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Aging represents the greatest risk factor for chronic diseases and mortality, but to understand it we need the ability to measure biological age. In recent years, many machine learning algorithms based on omics data, termed aging clocks, have been developed that can accurately predict the age of biological samples. However, there is currently no resource for systematic profiling of biological age. Here, we describeClockBase, a platform that features biological age estimates based on multiple aging clock models applied to more than 2,000 DNA methylation datasets and nearly 200,000 samples. We further provide an online interface for statistical analyses and visualization of the data. To show how this resource could facilitate the discovery of biological age-modifying factors, we describe a novel anti-aging drug candidate, zebularine, which reduces the biological age estimates based on all aging clock models tested. We also show that pulmonary fibrosis accelerates epigenetic age. Together,ClockBaseprovides a resource for the scientific community to quantify and explore biological ages of samples, thus facilitating discovery of new longevity interventions and age-accelerating conditions.

Recent studies suggest the existence of a natural rejuvenation event during early embryonic development of mice, followed by epigenetic aging. Here, by profiling embryonic DNA methylation in the African clawed frog, Xenopus laevis, we found that the epigenetic entropy basepoint maps to the gastrulation stage of embryogenesis and corresponds to a rapid increase in embryo transcript abundance. We further developed a frog aging clock, revealing that this species epigenetically ages. Application of this clock to developmental stages identified a decrease in epigenetic age during early embryogenesis, with the minimal age reached around gastrulation. By examining individual developmental trajectories of 6,457 embryos, we found that this stage is also accompanied by a higher incidence of disrupted development. Taken together, our data point to gastrulation as a critical stage for aging and natural rejuvenation, characterized by the lowest epigenetic age, increased mortality, nadir of DNA methylation entropy and rapid increase in embryo transcript abundance, defining aging ground zero as the basepoint where rejuvenation ends and the aging process begins.

Naked mole rats (NMRs) are the longest-lived rodents yet their stem cell characteristics remain enigmatic. Here, we comprehensively mapped the NMR hematopoietic landscape and identified unique features likely contributing to longevity. Adult NMRs form red blood cells in spleen and marrow, which comprise a myeloid bias toward granulopoiesis together with decreased B-lymphopoiesis. Remarkably, youthful blood and marrow single-cell transcriptomes and cell compositions are largely maintained until at least middle age. Similar to primates, the primitive stem and progenitor cell (HSPC) compartment is marked by CD34 and THY1. Stem cell polarity is seen for Tubulin but not CDC42, and is not lost until 12 years of age. HSPC respiration rates are as low as in purified human stem cells, in concert with a strong expression signature for fatty acid metabolism. The pool of quiescent stem cells is higher than in mice, and the cell cycle of hematopoietic cells is prolonged. By characterizing the NMR hematopoietic landscape, we identified resilience phenotypes such as an increased quiescent HSPC compartment, absence of age-related decline, and neotenic traits likely geared toward longevity.

Aging is the single largest risk factor for most chronic diseases, and thus possesses large socioeconomic interest to continuously aging societies. Consequently, the field of aging research is expanding alongside a growing focus from the industry and investors in aging research. This year's 8th Annual Aging Research and Drug Discovery (ARDD) meeting was organized as a hybrid meeting from August 30th to September 3rd 2021 with more than 130 attendees participating on-site at the Ceremonial Hall at University of Copenhagen, Denmark, and 1800 engaging online. The conference comprised of presentations from 75 speakers focusing on new research in topics including mechanisms of aging and how these can be modulated as well as the use of AI and new standards of practices within aging research. This year, a longevity workshop was included to build stronger connections with the clinical community., Aging, 14 (2), ISSN:1945-4589

The naked mole-rat (NMR) is an exceptionally long-lived rodent that shows no increase of mortality with age, defining it as a demographically non-aging mammal. Here, we perform bisulfite sequencing of the blood of > 100 NMRs, assessing > 3 million common CpG sites. Unsupervised clustering based on sites whose methylation correlates with age reveals an age-related methylome remodeling, and we also observe a methylome information loss, suggesting that NMRs age. We develop an epigenetic aging clock that accurately predicts the NMR age. We show that these animals age much slower than mice and much faster than humans, consistent with their known maximum lifespans. Interestingly, patterns of age-related changes of clock sites in Tert and Prpf19 differ between NMRs and mice, but there are also sites conserved between the two species. Together, the data indicate that NMRs, like other mammals, epigenetically age even in the absence of demographic aging of this species., The exceptionally long-lived naked mole-rat is characterized by the lack of increased mortality with aging. Here the authors perform epigenetic studies to show that naked mole-rats epigenetically age despite their non-increasing mortality rate.

Several interventions have recently emerged that were proposed to reverse rather than just attenuate aging, but the criteria for what it takes to achieve rejuvenation remain controversial. Distinguishing potential rejuvenation therapies from other longevity interventions, such as those that slow down aging, is challenging, and these anti‐aging strategies are often referred to interchangeably. We suggest that the prerequisite for a rejuvenation intervention is a robust, sustained, and systemic reduction in biological age, which can be assessed by biomarkers of aging, such as epigenetic clocks. We discuss known and putative rejuvenation interventions and comparatively analyze them to explore underlying mechanisms., Emerging interventions have suggested that biological aging can be reversed rather than just attenuated, but the criteria for what it takes to achieve rejuvenation remain controversial. In this review, we discuss known and putative rejuvenation interventions, exploring their connections within the context of aging biomarkers. We suggest that the prerequisite for classifying an intervention as rejuvenating is a robust and reproducible reduction in biological age, which can be assessed by high‐dimensional trackers of aging such as epigenetic clocks.

SUMMARYHeterochronic parabiosis (HPB) is known for its functional rejuvenation effects across several mouse tissues. However, its impact on the biological age of organisms and their long-term health remains unknown. Here, we performed extended (3-month) HPB, followed by a 2-month detachment period of anastomosed pairs. Old detached mice exhibited improved physiological parameters and lived longer than control isochronic mice. HPB drastically reduced the biological age of blood and liver based on epigenetic analyses across several clock models on two independent platforms; remarkably, this rejuvenation effect persisted even after 2 months of detachment. Transcriptomic and epigenomic profiles of anastomosed mice showed an intermediate phenotype between old and young, suggesting a comprehensive multi-omic rejuvenation effect. In addition, old HPB mice showed transcriptome changes opposite to aging, but akin to several lifespan-extending interventions. Altogether, we reveal that long-term HPB can decrease the biological age of mice, in part through long-lasting epigenetic and transcriptome remodeling, culminating in the extension of lifespan and healthspan.

There is a critical need for robust, high-throughput assays of biological aging trajectories. Among various approaches, epigenetic aging clocks emerged as reliable molecular trackers of the aging process. However, current methods for epigenetic age profiling are inherently costly and lack throughput. Here, we leverage the scAge framework for accurate prediction of biological age from very few bisulfite sequencing reads in bulk samples, thereby enabling drastic (100-1,000-fold) reduction in sequencing costs per sample. Our approach permits age assessment based on distinct assortments of CpG sites in different samples, without the need for targeted site enrichment or specialized reagents. We demonstrate the efficacy of this method to quantify the age of mouse blood samples across independent cohorts, identify the effect of calorie restriction as an attenuator of the aging process, and discern rejuvenation upon cellular reprogramming. We propose that this framework may be used for epigenetic age prediction in extremely high-throughput applications, enabling robust, large-scale and inexpensive interventions testing and age profiling.

Epigenetic “clocks” based on DNA methylation (DNAme) have emerged as the most robust and widely employed aging biomarkers, but conventional methods for applying them are expensive and laborious. Here, we developTagmentation-based Indexing forMethylationSequencing (TIME-Seq), a highly multiplexed and scalable method for low-cost epigenetic clocks. Using TIME-Seq, we applied multi-tissue and tissue-specific epigenetic clocks to over 1,600 mouse DNA samples. We also discovered a novel approach for age prediction from shallow sequencing (e.g., 10,000 reads) by adaptingscAgefor bulk measurements. In benchmarking experiments, TIME-Seq performed favorably against prevailing methods and could quantify the effects of interventions thought to accelerate, slow, and reverse aging in mice. Finally, we built and validated a highly accurate human blood clock from 1,056 demographically representative individuals. Our methods increase the scalability and reduce the cost of epigenetic age predictions by more than 100-fold, enabling accurate aging biomarkers to be applied in more large-scale animal and human studies.

Immunosenescence is a hallmark of aging and manifests as increased susceptibility to infection, autoimmunity, and cancer in the elderly. One component of immunosenescence is thymic involution, age‐associated shrinkage of the thymus, observed in all vertebrates studied to date. The naked mole rat (Heterocephalus glaber) has become an attractive animal model in aging research due to its extreme longevity and resistance to disease. Here, we show that naked mole rats display no thymic involution up to 11 years of age. Furthermore, we found large ectopic cervical thymi in addition to the canonical thoracic thymus, both being identical in their cell composition. The developmental landscape in naked mole rat thymi revealed overt differences from the murine T‐cell compartment, most notably a decrease of CD4+/CD8+ double‐positive cells and lower abundance of cytotoxic effector T cells. Our observations suggest that naked mole rats display a delayed immunosenescence. Therapeutic interventions aimed at reversing thymic aging remain limited, underscoring the importance of understanding the cellular and molecular mechanisms behind a sustained immune function in the naked mole rat., Naked mole‐rats do not display thymic involution by 11 years of age, in contrast to continuous thymus shrinkage in mice. The key markers of youthful thymus function Aire and Foxn1 decrease with age in mice, but are maintained in naked mole‐rats. Characterization of organ integrity and function in >30 year‐old naked mole‐rats could provide a blueprint to naturally maintain a healthy thymus.

Immunosenescence is a hallmark of aging and manifests as increased susceptibility to infection, autoimmunity, and cancer in the elderly. One component of immunosenescence is thymic involution, age-associated shrinkage of the thymus, observed in all vertebrates studied to date. The naked mole-rat (Heterocephalus glaber) has become an attractive animal model in aging research due to its extreme longevity and resistance to disease. Here we show that naked mole rats display no thymic involution up to 11 years of age. Furthermore, we found large ectopic cervical thymi in addition to the canonical thoracic thymus, both being identical in their cell composition. The developmental landscape in naked mole-rat thymi revealed overt differences from the murine T cell compartment, most notably a decrease of CD4+/CD8+ double-positive cells and lower abundance of cytotoxic effector T cells. Our observations suggest that naked mole rats display a delayed immunosenescence. Therapeutic interventions aimed at reversing thymic aging remain limited, underscoring the importance of understanding the cellular and molecular mechanisms behind a sustained immune function in the naked mole rat.

Naked mole-rats (NMRs) are the longest-lived rodents yet their stem cell characteristics remain enigmatic. Here we comprehensively mapped the NMR hematopoietic landscape and identified unique features likely contributing to longevity. Adult NMRs form red blood cells in spleen and marrow, which is a neotenic trait. A myeloid bias towards granulopoiesis in concert with decreased B-lymphopoiesis defines the marrow composition, resembling fetal leukopoiesis. Very similar to primates, the primitive stem cell compartment is marked by CD34 and THY1. Remarkably, stem and progenitor respiration rates are as low as in human cells, while NMR cells show a strong expression signature for fatty acid metabolism. The pool of quiescent stem cells is higher than in mice, and the cell cycle of hematopoietic cells is prolonged. Our work provides a platform to study immunology and stem cell biology in an animal model of exceptional longevity.TeaserJuvenile features of hematopoiesis shape the blood system of the longest-lived rodent.

Epigenetic clocks reveal a rejuvenation event during embryogenesis followed by aging., The notion that the germ line does not age goes back to the 19th-century ideas of August Weismann. However, being metabolically active, the germ line accumulates damage and other changes over time, i.e., it ages. For new life to begin in the same young state, the germ line must be rejuvenated in the offspring. Here, we developed a multi-tissue epigenetic clock and applied it, together with other aging clocks, to track changes in biological age during mouse and human prenatal development. This analysis revealed a significant decrease in biological age, i.e., rejuvenation, during early stages of embryogenesis, followed by an increase in later stages. We further found that pluripotent stem cells do not age even after extensive passaging and that the examined epigenetic age dynamics is conserved across species. Overall, this study uncovers a natural rejuvenation event during embryogenesis and suggests that the minimal biological age (ground zero) marks the beginning of organismal aging.

SUMMARYNaked mole-rats are the longest-lived rodents endowed with resistance to cancer and age-related diseases, yet their stem cell characteristics remain enigmatic. We profiled the naked mole-rat hematopoietic system down to single-cell resolution, and identified several unique features likely contributing to longevity. In adult naked mole-rats red blood cells are formed in spleen and marrow, a neotenic feature beneficial for hypoxic environments and to prevent anemia. Platelet numbers are lower compared to short-lived mice, which may preclude age-related platelet increase and thrombosis. T cells mature in thymus and lymph nodes, providing a supply of T cells after age-related thymus involution. The pool of quiescent stem cells is higher than in mice, and HSCs overexpress an oxidative phosphorylation signature, revealing a new paradigm of stem cell metabolism to benefit longevity and oppose oncogenesis. Our work provides a platform to study immunology and stem cell biology in an animal model of healthy aging.HIGHLIGHTSFlow cytometry labelling panel to purify viable naked mole-rat HSPCsThe spleen as the major site of erythropoiesis in the naked mole-ratNaked mole-rats show extrathymic T-cell development under homeostatic conditionsNaked mole-rat hematopoietic stem cells (HSCs) have high OXPHOS activity