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Given the pro and anti-geronic roles of the TGF-β superfamily in aging, we hypothesized that human longevity involves genetic variation in TGF-β signaling genes. Here we utilized a candidate functional genomic approach to identify and characterize functional variants in TGF- β signaling associated with human longevity. Targeted sequencing of 113 genes involved in aging- associated TGF- β signaling in an Ashkenazi Jewish centenarian cohort identified genetic variants robustly associated with human longevity. In particular, a centenarian-enriched intronic variant residing in a cell-type specific enhancer in SMAD3, a critical receptor-regulated TGF- β signal transducer, was identified. This non-coding SMAD3 variant (rs8040709) altered binding of ELK1, a member of the ETS family of transcription factor important for enhancer activity in certain cell types, resulting in reduced SMAD3 expression. Analysis of the variant in cell types derived from gene edited iPSCs demonstrated the variant reduced SMAD3 expression, senescence and inflammation in endothelial cells. In addition, heterozygosity in SMAD3 improved healthspan and reduced senescence in theErcc1-/Δprogeroid mouse model of accelerated aging. Taken together, these experiments demonstrate that variants in a cell type specific enhancer of SMAD3 resulted in reduced expression, senescence and inflammation and contributes to human longevity. Thus, SMAD3 represents a validated targeted for drug development for extending human healthspan.

Cells respond to a myriad of stressors by senescing, acquiring stable growth arrest, morphologic and metabolic changes, and a senescence-associated-secretory-phenotype (SASP). The heterogeneity of senescent cells (SnCs) and their SASP is vast, yet poorly characterized. SnCs have diverse roles in health and disease and are therapeutically targetable, making characterization of SnCs and harmonization of their nomenclature a priority. The Cellular Senescence Network (SenNet), a NIH Common Fund initiative, will leverage emerging single cell and spatial-omics to identify and map SnCs in numerous organs across the lifespan of humans and mice. A common coordinate framework will integrate the data, using validated, standardized methods, creating public 4-dimensional SnC atlases. Key SenNet deliverables include development of innovative tools/technologies to detect SnCs, biomarker discovery, common annotations to describe SnCs and extensive public data sets. The goal is to comprehensively understand and map SnCs for diagnostic and therapeutic purposes to improve human health.

Aging is the single largest risk factor for most chronic diseases, and thus possesses large socioeconomic interest to continuously aging societies. Consequently, the field of aging research is expanding alongside a growing focus from the industry and investors in aging research. This year's 8th Annual Aging Research and Drug Discovery (ARDD) meeting was organized as a hybrid meeting from August 30th to September 3rd 2021 with more than 130 attendees participating on-site at the Ceremonial Hall at University of Copenhagen, Denmark, and 1800 engaging online. The conference comprised of presentations from 75 speakers focusing on new research in topics including mechanisms of aging and how these can be modulated as well as the use of AI and new standards of practices within aging research. This year, a longevity workshop was included to build stronger connections with the clinical community., Aging, 14 (2), ISSN:1945-4589

Although cellular senescence is increasingly recognized as driving multiple age-related co-morbidities through the senescence-associated secretory phenotype (SASP), in vivo senescent cell identification, particularly in bulk or single cell RNA-sequencing (scRNA-seq) data remains challenging. Here, we generated a novel gene set (SenMayo) and first validated its enrichment in bone biopsies from two aged human cohorts. SenMayo also identified senescent cells in aged murine brain tissue, demonstrating applicability across tissues and species. For direct validation, we demonstrated significant reductions in SenMayo in bone following genetic clearance of senescent cells in mice, with similar findings in adipose tissue from humans in a pilot study of pharmacological senescent cell clearance. In direct comparisons, SenMayo outperformed all six existing senescence/SASP gene sets in identifying senescent cells across tissues and in demonstrating responses to senescent cell clearance. We next used SenMayo to identify senescent hematopoietic or mesenchymal cells at the single cell level from publicly available human and murine bone marrow/bone scRNA-seq data and identified monocytic and osteolineage cells, respectively, as showing the highest levels of senescence/SASP genes. Using pseudotime and cellular communication patterns, we found senescent hematopoietic and mesenchymal cells communicated with other cells through common pathways, including the Macrophage Migration Inhibitory Factor (MIF) pathway, which has been implicated not only in inflammation but also in immune evasion, an important property of senescent cells. Thus, SenMayo identifies senescent cells across tissues and species with high fidelity. Moreover, using this senescence panel, we were able to characterize senescent cells at the single cell level and identify key intercellular signaling pathways associated with these cells, which may be particularly useful for evolving efforts to map senescent cells (e.g., SenNet). In addition, SenMayo represents a potentially clinically applicable panel for monitoring senescent cell burden with aging and other conditions as well as in studies of senolytic drugs.

With age, senescent cells accumulate in various tissues where they contribute to loss of tissue homeostasis, aging, and age-related diseases through their inflammatory senescence-associated secretory phenotypes (SASPs). Senotherapeutics able to selectively eliminate senescent cells, termed senolytics, or suppress the detrimental SASPs, termed senomorphics, have been demonstrated to improve age-associated comorbidities and aging phenotypes. To discover novel senotherapeutics translatable to promote healthy longevity, we conducted a drug screening of diverse natural products based on the characteristic senescence-associated β-galactosidase activity. Several fucoidans from different brown seaweed were found to exhibit potent senotherapeutic activity. Fucoidans are long-chain sulfated polysaccharides found in various species of brown algae including seaweed. The best senomorphic fucoidan was able to suppress senescence in cultured senescent fibroblasts, in ex vivo human tissue explants, and in vivo in mouse models of natural and accelerated aging. Specifically, fucoidan reduced markers of cellular senescence and SASP in senescent mouse and human cells. Acute treatment of the fucoidan in naturally aged mice reduced tissue senescence, especially in the kidney and lung. Chronic treatment of the fucoidan in Ercc1-/Δ progeria mice attenuated composite aging symptoms and extended healthspan. Interestingly, preliminary mechanistic studies demonstrated that fucoidan can improve non-homologous end-joining-directed DNA damage repair and increase the mono-ADP-ribosylation activity of SIRT6, suggesting a relationship between cellular senescence, DNA repair, and SIRT6 signaling pathways. Collectively, fucoidans were identified as novel senotherapeutics with translational potential for reducing cellular senescence, ameliorating age-associated phenotypes, and extending healthspan as well as able improve DNA repair pathways through modulation of SIRT6 activity.

Cellular senescence is a potent tumor suppressor mechanism. However, the untoward effect is that the accumulation of senescent cells promotes loss of resilience, aging and age-related diseases. One approach to maintaining the benefits of senescence while preventing the negative consequences is senolytic therapies: drugs that do not prevent senescence, but selectively kill senescent cells. Since virtually any type of cell can become senescent, it is important to identify the lineages of senescent cells that are most potent at driving loss of tissue homeostasis and aging. This will enable honing development of senolytics. We used a genetic approach to drive increased genotoxic stress, a potent inducer of senescence, in a tissue specific manner. The impact of this targeted senescence on different organs and cell types will be discussed, identifying a lead target for senolytics.