Longevity Papers

Aging is a critical yet understudied determinant in pancreatic ductal adenocarcinoma (PDAC). Despite a strong epidemiological association with age, conventional PDAC preclinical models fail to capture the histopathological and stromal complexities that emerge in older organisms. Using an age-relevant syngeneic orthotopic model, we demonstrate that organismal aging accelerates PDAC progression and metastasis. Through transcriptomic profiling, we identify a conserved extracellular matrix gene signature enriched in cancer-associated fibroblasts (CAFs) from aged tumors, consistent with an augmented fibrotic landscape that supports immunosuppression, metastatic tropism, and poor prognosis. To directly test the functional impact of stromal aging, we employed heterochronic co-implantation models, revealing that revitalizing the aged tumor stroma with young CAFs restores immune infiltration and attenuates metastasis in older hosts. Conversely, aged CAFs, while immunosuppressive, fail to enhance metastasis in young hosts, suggesting that a youthful microenvironment exerts dominant regulatory control over disease progression. These findings demonstrate that stromal age is a critical modulator of both immune exclusion and metastatic behavior in PDAC. Importantly, our work establishes a new conceptual framework for understanding how aging shapes the tumor microenvironment in PDAC and opens a fertile avenue of investigation into age-specific stromal regulation. Moreover, this work raises compelling questions about the underlying molecular mechanisms, questions now accessible through our models, and lays the foundation for future efforts to therapeutically target stromal aging in PDAC.

Learning, reasoning, and working memory functions are attributed to the dorsolateral prefrontal cortex (DLPFC), a distinctive region of the human brain that is highly evolved in primates and exhibits notable variability among individuals. Environmental and genetic factors likely contribute to this variability, but little is known about how they influence changes within an individual brain across the lifespan as different cognitive tasks and challenges arise. Most genetic studies focus on DNA mutations or changes in overall gene expression levels. However, genes can also alter the form in which they are expressed through alternative splicing. Using RNA sequencing data from prenatal and postnatal human DLPFCs, we observed that many genes undergo dramatic shifts in their isoform preferences around the time of birth. We further found that thousands of genes continue to undergo gradual, temporally regulated changes in their preferred isoforms, a phenomenon we term \'isoswitching\'. In this study, we present isoswitching as a major force in brain development, capable of accurately predicting human brain age from prenatal stages through late adulthood and beyond eighty years of age. This represents the first demonstration of brain age prediction based solely on RNA sequencing data. We also report isoswitching in the brain of a closely related primate, the rhesus macaque.

A variety of physiological and pathological stimuli elicit the cellular senescence response. Immune cells are known to execute surveillance of infected, cancerous, and senescent cells, and yet senescent cells accumulate with age and drive inflammation and age-related disease. Understanding the roles of different immune cells in senescent cell surveillance could enable the development of immunotherapies against biological aging and age-related disease. Here, we report the role of human gamma delta ({gamma}{delta}) T cells in eliminating senescent cells. Human donor V{gamma}9v{delta}2 T cells selectively remove senescent cells of different cell types and modes of induction while sparing healthy cells, with parallel findings in mouse cells. We find that senescent cells express high levels of multiple {gamma}{delta} T cell ligands, including cell-surface BTN3A1. Individually blocking NKG2D or {gamma}{delta} TCR of {gamma}{delta} T cells only partially reduces V{gamma}9v{delta}2 T cell cytotoxicity, evidencing their versatility in senescence removal. {gamma}{delta} T cells expand in response to the induction of a mouse model of idiopathic pulmonary fibrosis (IPF), accompanied by the emergence of senescent cells, and colocalize with senescent cells in lung tissue from patients with IPF. Finally, we show that adoptive cell transfer of {gamma}{delta} T cells into an IPF mouse model reduces the number of p21-expressing senescent cells in affected lung tissue and improves outcomes. {gamma}{delta} T cells or modalities that activate their surveillance activity present a potent approach for removing senescent cells and their attendant contribution to aging and disease.

Understanding the dynamic interplay of proteins across different life stages and tissues is essential for deciphering the molecular mechanisms underpinning development, aging, and disease. Here, we present a comprehensive network-based framework that constructs and integrates 119 time- and tissue-specific protein-protein interaction (PPI) networks derived from transcriptomic data, offering insights into proteomic dynamics across the human lifespan. Based on this, we observed three distinct protein groups: (i) common-core proteins, expressed universally across all tissues and time points; (ii) time-/tissue-specific proteins, selectively expressed within specific temporal or spatial contexts; and (iii) time-/tissue-unique proteins, whose expression is restricted to specific points in space and time. Our analysis shows a clear gradient of network centrality, transitioning from the highly connected common-core proteins to more specialized time-/tissue-specific and unique proteins, mirroring a progressive shift in functional specificity. Further, we characterized the distinct molecular signatures of intrauterine to extrauterine life, delineating two key protein networks: the embryonic development network (EDev) and the environmental aging network (EAgi). Their network characterization and comparison highlighted specific communities within the EDev network enriched for developmental diseases, and specific EAgi communities involved in aging. This network classification allowed us to rank candidate anti-aging drugs and their molecular targets, laying the foundation for a systematic, data-driven, network-based investigation of development and aging, providing a roadmap for future research aimed at mitigating age-related diseases and promoting longevity.

Despite aging being a fundamental biological process which profoundly influences health and disease, the interplay between tissue-specific aging and mortality remains underexplored. This study applies machine learning on GTEx transcriptomic data to model tissue-specific biological ages across 12 different types of tissues and introduces an age-gap metric to quantify deviations from the chronological age. Our best models achieve an average RMSE of 6.44 years and an average R2 of 0.64. Age-gap statistics reveal significant tissue-specific aging patterns, identifying extreme agers and correlations between extreme aging and mortality. About 20% of subjects are found to exhibit extreme aging in one tissue, while 1% show multi-organ aging. These findings greatly emphasize the role of transcriptomics in aging research and its implications for health and longevity.

Aging induces functional declines in the mammalian brain, increasing its vulnerability to cognitive impairments and neurodegenerative disorders. Among various interventions to slow the aging process, caloric restriction (CR) has consistently demonstrated the ability to extend lifespan and enhance brain function across different species. Yet the precise molecular and cellular mechanisms by which CR benefits the aging brain remain elusive, especially at region-specific and cell type-specific resolution. In this study, we performed spatiotemporal profiling of mouse brains to elucidate the detailed mechanisms driving the anti-aging effects of CR. Utilizing highly scalable single-nucleus genomics and spatial transcriptomics platforms, EasySci and IRISeq, we profiled over 500,000 cells from 36 mouse brains across three age groups and conducted spatial transcriptomic analysis on twelve brain sections from aged mice under CR and control conditions. This comprehensive approach allowed us to explore the impact of CR on over 300 cellular states and assess region-specific molecular alterations. Our findings reveal that CR effectively modulates key aging-associated changes, notably by delaying the expansion of inflammatory cell populations and preserving cells critical to the neurovascular system and myelination pathways. Moreover, CR significantly reduced the expression of aging-associated genes involved in oxidative stress, unfolded protein stress, and DNA damage stress across various cell types and regions. A notable reduction in senescence-associated genes and restoration of circadian rhythm genes were observed, particularly in ventricles and white matter. Furthermore, CR exhibited region-specific restoration in genes linked to cognitive function and myelin maintenance, underscoring its targeted effects on brain aging. In summary, the integration of single-nucleus and spatial genomics provides a novel framework for understanding the complex effects of anti-aging interventions at the cellular and molecular levels, offering potential therapeutic targets for aging and neurodegenerative diseases.

Cellular senescence is a stress response mechanism marked by irreversible growth arrest, upregulation of antiapoptotic pathways, loss of cellular function, and remodelling of the cellular secretory profile. In both humans and mice, pancreatic {beta}-cells undergo senescence with age and insulin resistance. Targeted removal of senescent cells in mouse models of diabetes improves glucose homeostasis, demonstrating the role {beta}-cell senescence in diabetes progression. In contrast, {beta}-cell senescence also promotes immune surveillance, promoting {beta}-cell survival and function. Thus, a better understanding of senescent cells\' phenotypic and functional heterogeneity is needed to develop effective therapeutic strategies. Herein, we show that subpopulations of senescent {beta}-cells in mice and humans, which were identified through the expression of Cdkn1a (encoding p21Cip1) and Cdkn2a (encoding p16Ink4a) by single-cell RNA sequencing (scRNA-seq), flow cytometry, spatial transcriptomics, and spatial proteomics, exhibit distinct transcriptional and functional identities. The predominant senescent {beta}-cell subpopulation expressed Cdkn1a and was characterized by a lack of glucose responsiveness, high basal insulin secretion, and transcription of canonical SASP factors. The SASP of Cdkn1a-expressing {beta}-cells had non-cell autonomous effects on neighbouring cells. A subset of four SASP factors from Cdkn1a+ cells was sufficient to induce secondary senescence and {beta}-cell dysfunction in vitro. JAK inhibitors (JAK1/2 and JAK1/3) counteracted secondary senescence induction and restored {beta}-cell function in high-fat diet-fed mice and human islets from donors with or without Type 2 Diabetes.

Testicular aging commonly leads to testosterone deficiency and impaired spermatogenesis, yet the underlying mechanisms remain elusive. Here, we show that Leydig cells are particularly vulnerable to aging processes in testis. Single-cell RNA sequencing identifies the expression of Hmgcs2, the gene encoding rate-limiting enzyme of ketogenesis, decreases significantly in Leydig cells from aged mice. Additionally, the concentrations of ketone bodies β-hydroxybutyric acid and acetoacetic acid in young testes are substantially higher than that in serum, but significantly diminish in aged testes. Silencing of Hmgcs2 in young Leydig cells drives cell senescence and accelerated testicular aging. Mechanistically, β-hydroxybutyric acid upregulates the expression of Foxo3a by facilitating histone acetylation, thereby mitigating Leydig cells senescence and promoting testosterone production. Consistently, enhanced ketogenesis by genetic manipulation or oral β-hydroxybutyric acid supplementation alleviates Leydig cells senescence and ameliorates testicular aging in aged mice. These findings highlight defective ketogenesis as a pivotal factor in testicular aging, suggesting potential therapeutic avenues for addressing age-related testicular dysfunction.

Medical practice mainly addresses single diseases, neglecting multimorbidity as a heterogeneous health decline across organ systems. Aging is a multidimensional process and cannot be captured by a single metric. Therefore, we assessed global health in longitudinal studies, BLSA (n = 907), InCHIANTI (n = 986), and NHANES (n = 40,790), by examining disease severities in 13 bodily systems, generating the Body Organ Disease Number (BODN), reflecting progressive system morbidities. We used Bayesian ordinal models, regressing BODN over organ specific and all organs disease severities to obtain Body System-Specific Clocks and the Body Clock, respectively. The Body Clock is BODN weighted by the posterior coefficient of diseases for each individual. It supersedes the frailty index, predicting disability, geriatric syndrome, SPPB, and mortality with ≥90% accuracy. The Health Octo Tool, derived from Bodily System-Specific Clocks, the Body Clock and Clocks that incorporate walking speed and disability and their aging rates, captures multidimensional aging heterogeneity across organs and individuals.

How central and peripheral circadian clocks regulate protein metabolism and affect tissue mass homeostasis has been unclear. Circadian shifts in the balance between anabolism and catabolism control muscle growth rate in young zebrafish independent of behavioral cycles. Here, we show that the ubiquitin-proteasome system (UPS) and autophagy, which mediate muscle protein degradation, are each upregulated at night under the control of the muscle peripheral clock. Perturbation of the muscle transcriptional molecular clock disrupts nocturnal proteolysis, increases muscle growth measured over 12 h, and compromises muscle function. Mechanistically, the shifting circadian balance of Ror and Rev-erb regulates nocturnal UPS, autophagy, and muscle growth through altered TORC1 activity. Although environmental zeitgebers initially mitigate defects, lifelong muscle clock inhibition reduces muscle size and growth rate, accelerating aging-related loss of muscle mass and function. Circadian misalignment such as shift work, sleep deprivation, or dementia may thus unsettle muscle proteostasis, contributing to muscle wasting and sarcopenia.