Aging & Longevity

Frailty denotes a state of high vulnerability and, as proposed by Fried and colleagues, arises from "energetic collapse" across multiple physiological systems, in which altered energy metabolism undermines resilience. We suggest that dysregulation of acid-base balance represents a critical yet underappreciated mechanism driving this collapse. With aging, cumulative stress burden diminishes the capacity for intracellular and extracellular acid buffering, renal acid excretion and ventilatory...

Cellular senescence, a state of irreversible cell cycle arrest, plays a key role in neurodegenerative diseases, including Alzheimer's disease (AD). While senescent cells are emerging as potential therapeutic targets, the dynamics of their occurrence over time and the specific cell types most affected by AD are still not well understood. This study investigates age- and pathology-dependent changes in senescence markers, specifically p16, p21, and p53, using the amyloidogenic App^(NL-G-F) knock-in...

Aging impairs skeletal muscle mass and function, but the cell-type-resolved transcriptional states and intercellular signaling changes in human muscle aging remain incompletely mapped. Here, we constructed a single-nucleus RNA sequencing (snRNA-seq) atlas of human vastus lateralis muscle from adult (22-60 years) and elderly (99-101 years) male donors. We identified a comprehensive cellular census and discovered a profound reorganization of the myofiber transcriptional landscape. Aging was...

Ageing and cellular senescence significantly contribute to the progression of age-related diseases, particularly chronic obstructive pulmonary disease (COPD). Cellular senescence refers to the cessation of cell division in response to stress and damage. While senescent cells remain metabolically active, they secrete pro-inflammatory factors that drive disease progression. Senolytic therapies aim to selectively target and eliminate these senescent cells by inducing their apoptosis. This study...

Frailty is a state of reduced physiological resilience and increased vulnerability to adverse health outcomes, but its neurobiological mechanisms across the adult lifespan remain unclear. Emerging evidence suggests that white matter (WM) alterations may accompany frailty, but previous neuroimaging studies have focused mostly on older adults and used nonspecific MRI markers. This study investigates whether systemic frailty, quantified using a Frailty Index (FI), is associated with WM myelin...

Aberrant cell-cell communication (CCC) is a recognized hallmark of aging, yet comprehensive analyses of immune CCC-particularly in the context of healthy aging-remain limited. Using single-cell transcriptomics of PBMCs from centenarians (CEN), their offspring (CO), and elderly controls, we found that immune CCC in controls was characterized by myeloid-derived, self-amplifying SASP signals associated with immunosenescence and effector immune cell (EIC) exhaustion. In contrast, healthy-aging...

Chronological age is a common and non-modifiable factor for chronic disease, but does not fully explain age-related changes. Biological clocks have been developed to explore biological aging mechanisms. They could help identify protective factors against accelerated aging and associated diseases. We aim to assess the association between reduced epigenetic or inflammatory aging and ideal cardiovascular health or cardiovascular risk. We conducted a cross-sectional analysis of participants from the...

Emerging evidence implicates premature placental senescence as a central driver of pregnancy complications, though its underlying mechanisms remain elusive. Here, we report marked downregulation of IL33 (interleukin 33) in villi from unexplained recurrent pregnancy loss (URPL) patients, concomitant with elevated trophoblast senescence. More importantly, il33 knockout mice exhibited placental senescence and impaired trophoblast invasion. Mechanistically, senescent trophoblasts displayed metabolic...

Activation of RAS oncogenes in normal cells triggers a stable cell cycle arrest known as RAS-induced senescence (RIS), marked by persistent DNA damage and extensive epigenetic remodeling. Although bypassing RIS promotes tumorigenesis, the molecular mechanisms underlying this transition remain poorly defined. Here, we demonstrate that RIS cells accumulate high levels of R-loops-three-stranded DNA-RNA hybrids-that frequently co-localize with DNA G-quadruplexes formed on the non-template DNA...

Telomere healing seals the broken ends of DNA double-strand breaks by adding de novo telomeres. In the ciliate Paramecium, telomere healing results in chromosome fragmentation, which ultimately leads to clonal ageing. Despite its importance, where and how chromosomes fragment and undergo telomere healing, and to what extent sequence preferences exist, remain poorly understood. To investigate chromosome fragmentation, we enriched for telomere-containing sequences from the complex, highly...

Some organisms exhibit a remarkable ability to adapt their life history strategies within a single lifespan in response to dynamic biotic and abiotic cues, such as Caenorhabditis elegans larval facultative diapause. However, the molecular basis of how conspecific and prey cues are processed to conditionally alter the time to reproductive maturation remains largely unexplored. Here we discover that the longest transcript of the forkhead transcription factor FKH-7/FOXP is expressed and acts in C....

In populations of many animal species, including humans, mortality rates increase exponentially with advancing age. The scale and rate of increase can be set by two parameters, α and β, respectively, of the Gompertz equation. Interventions that extend lifespan can reduce either or both parameters. A long-standing supposition is that β corresponds to biological ageing rate, and α to ageing-independent causes of mortality. Here, we investigate the biological basis of α and β using the nematode...

The retina provides a unique window into systemic health, yet molecular mechanisms linking retinal features (oculomics) to clinical traits in aging remain unclear. In this study, we leveraged the homogeneous Canton 70 s Alumni Cohort (N = 258 females aged ~70 years) to minimize socio-demographic confounders and extracted oculomic features from fundus images using AutoMorph. Linear mixed-effects models identified 129 significant associations between oculomic and clinical features (p < 0.05)....

Caloric restriction (CR) extends lifespan across diverse organisms, but the effects of CR on human aging and on healthspan are only beginning to be uncovered. In this study, we applied proteomics to plasma samples collected longitudinally from participants achieving, on average, 14% CR over 2 years as part of the CALERIE trial. We identified that inhibition of the complement pathway is linked to lower inflammaging. In humans, the C3a/C3 ratio was significantly lowered by CR, thus reducing...

Aging is the strongest risk factor for Alzheimer's disease (AD), yet the role of age-associated DNA methylation (DNAm) changes in blood and their relevance to AD remains poorly understood. We performed a meta-analysis of blood DNAm samples from 475 dementia-free subjects aged over 65 years across two independent cohorts, the Framingham Heart Study (FHS) at Exam 9 and the Alzheimer's Disease Neuroimaging Initiative (ADNI). We adjusted for sex and immune cell-type proportions and corrected batch...

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Cognitive flexibility supports efficient switching between mental sets and contributes to the preservation of general cognition in aging. It relies on the integration between brain functional dynamics and structural architecture. However, how this structure-function integration changes with age and contributes to cognitive flexibility decline in older adults remains unclear. In this study, we investigated longitudinal aging-related changes in multimodal structure-function integration, quantified...

INTRODUCTION: The human brain exhibits complex functions that emerge from interactions among spatially distributed neural regions. Electroencephalography (EEG) microstate analysis has been widely adopted to capture transient topographies reflecting large-scale network dynamics; moreover, it has been linked to cognitive functions, intrinsic brain networks, and neuropsychiatric disorders. Building on this framework, we recently proposed a novel approach based on instantaneous frequency (IF),...