In the field of neurodegenerative diseases, especially sporadic Parkinson's disease (sPD) with dementia (sPDD), the question of how the disease starts and spreads in the brain remains central. While the prion-like proteins resulting from misfolding of α-synuclein have been designated as a culprit, recent studies suggest the involvement of additional factors. We found that oxidative stress, damaged DNA binding, cytosolic DNA sensing, and Toll-Like Receptor (TLR)4/9 activation pathways are strongly associated with the sPDD transcriptome, which has dysregulated type I Interferon (IFN) signaling. In sPD patients, we confirmed deletions of mitochondrial DNA (mtDNA) in the medial frontal gyrus, suggesting a potential role of damaged mtDNA in the disease pathophysiology.

To explore its contribution to pathology, we used spontaneous models of sPDD caused by deletion of type I IFN signaling (Ifnb-/-/Ifnar-/- mice). We found that the lack of neuronal IFNβ/IFNAR leads to oxidization, mutation, and deletion in mtDNA, which is subsequently released outside the neurons. Injecting damaged mtDNA into mouse brain induced PDD-like behavioral symptoms, including neuropsychiatric, motor, and cognitive impairments. Furthermore, it caused neurodegeneration in brain regions distant from the injection site, suggesting that damaged mtDNA triggers spread of PDD characteristics in an "infectious-like" manner.

We also discovered that the mechanism through which damaged mtDNA causes pathology in healthy neurons is independent of Cyclic GMP-AMP synthase and IFNβ/IFNAR, but rather involves the dual activation of TLR9/4 pathways, resulting in increased oxidative stress and neuronal cell death, respectively. Our proteomic analysis of extracellular vesicles containing damaged mtDNA identified the TLR4 activator Ribosomal Protein S3 as a key protein involved in recognizing and extruding damaged mtDNA.

These findings might shed light on new molecular pathways through which damaged mtDNA initiates and spreads PD-like disease, potentially opening new avenues for therapeutic interventions or disease monitoring.

In this study we examined immune system alterations early in the progression to Alzheimer's disease (AD). We observed multiple changes across the peripheral innate and adaptive immune systems associated with amyloid and cognitive status within our aging cohort. In the innate immune system, we observed increased plasmacytoid and myeloid dendritic cells in amyloid positive participants, but these changes were particularly pronounced in those with mild cognitive impairment. We also observed a decrease in total natural killer cells with amyloid positivity. When the adaptive immune system was examined, we observed increases in total T cells and B cells in amyloid positive participants.

To further understand alterations in the T cell pool we used flow cytometry to interrogate T cell differentiation and function. We observed an increase in differentiated CD4+ and CD8+ T cell phenotypes in amyloid positive participants with mild cognitive impairment. Surprisingly, we observed an increase in functional CD4+ and CD8+ T cells in amyloid positive cognitively normal participants, while those from amyloid positive mild cognitive impairment subjects had a dramatic increase in exhausted T cells. Importantly when T cell function was compared to cognitive status as determined by mini-mental state examination (MMSE), patients with the lowest score had the highest number of exhausted cells.

Understanding how inflammation and the immune response control the development of AD is critical to develop new treatments. While AD is a disease of the brain, our results demonstrate changes of the immune system in the blood. The increases in both plasmacytoid and myeloid dendritic cells are suggestive of an ongoing response in amyloid positive participants regardless of cognitive status that precedes dementia.

Given the numerous links between infection, inflammation, and AD our results suggest two models where T cells may be the nexus for disease. In the first, amyloid production is a response to simmering infections in periphery and brain with the multiple chronic pathogens all humans carry. Individuals who have strong T cell function control the replication of these pathogens and remain cognitively normal. This would explain why particpants who have the most functional T cells still have the highest MMSE score. But in individuals who lose T cell function, chronic pathogens reactivate, overstimulate innate responses, particularly type I interferon production, potentially leading to cognitive impairment. This is the model we favor and suggests rejuvenation of T cells by immune checkpoint inhibitors and other treatments may be a plausible ex vivo therapy for AD.

An alternative model posits that the cytokine production by the T cells while participants are cognitively normal drives the development of cognitive impairment. Support for this idea is provided by a recent study that used in vitro cultured stem cell derived neurons, astrocytes, and microglia incubated with healthy peripheral blood mononuclear cells (PBMCs) that showed increased microglial activation and inflammation driven by CD8+ T cells mediated by CXCR3 driven infiltration. While these are important and interesting results there are two reasons that a protective rather than pathogenic role for T cells may be warranted. First, from a teleological point of view the increased function may be a form of resilience helping to stave off disease from chronic innate inflammation as we described earlier. The second, is that several studies have observed an increase in IFNγ that is associated with slower symptomatic progression in AD. Discerning between these two models will require a longitudinal study to understand the exact temporal relationship between T cell function, exhaustion, and cognitive function.

Atherosclerosis is an insidious vascular disease with an asymptomatic debut and development over decades. The aetiology and pathogenesis of atherosclerosis are not completely clear. However, chronic inflammation and autoimmune reactions play a significant role in the natural course of atherosclerosis. The pathogenesis of atherosclerosis involves damage to the intima, immune cell recruitment and infiltration of cells such as monocytes/macrophages, neutrophils, and lymphocytes into the inner layer of vessel walls, and the accumulation of lipids, leading to vascular inflammation. The recruited immune cells mainly have a pro-atherogenic effect, whereas CD4+ regulatory T (Treg) cells are another heterogeneous group of cells with opposite functions that suppress the pathogenic immune responses. Present in low numbers in atherosclerotic plaques, Tregs serve a protective role, maintaining immune homeostasis and tolerance by suppressing pro-inflammatory immune cell subsets.

The development of atherosclerosis and the stability of atherosclerotic plaques are directly related to changes in the balance of the effector and suppressor populations of the immune system. Treg cells are key immunocytes that control immune responses and maintain tissue homeostasis. Therefore, manipulations aimed at regulating Treg cells are of interest for considering the development of personalised treatments for atherosclerosis. There are several general approaches to modulating Treg activity and Treg numbers in atherosclerosis, but promising preclinical and several clinical studies have suggested that adoptive Treg transfer may be a treatment option for atherosclerosis. For therapies based on adoptive cell transfer, two kinds of Treg cells can be used: polyclonally expanded Treg cells or antigen-specific Treg cells.

In early and ongoing studies of Treg-based adoptive therapies, a general ineffective approach is used: peripheral Treg cells are sorted, polyclonally expanded ex vivo, and infused in certain quantities into the bloodstream. However, this approach does not take into account a number of key factors. First, this approach ignores the functional state of Treg cells. Currently, Treg cells are isolated from peripheral blood mononuclear cells (PBMCs) and expanded ex vivo. Treg cells isolated from PBMCs are heterogeneous and largely represented by cells with induced FOXP3 expression. The lack of potent and stable FOXP3 expression and steady suppressive activity are the common problems in this approach to cell therapy. Second, it is important to increase the specificity of Treg-based adoptive therapy. Antigen-specific Treg cells have been shown to be more powerful in suppressing alloimmune responses in vitro and in vivo compared to polyclonally expanded Treg cells. Thereby, infusions of polyclonally expanded Treg cells with unknown antigen specificity cannot effectively inhibit the target cells and suppress undesirable immune responses and can lead to unwanted side effects.

Recently, new highly effective therapeutic approaches based on adoptive therapy with genetically engineered Treg cells have emerged, which can overcome the barriers to the use of Treg cells for immunotherapy of atherosclerosis and other immune-inflammatory diseases. These approaches include the application of cells with genetically modified T-cell receptors or with the expression of highly specific chimeric antigen receptors (CARs), as well as the use of genome editing techniques such as CRISPR/Cas9. CAR technology is a very promising tool, allowing T cells to be reprogrammed to overcome the limitations of native T cells. CAR-modified T cells have already been successfully applied for the treatment of certain types of cancer. Therefore, this technology can also be effective in the case of Treg cells.

In conclusion, a number of studies have shown that CD4+ Treg cells are crucial in the maintenance of peripheral tolerance and have an important role in the control of atherosclerosis-related inflammation. Therefore, Treg cells are a promising target of major research efforts focused on immune-modulating therapies against atherosclerosis. Developing anti-atherosclerotic Treg-based therapies faces challenges. However, rapid progress in genetic, epigenetic, and molecular aspects of cellular immunology gives hope for a fast-track solution.

Atherosclerosis (AS) is a prevalent vascular disease characterized by dyslipidemia and chronic inflammation. Despite the use of preventive lipid-lowering and anti-inflammatory therapeutic strategies, there is still a critical need for more effective treatment options. Recent research has revealed a significant accumulation of senescent cells in plaques positively correlated with plaque instability. Senescent cells in plaques aggravate chronic inflammation and accelerate AS progression generating a senescence-associated secretory phenotype (SASP) consisting of matrix remodeling proteases, chemokines, cytokines, growth factors, and lipids. Therefore, the targeted removal of senescent cells in plaques presents a promising therapeutic strategy for treating AS.

BCL-2 associated X protein (BAX), a natural inhibitor of the pro-survival protein, is a key pro-apoptotic protein and plays an essential role in regulating the mitochondrial apoptotic pathway. Increasing the intracellular active BAX level may trigger apoptosis in broad-spectrum senescent cells regardless of origin. Therefore, delivering Bax messenger RNA (mRNA) and the BAX activator BTSA1 to senescent cells may represent a novel approach for clearing senescent cells ("activate the activator").

Superparamagnetic iron oxide nanoparticles (SMN) have recently gained significant attention for targeted drug delivery due to their advanced targeting capacity, biodegradability, biological compatibility, and low toxicity. The ability for magnetic targeting is not dependent on cell types but on the recognition of the spatial location of the affected tissue, rendering it a suitable method for delivering drugs to senescent cells in plaques. Furthermore, small extracellular vesicles (EVs) with a diameter ranging from 30 to 150 nm exhibit favorable biocompatibility and cycling stability, and are well-suited for carrying protein and nucleic acid-based drugs. Thus, Bax mRNA-loaded EVs modified with SMN (EVSMN) hold significant potential as drug carriers for treating AS.

Even for targeted delivery, nanoparticles, including EVs, are accumulated in the liver, causing liver injury when Bax mRNA is excessively delivered. Therefore, repressing Bax translation in liver cells is imperative to avoid potential toxicity. MicroRNAs are key regulators of gene expression that destabilize target mRNAs or inhibit their translation. miR-122-5p (miR-122), is a liver-specific molecule with an estimated cellular abundance of 50,000-82,000 copies in adult liver cells, suggesting that Bax mRNA harboring miR-122 recognition sites in the 3'-untranslated region (3'-UTR) (termed as iBax) could be translationally repressed in liver cells.

Herein, a therapeutic EV (EViTx) was engineered with SMN conjugated on the surface, iBax mRNA encapsulated inside and BAX activator BTSA1 incorporated into the membrane. With external magnetic field (MF) navigation, EViTx, when targeted to atherosclerotic plaques, induced significant apoptosis in senescent cells regardless of origin. Notably, when delivered into liver cells, iBax mRNA was translationally repressed by miR-122 endogenously expressed in liver cells and thus had minimal hepatotoxicity. Repeated delivery of EViTx via tail vein injection achieved high therapeutic efficacy and low side effects in ApoE-/- mice. Hence, the EViTx-based strategy offers a promising treatment approach for AS and other age-related diseases.

Altered gut microbiome and host metabolism have been implicated in the process of aging. Aging is associated with changes in the gut microbiota, which in turn can affect host metabolism. The gut microbiota is a complex community of microorganisms that live in the gastrointestinal tract and play an important role in maintaining human health. As we age, the diversity and composition of the gut microbiota can change, with a decrease in beneficial bacteria and an increase in harmful bacteria. These changes in the gut microbiota can contribute to a number of age-related health problems, such as impaired immune function, inflammation, and metabolic dysfunction. For example, alterations in the gut microbiota have been linked to age-related diseases such as type 2 diabetes, cardiovascular disease, and cognitive decline.

The gut microbiome plays a critical role in host metabolism through a variety of mechanisms, including fermentation of dietary fibers, regulation of intestinal barrier function, regulation of immune function and bile acid metabolism, for instance, microbial derived short-chain fatty acids (SCFAs) can modulate various metabolic pathways in the host, including glucose metabolism and lipid metabolism, and can also affect immune function and inflammation. Overall, the relationship between the gut microbiota and host metabolism is complex and their joint action on aging still not fully understood. However, there is growing evidence to suggest that interventions aimed at modulating the gut microbiota, such as dietary changes or probiotics, may have potential therapeutic benefits for age-related metabolic disorders.

Hence, a well-controlled model system that reproduces faithfully the trajectories in the oral and gut microbiota with age is warranted and will provide a better understanding of the role played by them in the healthy development and aging of the host. Pigs are used as an excellent model to study the interaction between host microbiome and aging by combining multi-omics, because pigs share many similarities with humans in terms of their anatomy, physiology, and nutritional requirements. For example, the structure and function of the pig gut is similar to that of humans, as well as in organ development and disease progression. In addition, swine can be raised in a controlled environment and are readily available and relatively inexpensive compared to other animal models, which allows researchers to manipulate their diet and other environmental factors that may influence the host microbiome and aging process. Previous research has also been identified that pigs have a gut microbiome that is similar in composition to that of humans, with a high degree of microbial diversity and similar microbial taxa.

This study employed a comprehensive metagenomic analysis encompassing saliva and stool samples obtained from 45 pigs representing three distinct age groups, alongside serum metabolomics and lipidomics profiling. Our findings unveiled discernible modifications in the gut and oral microbiomes, serum metabolome, and lipidome at each age stage. Specifically, we identified 87 microbial species in stool samples and 68 in saliva samples that demonstrated significant age-related changes. Notably, 13 species in stool, including Clostridiales bacterium, Lactobacillus johnsonii, and Oscillibacter spp., exhibited age-dependent alterations, while 15 salivary species, such as Corynebacterium xerosis, Staphylococcus sciuri, and Prevotella intermedia, displayed an increase with senescence, accompanied by a notable enrichment of pathogenic organisms. Concomitant with these gut-oral microbiota changes were functional modifications observed in pathways such as cell growth and death (necroptosis), bacterial infection disease, and aging (longevity regulating pathway) throughout the aging process. Moreover, our metabolomics and lipidomics analyses unveiled the accumulation of inflammatory metabolites or the depletion of beneficial metabolites and lipids as aging progressed.

Skeletal stem and progenitor cells (SSPCs) perform bone maintenance and repair. With age, they produce fewer osteoblasts and more adipocytes leading to a loss of skeletal integrity. The molecular mechanisms that underlie this detrimental transformation are largely unknown. Single-cell RNA sequencing revealed that Notch signaling becomes elevated in SSPCs during aging.

To examine the role of increased Notch activity, we deleted Nicastrin, an essential Notch pathway component, in SSPCs in vivo. Middle-aged conditional knockout mice displayed elevated SSPC osteo-lineage gene expression, increased trabecular bone mass, reduced bone marrow adiposity, and enhanced bone repair. Thus, Notch regulates SSPC cell fate decisions, and moderating Notch signaling ameliorates the skeletal aging phenotype, increasing bone mass even beyond that of young mice. Finally, we identified the transcription factor Ebf3 as a downstream mediator of Notch signaling in SSPCs that is dysregulated with aging, highlighting it as a promising therapeutic target to rejuvenate the aged skeleton.

The influence of aging on intestinal stem cells and their niche can explain underlying causes for perturbation in their function observed during aging. Molecular mechanisms for such a decrease in the functionality of intestinal stem cells during aging remain largely undetermined. Using transcriptome-wide approaches, our study demonstrates that aging intestinal stem cells strongly upregulate antigen presenting pathway genes and over-express secretory lineage marker genes resulting in lineage skewed differentiation into the secretory lineage and strong upregulation of MHC class II antigens in the aged intestinal epithelium.

Mechanistically, we identified an increase in proinflammatory cells in the lamina propria as the main source of elevated interferon gamma (IFNγ) in the aged intestine, that leads to the induction of Stat1 activity in intestinal stem cells thus priming the aberrant differentiation and elevated antigen presentation in epithelial cells. Of note, systemic inhibition of IFNγ signaling completely reverses these aging phenotypes and restores the regenerative capacity of the aged intestinal epithelium.

DNA damage resulting from genotoxic injury can initiate cellular senescence, a state characterized by alterations in cellular metabolism, lysosomal activity, and the secretion of factors collectively known as the senescence-associated secretory phenotype (SASP). Senescence can have beneficial effects on our bodies, such as anti-cancer properties, wound healing, and tissue development, which are attributed to the SASP produced by senescent cells in their intermediate stages. However, senescence can also promote cancer and aging, primarily due to the pro-inflammatory activity of SASP.

Studying senescence is complex due to various factors involved. Genotoxic stimuli cause random damage to cellular macromolecules, leading to variations in the senescent phenotype from cell to cell, despite a shared program. Furthermore, senescence is a dynamic process that cannot be analyzed as a static endpoint, adding further complexity. Investigating SASP is particularly intriguing as it reveals how a senescence process triggered in a few cells can spread to many others, resulting in either positive or negative consequences for health.

Senescence is a dynamic process influenced by a variety of factors, which greatly affects SASP composition and functions. However, to our knowledge, there is no comprehensive secretome analysis that considers these influences. In this study, we performed a meta-analysis of 70 protein lists from 20 studies to clarify the induction process of senescence. The analysis revealed the following points: I) The IGF and IGFBP signaling pathways are representative common factors in senescent cells. II) The RUNX1 and UCH deubiquitination that regulates proteasome activity were enriched at the very early stage (1-3 days). III) SASP of the middle stage and late stage were enriched inflammatory pathway related protein, including IL-1, IL-4, IL-12, IL-13, and NF-kb. IV) There is a change in carbohydrate metabolism towards glycolysis during senescence induction. V) Senescent fibroblasts subjected to oncogene-induced senescence were found to be distinct from other senescent cells.

IGFBPs have been extensively linked to senescent cells. Studies have demonstrated that these IGFBPs can induce senescence at both the cellular and individual levels when administered to either the culture medium or living organisms. In our analysis, we consistently detected IGFBP4 and IGFBP7 in all datasets at the late stage. Furthermore, the IGF and IGFBP signaling pathway emerged as a common pathway in both the middle and late stages, irrespective of the type of stressor. These findings align with previous analyses and underscore the significant role of the IGF and IGFBP pathway in senescence. They suggest that factors associated with this pathway could serve as a universal marker for identifying senescent cells.

Age-induced degeneration of the neuromuscular junction (NMJ) is associated with motor dysfunction and muscle atrophy. While the impact of aging on the NMJ presynapse and postsynapse is well-documented, little is known about the changes perisynaptic Schwann cells (PSCs), the synaptic glia of the NMJ, undergo during aging. Here, we examined PSCs in young, middle-aged, and old mice in three muscles with different susceptibility to aging. Using light microscopy and electron microscopy, we found that PSCs acquire age-associated cellular features either prior to or at the same time as the onset of NMJ degeneration. Notably, we found that aged PSCs fail to completely cap the NMJ even though they are more abundant in old compared with young mice. We also found that aging PSCs form processes that either intrude into the synaptic cleft or guide axonal sprouts to innervate other NMJs.

We next profiled the transcriptome of PSCs and other Schwann cells (SCs) to identify mechanisms altered in aged PSCs. This analysis revealed that aged PSCs acquire a transcriptional pattern previously shown to promote phagocytosis that is absent in other SCs. It also showed that aged PSCs upregulate unique pro-inflammatory molecules compared to other aged SCs. Interestingly, neither synaptogenesis genes nor genes that are typically upregulated by repair SCs were induced in aged PSCs or other SCs. These findings provide insights into cellular and molecular mechanisms that could be targeted in PSCs to stave off the deleterious effects of aging on NMJs.

Aging is considered the deterioration of physiological functions along with an increased mortality rate. This scientific review focuses on the central importance of genomic instability during the aging process, encompassing a range of cellular and molecular changes that occur with advancing age. In particular, this review addresses the genetic and epigenetic alterations that contribute to genomic instability, such as telomere shortening, DNA damage accumulation, and decreased DNA repair capacity. Furthermore, the review explores the epigenetic changes that occur with aging, including modifications to histones, DNA methylation patterns, and the role of non-coding RNAs. Finally, the review discusses the organization of chromatin and its contribution to genomic instability, including heterochromatin loss, chromatin remodeling, and changes in nucleosome and histone abundance.

The simultaneous occurrence of these alterations, each with its activating or inhibiting role, affects DNA availability and contributes to genomic instability, overall decline in cellular function, and organismal dysregulation. Consequently, there is an increased susceptibility to age-related diseases such as cancer, cardiovascular diseases, and inflammation. Since the initial suggestion that DNA damage and genome instability are primary drivers and DNA repair is a key factor in aging, followed by the finding that defects in DNA repair can hasten the progression of various age-related diseases, significant progress has been made in understanding the detailed connections between genome instability and every facet of the aging process. Exploring the specific mechanisms by which DNA damage impacts each major process contributing to age-related diseases offers promising avenues to address aging at its fundamental causes, thereby mitigating diseases associated with aging.

Senolytics, which eliminate senescent cells from tissues, represent an emerging therapeutic strategy for various age-related diseases. Most senolytics target antiapoptotic proteins, which are overexpressed in senescent cells, limiting specificity and inducing severe side effects. To overcome these limitations, we constructed self-assembling senolytics targeting senescent cells with an intracellular oligomerization system. Intracellular aryl-dithiol-containing peptide oligomerization occurred only inside the mitochondria of senescent cells due to selective localization of the peptides by RGD-mediated cellular uptake into integrin αvβ3-overexpressed senescent cells and elevated levels of reactive oxygen species (ROS), which can be used as a chemical fuel for disulfide formation.

This oligomerization results in an artificial protein-like nanoassembly with a stable α-helix secondary structure, which can disrupt the mitochondrial membrane via multivalent interactions because the mitochondrial membrane of senescent cells has weaker integity than that of normal cells.

These three specificities (integrin αvβ3, high ROS, and weak mitochondrial membrane integrity) of senescent cells work in combination; therefore, this intramitochondrial oligomerization system can selectively induce apoptosis of senescent cells without side effects on normal cells. Significant reductions in key senescence markers and amelioration of retinal degeneration were observed after elimination of the senescent retinal pigment epithelium by this peptide senolytic in an age-related macular degeneration mouse model and in aged mice, and this effect was accompanied by improved visual function. This system provides a strategy for the treatment of age-related diseases using supramolecular senolytics.

While the wonders of modern medicine helped to double global life expectancy between 1920 and 2020, human health span has not followed the upward trend. Today, more than ever, people are living more years in poor health. The call to develop therapeutics that interfere with aging, helping people live not only longer but healthier lives, is increasing. So it isn't surprising that, even in the current economy, some up-and-coming longevity-focused biotech companies are managing to snag funds to push closer to the clinic with therapeutics that have the potential to transform how we age.

Rejuvenation Technologies posted 10.6 million in seed financing, led by Khosla Ventures, a firm headed by businessman and entrepreneur Vinod Khosla. Rejuvenation is looking to rewind the body's molecular aging clock by targeting telomere shortening. The biotech's platform is built around optimized telomerase mRNA encapsulated in custom tissue-targeted lipid nanoparticles. Khosla Ventures was a driving factor in the company's successful seed round. Vinod Khosla has been a name in the longevity space - and telomeres - since his involvement in funding Geron in the 1990s, when it was focused on modifying human aging by way of telomerase activity. As a leader in the space, his participation means something to other investors.

For Rejuvenation, the time was right to enter this space due to the convergence of knowledge and tools. The knowledge around the effect of telomere shortening on aging and age-related disease is not new. However, the mRNA technology the company will utilize has finally had its kinks worked out. "The challenge is delivery and that was what held us up for a few years. It was breakthroughs in 2019 and 2021 that brought ways to deliver messenger RNA with this efficiency and tolerability that it is now ready for the clinic."

In the current economy, attracting investors is no small feat. Yet progress in the longevity field is vital not only for society but also for the global financial burden, according to a cost-benefit analysis which suggests that aging research could be comparable or superior in cost-effectiveness to the most cost-effective global health interventions. Perhaps reflecting this need, the longevity sector is projected to be worth at least 600 billion by 2025, according to analysts.

Over the past five years, investors have shown an increased interest in the longevity space, with investment peaking in 2021 at a record-breaking 7.65 billion. 2022 financing came close to that high at 6.94 billion, pumped up from a 3 billion investment in Altos Labs. It can be hard to pinpoint the potential market size for a successful longevity therapeutic. "Studies are all over the map. One solid way to look at this is to see the statins market since it is effectively used as a longevity drug, namely for reducing cardiac risk. Most of them are off-patent, but it's still 15 billion a year in sales. If you like high-risk, high-return, cost-effective lifesaving projects, then aging research is an especially good investment because the level of existing funding is so low, and the size of the impact of success is so high."

Mesenchymal/medicinal stem/signaling cells (MSCs), well known for regenerative potential, have been involved in hundreds of clinical trials. Even if equipped with reparative properties, aging significantly decreases their biological activity, representing a major challenge for MSC-based therapies. Age-related joint diseases, such as osteoarthritis, are associated with the accumulation of senescent cells, including synovial MSCs. An impaired ability of MSCs to self-renew and differentiate is one of the main contributors to the human aging process.

Moreover, senescent MSCs (sMSCs) are characterized by the senescence-messaging secretome (SMS), which is typically manifested by the release of molecules with an adverse effect. Many factors, from genetic and metabolic pathways to environmental stressors, participate in the regulation of the senescent phenotype of MSCs. To better understand cellular senescence in MSCs, this review discusses the characteristics of sMSCs, their role in cartilage and synovial joint aging, and current rejuvenation approaches to delay/reverse age-related pathological changes, providing evidence from in vivo experiments as well.

The prevalence of type 2 diabetes is increasing rapidly, particularly among younger age groups. Estimates suggest that people with diabetes die, on average, 6 years earlier than people without diabetes. We aimed to provide reliable estimates of the associations between age at diagnosis of diabetes and all-cause mortality, cause-specific mortality, and reductions in life expectancy. For this observational study, we conducted a combined analysis of individual-participant data from 19 high-income countries using two large-scale data sources: the Emerging Risk Factors Collaboration (96 cohorts, median baseline years 1961-2007, median latest follow-up years 1980-2013) and the UK Biobank (median baseline year 2006, median latest follow-up year 2020). We calculated age-adjusted and sex-adjusted hazard ratios (HRs) for all-cause mortality according to age at diagnosis of diabetes using data from 1,515,718 participants.

For participants with diabetes, we observed a linear dose-response association between earlier age at diagnosis and higher risk of all-cause mortality compared with participants without diabetes. HRs were 2.69 when diagnosed at 30-39 years, 2.26 at 40-49 years, 1.84 at 50-59 years, 1.57 at 60-69 years, and 1.39 at 70 years and older. HRs per decade of earlier diagnosis were similar for men and women. Using death rates from the USA, a 50-year-old individual with diabetes died on average 14 years earlier when diagnosed aged 30 years, 10 years earlier when diagnosed aged 40 years, or 6 years earlier when diagnosed aged 50 years than an individual without diabetes. Using EU death rates, the corresponding estimates were 13, 9, or 5 years earlier.

A type of T cell known as an effector memory T cell (Tem) can become a critical driver of cytokine storms. The chain reaction appears to start when Tem cells interact with dendritic cells, which serve as the immune system's primary detector of viral and bacterial invasions. When the immune system wins the battle, most of the custom T cells stand down. But a few guards linger in the blood and other body tissues to be ready to "effect" a rapid response should the same type on infection occur again. Hence the name effector memory T cells.

However, ongoing encounters with Tem cells, such as those occurring when people have autoimmunity or live in a state of chronic inflammation, actually cause DNA strands within dendritic cells to break. This, in turn, prompts a DNA repair pathway that rapidly generates large numbers of inflammatory cytokines, including IL-1b, IL-6, and IL-12. This flood, or storm, of cytokines causes the tissue damage that occurs in autoinflammatory diseases including type 1 diabetes, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel diseases like Crohn's disease. For some people with these conditions, ongoing inflammation also increases their risk of developing cancer.

Researchers detected upregulation of expression of Tmem173 in dendritic cells following interactions with Tem cells. Tmem173 which encodes for stimulator of interferon genes (STING). The STING pathway has been described in previous research as being important to detect viral infections. But when Tem cells harm dendritic cells, the STING pathway does not follow the same route that it typically does when directly responding to viral infections. In this situation, STING teams up with the gene TRAF6 and the transcription factor NFkB to form an "axis" of activity that drives runaway production of innate inflammatory cytokines.

The researchers further reasoned that if they could prevent STING and TRAF6 from working together, they could cut off the inflammation chain reaction at an early stage. In mice gene-edited to lack the STING pathway, that's exactly what they found. When treated with a drug known to induce an intense T cell-mediated inflammatory response, these mice did not produce a flood of innate cytokines. The mouse study involved a whole-body elimination of STING. Attempting the same in humans would not be advisable because STING is used by a number of cell types outside the immune system in necessary ways. "Our goal will be to develop a highly focused method or methods for blocking STING within targeted immune cells, without disrupting its other important functions. If we can achieve that, we may have a powerful new tool for controlling hyper-inflammation."