In Caenorhabditis elegans, reduced insulin/IGF-1 signalling can promote longevity through a program that is genetically distinct from the dauer developmental pathway, and requires SKN-1-dependent collagen remodelling that is a broadly essential feature of longevity assurance pathways. In the roundworm Caenorhabditis elegans, reduced insulin/IGF-I signalling can promote longevity by inducing the dauer larva stage, a state of suspended animation enabling survival in harsh conditions. Collin Ewald et al. now describe a mechanism by which reduced insulin/IGF-1 signalling promotes longevity through a program genetically distinct from the dauer developmental pathway. This process, which requires the longevity factor SKN-1/Nrf for lifespan extension when insulin/IGF-I signalling is low, induces the expression of collagens and other extracellular matrix genes. Importantly, overexpression of collagens alone can extend the lifespan of C. elegans. Interventions that delay ageing mobilize mechanisms that protect and repair cellular components1,2,3, but it is unknown how these interventions might slow the functional decline of extracellular matrices4,5, which are also damaged during ageing6,7. Reduced insulin/IGF-1 signalling (rIIS) extends lifespan across the evolutionary spectrum, and in juvenile Caenorhabditis elegans also allows the transcription factor DAF-16/FOXO to induce development into dauer, a diapause that withstands harsh conditions1,2. It has been suggested that rIIS delays C. elegans ageing through activation of dauer-related processes during adulthood2,8,9, but some rIIS conditions confer robust lifespan extension unaccompanied by any dauer-like traits1,10,11. Here we show that rIIS can promote C. elegans longevity through a program that is genetically distinct from the dauer pathway, and requires the Nrf (NF-E2-related factor) orthologue SKN-1 acting in parallel to DAF-16. SKN-1 is inhibited by IIS and has been broadly implicated in longevity12,13,14, but is rendered dispensable for rIIS lifespan extension by even mild activity of dauer-related processes. When IIS is decreased under conditions that do not induce dauer traits, SKN-1 most prominently increases expression of collagens and other extracellular matrix genes. Diverse genetic, nutritional, and pharmacological pro-longevity interventions delay an age-related decline in collagen expression. These collagens mediate adulthood extracellular matrix remodelling, and are needed for ageing to be delayed by interventions that do not involve dauer traits. By genetically delineating a dauer-independent rIIS ageing pathway, our results show that IIS controls a broad set of protective mechanisms during C. elegans adulthood, and may facilitate elucidation of processes of general importance for longevity. The importance of collagen production in diverse anti-ageing interventions implies that extracellular matrix remodelling is a generally essential signature of longevity assurance, and that agents promoting extracellular matrix youthfulness may have systemic benefit.

Proteins are the building blocks of life. While proteins and their localization within cells and sub-cellular compartments are well defined, the proteins predicted to be secreted to form the extracellular matrix - or matrisome - remain elusive in the model organism C. elegans. Here, we used a bioinformatic approach combining gene orthology and protein structure analysis and an extensive curation of the literature to define the C. elegans matrisome. Similar to the human genome, we found that 719 out of ~20,000 genes (~4%) of the C. elegans genome encodes matrisome proteins, including 181 collagens, 35 glycoproteins, 10 proteoglycans, and 493 matrisome-associated proteins. We report that 173 out of the 181 collagen genes are unique to nematodes and are predicted to encode cuticular collagens, which we are proposing to group into five clusters. To facilitate the use of our lists and classification by the scientific community, we developed an automated annotation tool to identify ECM components in large datasets. We also established a novel database of all C. elegans collagens (CeColDB). Last, we provide examples of how the newly defined C. elegans matrisome can be used for annotations and gene ontology analyses of transcriptomic, proteomic, and RNAi screening data. Because C. elegans is a widely used model organism for high throughput genetic and drug screens, and to study biological and pathological processes, the conserved matrisome genes may aid in identifying potential drug targets. In addition, the nematode-specific matrisome may be exploited for targeting parasitic infection of man and crops.

Inhibition of the master growth regulator mTORC1 (mechanistic target of rapamycin complex 1) slows ageing across phyla, in part by reducing protein synthesis. Various stresses globally suppress protein synthesis through the integrated stress response (ISR), resulting in preferential translation of the transcription factor ATF-4. Here we show inC. elegansthat inhibition of translation or mTORC1 increases ATF-4 expression, and that ATF-4 mediates longevity under these conditions independently of ISR signalling. ATF-4 promotes longevity by activating canonical anti-ageing mechanisms, but also by elevating expression of the transsulfuration enzyme CTH-2 to increase hydrogen sulfide (H₂S) production. This H₂S boost increases protein persulfidation, a protective modification of redox-reactive cysteines. The ATF-4/CTH-2/H₂S pathway also mediates longevity and increased stress resistance from mTORC1 suppression. Increasing H₂S levels, or enhancing mechanisms that H₂S influences through persulfidation, may represent promising strategies for mobilising therapeutic benefits of the ISR, translation suppression, or mTORC1 inhibition.

The biomechanical properties of extracellular matrices (ECM) and their consequences for cellular homeostasis have recently emerged as a driver of aging. Here we review the age-dependent deterioration of ECM in the context of our current understanding of the aging processes. We discuss the reciprocal interactions of longevity interventions with ECM remodeling. And the relevance of ECM dynamics captured by the matrisome and the matreotypes associated with health, disease, and longevity. Furthermore, we highlight that many established longevity compounds promote ECM homeostasis. A large body of evidence for the ECM to qualify as a hallmark of aging is emerging, and the data in invertebrates is promising. However, direct experimental proof that activating ECM homeostasis is sufficient to slow aging in mammals is lacking. We conclude that further research is required and anticipate that a conceptual framework for ECM biomechanics and homeostasis will provide new strategies to promote health during aging.

Accumulation of damage is generally considered the cause of aging. Interventions that delay aging mobilize mechanisms that protect and repair cellular components. Consequently, research has been focused on studying the protective and homeostatic mechanisms within cells. However, in humans and other multicellular organisms, cells are surrounded by extracellular matrices (ECMs), which are important for tissue structure, function, and intercellular communication. During aging, components of the ECM become damaged through fragmentation, glycation, crosslinking, and accumulation of protein aggregation, all of which contribute to age-related pathologies. Interestingly, placing senescent cells into a young ECM rejuvenates them. Furthermore, we found that many longevity-assurances pathways reactivate de novo synthesis of ECM proteins during aging. This raises the question of what constitutes a young ECM to reverse aging or maintain health? In order to make inroads to answering this question, I suggest a systems-level approach of quantifying the matrisome or ECM compositions reflecting health, pathology, or phenotype and propose a novel term, the “matreotype,” to describe this. The matreotype is defined as the composition and modification of ECM or matrisome proteins associated with or caused by a phenotype, such as longevity, or a distinct and acute physiological state, as observed during aging or disease. Every cell type produces its unique ECM. Intriguingly, cancer-cell types can even be identified based on their unique ECM composition. Thus, the matreotype reflects cellular identity and physiological status. Defined matreotypes could be used as biomarkers or prognostic factors for disease or health status during aging with potential relevance for personalized medicine. Treatment with biologics that alter ECM-to-cell mechanotransduction might be a strategy to reverse age-associated pathologies. An understanding of how to reverse from an old to a young matreotype might point toward novel strategies to rejuvenate cells and help maintain tissue homeostasis to promote health during aging.