Biology subjects

Zahn, S.

Publications and source records attributed to Zahn, S..

4 recordsLinked to original sources

bioRxiv2026

An epigenetic palimpsest: the King penguin's blood methylome reveals conserved hematopoietic ageing

Age-associated DNA methylation is conserved across vertebrates, but whether epigenetic ageing reflects cellular ageing programmes or age-dependent shifts in cell composition remains unresolved. Here, using 126 whole-blood methylomes from known-age King penguins (Aptenodytes patagonicus), we exploit a vertebrate system in which nucleated erythrocytes dominate peripheral blood, minimizing the influence of leukocyte heterogeneity. We identify a core set of 409 ageing-associated genes showing lifelong, clock-like methylation change. These genes are strongly enriched for regulators of hematopoietic stem and progenitor cell (HSPC) function and niche communication. Integration of methylome, transcriptome and chromatin-accessibility data reveals that many of the strongest ageing signals derive from genes inactive in mature erythrocytes, consistent with the persistence of epigenetic states from ancestral hematopoietic progenitors. A comparison with methylation profiles from 1,501 humans identified a conserved cross-species subset of ageing genes, and a human epigenetic age model constructed solely from orthologues of penguin ageing genes predicts chronological age with high accuracy while remaining largely insensitive to blood cell composition. We propose that blood epigenetic ageing signatures contain a long-lived cellular memory of stem-cell ageing, that may represent an evolutionarily ancient layer of the vertebrate ageing process.

systems biology↗

bioRxiv2024

Sedentary life accelerates epigenetic ageing in King penguins

Introductory paragraphAdvances in medicine and food security have contributed to an increase in human lifespan1. Yet, the associated rise in sedentary behaviour and in obesity2,3 already threatens these gains4. Indeed, a growing body of evidence supports the central role of nutrient sensing and energy management pathways in regulating ageing rate and healthspan5,6, but the diversity of human lifestyles challenges our ability to identify the genetic and epigenetic drivers of this age acceleration. Here, we examine how the transition of wild King penguins to zoo husbandry can closely mimic the shift to a Western lifestyle in humans, and shed light on evolutionarily conserved epigenetic changes in responses to sedentary conditions. We show that, just like modern humans, zoo-housed King penguins experience an extended lifespan, but this comes at the cost of accelerated epigenetic ageing throughout life. This accelerated ageing is associated with differential methylation in key growth and maintenance pathways including the mTOR and PI3K/Akt networks, as well as in specific pathways of lipid-rich diet adaptation and heart-function. Our results demonstrate the deeply conserved link between sedentary behaviour and food availability on the one hand, and age acceleration on the other. Such evolutionary evidence may in turn help us to improve risk detection and, ultimately, therapeutics for lifestyle-induced age acceleration in humans7.

genomics↗

bioRxiv2023

Early-life environmental effects on mitochondrial aerobic metabolism: an experimental brood size manipulation in wild great tits

Parental care (including postnatal provisioning) is a major component of the offsprings early-life environment. In avian species, the number of chicks in the nest and subsequent sibling competition for food are known to affect chicks growth, leading in some cases to long-lasting effects for the offspring. Because of its central role in converting energy, variation in the offsprings mitochondrial metabolism could be an important pathway underlying variation in growth patterns. Here, we performed a brood size manipulation in great tits (Parus major) to unravel its impact on offsprings mitochondrial metabolism and reactive oxygen species (ROS) production in red blood cells. We investigated the effects of brood size on chicks growth and survival, and tested for long-lasting effects on juvenile mitochondrial metabolism and phenotype. As expected, chicks raised in reduced broods had a higher body mass compared to enlarged and control groups. However, mitochondrial metabolism and ROS production were not significantly affected by the treatment either at chick or juvenile stages. Chicks in very small broods were smaller in size and had higher mitochondrial metabolic rates. The nest of rearing has a significant effect on nestling mitochondrial metabolism, yet variation in mitochondrial metabolism at the early-life stages are not associated with survival chances. The contribution of the rearing environment in determining offspring mitochondrial metabolism emphasizes the plasticity of mitochondrial metabolism in changing environments. Further studies would be needed to closely investigate what are the major environmental cues affecting the offspring mitochondrial metabolism during the growth period.

physiology↗

bioRxiv2021

Prolonging coagulant activity of factor Xa under hemophilic conditions by site-specific N-glycosylation of the surface-exposed autolysis loop

The regulation of Factor X (FX) is critical to maintain hemostasis. To gain insights to the regulation of the active and zymogen form of coagulation FX, we probed specific molecular interactions by introducing novel N-linked glycosylations on the surface-exposed loop spanning residues 143-150 (chymotrypsin numbering) of FX. Introduction of N-glycans in the autolysis loop of these FX variants decreased Factor VIIa (FVIIa)-mediated activation ~3-fold and prothrombin activation 2- to 10-fold presumably through steric hinderance. Prothrombin activation was, however, recovered in presence of cofactor Factor Va (FVa) despite a reduced prothrombinase assembly. The introduced N-glycans exhibited position-specific effects on the interaction with two FXa inhibitors: tissue factor pathway inhibitor (TFPI) and antithrombin (ATIII). Ki for the inhibition by full-length TFPI of these FXa variants was increased by 7- to 1150-fold, while ATIII inhibition in the presence of the heparin-analogue Fondaparinux was modestly increased by 2- to 15-fold compared to wild type. To probe the in vitro hemostatic effect of the FX variants, the thrombin generation potential in FX-depleted plasma was evaluated. When supplemented in zymogen form, the FX variants exhibited reduced thrombin generation activity relative to wild-type FX, whereas enhanced procoagulant activity was measured for activated FX variants with N-glycosylation at positions 148-150. These results indicate that residues of the surface-exposed autolysis loop and residues close by participate in FX activation, proteolytic activity and inhibition of FXa by TFPI and ATIII. In plasma-based assays, a modest decrease in FX-activation rate appeared to compensate for the collective reduction in inhibitor interactions.

biochemistry↗