Longevity Papers

Tissue-resident alveolar macrophages (AMs) rely on intrinsic stem-like programs for self-renewal and maintenance, yet the transcriptional networks that support these functions and their relevance to post-viral lung disease remain largely unknown. Here, we identify TCF4 (Tcf7l2) as a critical transcription factor that governs AM maturation and stemness. Loss of TCF4 impaired AM proliferation, shifted their identity toward a pro-inflammatory phenotype, and exacerbated host morbidity following influenza or SARS-CoV-2 infection. Conversely, enforced TCF4 expression promoted the expansion of mature AMs, and supported lung recovery, thereby protecting against severe acute viral disease. Mechanistically, TCF4 antagonized {beta}-catenin-driven inflammatory transcription while preserving oxidative phosphorylation, defining a reciprocal regulatory axis essential for AM function. Notably, respiratory viral infections and exuberant interferon signaling suppressed TCF4 expression, which remains chronically reduced in murine and human lungs with post-COVID fibrosis. This downregulation is associated with persistent KRT8hi dysplastic epithelium and collagen deposition. Moreover, aging diminished TCF4 levels and enforced TCF4 expression dampened age-associated decline of AM self-renewal. Furthermore, in vivo TCF4 overexpression after viral clearance enhanced mature AM accumulation, promoted lung epithelium regeneration, attenuated chronic tissue fibrosis and restored pulmonary physiologial function in aged lungs in a model of persistent pulmonary fibrosis post-acute viral infection. These findings have established TCF4 as a key regulator of AM stemness and identified a promising therapeutic target for long COVID and related chronic lung diseases through the modulation of embryonic-derived macrophage regenerative capacity by targeting TCF4.

Aging, a universal biological process in complex organisms, is increasingly recognized to be driven by progressive loss of epigenetic information, as proposed in the Information Theory of Aging (ITOA). However, research on anti-aging peptides remains scarce, with most existing efforts confined to derivatives of natural proteins, while systematic design attempts are virtually absent. This limitation not only restricts discovery within the evolutionary sequence space but also hampers the identification of candidates with novel mechanisms and improved efficacy. Here, we present ElixirSeeker2, the first computational framework for de novo design of anti-aging peptides. By integrating modeling of known anti-aging peptides, activity scoring from the IC50 database, and penalty constraints from toxic peptides, ElixirSeeker2 enables large-scale virtual screening and identification of novel peptide candidates. Several lead peptides demonstrated significant effects in delaying cellular senescence, restoring cellular functions in vitro and in enhancing locomotor activity of aged Caenorhabditis elegans. This study not only validates the feasibility of de novo design in anti-aging interventions but also establishes a strategy for the development of next-generation biologics.

Mitochondrial dysfunction is a central driver of cellular senescence, a core hallmark of aging. While intrinsic mechanisms have been extensively reviewed, this article offers a novel paradigm by emphasizing the critical role of interorganellar communication in mitochondria-mediated senescence. We present a systematic dissection of the molecular mechanisms underlying functional crosstalk between mitochondria and key organelles, including the endoplasmic reticulum (ER), lysosomes, and peroxisomes. A particular focus is placed on established regulatory hubs such as mitochondria-associated ER membranes (MAMs), which orchestrate calcium signaling, lipid metabolism, and inflammatory responses. We further explore emerging pathways involving lysosomal mitochondrial coordination in nutrient sensing and mitophagy, and peroxisomal mitochondrial cooperation in redox balance and lipid homeostasis. By elucidating how defects in these dynamic networks propagate mitochondrial damage and execute senescence, this review establishes a unified framework for aging as integrated organelle network dysfunction. This synthesis advances fundamental aging biology and identifies novel molecular targets, providing a foundation for developing therapeutic strategies targeting organelle networks against age related pathologies.

Senolytic therapy, which targets and selectively eliminates senescent cells, has emerged as a promising strategy for treating various age-related diseases. However, its clinical application is often limited by poor bioavailability, off-target toxicity, and the need for invasive administration routes. To overcome these challenges, we developed N201-gal, a novel β-galactosidase-reactive senolytic prodrug that self-assembles into stable nanoparticles, enabling oral administration and improved systemic bioavailability. Once internalized by senescent cells, N201-gal responds to β-galactosidase overexpression, triggering controlled drug release and inducing selective apoptosis in senescent cells while sparing normal cells. The nanoparticle formulation exhibited favorable physicochemical properties, including uniform particle size and pH stability suitable for gastrointestinal absorption. In vitro study shows that N201-gal demonstrated potent senolytic activity and reduced the expression of senescence-associated markers in retinal pigment epithelial (RPE) cells. In addition, in vivo study also shows that oral administration of N201-gal in a mouse model of doxorubicin-induced retinal senescence model significantly restored retinal tissue integrity and visual function through the targeted clearance of senescent cells. These findings highlight the potential of self-assembling senolytic prodrugs as a noninvasive and targeted therapeutic platform for age-related degenerative diseases.

Complex diseases often exhibit sex dimorphism in morbidity and prognosis, many of which are age-related. However, the underlying mechanisms of sex-dimorphic aging remain foggy, with limited studies across multiple tissues. We systematically analyzed ~17,000 transcriptomes from 35 human tissues to quantitatively evaluate the individual and combined contributions of sex and age to transcriptomic variations. We discovered extensive sex dimorphisms during aging with distinct patterns of change in gene expression and alternative splicing (AS). Intriguingly, the male-biased age-associated AS events have a stronger association with Alzheimer's disease, and the female-biased events are often regulated by several sex-biased splicing factors that may be controlled by estrogen receptors. Breakpoint analysis showed that sex-dimorphic aging rates are significantly associated with decline of sex hormones, with males having a larger and earlier transcriptome change. Collectively, this study uncovered an essential role of sex during aging at the molecular and multi-tissue levels, providing insight into sex-dimorphic regulatory patterns.

The human brain develops and matures over an exceptionally prolonged period of time that spans nearly two decades of life. Processes that govern species-specific aspects of human postnatal brain development are difficult to study in animal models. While human brain organoids offer a promising in vitro model, they have thus far been shown to largely mimic early stages of brain development. Here, we developed human brain organoids for an unprecedented 5 years in culture, optimizing growth conditions able to extend excitatory neuron viability beyond previously-known limits. Using module scores of maturation-associated genes derived from a time course of endogenous human brain maturation, we show that brain organoids transcriptionally age with cell type-specificity through these many years in culture. Whole-genome methylation profiling reveals that the predicted epigenomic age of organoids sampled between 3 months and 5 years correlates precisely with time spent in vitro, and parallels epigenomic aging in vivo. Notably, we show that in chimeric organoids generated by mixing neural progenitors derived from "old" organoids with progenitors from "young" organoids, old progenitors rapidly produce late neuronal fates, skipping the production of earlier neuronal progeny that are instead produced by their young counterparts in the same co-cultures. The data indicate that human brain organoids can mature and record the passage of time over many years in culture. Progenitors that age in organoids retain a memory of the time spent in culture reflected in their ability to execute age-appropriate, late developmental programs.

Aging is commonly associated with a decline in memory abilities, yet some individuals remain resilient to such changes. Memory processing has been shown to rely on adult neurogenesis, a form of hippocampal plasticity, but whether the integration and role of long-lived adult-born neurons (ABNs) generated during early adult life also contribute to cognitive resilience and to such inter-individual differences remain unknown. Using a pseudo-longitudinal approach in rats characterized as resilient or vulnerable to cognitive aging, we examined the survival, senescence, morphology, glutamatergic connectivity, and mitochondrial health of ABNs. To achieve this, we combined approaches based on thymidine analogues and retroviral labeling using Moloney murine leukemia viruses. While ABNs survival, entry into senescence and dendritic gross morphology did not differ between resilient and vulnerable rats, resilient animals exhibited preserved glutamatergic synaptic input and maintained mitochondrial homeostasis in the proximal dendrites of ABNs. Interestingly, bypassing this reduction in glutamatergic inputs in vulnerable rats through direct optogenetic stimulation was sufficient to rescue their memory retrieval abilities, indicating that ABNs themselves remain intrinsically functional despite reduced input. Overall, our data indicate that maintaining long-lived ABNs within the neuronal network is essential for successful cognitive aging, highlighting their potential as a therapeutic target for restoring cognitive functions in old age.

The roles of cells in systemic aging have been systematically investigated, while the roles of the extracellular matrix (ECM) and its degradation have been largely overlooked. Herein, we show that the serum contents of elastin-, hyaluronic acid- and fibronectin-derived fragments are all positively correlated with age. Elastin-derived fragments exhibited the most potent lifespan-shortening effects in mice and a positive correlation with various aging indicators in a human cohort (n = 1,068). Mechanistically, the VGVAPG oligopeptide (E-motif) in elastin-derived fragments activated monocytes and macrophages through NEU1, a component of the elastin receptor complex, which consequently caused an inflammatory response. Therapeutically, a NEU1 inhibitor extended lifespan by up to 17% in wild-type naturally aged mice and alleviated aging-related phenotypes in wild-type mice, immune-humanized mice and pigs. This study uncovers that degraded ECM acts as a circulating driver of aging, providing an anti-aging intervention strategy focused on particular elastin fragment signals.

Centenarians provide valuable insights into the biological mechanisms underlying human longevity and potential gerotherapeutic targets. We previously identified two linked missense variants in SIRT6 that are enriched in Ashkenazi Jewish centenarians. To investigate their functional impact in physiologically relevant cellular contexts, we generated human embryonic stem cells carrying these variants through precise genomic knock-in and differentiated them into somatic lineages. Functional characterization revealed that the centenarian variants endogenously elevated SIRT6 protein levels through weakened interaction with vimentin, and altered SIRT6 enzymatic activities including enhanced mono-ADP-ribosyl transferase activity and reduced deacetylase activity. These variants delayed replicative and progerin-induced cellular senescence, preserving genome stability through maintenance of DNA repair pathways and suppression of transposable element derepression. Moreover, pharmacologically mimicking the centenarian variants using SIRT6 activator Fucoidan-FV partially ameliorated premature aging-associated molecular defects in progeria fibroblasts. Together, our findings demonstrate that rare centenarian variants exert multifaceted effects on SIRT6 and enhance cellular resilience, providing insights for developing geroprotective therapies informed by genetic discoveries in exceptionally long-lived individuals.

Telomere homeostasis serves as a key regulatory mechanism linking aging and cancer. While telomere attrition imposes a proliferative barrier by inducing cellular senescence, abnormal telomere elongation circumvents this constraint, thereby granting malignant cells unlimited replicative capacity. This study systematically explores the causal relationship between telomere length and cancer risk, with the goal of elucidating the molecular pathways involved in telomere-driven tumorigenesis.

Poor circadian health is increasingly recognized as a determinant of aging and chronic diseases, yet longitudinal evidence in free-living populations remains limited. Most prior studies have been restricted to cross-sectional designs or short 7-day monitoring, precluding insight into long-term aging dynamics. To address this gap, we analyzed multi-year consumer wearable data linked with electronic health records from the All of Us Research Program to evaluate circadian rest-activity rhythms as longitudinal predictors of biological aging. Among 2,222 participants (median age 60.6 years, 68.5% female) contributing 8,447 person-years of Fitbit activity data with annual biological age estimates (PhenoAge), we performed high-dimensional digital phenotyping integrating functional data analysis with conventional rhythm metrics. Higher rhythm intensity reduced the odds of accelerated aging by 26-46%, greater regularity lowered the odds by 9-13%, whereas delayed acrophase increased the odds by 22%. Sex-stratified analyses revealed universal protection from rhythm intensity in both sexes, but stronger timing- and regularity-related vulnerabilities to accelerated aging in females (12-18% higher odds). In contrast, males exhibited a biphasic instability phenotype, characterized by early-morning surges and late-evening rebounds, uniquely linked to accelerated aging. This study provides the first large-scale longitudinal evidence establishing circadian rest-activity rhythms derived from consumer wearables as digital biomarkers of aging trajectories. With the growing scalability and ubiquity of consumer devices, our findings pave the way toward scalable aging risk assessment, targeted interventions, and advancing digital precision medicine to promote healthy longevity at the population level.