Research articles

Sekiya and colleagues identify that, in response to reductive metabolism, CtBP2 is secreted via exosomes and regulates metabolism in recipient cells via CYB5R3 and AMPK. Exosomal CtBP2 administration extends lifespan and healthspan in aged mice, and serum levels of CtBP2 decline with age in humans.

Elyahu and colleagues describe the reciprocal interplay between senescent cells (SCs) and a helper T cell population that accumulates during aging. They show that selective depletion of this T cell population increases SC accumulation, accelerates frailty and limits lifespan in mice.

This genomic study of magnetic resonance imaging-based brain age in 56,348 people identifies 59 genetic loci, links brain aging to mental and physical health, and suggests high blood pressure and type 2 diabetes as causal factors of brain aging.

Wang, He, Gong and colleagues identify an age-related decline in the palmitoyltransferase ZDHHC11 in chondrocytes that leads to senescence and the pathogenesis of osteoarthritis, highlighting the potential of targeted ZDHHC11 delivery as a therapeutic strategy for osteoarthritis.

The contribution of the extracellular matrix and its degradation to the aging process is not well understood. Here, the authors show that degraded elastin fragments, which increase in the circulation with age, promote aging, while counteracting elastin fragment signals alleviates inflammation, promotes healthy aging and extends lifespan.

Bodogai et al. identify a unique subset of CD8⁺ T cells expressing CD39 and CD73 that accumulate during aging and are recruited to and actively promote tumor progression by suppressing antitumor CD4⁺ T cells. Targeting their function or recruitment attenuates tumor growth in aged mice.

Using a zebrafish-based screen, Civiletto and colleagues identify the herb-derived metabolites thymol and carvacrol as activators of autophagy and mitophagy, demonstrating their therapeutic potential in C. elegans and mouse models.

Sehgal et al. report Systems Age as a framework to capture within-person heterogeneity in aging using a single blood-based epigenetic assay that measures aging across 11 body systems and identifies aging subtypes, enabling personalized prediction of disease risk and tailoring of longevity interventions.

Afshar, Dammer et al. identify plasma proteins associated with Alzheimer’s disease brain pathologies and find that many plasma proteins related to cognitive function are not associated with these pathologies.

Hu et al. identify border-associated macrophages as early targets of brain aging. These cells acquire senescence-associated properties, which are transmittable via migrasomes carrying the apoptosis inhibitor of macrophage. Blocking migrasome production attenuates cognitive decline in aged mice.

Membraneless organelles formed by liquid–liquid phase separation regulate cellular processes. Here Bai et al. show that mitochondria-associated translation organelles (MATOs) consisting of RNA-binding proteins and translation machinery mediate localized synthesis of mitochondrial proteins to promote mitochondrial health and extend lifespan in worms.

Aging is a risk factor for Parkinson’s disease; however, how DNA damage accumulation, a hallmark of aging, contributes to its pathophysiology remains incompletely understood. Here, the authors identify a blood-based DNA damage signature that is associated with disease progression in patients with Parkinson’s disease.

Aging is a risk factor for neurodegenerative diseases associated with protein aggregation. Here the authors identify age-related hyperactivation of EPS8/RAC signaling in C. elegans as a driver of pathological protein aggregation, highlighting EPS8 and its regulators as potential therapeutic targets.

Gonzalez-Hurtado, Leveau and colleagues characterize adipose resident tissue macrophages across lifespan in mice, finding that nerve-associated macrophages, which mitigate inflammation and control lipolysis and catecholamine resistance, are lost during aging.

Lee et al. show that the circadian clock protein REV-ERBα controls brain NAD⁺ levels by regulating the NAD⁺-consuming enzyme CD38. Global or astrocytic REV-ERBα deletion or pharmacologic REV-ERB inhibition protects against tau pathology in mice.

Declining oocyte quality contributes to age-related reduction in fertility; however, the underlying mechanisms are incompletely understood. Here Liu et al. reveal that replenishing mevalonate pathway metabolites and supplementation with a natural compound, 8-isopentenyl flavone, improve aged oocyte quality by restoring cortical F-actin through CDC42 and RAC1 prenylation.

Montoliu-Gaya, Salvadó et al. develop a blood-based model using tau biomarkers measured in a single analysis enabling biological staging of Alzheimer’s disease to support the diagnosis, prognosis and identification of patients likely to benefit from targeted therapies.

With aging, somatic mutations accumulate in cellular DNA; however, whether they drive age-related functional decline is incompletely understood. Here the authors show that these mutations can weaken muscle repair and reduce strength after injury, suggesting they play a role in age-related physical decline in mouse muscle.

The authors identify ferritin light chain 1 (FTL1), an iron-associated protein, as a pro-aging neuronal factor that increases with age and promotes cognitive decline. Targeting FTL1 in the brain improved cognition in old mice.

To better understand the etiology of frailty, the authors perform a large genetic study. They identified 45 additional variants and implicated MET, CHST9, ILRUN, APOE, CGREF1 and PPP6C as potential causal genes, linking frailty to immune regulation, metabolism and cellular signaling.