Aging & Longevity

In this issue of Molecular Cell, Sohn et al.¹ explore how endogenous dsRNAs influence organismal aging and identify an unexpected function of the aminoacyl-tRNA synthetase FARS-1/FARSA in regulating mitochondrial dsRNA homeostasis to balance longevity and innate immunity.

Increasing evidence suggests that epigenetic dysregulation is both a hallmark and a potential driving force of aging. As a multifactorial, non-linear, and systemic biological process, aging likely results from a progressive imbalance in a complex epigenetic network involving DNA, histones, RNA, and non-coding sequences. These interconnected alterations collectively lead to core aging features such as genomic instability, heightened inflammation, and loss of cellular identity. In this review, we...

CONCLUSIONS: Cardiometabolic biomarker domains, particularly glycaemic dysfunction, were reproducibly associated with incident mobility limitation. A simple biomarker-burden score captured a relevant but incomplete component of functional ageing risk.

Obesity increases the risk of common diseases and mortality, placing a significant burden on our aging society. Bariatric surgery results in significant weight loss; however, the amount of associated health gain is currently less studied, particularly in the first two years. We modelled mortality-associated biological age according to established blood markers in a prospective cohort of 505 patients that underwent bariatric surgery. The difference between biological age and chronological age...

Cellular senescence is a highly heterogeneous state of cell stress response that deleteriously accumulates with age and contributes to age-related dysfunction. While the heterogeneity across cell types is well documented, variation within the same cell type is only beginning to be understood. Here, we show primary human lung fibroblasts from either donors who are healthy or diagnosed with idiopathic pulmonary fibrosis (IPF) exhibit a subtle form of heterogeneity over time after DNA damage....

Hippocampal volume is associated with memory and is critical in Alzheimer's disease, but few studies have examined hippocampal subfield volume changes during healthy aging. Herein, we utilize submillimeter MRI to examine age- and sex-specific subfield volumetric changes in 206 participants (M(age) = 53.05 years, range = 21-87, N(female) = 110). Total intracranial volume was regressed out and hierarchical regression was performed to examine subfield volume changes with age. To identify inflection...

Radiotherapy (RT) efficacy is limited by RT-induced immune resistance. Here we show that RT upregulates programmed death ligand 1 (PD-L1) on senescent tumor cells (STCs) via bromodomain-containing protein 4 (BRD4) signaling, thereby promoting immune evasion. To counter this, we develop POLY-Senolytic, a polymeric senolytic nanoparticle formed by conjugating an acid-responsive polymer to a peptide-based BRD4 PROteolysis-TArgeting Chimera via a reduction-cleavable disulfide bond. The...

Life is a constant struggle against disorder. As we age, our ability to maintain internal order declines. In the healthy human brain, order is observable in the form of functionally segregated brain network communities that exhibit spatial consistency. These communities associate with distinct cognitive and physical functions. When mapped into the brain, they form a functional "landscape". We assessed the spatial disorder of these landscapes in older adults with a wide range of mobility using a...

Phosphatidylinositol 3-kinase (PI3K) integrates insulin/IGF signaling (IIS) and Ras inputs to control lifespan, metabolism and growth. Yet the organismal consequences of selective structural perturbations remain poorly understood. Using structure-guided CRISPR/Cas9-dependent genome editing, we dissected functions of AGE-1, the sole Class IA PI3K catalytic subunit in Caenorhabditis elegans. An endogenously tagged AGE-1, containing a long flexible linker, epitope and fluorescent tag, retained full...

Reducing protein synthesis extends lifespan across taxa, but pharmacological strategies to safely attenuate translation remain limited. Tetracyclines are clinically used antibiotics long observed to exert beneficial effects in age-associated diseases and extend lifespan in model organisms, though the underlying mechanisms remain unclear. Here, we systematically profiled commercially available tetracyclines and show that translation attenuation is a general property of the tetracycline class....

Deterioration of the blood-brain barrier (BBB), including impaired neurovascular uncoupling, contributes to cognitive decline in aging. The BBB is formed principally by brain microvascular endothelial cells (ECs), and ECs throughout the body are enriched for the transcription factor Krüppel-like factor 4 (KLF4). Because KLF4 levels in ECs decrease with age, we tested whether that decline contributes to aging-related BBB deterioration, neurovascular dysfunction, and cognitive impairment. Using...

Age and early life adversity (ELA) are key determinants of health, but whether they affect similar physiological mechanisms across tissues is unknown. We generated DNA methylation (DNAm) profiles across 14 tissues in 237 semi-free-ranging rhesus macaques with naturally occurring ELA. Age-associated DNAm was predominantly tissue dependent, yet tissue-specific epigenetic clocks showed that epigenetic aging was relatively consistent within individuals. ELA effects were adversity dependent, but each...

Cognitive decline is a major challenge in aging. Transcranial alternating current stimulation (tACS) modulates neural oscillations, potentially aiding cognition. Due to variation in late-life tACS studies, we conducted the first meta-analysis in older adults (≥ 60 years) to estimate pooled cognitive effects and determine if protocol parameters explain outcome variability. We searched Medline/PubMed, Embase, Cochrane Library, and ClinicalTrials.gov (up to September 17, 2025) for studies examining...

CONCLUSIONS: These findings emphasize the importance of sex-specific nutritional interventions and stable food supply systems for preventing frailty in aging populations.

Metformin use may be associated with reduced risk of all-cause mortality as well as prevent the onset of diseases of aging, namely cardiovascular diseases (CVD), cancer, and dementia. We systematically reviewed recent studies to determine whether metformin can promote healthspan in people with type 2 diabetes mellitus (T2DM). A comprehensive literature search was conducted using Medline, Embase, and Scopus for randomized controlled trials (RCTs) and cohort studies evaluating the effect of...

Aging-related declines in spatial navigation pose significant challenges for older adults' independence and quality of life. Among navigational deficits, older adults have been shown to demonstrate deficits in utilizing allocentric (i.e., world-centered) information and rely on egocentric (i.e., body-centered) cues during navigation, resulting in reference frame bias. We investigated naturalistic navigation performance and allocentric knowledge formation in younger adults (N = 30) and older...

INTRODUCTION: Healthy aging is often accompanied by a loss of hearing sensitivity and a reduced ability to understand speech in both quiet and noisy environments. From a physiological perspective, neural oscillations are thought to fundamentally contribute to parse the speech signal into meaningful units and to extract linguistically relevant information at multiple hierarchical levels. Given that syllables are essential structural elements of the speech signal that recur with quasi-rhythmic...

CONCLUSION: These findings indicate that amyloidosis is associated with reduced reliability of spatial memory performance and impaired handling of competing spatial information, particularly under conditions requiring flexible updating of overlapping mnemonic representations. The results further suggest increased vulnerability to interference-related spatial memory deficits with age. Together, these findings support the utility of the OUL paradigm for studying memory updating impairments in...

Substantial heterogeneity in cognitive ageing is well documented. Such heterogeneity has been attributed to individual differences in brain maintenance - i.e., the relative preservation of neural resources in ageing. However, large-scale longitudinal evidence is currently lacking. In this study, we pooled data from three longitudinal population-based Swedish cohorts (total N = 1 356, 60-93 years at baseline, maximum follow-up duration: 7 years) to assess whether global brain maintenance is...

Hutchinson-Gilford progeria syndrome (HGPS) is an ultra-rare premature aging disorder caused predominantly by a de novo LMNA c.1824C>T mutation that produces progerin, a truncated and permanently farnesylated lamin A isoform. Progerin accumulation disrupts nuclear lamina integrity and chromatin organization, inducing persistent DNA damage responses, telomere attrition, mitochondrial dysfunction, and cellular senescence. These processes drive a multisystem clinical phenotype characterized by...