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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.

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.

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 (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