Aging & Longevity

The limited benefits of high-density lipoprotein (HDL)-targeted therapies have shifted the research focus to HDL quality; some HDL subtypes may be pro-atherogenic and may counteract the potential benefits of HDL therapies. This study investigated the pathological mechanism of H5, a highly electronegative and compositionally abnormal HDL subfraction characterized by impaired cholesterol efflux. We used anion-exchange chromatography to separate HDL into five subfractions (H1-H5) from blood from...

As populations age worldwide, pathological neurodegeneration with subsequent cognitive decline has emerged as a pressing public health challenge. As effective treatments remain limited once neurodegeneration has occurred, prevention and delay of decline onset are crucial. While physical exercise is associated with improved cognition, exercise-specific mechanisms remain unclear. We therefore examined the effects of 12 weeks explosive lower-body resistance training (RT) in community-dwelling older...

Cerebral small vessel disease is a major contributor to stroke and cognitive decline and is characterized by white matter hyperintensities (WMH) and microstructural alterations detectable via diffusion-weighted imaging parameters, including free water (FW) and fractional anisotropy (FA). Hispanic/Latino populations experience a high burden of vascular risk factors. However, the impact of these factors on white matter integrity across diverse heritage groups remains underexplored in this...

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CONCLUSIONS AND IMPLICATIONS: Rural nursing homes exhibited disaster resilience under baseline disaster conditions but not during evacuation. It is possible that evacuation exposes rural nursing home residents to structural and operational constraints that may differentially compromise postdisaster survival. Future federal and state guidance may benefit from aligning preparedness standards with the distinct constraints of rural nursing homes.

Cellular senescence is one of the best-studied biological programs, yet it continues to reveal unexpected aspects. In this issue of Developmental Cell, Durik et al.¹ describe how senescent cells shed large cytoplasmic fragments that promote their survival and may represent a mechanism of communication with neighboring cells.

Somatic mutations accumulate throughout life in every cell, and this process constitutes one of the hallmarks of aging-genomic instability. Caloric restriction (CR) has been shown to extend lifespan across diverse species. Using high-fidelity duplex DNA sequencing of bulk liver, bulk kidney, hepatocytes, and cerebellar neurons, we found that CR in mice reduces genome-wide somatic mutation burdens across multiple tissues and cell types. CR reduced both substitution and insertion/deletion burdens,...

Current brain atlases are largely descriptive, cataloging correlative molecular snapshots such as gene expression signatures yet offering limited functional insight. Here, we develop a scalable, cell-type-resolved in vivo CRISPR interference (CRISPRi) platform enabling systematic gene function profiling in the mouse brain. Through genome-wide screens across four neuronal populations at three time points spanning youth to aging, we identify neuronal essential genes missed in vitro and define a...

Anderson-Fabry disease (AFD) is a rare X-linked lysosomal storage disorder characterized by marked clinical heterogeneity and incompletely understood genotype-phenotype correlations. While X-chromosome inactivation has been extensively investigated, the contribution of autosomal epigenetic mechanisms to phenotypic variability remains poorly defined. Here, we performed an exploratory genome-wide DNA methylation analysis in 32 AFD patients (22 females and 10 males; mean age 51.7 years) recruited...

GAIP-interacting protein C-terminal 1 (GIPC1/GIPC) is a well-established protein in the field of cancer biology. Recent studies have revealed that GIPC1 may exert opposing, context-dependent functions in various diseases or physiological processes, although the underlying regulatory mechanisms remain to be explored. Since GIPC1 contains a PDZ domain that interacts with various proteins, this domain is a promising therapeutic target. Molecular probes designed against the GIPC1-PDZ domain could...

As the body ages, chronic low-grade inflammation, metabolic dysregulation, and loss of tissue resilience occur; however, the pathways linking these processes have not been fully characterized. Beyond traditional host defence, the canonical complement C3a-C3AR1 signalling axis has been identified as an ageing-sensitive pathway. Studies involving naturally aged animals, older human cohorts, and models of age-related diseases indicate that chronic C3a-C3AR1 signalling can drive the reprogramming of...

The evolutionary biology of aging is fundamental to understanding the mechanisms of aging and how to develop anti-aging treatments. Thus far most evolutionary theory concerns the genetics of aging with limited physiological integration. Here we present an intuitive evolutionary framework built on how physiology is regulated and how this regulation itself ages. Life has evolved to secure reproduction and avoid system failure in early life, and it is the regulation that evolves in response to...

Skeletal muscle stem cells (MuSC) are the guardians of muscle regeneration, sustaining tissue integrity through a delicate balance of quiescence, activation, and lineage commitment. While numerous molecular cues have been implicated in regulating these processes, the influence of androgen receptor (AR) signaling, an essential hormonal pathway for male muscle physiology, has remained largely unexplored. Here, we show that AR expression defines quiescent MuSC and acts as a safeguard of their...

Proteins generally begin with methionine, which is often removed to expose the second residue. RuBP carboxylase/oxygenase (Rubisco), the most abundant enzyme on Earth and a major carbon and nitrogen reservoir, escapes this paradigm. Its catalytic subunit, RbcL, undergoes unusual amino terminal maturation, including atypical initiator methionine-serine cleavage and proline acetylation, a modification not seen in other biological systems. We define a specialized pathway of two sequential...

ObjectiveThis study examines how life expectancy (LE) without and with depression differs by living arrangement among older adults in Japan, with particular attention to gender differences.MethodsData were drawn from the Nihon University Japanese Longitudinal Study of Aging (1999-2009). Multistate life table methods were used to estimate LE spent without and with depression among adults aged 65 years and older across different living arrangements.ResultsPronounced gender differences were...

Limbal niche cells (LNCs) serve as essential regulators of limbal microenvironmental homeostasis and corneal epithelial wound repair, representing a promising therapeutic resource for limbal stem cell deficiency (LSCD). However, their clinical application is constrained by replicative aging during in vitro expansion. In this study, we investigated whether a three-dimensional (3D) Matrigel-based culture system could modulate replicative aging in LNCs. Compared with conventional two-dimensional...

The female brain undergoes substantial reorganization during major hormonal transitions, yet whether puberty, pregnancy, and menopause engage shared or distinct neuroplastic mechanisms remains unknown. We compared longitudinal structural brain changes across all three major hormonal life events using identical analytical methods within a single cohort framework (n = 1095), with stable control groups to control for normative developmental and aging trajectories. Both pre-to-post menarche and...

Endocrine organs translate nutrient, stress and circadian cues into hormone outputs that coordinate whole-body physiology. Cellular senescence can distort this communication by changing endocrine-cell identity, stimulus-secretion coupling, secretory timing and local immune or paracrine signaling. Evidence is strongest in pancreatic β-cells and the adrenal zona fasciculata, where composite senescence phenotypes have been linked to endocrine dysfunction and modified by targeted perturbations....

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Retinal pigment epithelium (RPE) senescence acts as a core driver of subretinal fibrosis, a major irreversible pathological feature that exacerbates age-related macular degeneration (AMD). Mitophagy is essential for maintaining RPE homeostasis during aging. However, the upstream molecular mechanisms underlying mitophagy impairment in senescent RPE remain poorly defined. Here, we show that lysosomal-associated transmembrane protein 5 (LAPTM5) is significantly upregulated in human AMD specimens...