Longevity Papers

Senescent cells secrete a senescence-associated secretory phenotype (SASP), which can induce senescence in neighboring cells. Human dermal papilla (DP) cells lose their original hair inductive properties when expanded in vitro, and rapidly accumulate senescent cells in culture. Protein and RNA-seq analysis revealed an accumulation of DP-specific SASP factors including IL-6, IL-8, MCP-1, and TIMP-2. We found that combined senolytic treatment of dasatinib and quercetin depleted senescent cells, and reversed SASP accumulation and SASP-mediated repressive interactions in human DP culture, resulting in an increased Wnt-active cell population. In hair reconstitution assays, senolytic-depleted DP cells exhibited restored hair inductive properties by regenerating de novo hair follicles (HFs) compared to untreated DP cells. In 3D skin constructs, senolytic-depleted DP cells enhanced inductive potential and hair lineage specific differentiation of keratinocytes. These data revealed that senolytic treatment of cultured human DP cells markedly increased their inductive potency in HF regeneration, providing a new rationale for clinical applications of senolytic treatment in combination with cell-based therapies.

Hematopoietic stem cells (HSCs) responsible for blood cell production and their bone marrow regulatory niches undergo age-related changes, impacting immune responses and predisposing individuals to hematologic malignancies. Here, we show that the age-related alterations of the megakaryocytic niche and associated downregulation of Platelet Factor 4 (PF4) are pivotal mechanisms driving HSC aging. PF4-deficient mice display several phenotypes reminiscent of accelerated HSC aging, including lymphopenia, increased myeloid output, and DNA damage, mimicking physiologically aged HSCs. Remarkably, recombinant PF4 administration restored old HSCs to youthful functional phenotypes characterized by improved cell polarity, reduced DNA damage, enhanced in vivo reconstitution capacity, and balanced lineage output. Mechanistically, we identified LDLR and CXCR3 as the HSC receptors transmitting the PF4 signal, with double knockout mice showing exacerbated HSC aging phenotypes similar to PF4-deficient mice. Furthermore, human HSCs across various age groups also respond to the youthful PF4 signaling, highlighting its potential for rejuvenating aged hematopoietic systems. These findings pave the way for targeted therapies aimed at reversing age-related HSC decline with potential implications in the prevention or improvement of the course of age-related hematopoietic diseases. Key PointsO_LIAge-related attrition of the megakaryocytic niche and associated PF4 downregulation is a central mechanism in HSC aging. C_LIO_LIPF4 supplementation, acting on LDLR and CXCR3 receptors, rejuvenates the function of aged HSCs. C_LI

Genome instability is a hallmark of aging, with the highly repetitive ribosomal DNA (rDNA) within the nucleolus being particularly prone to genome instability. Nucleolar enlargement accompanies aging in organisms ranging from yeast to mammals, and treatment with many antiaging interventions results in small nucleoli. Here, we report that an engineered system to reduce nucleolar size robustly extends budding yeast replicative lifespan in a manner independent of protein synthesis rate or rDNA silencing. Instead, when nucleoli expand beyond a size threshold, their biophysical properties change, allowing entry of proteins normally excluded from the nucleolus, including the homologous recombinational repair protein Rad52. This triggers rDNA instability due to aberrant recombination, catastrophic genome instability and imminent death. These results establish that nucleolar expansion is sufficient to drive aging. Moreover, nucleolar expansion beyond a specific size threshold is a mortality timer, as the accompanying disruption of the nucleolar condensate boundary results in catastrophic genome instability that ends replicative lifespan.

It is a common observation that individuals within a species age at different rates. Variation in both genetics and environmental interaction are generally thought responsible. Surprisingly, even genetically identical organisms cultured under environmentally homogeneous conditions age at different rates, implying a more fundamental cause of aging. Here we have examined the basis for lifespan variance in haploid, single-celled yeast of Saccharomyces cerevisiae. The probabilistic nature of metabolism means metabolites often, but not always, follow the same route through the metabolic network. We speculate redundancy in metabolic pathway choice is sufficient to explain lifespan variance. To interrogate the reaction flux space of S. cerevisiae we used a model of its intermediary metabolism, comprising 1,150 genes, 4,058 reactions, and 2,742 metabolites (yeast GEM_v8.5.0). We restricted traffic through the metabolic network by knocking out each of the 1,150 genes, then generated a total of 406,500 flux distributions spanning the solution space of the resulting 812 viable mutants. We collected replicative life span (RLS) data for the 812 viable mutants, corresponding to 66,400 individual cells. Four approaches were then employed to test whether reaction flux configuration could be used to predict lifespan: Principal Component Analysis (PCA) in conjunction with non-linear modeling of RLS; deep learning of RLS using either a Regression Neural Network (RNN) or a Classification Neural Network (CfNN); and deep learning using a convolutional neural network (CNN) following conversion of flux distributions to pixelated images. The four approaches reveal a core network of highly correlated reactions controlling aging rate that is sufficient to explain all lifespan variance. It includes biosynthetic pathways encompassing ceramides, monolysocardiolipins, phosphoinositides, porphyrin and glycerolipids. Our data lead to two novel conclusions. First, variance in the replicative lifespan of S. cerevisiae is an emergent property of its metabolic network. Second, there is convergence among metabolic configurations toward three meta-stable flux states - one associated with extended life, another with shortened life, and a third with wild type life span. One Sentence SummaryTraffic routes and rates through the metabolic network of S. cerevisiae fully account for variance in replicative lifespan.