Collin Y. Ewald

Proteostasis, the maintenance of a healthy proteome, is a fundamental pillar of cellular and organismal health that declines with age. While the intracellular proteostasis network (PN) is well‐characterised, proteostasis mechanisms acting in the extracellular space remain understudied. Yet, these mechanisms face unique challenges and are critical for ensuring functional systemic signalling, immune surveillance and structural integrity. In contrast to the cytosol, extracellular environments lack ATP‐activated chaperones and a comprehensive ubiquitin‐proteasome system and instead rely on specialised secreted chaperones, extracellular proteases and receptor‐mediated clearance mechanisms. This review examines the emerging landscape of the extracellular proteostasis network (exPN) and its challenges with age. We discuss how age‐related remodelling of the extracellular proteome, shifts in extracellular physicochemical properties and disrupted fluid dynamics collectively create a permissive environment for protein misfolding and aggregation. We evaluate current experimental models of extracellular protein damage and examine how exPN factors target specific stages of the aggregation process to cooperatively safeguard extracellular proteome integrity. Analysis of recent human proteomic data spanning the life course uncovers an unexpected upregulation of exPN components with age. We further explore the role of extracellular proteostasis in inflammageing, a defining hallmark of ageing. Finally, we highlight strategies that bolster extracellular proteostasis as a promising frontier for extending healthspan, limiting age‐associated protein aggregation and restoring extracellular matrix homeostasis. By adopting an ageing‐centred perspective, we move beyond the disease context to present a holistic overview of extracellular proteostasis in organismal health, thereby positioning the exPN as a critical yet under‐exploited target for biomedical intervention.

Constitutive activation of hypoxia-inducible factor 1 (HIF-1) in vhl-1(ok161) mutant Caenorhabditis elegans induces a characteristic phenotype marked by extended lifespan, reduced body size, and broad metabolic reprogramming. However, the underlying determinants mediating these adaptations remain incompletely understood. Here, we show that HIF-1 activation drives a distinct sulfur metabolic state characterized by the accumulation of hydrogen sulfide (H₂S) and persulfide species, accompanied by extensive remodeling of the mitochondrial proteome and altered stress sensitivity. Strikingly, these organismal and metabolic phenotypes require the mitochondrial sulfide:quinone oxidoreductase SQRD-1 (SQOR), which catalyzes the first step of sulfide oxidation. Loss of sqrd-1 abolishes the lifespan extension and small-body phenotype of vhl-1 mutants and reverses their proteomic, mitochondrial, and metabolic profiles toward wild-type levels. Mechanistically, SQRD-1-dependent sulfide oxidation establishes a redox state that shapes mitochondrial function, including suppression of respiratory capacity and modulation of oxidative stress responses. Consistent with this, quantitative proteomics revealed coordinated regulation of mitochondrial pathways and sulfur oxidation enzymes in vhl-1 mutants that is lost in vhl-1;sqrd-1 double mutants. Functional analyses identified mitochondrial complex I subunits (NUO-4 and NUO-5) as downstream effectors linking this metabolic state to lifespan and body-size regulation. Together, these findings identify SQRD-1 as a critical determinant of the metabolic and physiological outcomes of chronic HIF-1 activation, defining a sulfide-dependent redox state that couples hypoxia signaling to mitochondrial function and organismal adaptation. This work highlights mitochondrial sulfide oxidation as a key regulatory node in hypoxia responses and a potential target for modulating stress resistance and metabolic health.

How is it possible to double the lifespan of an organism already close to death? Many biological theories of aging fail to explain this phenomenon. At the Physics of Aging workshop, we presented and discussed late-life lifespan extension in Caenorhabditis elegans to illustrate how a simple stochastic dynamical systems model can account for dramatic geriatric interventions. We build on a Langevin-type instability framework in which aging is a manifestation of dynamical instability–a scenario where stochastic fluctuations amplify over time, driving the system toward a failure thresh-old at which death occurs as a first-passage event. The instability rate α (equivalently, the inverse of the mortality-rate doubling time) quantifies the speed of this divergence: a larger α means faster exponential growth of z , a steeper Gompertz slope, and a shorter lifespan. The failure threshold z _max ≈α/g , where g is the strength of nonlinear feedback, marks the point beyond which the system diverges irreversibly—physiologically, the saturation of metabolic and regulatory capacity. Within this dynamical-systems framework, auxin-induced degradation of the insulin/IGF-1 receptor DAF-2 in very old animals is naturally interpreted as a late shift in stability parameters that nearly doubles remaining lifespan without resetting accumulated structural damage. This interpretation reconciles the persistence of many senescent pathologies with restored proteostasis and stress resilience, and it shows that targeting the dynamical instability of the regulatory network–rather than reversing damage—can strongly reshape survival trajectories in unstable animals. More broadly, our work exemplifies how physics-inspired low-dimensional stochastic models can capture key features of aging, and we hope it will inspire more collaborations between biologists and physicists to work on late-life interventions.

Plasma proteomic aging clocks estimate biological age and are linked to age‐related diseases, but thus far, there has been little focus on circulating extracellular matrix (ECM) proteins, which play a central role in tissue structure and age‐related decline. Here, we use publicly available proteomic datasets to profile plasma ECM protein abundances across the human lifespan and reveal a distinct U‐shaped trajectory with age. Our ECM‐based aging clock, constructed from 14 plasma proteins, accurately predicts chronological age and remains robust across independent validations and different biofluids. Notably, this ECM clock distinguishes between healthy and diseased states. Cross‐species comparisons show that while specific predictive ECM proteins differ between humans and rodents, species‐specific ECM clocks reliably track aging, and rejuvenation interventions can reverse ECM aging signatures. We prioritize ECM proteins implicated causally in disease and explored drugs targeting these proteins. These findings establish circulating ECM proteins as sensitive biomarkers of aging and disease and suggest that targeting ECM remodeling may offer new strategies for promoting healthy aging.

Biological aging clocks capture heterogeneous rates of aging in individuals and transform current medical practice toward translational preventive medicine. Here, we developed a clinical aging clock based on routine blood biochemistry markers from 59,741 healthy samples in a Southeast Asian cohort. We established a novel correction method to address the systematic skew in predictions from first-generation clocks. This correction improved the accuracy of age-acceleration predictions for disease risks and enhanced interpretability for disease-driven and organ-specific aging processes without relying on mortality data. Based on only seven biomarkers, our clock accurately predicts both self-reported and physician-annotated ICD health data, indicating an increased hazard ratio. Importantly, the clock is robust even in the presence of acute infections or transient immune activation. To demonstrate the multi-ethnic generalizability of our biological age clock, we validated our approach using data from both the NHANES and UK Biobank cohorts. Our approach demonstrates the feasibility of a simple, robust, and interpretable clinical aging clock with potential for real-world implementation in personalized health monitoring and preventive care.

Collagen supplementation has gained attention with increasing claims regarding its beneficial effects on healthy aging based on clinical observations and lifespan extension in pre-clinical models; however, how and which part of an ingested collagen promotes healthy longevity is unknown. Here, we identified the minimal required unit of ingested collagen, which consists of the proper ratio of three glycine to one proline to one hydroxyproline that was sufficient to increase the motility-healthspan and lifespan of C. elegans , as well as collagen homeostasis in human fibroblasts in vitro. Supplementation in 20-month-old mice improved grip strength and prevented age-related fat accumulation. In a clinical observational trial (ISRCTN93189645, 03.07.2025), oral supplementation in humans demonstrated improved skin features within three months and a reduction in biological age by 1.4 years ( p = 0.04) within 6 months. Thus, a ratio of three amino acids elicits evolutionarily conserved health benefits from ingested collagens.

Before human genome sequencing, a genome-wide study of sibling centenarian pairs identified a longevity-associated locus on chromosome 4. Here, we mapped the genes in this locus and identified a collagen gene, COL25A1. Introducing an SNP linked to longevity that changes a serine predicted to be phosphorylated to leucine in COL25A1, into col-99, the C. elegans ortholog, extended lifespan. These col-99(gk694263[S106L]) SNP-mutants exhibited enhanced innate immune-related transcriptional responses, and their lifespan extension was abolished by inhibiting the p38 MAPK pathway. YAP-1, a transcriptional co-activator responsive to extracellular matrix changes, was essential for this longevity. Mechanistically, we find that this SNP modifies furin-mediated cleavage of this transmembrane collagen in vitro, and expressing the cleaved extracellular domain of COL-99 alone was sufficient to prolong C. elegans’ lifespan. These findings reveal a potential mechanism by which a human centenarian-associated SNP in COL25A1 influences furin cleavage and shedding of the collagen ectodomain to promote healthy longevity.

Investigations into human longevity are increasingly focusing on healthspan enhancement, not just lifespan extension. Lifestyle modifications and nutritional choices, including food supplements, can significantly affect aging and general health. Phytochemicals in centenarians’ diets, such as those found in Timut pepper, a Nepalese spice with various medicinal properties, may contribute to their longevity. Similarly, Sichuan pepper, a related species, has demonstrated anti-inflammatory and neuroprotective activities. With the broader purpose of uncovering a novel treatment to address aging and its comorbidities, this study aims to investigate the potential lifespan- and healthspan-promoting effects of Timut pepper using the model organism Caenorhabditis elegans. We show that Timut pepper extract extends C. elegans’ lifespan at different maintenance temperatures and increases the proportion of active nematodes in their early adulthood. In addition, we show that Timut pepper extract enhances speed and distance moved as the nematodes age. Finally, Timut pepper extract assures extracellular matrix homeostasis by slowing the age-dependent decline of collagen expression.

Little is known about the possibility of reversing age-related biological changes when they have already occurred. To explore this, we have characterized the effects of reducing insulin/IGF-1 signaling (IIS) during old age. Reduction of IIS throughout life slows age-related decline in diverse species, most strikingly in the nematode Caenorhabditis elegans. Here we show that even at advanced ages, auxin-induced degradation of DAF-2 in single tissues, including neurons and the intestine, is still able to markedly increase C. elegans lifespan. We describe how reversibility varies among senescent changes. While senescent pathologies that develop in mid-life were not reversed, there was a rejuvenation of the proteostasis network, manifesting as a restoration of the capacity to eliminate otherwise intractable protein aggregates that accumulate with age. Moreover, resistance to several stressors was restored. These results support several new conclusions. (1) Loss of resilience is not solely a consequence of pathologies that develop in earlier life. (2) Restoration of proteostasis and resilience by inhibiting IIS is a plausible cause of the increase in lifespan. And (3), most interestingly, some aspects of the age-related transition from resilience to frailty can be reversed to a certain extent. This raises the possibility that the effect of IIS and related pathways on resilience and frailty during aging in higher animals might possess some degree of reversibility.