Longevity Papers

The intestinal epithelium serves as a physical and functional barrier against harmful substances, preventing their entry into the circulation and subsequent induction of a systemic immune response. Gut barrier dysfunction has recently emerged as a feature of ageing linked to declining health, and increased intestinal membrane permeability has been shown to promote heightened systemic inflammation in aged hosts. Concurrent with age-related changes in the gut microbiome, the thymic microenvironment undergoes a series of morphological, phenotypical and architectural alterations with age, including disorganisation of the corticomedullary junction, increased fibrosis, increased thymic adiposity and the accumulation of senescent cells. However, a direct link between gut barrier dysbiosis and thymic involution leading to features of immune ageing has not been explored thus far. Herein, we reveal strong associations between enhanced microbial translocation and the peripheral accumulation of terminally differentiated, senescent and exhausted T cells and the compensatory expansion of regulatory T cells in older adults. Crucially, we demonstrate that aged germ-free mice are protected from age-related increases in intestinal permeability, highlighting the direct impact of mucosal permeability on thymic ageing. Together, these findings establish a novel mechanism by which gut barrier dysfunction drives systemic activation of the immune system during ageing through thymic involution. This enhances our understanding of drivers of T cell ageing and opens up the possibility for the use of microbiome-based interventions to restore immune homeostasis and promote healthy ageing in older adults.

Cellular senescence is a stress response that restrains the growth of aged, damaged or abnormal cells. Thus, senescence has a crucial role in development, tissue maintenance and cancer prevention. However, lingering senescent cells fuel chronic inflammation through the acquisition of a senescence-associated secretory phenotype (SASP), which contributes to cancer and age-related tissue dysfunction. Recent progress in understanding senescence has spurred interest in the development of approaches to target senescent cells, known as senotherapies. In this Review, we evaluate the status of various types of senotherapies, including senolytics that eliminate senescent cells, senomorphics that suppress the SASP, interventions that mitigate senescence and strategies that harness the immune system to clear senescent cells. We also summarize how these approaches can be combined with cancer therapies, and we discuss the challenges and opportunities in moving senotherapies into clinical practice. Such therapies have the potential to address root causes of age-related diseases and thus open new avenues for preventive therapies and treating multimorbidities.

The aging of the immune system substantially impacts individual immune responses, yet accurately quantifying immune age remains a complex challenge. Here we developed IMMClock, a novel immune aging clock that uses gene expression data to predict the biological age of individual CD8 T cells, CD4 T cells, and NK cells. The accuracy of IMMClock is first validated across multiple independent datasets, demonstrating its robustness. Second, utilizing the IMMClock, we find that intrinsic cellular aging processes are more strongly altered during immune aging than differentiation processes. Thirdly, our analysis confirms the strong associations between immune aging and established processes such as cellular senescence, exhaustion, and telomere length at the single cell level. Furthermore, immune aging is accelerated under several disease conditions such as type 2 diabetes, heart disease, and cancer. Finally, we apply IMMClock to analyze a perturb-seq gene activation screen of T cell functionality. We find that the post-perturbation immune age of individual T cells is strongly correlated with their pre-perturbation immune age. Furthermore, the immune age at resting state of individual T cells is strongly predictive of their post-stimulation activation state. Overall, IMMClock advances our understanding of immune aging by providing precise, single-cell level age estimations. Its future applications hold promise for identifying interventions that concomitantly rejuvenate and activate T cells, potentially enhancing efforts to counteract age-related immune decline.

Aging, the predominant risk factor for numerous diseases, manifests in various forms across the structure and architecture of tissues of the human body, offering the opportunity to quantify and interpret tissue-specific aging. To address this, we present a comprehensive assessment of tissue changes occurring during human aging, utilizing a vast array of whole slide histopathological images from the Genotype-Tissue Expression Project (GTEx). We analyzed 25,712 images from 40 distinct tissue types across 983 individuals, applying deep learning to quantify the nuanced morphological changes that tissues undergo with age. We developed tissue clocks--predictors of biological age based on tissue images--which achieved a mean prediction error of 4.9 years and were associated with telomere attrition, the incidence of subclinical pathologies, and comorbidities. In a systematic assessment of biological age rates across organs, we identified pervasive non-uniform rates of aging across the human lifespan, with some organs exhibiting earlier changes (20-40 years old) and others showing bimodal patterns of age-related changes. We also uncovered several associations between demographic, lifestyle, and medical history factors and tissue-specific acceleration or deceleration of biological age, highlighting potential modifiable risk factors that influenced the aging process at the tissue level. Finally, by combining paired histological images and gene expression data, we developed a strategy to predict tissue-specific age gaps from blood samples. This approach was validated in external cohorts of both healthy individuals and those with chronic diseases, revealing the organs most differentially affected by aging in disease contexts. This work offers a new perspective on the aging process by positioning tissue structure as an integrator of cellular and molecular changes that reflect the physiological state of organs. These findings underscore the value of histopathological imaging as a tool for understanding human aging and provide a foundation for the exploration of tissue-specific aging processes in age-associated diseases.

Cellular senescence is not only associated with ageing but also impacts physiological and pathological processes, such as embryonic development and wound healing. Factors secreted by senescent cells affect their microenvironment and can induce spreading of senescence locally. Acute severe liver disease is associated with hepatocyte senescence and frequently progresses to multi-organ failure. Why the latter occurs is poorly understood. Here we demonstrate senescence development in extrahepatic organs and associated organ dysfunction in response to liver senescence using liver injury models and genetic models of hepatocyte-specific senescence. In patients with severe acute liver failure, we show that the extent of hepatocellular senescence predicts disease outcome, the need for liver transplantation and the occurrence of extrahepatic organ failure. We identify the TGFβ pathway as a critical mediator of systemic spread of senescence and demonstrate that TGFβ inhibition in vivo blocks senescence transmission to other organs, preventing liver senescence induced renal dysfunction. Our results highlight the systemic consequences of organ-specific senescence, which, independent of ageing, contributes to multi-organ dysfunction.

Aging is characterized by a gradual decline in function, partly due to accumulated molecular damage. Human skin undergoes both chronological aging and environmental degradation, particularly UV-induced photoaging. Detrimental structural and physiological changes caused by aging include epidermal thinning due to stem cell depletion and dermal atrophy associated with decreased collagen production. Here, we present a comprehensive single-cell atlas of skin aging, analyzing samples from young, middle-aged, and elderly individuals, including both sun-exposed and sun-protected areas. This atlas reveals age-related cellular composition and function changes across various skin cell types, including epidermal stem cells, fibroblasts, hair follicles, and endothelial cells. Using our atlas, we have identified basal stem cells as a highly variable population across aging, more so than other skin cell populations such as fibroblasts. In basal stem cells, we identified ATF3 as a novel regulator of skin aging. ATF3 is a transcriptional factor for genes involved in the aging process, with its expression reduced by 20% during aging. Based on this discovery, we have developed an innovative mRNA-based treatment to mitigate the effects of skin aging. Cell senescence decreased 25% in skin cells treated with ATF3 mRNA, and we observed an over 20% increase in proliferation in treated basal stem cells. Importantly, we also found crosstalk between keratinocytes and fibroblasts as a critical component of therapeutic interventions, with ATF3 rescue of basal cells significantly enhancing fibroblast collagen production by approximately 200%. We conclude that ATF3-targeted mRNA treatment effectively reverses the effects of skin aging by modulating specific cellular mechanisms, offering a novel, targeted approach to human skin rejuvenation.

Several mouse lines with congenital growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis disruption have shown improved health and extended lifespan. The current study investigated how inactivating this axis, specifically during aging, impacts the healthspan. We used a tamoxifen-inducible global GH receptor (GHR) knockout mouse model starting at 12 months and followed the mice until 24 months of age (iGHRKO

As societies age, policy makers need tools to understand how demographic aging will affect population health and to develop programs to increase healthspan. The current metrics used for policy analysis do not distinguish differences caused by early-life factors, such as prenatal care and nutrition, from those caused by ongoing changes in peoples bodies due to aging. Here we introduce an adapted Pace of Aging method designed to quantify differences between individuals and populations in the speed of aging-related health declines. The adapted Pace of Aging method, implemented in data from the US Health and Retirement Study and English Longitudinal Study of Aging (N=21,463), integrates longitudinal data on blood biomarkers, physical measurements, and functional tests. It reveals stark differences in rates of aging between population subgroups and demonstrates strong and consistent prospective associations with incident morbidity, disability, and mortality. Pace of Aging can advance the population science of healthy longevity.

Mosaic loss of the Y chromosome (mLOY) is the most common somatic event in men, strongly associated with aging and various health conditions. Current methods for detecting mLOY primarily rely on DNA genotyping arrays. Here, we present MosCoverY, a novel method for estimating mLOY from NGS sequencing data that can be applied to both exome and genome sequencing. MosCoverY addresses the challenges posed by the structure of the Y chromosome by focusing on single-copy genes and normalizing their coverage against autosomal exons matched by length and GC content. We validated MosCoverY using data from 212,062 male participants in the UK Biobank, comparing its results to those obtained using genotyping- or whole genome sequencing-based methods. MosCoverY identified mLOY in 5.6% of men, demonstrating performance that was comparable to the other methods. MosCoverY also replicated known associations between mLOY, age, smoking, all-cause mortality, and germline genetic loci, showing the strongest associations in many cases. MosCoverY offers a valuable tool for detecting mLOY from exome data in population-scale studies.