balance control. However, some studies also implied that certain designs may have potential negative effects, including toe-beveled, minimal outsole, less-fixation, and barefoot condition. The lack of comprehensive descriptions of experimental footwear...

CONCLUSIONS: A higher cognitive reserve is linked to a decreased risk of developing frailty, slower progression, and a greater likelihood of improvement from pre-frailty to non-frailty, suggesting that lifelong cognitive enrichment enhances the physiological reserve beyond cognition. These findings suggest that interventions and policies that support the development of cognitive reserve across the life course may contribute to healthier frailty trajectories in later life.