Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.64898/2025.12.31.697195

Senescence-inhibitory Δ133p53α counteracts accelerated ageing and mortality

Yamada, L.·Liu, H.·von Muhlinen, N.·Harris, C. C.·Horikawa, I.
View original source ↗Export metadata ↓

Abstract

Research on progeria not only contributes to treatments for the disease but also enhances our understanding of physiological ageing1. Mouse models of progeria recapitulate pathological ageing phenotypes seen in patients, including cardiovascular defects, increased cellular senescence, systemic inflammation, DNA damage accumulation, and shortened lifespan2. In cultured cells from Hutchinson-Gilford progeria syndrome (HGPS) patients, the human p53 isoform {Delta}133p53 was previously shown to inhibit p53-mediated cellular senescence, proinflammatory IL-6 production, and DNA damage accumulation, and to extend cellular replicative lifespan3. Here we show that, in a heterozygous HGPS mouse model4, transgenic expression of {Delta}133p53 reproduces these in vitro-observed effects across multiple organs in vivo and extends median lifespan by 11% (387 versus 349 days, P = 0.0379). In the aorta and skin, {Delta}133p53 abrogates progeria-characteristic pathological changes and preserves tissue integrity. Our data further suggest that {Delta}133p53 may promote a broad spectrum of ageing-counteracting mechanisms, including bone homeostasis, metabolic fitness, antioxidant defense, youthful epigenome, and tissue stemness. Together with the anti-inflammatory and tissue-preserving effects of {Delta}133p53 in naturally aged mice and its age-associated downregulation in human tissues, this study suggests that {Delta}133p53-based therapeutic strategies may be applicable not only to HGPS but also as broader interventions for preventing or delaying ageing.

Explore related subjects

physiologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Yamada, L., Liu, H., von Muhlinen, N., Harris, C. C., Horikawa, I.. 2026-01-02. Senescence-inhibitory Δ133p53α counteracts accelerated ageing and mortality. https://doi.org/10.64898/2025.12.31.697195

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

DEPP1 connects nutrient and oxygen availability to maintenance of muscle mass

Nutrients and oxygen are sensed within the muscle to control growth and disruption of either signal is sufficient to lead to muscle atrophy. While nutrient limitation is sensed via a conserved transcriptional atrophy program (commonly referred to as atrogenes) dictated via the Forkhead box O (FoxO) transcription factors, how low oxygen promotes muscle loss remains unknown. Accordingly, the downstream mechanisms that initiate muscle loss when oxygen and nutrients are limiting are only partly understood. Here, we find Hypoxia Inducible Factor (HIF), the master regulator of our adaptation to low oxygen, is necessary and sufficient to mediate muscle loss under hypoxia in mice. RNA sequencing in skeletal muscle isolated from starved or hypoxic mice identifies Decidual Protein Induced by Progesterone 1 (Depp1), which is induced in skeletal muscle when nutrients or oxygen is limiting via FoxO1 and HIF activation, respectively. Whole body Depp1 loss in mice reduces muscle loss under fasting and hypoxia and skeletal muscle Depp1 overexpression is sufficient to mediate muscle atrophy. Mechanistically, Depp1 localizes to the mitochondria and is necessary to control autophagy activation and mitochondrial degradation in skeletal muscle. Taken together, our studies nominate Depp1 as a new atrogene necessary for muscle loss under multiple atrophy scenarios involving FoxO and HIF.

physiology↗
bioRxiv2026

The CREB-regulated co-activators 2/3, have a role, in vivo, in osteoblastic gene expression.

Many hormones and substances acting through G-protein coupled receptors and protein kinase A (PKA) activation inhibit the salt-inducible kinases (SIKs) by phosphorylation. SIKs tonically phosphorylate CREB-regulated transcriptional coactivators (CRTC1, 2 and 3), sequestering them in the cytoplasm and, thus, preventing their translocation into the nucleus. Once in the nucleus, CRTCs bind CREB family member transcription factors and enhance their activity. We and others have shown that parathyroid hormone (PTH) activation of PKA and resultant SIK2/3 inhibition allows CRTC2/3 nuclear translocation. One of the major actions of CRTC2/3 in the osteoblast lineage is the regulation of transcription of Rankl, as well as other PTH-controlled genes. However, little is known about the role of these co-activators in the osteoblast lineage in vivo. Here, we have investigated whether there are basal effects in vivo on bone examined at 2 different ages of conditional deletion of these two co-activators in the osteoblast lineage using Col2.3-Cre. We found significant increases in body weight, length, bone mineral density, bone volume/total volume, trabecular thickness and number with decreased trabecular separation in young (2 months old) male mice, all of which dissipated by 6 months of age. Female mice showed minimal changes in the bone phenotype at either age. Nevertheless, there were gene expression changes in bones of both sexes at both ages, and in particular decreases in Rankl, Runx2 and Sost, and accompanying changes in Wnt pathway genes. These effects may explain the changes in the bone phenotype in the young male mice, but it is notable that there is a sexual dimorphism in the action of CRTC2 and CRTC3. Overall, the work supports the data from research in vitro and forms a basis for investigation of the role of these co-activators in PTH action in vivo.

physiology↗
bioRxiv2026

Cholinergic impairment in the dorsal motor nucleus of the vagus during experimental Alzheimer's disease

Cholinergic neurons in the dorsal motor nucleus of the vagus (DMN) in the brainstem are a key source of efferent vagus nerve fibers that regulate vital functions, including heart rate and inflammation. Whether the integrity of DMN cholinergic neurons is affected during Alzheimer's disease (AD) remains unknown. Here, in female and male mice with experimental AD (5xFAD), which exhibit age-dependent memory impairment, basal forebrain cholinergic neurodegeneration, and microglial alterations, we observe a reduction in cholinergic neuron density in the DMN at 6 and 10 months of age. Furthermore, while an important physiological function of DMN cholinergic signaling, such as suppression of heart rate, is preserved in control mice upon electrical DMN stimulation, the extent of suppression diminishes with age in both female and male 5xFAD mice. In addition, while electrical DMN stimulation lowers pro-inflammatory cytokine levels in control mice subjected to endotoxemia, this anti-inflammatory effect is diminished with age in 5xFAD mice, with females showing earlier dysfunction at 6 months. These results reveal previously unrecognized age-dependent cholinergic deficits in the DMN and disrupted brain - to - periphery vagus nerve circuits in experimental AD. These findings advance our understanding of AD mechanisms and are of interest for the development of conceptually novel therapies.

physiology↗