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Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly 1 , 2 . To define the contribution of immune system ageing to organism ageing, here we selectively deleted Ercc1 , which encodes a crucial DNA repair protein 3 , 4 , in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence 5 – 7 in the immune system only. We show that Vav-iCre +/− ;Ercc1 −/fl mice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice 8 – 10 . Notably, non-lymphoid organs also showed increased senescence and damage, which suggests that senescent, aged immune cells can promote systemic ageing. The transplantation of splenocytes from Vav-iCre +/− ;Ercc1 −/fl or aged wild-type mice into young mice induced senescence in trans , whereas the transplantation of young immune cells attenuated senescence. The treatment of Vav-iCre +/− ;Ercc1 −/fl mice with rapamycin reduced markers of senescence in immune cells and improved immune function 11 , 12 . These data demonstrate that an aged, senescent immune system has a causal role in driving systemic ageing and therefore represents a key therapeutic target to extend healthy ageing. An aged, senescent immune system has a causal role in driving systemic ageing, and the targeting of senescent immune cells with senolytic drugs has the potential to suppress morbidities associated with old age.

Constitutive NF‐κB activation is associated with cellular senescence and stem cell dysfunction and rare variants in NF‐κB family members are enriched in centenarians. We recently identified a novel small molecule (SR12343) that inhibits IKK/NF‐κB activation by disrupting the association between IKKβ and NEMO. Here we investigated the therapeutic effects of SR12343 on senescence and aging in three different mouse models. SR12343 reduced senescence‐associated beta‐galactosidase (SA‐β‐gal) activity in oxidative stress‐induced senescent mouse embryonic fibroblasts as well as in etoposide‐induced senescent human IMR90 cells. Chronic administration of SR12343 to the Ercc1−/∆ and Zmpste24−/− mouse models of accelerated aging reduced markers of cellular senescence and SASP and improved multiple parameters of aging. SR12343 also reduced markers of senescence and increased muscle fiber size in 2‐year‐old WT mice. Taken together, these results demonstrate that IKK/NF‐κB signaling pathway represents a promising target for reducing markers of cellular senescence, extending healthspan and treating age‐related diseases. Constitutive IKK/NF‐κB activation is associated with cellular senescence and aging. Here we demonstrate that pharmacological inhibition of IKK/NF‐κB activation by the small molecule SR12343 reduced senescence and SAPS factors in cell culture, improved healthspan in mice with accelerated aging, and reduced markers of senescence and pathology in multiple tissues of both accelerated and naturally aged mice. Therefore, IKK/NF‐κB pathway is a promising target for aging interventions to treat age‐related diseases.

ABSTRACT Extracellular vesicles (EVs) are secreted by most cell types, transmitting crucial signaling molecules like proteins, small RNAs, and DNA. We previously demonstrated that EVs from murine and human mesenchymal stem cells (MSCs) functioned as senomorphics to suppress markers of senescence and the inflammatory senescence‐associated secretory phenotype (SASP) in cell culture and in aged mice. Here we demonstrate that EVs from additional types of human adult stem cells and embryonic progenitor cells have a senomorphic activity. Based on their miRNA profiles showing prevalence in stem cell EVs versus nonstem cell EVs and the number of age‐related genes targeted, we identified eight miRNAs as potential senomorphic miRNAs. Analysis of these miRNAs by transfection into etoposide‐induced senescent IMR90 human fibroblasts revealed that each of the miRNAs alone regulated specific senescence and SASP markers, but none had complete senomorphic activity. Evaluation of ~300 combinations of miRNAs for senotherapeutic activity identified a senomorphic cocktail of miR‐181a‐5p, miR‐92a‐3p, miR‐21‐5p, and miR‐186‐5p that markedly reduced the expression of p16INK4a, p21Cip1, IL‐1β, and IL‐6 and the percentage of SA‐ß‐gal‐positive cells. Transcriptome analysis identified multiple pathways affected by the miRNA cocktail, including cellular senescence and inhibition of PCAF and HIPK2 in the p53 signaling pathway. Finally, treatment of aged mice with liposomes containing the four miRNA cocktail suppressed markers of senescence and inflammation in multiple tissues. These studies suggest that EVs derived from stem cells suppress senescence and inflammation, at least in part, through miRNAs and that a senomorphic miRNA cocktail could be used to target senescence and inflammation to extend health span. A senomorphic miRNA cocktail (E5), consisting of miR‐181a‐5p, miR‐92a‐3p, miR‐21‐5p, and miR‐186‐5p, was identified from a pool of miRNAs enriched in extracellular vesicles (EVs) derived from multiple functional human stem cell types. E5 reduces senescence and SASP markers both in cell culture and in aged mice. Mechanistically, E5 targets key regulators of the p53 pathway, including PCAF and HIPK2, leading to decreased p53 phosphorylation and acetylation. These effects result in downregulation of p16INK4a, p21Cip1, IL‐1β, and IL‐6 expression, and a reduction in SA‐β‐gal+ and γ‐H2AX+ cells across multiple tissues, indicating the senomorphic potential of E5 for healthspan extension.

Age‐related macular degeneration (AMD) is a major cause of vision loss in older adults. AMD is caused by degeneration in the macula of the retina. The retina is the highest oxygen consuming tissue in our body and is prone to oxidative damage. DNA damage is one hallmark of aging implicated in loss of organ function. Genome instability has been associated with several disorders that result in premature vision loss. We hypothesized that endogenous DNA damage plays a causal role in age‐related retinal changes. To address this, we used a genetic model of systemic depletion of expression of the DNA repair enzyme ERCC1‐XPF. The neural retina and retinal pigment epithelium (RPE) from Ercc1−/Δ mice, which models a human progeroid syndrome, were compared to age‐matched wild‐type (WT) and old WT mice. By 3‐months‐of age, Ercc1−/Δ mice presented abnormal optokinetic and electroretinogram responses consistent with photoreceptor dysfunction and visual impairment. Ercc1−/Δ mice shared many ocular characteristics with old WT mice including morphological changes, elevated DNA damage markers (γ‐H2AX and 53BP1), and increased cellular senescence in the neural retinal and RPE, as well as pathological angiogenesis. The RPE is essential for the metabolic health of photoreceptors. The RPE from Ercc1−/Δ mice displayed mitochondrial dysfunction causing a compensatory glycolytic shift, a characteristic feature of aging RPE. Hence, our study suggests spontaneous endogenous DNA damage promotes the hallmarks of age‐related retinal degeneration. Spontaneous endogenous DNA damage drives key hallmarks of age‐related retinal degeneration, including visual impairment, photoreceptor cell loss, dysmorphic RPE, mitochondrial dysfunction, and cellular senescence. Therefore, Ercc1−/Δ mice represent a valuable model for further mechanistic studies on age‐related retinal degeneration and for rapid testing of potential therapeutic interventions.

Cover legend: The cover image is based on the article Identification of Senomorphic miRNAs in Embryonic Progenitor and Adult Stem Cell‐Derived Extracellular Vesicles by Tianpeng Zhang et al., https://doi.org/10.1111/acel.70071.

While direct cell transplantation holds great promise in treating many debilitating diseases, poor cell survival and engraftment following injection have limited effective clinical translation. Though injectable biomaterials offer protection against membrane‐damaging extensional flow and supply a supportive 3D environment in vivo that ultimately improves cell retention and therapeutic costs, most are created from synthetic or naturally harvested polymers that are immunogenic and/or chemically ill‐defined. This work presents a shear‐thinning and self‐healing telechelic recombinant protein‐based hydrogel designed around XTEN – a well‐expressible, non‐immunogenic, and intrinsically disordered polypeptide previously evolved as a genetically encoded alternative to PEGylation to “eXTENd” the in vivo half‐life of fused protein therapeutics. By flanking XTEN with self‐associating coil domains derived from cartilage oligomeric matrix protein, single‐component physically crosslinked hydrogels exhibiting rapid shear thinning and self‐healing through homopentameric coiled‐coil bundling are formed. Individual and combined point mutations that variably stabilize coil association enables a straightforward method to genetically program material viscoelasticity and biodegradability. Finally, these materials protect and sustain viability of encapsulated human fibroblasts, hepatocytes, embryonic kidney (HEK), and embryonic stem‐cell‐derived cardiomyocytes (hESC‐CMs) through culture, injection, and transcutaneous implantation in mice. These injectable XTEN‐based hydrogels show promise for both in vitro cell culture and in vivo cell transplantation applications. Shear‐thinning and self‐healing telechelic recombinant protein‐based hydrogels based on XTEN are introduced. Point mutations to self‐associating coil domains yield materials with programmable viscoelasticity and biodegradability. These materials protect and sustain viability of human fibroblasts, hepatocytes, HEK, and embryonic stem‐cell‐derived cardiomyocytes cultured within these genetically encodable biopolymer networks following in vivo injection. Such injectable hydrogels hold promise for therapeutic cell transplantation.

Injectable Cell Therapies Single‐component protein hydrogels assembled through homopentameric coiled‐coil bundling exhibit rapid shear thinning and self‐healing, protecting and sustaining viability of encapsulated cells through culture, injection, and transcutaneous implantation. More details can be found in article number 2301708 by Cole A. DeForest and co‐workers.

Cellular senescence is a key driver of the aging process and contributes to tissue dysfunction and age-related pathologies. Senolytics have emerged as a promising therapeutic intervention to extend healthspan and treat age-related diseases. Through a senescent cell-based phenotypic drug screen, we identified a class of conjugated polyunsaturated fatty acids, specifically α-eleostearic acid and its methyl ester derivative, as novel senolytics that effectively killed a broad range of senescent cells, reduced tissue senescence, and extended healthspan in mice. Importantly, these novel lipids induced senolysis through ferroptosis, rather than apoptosis or necrosis, by exploiting elevated iron, cytosolic PUFAs and ROS levels in senescent cells. Mechanistic studies and computational analyses further revealed their key targets in the ferroptosis pathway, ACSL4, LPCAT3, and ALOX15, important for lipid-induced senolysis. This new class of ferroptosis-inducing lipid senolytics provides a novel approach to slow aging and treat age-related disease, targeting senescent cells that are primed for ferroptosis.

Accumulation of senescent cells drives aging and age-related diseases. Senolytics, which selectively kill senescent cells, offer a promising approach for treating many age-related diseases. Using a senescent cell-based phenotypic drug discovery approach that combines drug screening and drug design, we developed two novel flavonoid senolytics, SR29384 and SR31133, derived from the senolytic fisetin. These compounds demonstrated enhanced senolytic activities, effectively eliminating multiple senescent cell types, reducing tissue senescence in vivo, and extending healthspan in a mouse model of accelerated aging. Mechanistic studies utilizing RNA-Seq, machine learning, network pharmacology, and computational simulation suggest that these novel flavonoid senolytics target PARP1, BCL-xL, and CDK2 to induce selective senescent cell death. This phenotype-based discovery of novel flavonoid senolytics, coupled with mechanistic insights, represents a key advancement in developing next-generation senolyticss with potential clinical applications in treating aging and age-related diseases.

Aging is marked by the accumulation of senescent cells (SnCs), which contribute to tissue dysfunction and age-related diseases. Senotherapeutics, including senolytics which specifically induce lysis of SnCs and senomorphics, which suppress the senescence phenotype, represent promising therapeutic interventions for mitigating age-related pathologies and extending healthspan. Using a phenotypic-based senescent cell screening assay, we identified fucoidans, a class of sulfated polysaccharides derived from brown algae and seaweed, as novel senotherapeutics. In particular, fucoidan from Fucus vesiculosus (Fucoidan-FV) displayed potent senomorphic activity in different types of SnCs, reduced senescence in multiple tissues in aged mice, and extended healthspan in a mouse model of accelerated aging. Fucoidan-FV also enhanced the deacetylation and mono-ADP-ribosylation (mADPr) activity of SIRT6 and improved DNA repair and reduced senescence, in part, through SIRT6-dependent pathways. In addition, Fucoidan-FV downregulated genes associated with inflammation, Wnt signaling, and ECM remodeling pathways in SnCs and increased expression of genes involved with DNA repair. These findings support the translational potential of fucoidans as novel senotherapeutics that also are able to improve SIRT6-mediated DNA repair.