Species of mammals differ dramatically in their maximum lifespan and cancer susceptibility. We investigate mammalian species that naturally evolved long lifespan and cancer resistance with the goal of understanding molecular mechanisms of longevity and cancer resistance and then applying them to benefit human health. I will present our recent data on the mechanisms that are responsible for longevity in long-lived animals such as naked mole-rat, bowhead whale, and bats. I will also discuss our recent comparative transcriptomics and proteomics studies.

Ca²⁺ acts as a versatile signal to control a myriad of cellular activities. Ca²⁺ signals can be embodied in highly dynamic forms such as Ca²⁺ transients that differ in frequency, amplitude and duration. We previously demonstrated that in multicellular organisms, autophagy stimuli elicit Ca²⁺ transients on the outer surface of the ER membrane, whose amplitude, frequency and duration are controlled by the metazoan-specific ER transmembrane autophagy protein EPG4/EI24. The global and regional ER Ca²⁺ transients persist during the period of induction. The ER Ca²⁺ transients trigger liquid-liquid phase separation of the autophagosome-initiating FIP200 complex. The resultant liquid-like FIP200 condensates associate with the ER via interaction with the ER transmembrane proteins VAPA/B and ATL2/3, and further assemble into autophagosome formation sites, followed by the recruitment of the VPS34 complex and other autophagy proteins for IM nucleation and expansion. Components of the FIP200 complex contain no Ca²⁺-binding motifs. I will talk about our progress in revealing the mechanism by which ER Ca²⁺ transients are sustained during the period of autophagy induction and how they are decoded to trigger the formation of ER-associated FIP200 condensates.

The choroid plexus (CP) serves as the primary source of cerebrospinal fluid (CSF). The blood-CSF barrier, composed of tight junctions among the epithelial cells in CP, safeguards CSF from unrestricted exposure to bloodborne factors. Its age-dependent disruption is thus involved in the loss of brain homeostasis and neural disorders in aged animals. However, the ageing of the blood-CSF barrier is poorly understood. In my talk, I will present our recent findings on how Cathepsin S (CTSS), a protease secreted by macrophages in the CP, impairs the blood-CSF barrier. Inhibiting CTSS in aged CP rejuvenates the barrier and improves brain function. Our findings reveal a critical interaction between immune and barrier cells driving ageing in the CP and brain. They highlight CTSS as a potential target for enhancing brain homeostasis in ageing and emphasize the significant role of circulating proteinases in the ageing process.

Mitochondrial DNA (mtDNA) is exclusively inherited through the maternal lineage, and mutations within this genetic material can lead to severe, maternally transmitted mitochondrial diseases. Purifying selection plays a crucial role in shaping maternal transmission dynamics. However, the intricacies of this process in mammalian maternal inheritance, and its potential modulation by factors such as maternal age, remain largely unexplored. A comprehensive understanding of the mechanisms behind this process is crucial for devising strategies to manipulate transmission patterns and potentially prevent maternally transmitted mitochondrial diseases. In this context, I will introduce how we employ cutting-edge techniques for editing mouse mtDNA to create models of mitochondrial disease and how we utilize these models to dissect the details of purifying selection in maternal transmission. Our study sheds light on the complex interplay of genetics and maternal factors that govern mitochondrial inheritance.

Lysosomes are key organelles within cells, constituting an acidic subcellular environment and containing approximately 60 different types of hydrolytic enzymes. With the aid of these acidic hydrolytic enzymes, lysosomes are highly metabolically active and can digest various macromolecules delivered through endocytic, phagocytotic, and autophagic processes. Moreover, lysosomes function as a "signaling hub" that integrates metabolic inputs, organelle interaction, and longevity control. Research in my group aims to understand how lysosomal metabolism and lysosomal signaling are coupled to orchestrate cellular homeostasis and organismal fitness. We discovered a pro-longevity lysosomal acidic lipase that increases lysosomal lipolysis and promotes longevity in Caenorhabditis elegans. We revealed both cell-autonomous and cell-nonautonomous signaling mechanisms underlying its longevity effect. More recently, through organelle-specific proteomic profiling and single-cell transcriptomic profiling across all cell types, we systematically elucidated how induced lysosomal lipolysis influences organellar communication and tissue health to promote organismal longevity. Furthermore, we uncovered that this lysosomal signaling also regulates the transgenerational inheritance of longevity. Together, these findings provide new insights into understanding the crucial role of lysosomal signals in regulating longevity at various levels, from the organelle to the organ, and even across generations.

Emerging evidence suggests that early-life factors have profound and enduring effects on adult outcomes. When these effects are adverse during early life, they often result in irreversible consequences and may contribute to the development of incurable diseases in adulthood. However, the precise early-life factors and the mechanisms underlying this spatiotemporal programming process remain poorly understood. To address these knowledge gaps, our laboratory has integrated the disciplines of genetics, biochemistry, and physiology, utilizing various model systems such as the nematode C. elegans, cultured cells, and mouse models. In this presentation, I will introduce our latest work on identifying determinants in early life that shape adult health and traits, including maternal nutrient availability and maternal aging. Finally, I will share our ongoing efforts aimed at elucidating the early-life programming of adult proteostasis and its genetic basis, highlighting the potential for early precautions against adult-onset diseases associated with proteostasis decline.

Premature ovarian insufficiency (POI) is a major disease responsible for infertility and aging-associated diseases of women in modern society. Basic and clinical studies revealed the potential correlation between metabolic disorders and POI. In the current study, we performed a multi-omics analysis as well as detailed mechanistic studies on a cohort of ~200 patients with POI and ~100 matched health volunteers. With this cohort, we identified that the transient insufficiency of branch chain amino acid (BCAA) induced an abnormal elevation of IFN-γ and ceramide via a long-term metabolic memory, which contributed to the development of POI. Mechanistically, IFN-γ perturbed the ceramide metabolism of granulosa by affecting the phosphorylation of a transporter. Phenotypic screen targeting the harmful effects of ceramide revealed that the treatment of an approved drug improved the ovarian functions in the mice with POI or natural aging via a non-canonical mechanism. Our study revealed the fundamental effects of metabolic memory on ovarian aging, which led to the identification of the potential targeted therapy for POI.

The nervous system plays a crucial role in coordinating organism-wide mitochondrial proteostasis, essential for maintaining resilience during stress and aging. Our study uncovers mechanisms by which neuronal mitochondrial stress triggers responses in distant tissues through morphogens, such as the Wnt/EGL-20 and transforming growth factor beta (TGF-β) DAF-7 signaling pathways, leading to lifespan extension in C. elegans. Additionally, GPCR signaling in two sensory neurons regulates the systemic mitochondrial stress response, influencing physiological traits in peripheral tissues via neuropeptide release.

Notably, we found that neuronal mitochondrial stress impacts germ cell function, driving maternal transmission of elevated mitochondrial DNA (mtDNA) and establishing a transgenerational "stress memory." This memory enhances stress tolerance and extends the lifespan of the progeny. Our research also identified a conserved transmembrane protein critical for maintaining Ca²⁺ homeostasis, supporting calcium oscillations and proper neurotransmission under mitochondrial stress.

Ongoing studies are exploring how neuronal mitochondrial stress interacts with host genetic diversity and microbiota, highlighting the need for personalized strategies to target mitochondrial pathways and develop effective aging interventions.

Time-restricted feeding (TRF) is an innovative behavioral nutrition intervention rooted in the science of circadian rhythm, which governs the body’s biological clock. TRF emphasizes a structured daily cycle of feeding and fasting, not necessarily requiring a reduction in calorie intake. By aligning eating patterns with circadian rhythms, TRF aims to optimize metabolic health and function.Studies in various model organisms have demonstrated that TRF can deliver a wide range of benefits across multiple organ systems, including the liver, heart, and kidney. These benefits lead to a reduction in the prevalence and severity of age-related chronic diseases, such as cardiovascular disease, diabetes, and kidney diseases. Some TRF regimens have also shown potential to extend lifespan in both male and female organisms, suggesting a profound impact on overall longevity.

Data on eating patterns from both shift workers and non-shift workers indicate that a large portion of people consume calories over an extended period, which can disrupt circadian rhythms and contribute to metabolic imbalances. Consequently, many individuals could benefit from adopting time-restricted eating (TRE), to optimize metabolic processes. Early findings from controlled human studies indicate that both shift workers and non-shift workers with metabolic disease burdens—such as obesity, glucose intolerance, and cardiovascular issues—can experience specific metabolic improvements through TRE. This presentation will offer a comprehensive overview of the concept of time-restricted feeding, detailing findings from animal research and examining the translation of these benefits to human health.

Aging and obesity share significant overlap in terms of comorbidities and pathological changes in adipose tissue, suggesting a common underlying mechanism. Adipose tissue, as a direct contributor to obesity, is also identified as a driving tissue in aging, exhibiting the earliest and most significant changes. This makes it a unique system for studying both aging and obesity. We recently identified IgG as an aging factor that accumulates in adipose tissue, promoting chronic inflammation and fibrosis, which in turn lead to metabolic decline. We further demonstrate that IgG predominantly accumulates in adipose tissue during obesity development in a recycling-dependent manner, triggering insulin resistance and macrophage infiltration. Intriguingly, IgG interacts with interaction the insulin receptor's ectodomain to hinder insulin binidng, consequently obstructing insulin signaling and adipocyte functions. Targeting IgG rectified metabolic degeneration in aging and obesity. In summary, our work suggests that aging and obesity is welded by IgG since the early stage to drive metabolic decline, therefore enlightening IgG as a potential therapeutic target to maximize healthspan.

Although neuronal cell death is the pathological hallmark of AD, whether it is pathogenic for neurodegeneration is undetermined. Here we demonstrated the pathogenic role of neuron death in Tau-related neurodegeneration. Tau-neurons died via necroptosis, dependent on ZBP1 sensitized by Z-RNAs (an unusual left-handed conformation). The endogenous Z-RNAs were transcripts of reactivated transposable elements (TEs) originally silenced in heterochromatin. Clinical data revealed that the expression level of ZBP1 in excitatory neuron exhibited negative correlation with cognitive diagnosis of AD patients. Zbp1 haploinsufficiency was sufficient to alleviate AD symptoms in Tau-transgenic mouse model implying therapeutic intervention targeting ZBP1 might significantly slow down the progression of neurodegeneration of AD patients.

To systematically understand human aging, we performed large-scale, single-cell profiling of immune cells in the blood of 166 healthy individuals aged 25 to 85, generating a dataset of approximately 2 million cells covering 55 immune subpopulations. We identified significant age-related changes in 12 subpopulations, including increased GZMK+CD8+ and HLA-DR+CD4+ T cells, alongside a decrease in NKG2C+GZMB-CD8+ T cells, indicating shifts in immune function over time. Additionally, we observed an age-associated rise in type 2/IL-4-expressing memory T cell subpopulations, suggesting a systemic reprogramming in immune response with age. Complementing these findings, they characterized recent thymic emigrants (RTEs)—a subset of naive T cells reflecting thymic output—using markers such as CD38hi, SOX4, IKZF2, and TOX, revealing age-related declines in RTEs and an increase in mature CXCR3hi cells. Together, these insights into immune remodeling with age help assess thymic health and provide valuable data for understanding immunity and responsiveness to infections and vaccines in aging populations.

Microglia play a crucial role in limiting Alzheimer's disease (AD) progression by managing amyloid-β (Aβ) pathology through a balance of activating and inhibitory signals from distinct cell surface receptors. One such receptor, TREM2, is essential for microglial responses to Aβ, and the R47H variant of TREM2 increases AD risk by impairing ligand binding. In mouse models with Aβ accumulation, defective TREM2 function exacerbates tissue damage, suggesting that TREM2 activation could be beneficial in AD. We examined the effects of an anti-human TREM2 agonistic monoclonal antibody (mAb) in mice expressing either the common variant of TREM2. Prolonged treatment with the anti-TREM2 mAb reduced plaque burden, improved behavior, and moderated microglial inflammation. Additionally, we found that the inhibitory receptor LILRB4 is highly expressed in microglia surrounding Aβ plaques in AD patients. In transgenic mice expressing human LILRB4 and develop Aβ plaques, treatment with an anti-human LILRB4 monoclonal antibody (mAb) reduced Aβ levels, improved some behavioral deficits, and increased microglial activity. Binding studies demonstrated that LILRB4 interacts with apolipoprotein E (ApoE), and the anti-LILRB4 mAb effectively blocks this interaction. These findings suggest that blocking LILRB4 could be as promising a therapeutic strategy for AD as activating TREM2.

A wide range of phenotypes are considered hallmarks of aging, but it is often unclear whether a specific phenotype is a cause or consequence or both of aging. The Free Radical Theory of Aging posits that oxidative metabolism and resulting free radicals increase with age, which may drive aging by inducing mutations in the nuclear genome. However, various antioxidant treatments do not seem to be effective as hoped in delaying aging and in treating age-related diseases, and some recent studies even suggest limited impact of mitochondria-generated free radicals on the nuclear genome. We aim to systematically address this puzzle by generating hydrogen peroxide (H₂O₂) in different cellular compartments to determine the relative contribution of different redox routes to aging. We found that mitochondria-derived H₂O₂ can quickly release into cytosol, endoplastic reticular (ER) and nucleus, and different cell types have evolved different antioxidative strategies to cope with such oxidative stress. Strikingly, intra-mitochondrial H₂O₂ is particularly potent in inducing DNA damage and cell senescence, which is mediated, at least in part, by the communication between mitochondria and ER, suggesting a key membrane-protected redox route to induce cell senescence during aging. These findings have important implications in developing antioxidant-based strategies to treat aging and age-related diseases.

Aging research has slowly gained momentum over the last three decades and now become a mature field of scientific endeavour. This has occurred only just in time, as aging is likely the largest medical challenge of the 21st Century. Aging is now recognized as the biggest risk factor for the onset of chronic diseases and the biggest predictor of complications in many infectious diseases. Given that over 20% of the population will be over 65 years of age in the not-too-distant future, it is imperative that strategies are developed to slow or reverse aging processes. Fortunately, as a result mostly of research in animal models, there are no shortage of interventions that have the potential to extend human healthspan. I will delineate strategies employed to evaluate longevity interventions in pre-clinical models and lessons learned. Delaying aging in animals is one thing, but validating them for efficacy in humans is entirely different. Here, I will discuss strategies to "get human" illustrating possible interventions that have a likelihood of success and discussing the possible clinical endpoints to test them in the clinic. People have tried to delay or reverse aging for millennia, and it certainly appears possible that delaying aging can be achieved in the near future. Whether reversal of aging is possible remains and open question and the successful strategies to achieve this audacious goal may be fundamentally different in nature.

Identifying molecular events that drive cancer development is critical for pinpointing high-risk populations and developing precise strategies for early detection. Here, we present a comprehensive map delineating how somatic clone expansion and evolution contribute to the progression of normal esophageal epithelium to esophageal squamous cell carcinoma (ESCC). In a body map of morphologically normal human tissues, we observed macroscopic somatic clones that expanded to hundreds of micrometers, particularly within the esophagus. Genomic analyses across multiple stages in ESCC development underscore a pivotal role for TP53 biallelic inactivation and its induced copy number alterations in initiating tumor clone formation starting from the early precancerous stage. Using single-cell RNA sequencing and spatial transcriptomics, we further illuminate the evolution of transformed epithelial cell in expression profiles and spatial organization, uncovering their critical role in the recruiting normal fibroblasts and converting them into cancer-associated fibroblasts (CAFs) during ESCC progression. These findings deepen our understanding of the early molecular events that drive esophageal carcinogenesis.

Clonal hematopoiesis (CH) represents the clonal expansion of hematopoietic stem cells (HSCs) and their progeny driven by somatic mutations. Accurate risk assessment of CH is critical for disease prevention and clinical decision-making. The size of CH has been showed to associate with higher disease risk, yet factors influencing the size of CH are unknown. In addition, the characteristics of CH in long-lived individuals are not well documented. Here we report an in-depth analysis of clonal hematopoiesis in longevous (≥90 years old) and common (60~89 years old) elderly groups. Utilizing targeted deep sequencing, we found that the development of CH is closely related to age and the expression of aging biomarkers. The longevous elderly group exhibited a significantly higher incidence of CH and significantly higher frequency of TET2 and ASXL1 mutations, suggesting that certain clonal hematopoiesis could be beneficial to prolong life. Intriguingly, the size of CH neither correlate significantly to age, in the range of 60-110 years old, nor to the expression of aging biomarkers. Instead, we identified a strong correlation between large CH size and the number of mutations per individual. These findings provide a risk assessment biomarker for CH, and suggest that the evolution of the CH is influenced by factor(s) in addition to age. Acute myeloid leukemia (AML) is an aging-related and heterogeneous hematopoietic malignancy. In analysis of AML, we found that, alongside age, the frequency of gene fusions defined in the World Health Organization (WHO) classification decreased, while the positive rate of gene mutations, especially CH-related ones, increased. We used Umbilical cord blood (UCB) infusion as an adjuvant consolidation therapy in elderly AML patients. We found that compared to concurrent standard care, this regimen demonstrated superior outcomes. The 2-year overall survival (OS) and event-free survival (EFS) rates compared to standard care were 76.9% vs 44.7% and 62.8% vs 29.4%, respectively. Single-cell transcriptome analysis identified enhanced anti-tumor and anti-aging properties of UCBand. Suggest that anti-aging therapy may serve as a new and promising dimension in combined cancer treatment.

Cellular senescence plays critical roles in aging, regeneration, and disease, yet the ability to discern its contributions across various cell types to these biological processes remains limited. In this study, we generated an in vivo genetic toolbox, consisting of three p16^Ink4a-related intersectional genetic systems, enabling pulse-chase tracing (Sn-pTracer), Cre-based tracing and ablation (Sn-cTracer), and gene manipulation combined with tracing (Sn-gTracer) of defined p16^Ink4a+ cell types. Using liver injury and repair as an example, we found that macrophages and endothelial cells (ECs) represent distinct senescent cell populations with different fates and functions during liver fibrosis and repair. Notably, clearance of p16^Ink4a+ macrophages significantly mitigates hepatocellular damage, whereas eliminating p16^Ink4a+ ECs aggravates liver injury. Additionally, targeted reprogramming of p16^Ink4a+ ECs through Kdr overexpression markedly reduces liver fibrosis. This study illuminates the functional diversity of p16^Ink4a+ cells and offers insights for developing cell type-specific senolytic therapies in the future.

George Williams once wrote, It is remarkable that after a seemingly miraculous feat of morphogenesis a complex metazoan should be unable to perform the much simpler task of merely maintaining what is already formed." Nonetheless, it is also true that the progress made in the last decades in unraveling the cellular and molecular processes that underlie development is already having and will certainly have major clinical implications for human disease and aging. Amongst the major advances is our enhanced understanding on the role played by the epigenome during embryogenesis. Disease and aging are associated with altered epigenetic mechanisms of gene regulation. I will discuss some of the epigenetic changes that occur during development disease and aging, and how partial reprogramming and epigenetic changes elicited by the Yamanaka factors might be a potential avenue to restore cell health and resilience through cellular rejuvenation programming to reverse disease, injury, and the disabilities that can occur throughout life.

Intermittent fasting has gained global popularity for its health benefits, but how it impacts somatic stem cells and tissue biology remains elusive. Here, we report that commonly used intermittent fasting regimens inhibit hair follicle regeneration by selectively inducing apoptosis in activated hair follicle stem cells (HFSCs). This effect is not due to reduced calorie intake, circadian rhythm alterations, or activation of the classical mTORC1 cellular nutrient-sensing mechanism. Instead, fasting activates crosstalk between adrenal glands and dermal adipocytes in the skin, triggering the rapid release of free fatty acids into the niche. This disrupts the normal metabolism of HFSCs and elevates their cellular reactive oxygen species levels, causing oxidative damage and apoptosis. Our study uncovers an inhibitory effect of intermittent fasting on tissue regeneration, and identifies interorgan communication between adrenal glands and niche adipocytes that functions to eliminate activated stem cells and halt tissue regeneration during periods of unstable nutrient supply.

Pancreatic β cells are the sole producers of insulin in humans and nearly all other vertebrates. However, generating functional β cells in vitro has proven to be a challenging task. In our recent study, we identified a novel Procr cell population within adult mouse pancreatic islets. These cells lack differentiation markers and exhibit characteristics of epithelial-to-mesenchymal transition (EMT). Through genetic lineage tracing, we discovered that Procr islet cells undergo clonal expansion and generate all four endocrine cell types during adult homeostasis. When isolated, Procr cells, which comprise approximately 1% of islet cells, can form islet-like organoids when cultured at clonal density. These organoids can be exponentially expanded over extended periods through serial passaging, with differentiation inducible at any point in culture. The differentiated islet organoids are predominantly composed of β cells, with α, δ, and PP cells present at lower frequencies. These organoids are glucose-responsive and capable of secreting insulin. When transplanted into diabetic mice, the islet organoids effectively restore normoglycemia. Our findings demonstrate the presence of a population of resident stem/progenitor cells within the adult pancreatic islet. We will also discuss the relevance of these progenitors in human islets. Utilizing these resident stem/progenitor cells to develop a strategy for the expansion of human islets could significantly advance diabetes treatment and provide new opportunities for modeling genetic diseases.

Aging is a systems level process and needs systems level models to quantify. We have recently focused our attention on phenotypic images and single cell clocks using a combination of experimental and computational approaches, most recently artificial intelligence (AI). Our deep learning AI models trained on either chronological age or perceived age of the 3D facial images can precisely estimate individuals’ aging status, and infer the molecular regulators mediating the impact of lifestyles (Xia et al., 2020). We further developed thermal facial image based aging clocks using AI and found that compared to 3D facial aging clocks, thermal facial aging clocks are more strongly associated with metabolic states, and the aging rates measured by them are accelerated by metabolic diseases and decelerated by adequate sleep and exercise. I will also briefly discuss our single cell based human blood aging clocks and Senescence Identification (SenCID) program (Tao et al. 2024).

Guang-Hui Liu and his team, focused on deciphering the mechanisms, early detection, and intervention of aging, have established a comprehensive study system that includes primate organ aging and human stem cell senescence. They have constructed a multi-tiered "aging atlas" covering organ, cellular, and molecular levels and devised methods to assess biological age within the Chinese population. Their research indicates that heterochromatin erosion is a key driver of aging and shows that the reactivation of endogenous retroviruses can accelerate the aging process. The team has also developed innovative strategies for aging intervention. These efforts have provided new insights into aging mechanisms and laid the groundwork for early warning systems, strategic interventions, and clinical applications for age-related diseases.