Metformin decelerates aging clock in male monkeys.

In a rigorous 40-month study, we evaluated the geroprotective effects of metformin on adult male cynomolgus monkeys, addressing a gap in primate aging research. The study encompassed a comprehensive suite of physiological, imaging, histological, and molecular evaluations, substantiating metformin's influence on delaying age-related phenotypes at the organismal level. Specifically, we leveraged pan-tissue transcriptomics, DNA methylomics, plasma proteomics, and metabolomics to develop innovative monkey aging clocks and applied these to gauge metformin's effects on aging. The results highlighted a significant slowing of aging indicators, notably a roughly 6-year regression in brain aging. Metformin exerts a substantial neuroprotective effect, preserving brain structure and enhancing cognitive ability. The geroprotective effects on primate neurons were partially mediated by the activation of Nrf2, a transcription factor with anti-oxidative capabilities. Our research pioneers the systemic reduction of multi-dimensional biological age in primates through metformin, paving the way for advancing pharmaceutical strategies against human aging.

HALL: a comprehensive database for human aging and longevity studies.

Diverse individuals age at different rates and display variable susceptibilities to tissue aging, functional decline and aging-related diseases. Centenarians, exemplifying extreme longevity, serve as models for healthy aging. The field of human aging and longevity research is rapidly advancing, garnering significant attention and accumulating substantial data in recent years. Omics technologies, encompassing phenomics, genomics, transcriptomics, proteomics, metabolomics and microbiomics, have provided multidimensional insights and revolutionized cohort-based investigations into human aging and longevity. Accumulated data, covering diverse cells, tissues and cohorts across the lifespan necessitates the establishment of an open and integrated database. Addressing this, we established the Human Aging and Longevity Landscape (HALL), a comprehensive multi-omics repository encompassing a diverse spectrum of human cohorts, spanning from young adults to centenarians. The core objective of HALL is to foster healthy aging by offering an extensive repository of information on biomarkers that gauge the trajectory of human aging. Moreover, the database facilitates the development of diagnostic tools for aging-related conditions and empowers targeted interventions to enhance longevity. HALL is publicly available at https://ngdc.cncb.ac.cn/hall/index.

Aging induces region-specific dysregulation of hormone synthesis in the primate adrenal gland.

Adrenal glands, vital for steroid secretion and the regulation of metabolism, stress responses and immune activation, experience age-related decline, impacting systemic health. However, the regulatory mechanisms underlying adrenal aging remain largely uninvestigated. Here we established a single-nucleus transcriptomic atlas of both young and aged primate suprarenal glands, identifying lipid metabolism and steroidogenic pathways as core processes impacted by aging. We found dysregulation in centripetal adrenocortical differentiation in aged adrenal tissues and cells in the zona reticularis region, responsible for producing dehydroepiandrosterone sulfate (DHEA-S), were highly susceptible to aging, reflected by senescence, exhaustion and disturbed hormone production. Remarkably, LDLR was downregulated in all cell types of the outer cortex, and its targeted inactivation in human adrenal cells compromised cholesterol uptake and secretion of dehydroepiandrosterone sulfate, as observed in aged primate adrenal glands. Our study provides crucial insights into endocrine physiology, holding therapeutic promise for addressing aging-related adrenal insufficiency and delaying systemic aging.

DNA methylation clocks for estimating biological age in Chinese cohorts.

Epigenetic clocks are accurate predictors of human chronological age based on the analysis of DNA methylation (DNAm) at specific CpG sites. However, a systematic comparison between DNA methylation data and other omics datasets has not yet been performed. Moreover, available DNAm age predictors are based on datasets with limited ethnic representation. To address these knowledge gaps, we generated and analyzed DNA methylation datasets from two independent Chinese cohorts, revealing age-related DNAm changes. Additionally, a DNA methylation aging clock (iCAS-DNAmAge) and a group of DNAm-based multi-modal clocks for Chinese individuals were developed, with most of them demonstrating strong predictive capabilities for chronological age. The clocks were further employed to predict factors influencing aging rates. The DNAm aging clock, derived from multi-modal aging features (compositeAge-DNAmAge), exhibited a close association with multi-omics changes, lifestyles, and disease status, underscoring its robust potential for precise biological age assessment. Our findings offer novel insights into the regulatory mechanism of age-related DNAm changes and extend the application of the DNAm clock for measuring biological age and aging pace, providing the basis for evaluating aging intervention strategies.

Single-nucleus transcriptomics reveals a gatekeeper role for FOXP1 in primate cardiac aging.

Aging poses a major risk factor for cardiovascular diseases, the leading cause of death in the aged population. However, the cell type-specific changes underlying cardiac aging are far from being clear. Here, we performed single-nucleus RNA-sequencing analysis of left ventricles from young and aged cynomolgus monkeys to define cell composition changes and transcriptomic alterations across different cell types associated with age. We found that aged cardiomyocytes underwent a dramatic loss in cell numbers and profound fluctuations in transcriptional profiles. Via transcription regulatory network analysis, we identified FOXP1, a core transcription factor in organ development, as a key downregulated factor in aged cardiomyocytes, concomitant with the dysregulation of FOXP1 target genes associated with heart function and cardiac diseases. Consistently, the deficiency of FOXP1 led to hypertrophic and senescent phenotypes in human embryonic stem cell-derived cardiomyocytes. Altogether, our findings depict the cellular and molecular landscape of ventricular aging at the single-cell resolution, and identify drivers for primate cardiac aging and potential targets for intervention against cardiac aging and associated diseases.

Decoding aging-dependent regenerative decline across tissues at single-cell resolution.

Regeneration across tissues and organs exhibits significant variation throughout the body and undergoes a progressive decline with age. To decode the relationships between aging and regenerative capacity, we conducted a comprehensive single-cell transcriptome analysis of regeneration in eight tissues from young and aged mice. We employed diverse analytical models to study tissue regeneration and unveiled the intricate cellular and molecular mechanisms underlying the attenuated regenerative processes observed in aged tissues. Specifically, we identified compromised stem cell mobility and inadequate angiogenesis as prominent contributors to this age-associated decline in regenerative capacity. Moreover, we discovered a unique subset of Arg1+ macrophages that were activated in young tissues but suppressed in aged regenerating tissues, suggesting their important role in age-related immune response disparities during regeneration. This study provides a comprehensive single-cell resource for identifying potential targets for interventions aimed at enhancing regenerative outcomes in the aging population.

Determining a multimodal aging clock in a cohort of Chinese women.

BACKGROUND: Translating aging rejuvenation strategies into clinical practice has the potential to address the unmet needs of the global aging population. However, to successfully do so requires precise quantification of aging and its reversal in a way that encompasses the complexity and variation of aging. METHODS: Here, in a cohort of 113 healthy women, tiled in age from young to old, we identified a repertoire of known and previously unknown markers associated with age based on multimodal measurements, including transcripts, proteins, metabolites, microbes, and clinical laboratory values, based on which an integrative aging clock and a suite of customized aging clocks were developed. FINDINGS: A unified analysis of aging-associated traits defined four aging modalities with distinct biological functions (chronic inflammation, lipid metabolism, hormone regulation, and tissue fitness), and depicted waves of changes in distinct biological pathways peak around the third and fifth decades of life. We also demonstrated that the developed aging clocks could measure biological age and assess partial aging deceleration by hormone replacement therapy, a prevalent treatment designed to correct hormonal imbalances. CONCLUSIONS: We established aging metrics that capture systemic physiological dysregulation, a valuable framework for monitoring the aging process and informing clinical development of aging rejuvenation strategies. FUNDING: This work was supported by the National Natural Science Foundation of China (32121001), the National Key Research and Development Program of China (2022YFA1103700 and 2020YFA0804000), the National Natural Science Foundation of China (81502304), and the Quzhou Technology Projects (2022K46).

Heterochronic parabiosis induces stem cell revitalization and systemic rejuvenation across aged tissues.

The young circulatory milieu capable of delaying aging in individual tissues is of interest as rejuvenation strategies, but how it achieves cellular- and systemic-level effects has remained unclear. Here, we constructed a single-cell transcriptomic atlas across aged tissues/organs and their rejuvenation in heterochronic parabiosis (HP), a classical model to study systemic aging. In general, HP rejuvenated adult stem cells and their niches across tissues. In particular, we identified hematopoietic stem and progenitor cells (HSPCs) as one of the most responsive cell types to young blood exposure, from which a continuum of cell state changes across the hematopoietic and immune system emanated, through the restoration of a youthful transcriptional regulatory program and cytokine-mediated cell-cell communications in HSPCs. Moreover, the reintroduction of the identified rejuvenating factors alleviated age-associated lymphopoiesis decline. Overall, we provide comprehensive frameworks to explore aging and rejuvenating trajectories at single-cell resolution and revealed cellular and molecular programs that instruct systemic revitalization by blood-borne factors.