Fight Aging! Newsletter, April 3rd 2023

As opposed to being monolithic in function and morphology, astrocytes differ significantly depending on both tissue and cellular localization. While these characterizations have been recognized for some time, functional distinctions have only recently been investigated. Historically, in response to damage, astrocytes have been characterized as adopting a reactive phenotype. In contrast to the typically quiescent state of mature astrocytes, reactive astrocytes can become highly proliferative, and this astrogliosis is the foundation for glial scar formation.

To best support the central nervous system (CNS) in a system that can suffer from a variety of insults, astrocytes have seemingly evolved a diverse reactive response. Reactive phenotypic polarization depends on the nature of the inducing stimuli. Rather than eliciting a single response to CNS injury or insult, astrocyte reactivity is highly heterogenous. Borrowing from the nomenclature used to describe reactive macrophages and microglia, in response to tissue damage and ischemia, astrocytes adopt a neuroprotective A2 phenotype. A2s fit the traditional reactive astrocyte profile and have proliferative functions, resulting in glial scar formation, debris clearance, and blood-brain barrier (BBB) repair. They upregulate neurotrophic factors and pro-synaptic thrombospondins, thereby promoting neuronal growth and supporting synaptic repair. In contrast, neuroinflammation, infection, and aging induces a cytotoxic A1 reactive astrocyte phenotype. Neurotoxic A1 reactive astrocytes are pro-inflammatory and associated with neurodegeneration and chronic neuropathic pain, in addition to a repression of functions related to supporting neuronal survival and synaptogenesis.

The use of A1/A2 nomenclature is not universally accepted, as such a stringent dichotomy fails to accurately represent the diversity within each subset of cells. This system of classification can also give the false impression of reactive states being either entirely "helpful" or "harmful", when in reality these reactive states likely evolved to serve various functional purposes.

The environment of the aging brain can exacerbate inflammatory effects and contribute to gradual neuronal damage. During the course of normal aging, as opposed to age-associated pathologies like Alzheimer's disease, glia cells undergo a variety of physiological and functional changes. In addition to promoting neuroprotective signaling pathways, microglia in an aging brain upregulate expression of immune system response receptors, effectively becoming more sensitive to insults, and increasing production of pro-inflammatory signals. The neuroinflammatory astrocyte response in the brain that arises in advanced age is compounded by inflammation. In the absence of activated microglia cytokine secretion, age-induced astrocyte reactivity is reduced, supporting the role of activated microglia in age-associated A1-like responses.

Targeting or blocking astrocyte polarization may prove to be an effective avenue of symptom management and treatment for a host of neurodegenerative or neuroinflammatory disorders. The selective serotonin reuptake inhibitor (SSRI) Fluoxetine was found to inhibit neurotoxic astrocyte polarization upon inflammatory stimulation both in vitro and in vivo. The increased concentration of A1-associated markers in a chronic mild stress mouse model was rescued with Fluoxetine treatment. Using pharmacological inhibitors and siRNA technology, astrocytic 5HT2BR and downstream β-arrestin2 signaling were identified as the targets of the Fluoxetine-mediated inhibition of A1-like astrocyte polarization. Recently, NLY01, a GLP-1R agonist, has been investigated as a neuroprotective agent in Parkinson's disease, and was found to directly prevent microglia from inducing astrocyte polarization. These studies suggest that both current well-established therapies and those yet to be developed could be of use as neurotoxic reactive astrocyte inhibitors that will be applicable to a wide array of neuropathologies. Continued investigation into the near-ubiquitous pathological roles of these reactive pro-inflammatory A1-like astrocytes will have important implications for how neuropathologies are studied and ultimately treated.

For decades, one of the dominant theories in ageing research has been that ageing results from the accumulation of DNA changes, mainly genetic mutations, which prevent more and more genes from functioning properly over time. These malfunctions, in turn, can cause cells to lose their properties, leading to the breakdown of tissues and organs and ultimately to ageing and diseases. However, the emerging evidence claims that epigenetic information loss over time is the major cause of mammalian ageing, and epigenetic regulation can restore youthful gene expression patterns. For epigenetic rejuvenation, developing safe and stable strategies that modulate the epigenetic landscape of aged cells to a primitive state are important for cells to exert rejuvenating effects without cancer risk. Furthermore, systematic comparisons of epigenetic dynamics during ageing and partial reprogramming will contribute to identifying key checkpoints for reversing the ageing process and inform the design of potential intervention strategies for ageing-related diseases.

Pathological accumulation of senescent cells (SCs) is also associated with ageing and a range of diseases, and SCs may be potential pharmacological targets for delaying the ageing process. In respect of targeting SCs, there are still many potential markers, like chromatin dynamics and transcriptional signaling, and pharmacological interventions deserving exploitation, to effectively regulate the secretory phenotype of SCs. SC elimination and senescence-associated secretory phenotype inhibition have shown some efficacy in clinical studies of treating functional degeneration and chronic diseases in ageing.

Targeting the cell microenvironment and systemic signals makes sense for tissue-specific cell and organism rejuvenation. Stem cells play a crucial role in maintaining tissue homeostasis, and cell microenvironments also regulate stem cell behavior, which together form a regenerative unit. External signals from the ageing microenvironment appear to dominate the intrinsic function of young stem cells. In contrast, signals from the young microenvironment may have a limited effect on the regeneration of aged stem cells. It would be interesting to identify the genes or pathways that make aged stem cells insensitive to external signals in young microenvironment.

Although many clinical trials registered for stem cell treatments, an effective and safe stem cell therapy to slow or reverse tissue ageing has not yet been identified. Several obstacles still need to be overcome, including proper differentiation and integration of cells in tissues, maintenance of the youth of stem cells and their progeny in ageing tissues, and prevention of tumorigenesis. It will be important to determine the specific mechanisms, which have the potential to provide better treatment pathways - using stem cell transplantation or utilizing endogenous stem cell banks. Recent advances in single-cell transcriptomics and pedigree tracing techniques provide a systematic understanding of stem cell ageing mechanisms. The systematic identification of gene networks, involved in functional changes, age-dependent changes in RNA and protein and metabolite molecules, and cellular interactions, will contribute to further studies on stem cells in tissue repair and ageing-related diseases.

Despite the great progress in cellular rejuvenation, the potential limitations have led to cellular rejuvenation rarely being tested in human studies. Cellular rejuvenation for reversing ageing and age-related diseases as well as cancers has been extensively studied. While cellular rejuvenation holds great promise, key questions remain to be addressed.

(1) Cellular reprogramming strategy can reverse age-related physiological changes and promote tissue regeneration by resetting the epigenetic clock and changing cell fate, but the problems such as relatively low reprogramming efficiency and potential safety concerns, remain the obstacle in the path of its application.

(2) The pharmacological delivery system is difficult to express the pluripotency factors with high efficacy. The toxicity might be induced by drug combinations, then reducing the effectiveness of the cocktail and causing side effects in normal cells.

(3) Clearance of SCs and decreasing SASP exert a beneficial effect on organ repair and disease treatment, but poor cell selectivity of senolytics may result in the damage of normal tissue, and SASP inhibitors targeting specific secretory factors also have limited therapeutic effects on multiple factors-mediated diseases. Besides, completely senescence-specific markers are still absent.

(4) Stem cell therapy as a rejuvenative strategy holds great promise in the reversal of ageing and alleviation of diseases. Despite the advances in many clinical trials of stem cell therapy, optimizing in vitro culture environment, improving the delivery system of stem cells, and reducing immune rejection are still the major challenges to obtain high-quality stem cells and enhance that therapeutic effect.

(5) Restoring defective intercellular communications by the inhibition of inflammation can rejuvenate ageing-impaired changes, but long-term inflammation inhibition may lead to immunosuppression.

Collectively, cellular rejuvenation holds great promise for preventing and treating ageing-related diseases from different dimensions. A healthy and rejuvenated state of the organism can maintain stable characteristics and biological functions without excessive ageing-related degeneration or deterioration. The development of various cellular rejuvenation strategies now provides compelling evidences that the ageing process is not irreversible. Particularly, the effectiveness of stem cell therapy and dietary restriction has been tested in the real world, yielding to desired results. Hopefully, there is a great possibility of translation of these rejuvenation strategies to address human ageing, age-associated diseases, and cancers. Therefore, it is reasonable to expect that clinical rejuvenation approaches to treat ageing-related diseases and even to reverse ageing will be boomed within the next two or three decades.

Maintenance of protein homeostasis (proteostasis) has emerged as fundamentally and preferentially important for stem cells. Proteostasis disruption impairs stem cell self-renewal, which contributes to poor ex vivo expansion and is associated with degenerative disorders, cancer predisposition syndromes, and age-related pathologies in vivo. To maintain proteostasis, cells employ a network of pathways to balance protein synthesis, folding, trafficking, and degradation. Despite being highly conserved, the proteostasis network can be specifically configured to support stem cell fitness and longevity.

Stem cells exhibit and depend on unusually low protein synthesis rates compared with restricted progenitors. Modest increases in protein synthesis disrupt stem cell proteostasis and impair self-renewal by increasing the biogenesis of misfolded proteins, but similar changes minimally impact progenitors. Similarly, activation of the unfolded protein response (UPR) has dichotomous effects in stem and progenitor cells. UPR activation safeguards the integrity of the stem cell pool by preferentially inducing apoptosis in stressed stem cells, whereas it typically promotes an adaptive response in progenitors.

In embryonic stem cells, high proteasome activity can provide the capacity for substantial proteostasis buffering by degrading and preventing the accumulation of misfolded proteins. In contrast, proteasome activity is low within some stem cells such as neural stem cells and hematopoietic stem cells (HSCs). This raises a fundamental paradox: if somatic stem cells are highly dependent on proteostasis maintenance, why do they have such limited proteasome capacity to degrade misfolded proteins?

Here, we show that in contrast to most cells that primarily utilize the proteasome to degrade misfolded proteins, HSCs preferentially traffic misfolded proteins to aggresomes in a Bag3-dependent manner and depend on aggrephagy, a selective form of autophagy, to maintain proteostasis in vivo. When autophagy is disabled, HSCs compensate by increasing proteasome activity, but proteostasis is ultimately disrupted as protein aggregates accumulate and HSC function is impaired. Bag3-deficiency blunts aggresome formation in HSCs, resulting in protein aggregate accumulation, myeloid-biased differentiation, and diminished self-renewal activity. Furthermore, HSC aging is associated with a severe loss of aggresomes and reduced autophagic flux. Protein degradation pathways are thus specifically configured in young adult HSCs to preserve proteostasis and fitness but become dysregulated during aging.

The thymus is required for the development of a functional adaptive immune system, facilitating the generation of self-tolerant T cells that can respond to foreign antigens. Thymic epithelial cells (TECs) are divided into cortical and medullary (c/m) TECs, based on their location and function. Age-related involution of the thymus results in decreased thymic function and naive T cell output and increased autoimmunity and disease risk.

Thymic organoids cultured at the air-liquid interface allow for the interrogation of thymic function and T cell development. Functional human reaggregated thymic organoid cultures (RTOCs) made with expanded 1° TECs and thymic mesenchyme (TM) combined with allogenic cord blood-derived hematopoietic stem cells (HSCs) support T cell development in vitro and in vivo. However, RTOCs depend on 1° tissue access, are allogeneic, and do not support negative selection.

Recently, we reported the directed differentiation of induced PSCs (iPSC) to functional thymic epithelial progenitors (TEPs) that support murine T cell development after transplantation in nude mice. While differentiation of TEPs from human iPSCs has been demonstrated by multiple groups, in vitro generation of functional TECs has yet to be achieved. We sought to develop a thymic organoid model with isogenic hPSC-derived cell compartments that supports patient-specific TEC and T cell development in vitro.

We combined hPSC-derived TEPs, hematopoietic progenitor cells (HPCs), and mesenchymal cells to generate functional isogenic stem cell-derived thymic organoids (sTOs). sTOs support TEC development as demonstrated by HLA-DR, CD205, KRT5, and autoimmune regulator (AIRE) expression after 2-4 weeks in vitro, even in the absence of HPCs. AIRE, HLA-DR, and tissue-restricted antigen (TRA) expression suggests the potential for negative selection in this system. Importantly, sTOs support T cell development, including some regulatory T cells (Tregs). For the first time, to our knowledge, we demonstrate the generation of functional hPSC-derived TECs in vitro.

Alzheimer's Disease (AD) is a progressive neurodegenerative disease seen with advancing age. Recent studies have revealed diverse AD-associated cell states, yet when and how they impact the causal chain leading to AD remains unknown. To reconstruct the dynamics of the brain's cellular environment along the disease cascade and to distinguish between AD and aging effects, we built a comprehensive cell atlas of the aged prefrontal cortex from 1.64 million single-nucleus RNA-seq profiles. We associated glial, vascular, and neuronal subpopulations with AD-related traits for 424 aging individuals, and aligned them along the disease cascade using causal modeling. We found two predicted trajectories in the cellular landscape, termed (a) progression of AD (prAD) and (b) Alternative Brain Aging (ABA).

At the subpopulation level, microglial nuclei profiles were partitioned into 16 subpopulations, including proliferative (Mic.1), surveilling (Mic.2-5; expressing CX3CR1), reacting (Mic.6-8; TMEM163), enhanced-redox (Mic.9-10; FLT1), stress response (Mic.11; NLRP1, TGFBR1, upregulating genes of heat response, cellular senescence and NLRP1 inflammasome), interferon response (Mic.14, IFI6), inflammatory (Mic.15; CCL3/CCL4, NFKB1, NLRP3), SERPINE1 expressing (Mic.16) and lipid-associated (Mic.12-13; APOE) subpopulations. The lipid-associated Mic.12 and Mic.13 both expressed the AD risk genes APOE and GPNMB, with Mic.13 also expressing high levels of SPP1 and TREM2 compared to other subpopulations.

Astrocytes were partitioned into 10 subpopulations - homeostatic-like (Ast.1-2), enhanced-mitophagy (Ast.3; PINK1), reactive-like Ast.4 (GFAP, ID3) and Ast.5 (GFAP, SERPINA3, OSMR), interferon-responding (Ast.7; IFI6), and stress response (Ast.8-10): Ast.8, expressing heat stress and DNA damage, calcium, and sterol metabolism genes; Ast.9, expressing heat and oxidative stress response, tau binding and necroptosis genes; and Ast.10 (SLC38A2), expressing oxidative stress and ROS, metallothioneins and zinc ion homeostasis genes.

Oligodendrocyte lineage cells were partitioned into 13 subpopulations of mature oligodendrocytes (Oli.1-13), such as the stress response Oli.13 (SLC38A2), 3 subpopulations of oligodendrocyte precursor cells (OPC.1-3), one committed oligodendrocyte precursor (COP) subpopulation and one newly formed oligodendrocytes (NFOL) subpopulation. The newly discovered diversity of OPCs are of particular interest, and included an enhanced-mitophagy subpopulation (OPC.1; PINK1), which had higher expression of AD risk genes (e.g. APOE, CLU), and an axon projection/regeneration associated subpopulation (OPC.3; SERPINA3, OSMR).

Specifically, we suggest the following sequence of events underlying the prAD trajectory: At the early stages, selective homeostatic glial subpopulations decrease in proportion alongside an increase of, first, the lipid-associated microglia subpopulation APOE+ Mic.12 subpopulation that is itself influenced by advancing age and contributes to the accumulation of amyloid-β proteinopathy, and up-regulates immune activation pathways. Then, a distinct but related Mic.13 subpopulation of APOE+TREM2+ microglia that are influenced by APOEε4 (the strongest genetic risk factor for AD) contributes to the subsequent accumulation of tau proteinopathy.

At the next stage of the AD cascade, with the accumulation of tau proteinopathy, we observed a transient increase in the proportions of Ast.3 and OPC.1, which both upregulate genes associated with high energy demand and enhanced-mitophagy, as well as oxidative phosphorylation and glutamate secretion. OPC.1 further upregulates genes associated with response to oxidative stress aligning with reports suggesting the increased vulnerability of OPCs to oxidative stressors that are rising during this phase.

At the last stage of the AD cascade, we observed further increase in Mic.12 and Mic.13 proportions, together with a coordinated increase of Ast.10 and Oli.13, with Ast.10 playing an important role mediating the effect of tau proteinopathy on the increased rate of cognitive decline. Both Ast.10 and Oli.13 express stress response genes, with Ast.10 mainly demonstrating response to oxidative stress while Oli.13 showing response to heat stress and unfolded protein. Cognitive decline appears to be directly affected by Ast.10 that is driven by both tau and Mic.13, suggesting that the proportion of this astrocyte subpopulation may be a point of convergence for different processes leading to cognitive dysfunction.

While Mic.12 offers a good target with which to perturb the accumulation of Aβ proteinopathy to enhance therapeutic options centered on anti-amyloid-β antibodies, preventing polarization of microglia and astrocytes into Mic.13 and Ast.10 respectively, may have more immediate impact in helping to prevent cognitive impairment. The latter strategy would also be better suited for individuals who are already Aβ+ and are at risk of tauopathy.

On the other hand, these subpopulations do not appear to be relevant to the alternative brain aging (ABA) trajectory, where we found a selective decrease in homeostatic glial subpopulations and an increase in reactive microglial subpopulations. At the next stage, we observed increased proportions of reactive-like Ast.5 and OPC.3, both expressing the markers SERPINA3 and OSMR. Among participants in ABA, we found constant levels of neocortical amyloid, very limited neocortical tau and varying dynamics of cognitive decline. Thus, more work is needed to better understand this trajectory and its interesting, defining glial subpopulations.

Intermittent fasting (IF) is an eating pattern in which individuals go extended periods with little or no energy intake after consuming regular food in intervening periods. IF includes alternate-day fasting (ADF), modified fasting (MF), time-restricted fasting (TRF), and fasting-mimicking diet (FMD). Studies showed that IF increases the average lifespan of rats by 14-45% and mice by only 4-27%. Further, dietary restriction increases fatty acid oxidation by maintaining mitochondrial network homeostasis and functional coordination with the peroxisome, thereby promoting longevity.

Clinical studies demonstrated that long-term IF improves cognitive disorders and reduces oxidative stress in middle-aged adults. It also delays the onset of age-related brain damage. Moreover, nutrient-sensing signaling pathways such as the AMPK, SIRT1, mTOR, and insulin/IGF-1 pathways are downregulated during IF, blocking cell proliferation and activating stress factors, thereby negatively regulating various aging signals. IF can also protect the heart from ischemic damage, reduce body mass index and blood lipids, improve glucose tolerance, and reduce the incidence of coronary artery disease by increasing levels of the growth hormone. This in turn increases lipolysis and insulin secretion in addition to reducing other glucose metabolism pathway markers.

Macroautophagy requires the conjugation of members of the ATG8 family, ubiquitin-like proteins including LC3 and GABARAP, to phosphatidylethanolamine (PE). This enables double-membrane vesicles termed autophagosomes to recruit ATG8 proteins, which mediate loading and maturation of cargo. More recently, autophagy-independent functions of ATG8 proteins have been discovered. Several recent studies have highlighted these additional roles of ATG8 proteins leading to alternative fates of their cargo in degradation and secretion, together referred to as non-canonical autophagy (NCA). With age, there is a general decrease in efficiency of degradative autophagy, both canonical and NCA. Additionally, in what is likely a response to age-associated decreased degradation through the lysosome is the shift to "secretory autophagy" (SA), release of material into the extracellular space. However, owing to the overlap of the initial steps of autophagosome formation, SA also decreases with age. Understanding the mechanisms that differentially initiate and regulate NCA will help identify how defects in these pathways contribute to aging and disease.

One of the defining hallmarks of aging is altered intercellular communication, with a prominent example being "inflammaging", or the chronic inflammation that further amplifies the aging process. Growing evidence identifies inflammaging as the driver for NCA in aged microglia. SA has been shown to maintain proteostasis when autophagy is inhibited by blocking fusion with the lysosome in vitro. However, the downstream effect of this is the release of cargo into the extracellular space, and, depending on what was targeted for degradation but is now in the extracellular space, can itself induce an immune response. Hyperactivation of macrophages will lead to increased phagocytosis of the discarded cargo, bringing it back into the cell to attempt to be cleared. However, if the limitation is at the lysosome, the effort is futile and will lead to deposition of aggregated proteins both intracellularly and in the extracellular space. Thus, chronic inflammation seen with aging is a likely driver for aggregation-associated diseases, including many neurodegenerative diseases.

The role of NCA in aging and age-related diseases is still under intense investigation. It is still not clear how cargo is recruited for NCA, whether NCA and canonical autophagy coexist, if differential signals direct the decision to complete canonical versus NCA, and whether the cell has a preference for either type. Alternatively, NCA may only be initiated when canonical autophagy cannot meet cellular requirements, and thus becomes the dominant response for cargo clearance. Furthermore, the molecular pathways and vesicular trafficking in SA are not fully described, but canonical autophagy machinery is required for the initiation. So, if the same machinery is needed, but there are different outcomes, what determines if degradation occurs in the lysosome or if SA is induced? Moreover, with so many pathways to deliver cargo to the lysosomes for degradation, does everything come down to functional lysosomes? This seems to be the case, since the switch from degradation to SA does not solve the overall problem in neurodegenerative diseases.

Nuclear clearance and cytoplasmic aggregation of the RNA-binding protein TDP-43 is the hallmark of neurodegenerative diseases called TDP-43 proteinopathies. This includes almost all instances of amyotrophic lateral sclerosis (ALS) and about half of frontotemporal dementia. In ALS, the motor neurons that innervate and trigger contraction of skeletal muscles degenerate, resulting in paralysis. One of the most highly abundant motor neuron mRNAs encodes stathmin-2, a protein necessary for axonal regeneration and maintenance of neuromuscular junctions (NMJs).

Recognizing that stathmin-2 is essential for axonal recovery after injury and NMJ maintenance, a central interest in TDP-43 proteinopathies is to determine the mechanism through which TDP-43 enables correct processing of STMN2 mRNAs and to develop methods to restore stathmin-2 synthesis in neurons with TDP-43 dysfunction. We found that TDP-43 binding to the first intron of the STMN2 pre-mRNA was required to suppress cryptic splicing and polyadenylation. Correct processing of this modified STMN2 pre-mRNA was restored by binding, suggesting that TDP-43 normally functions by sterically blocking access to the cryptic sites of RNA-processing factors.

Rescue of stathmin-2 expression and axonal regeneration after injury in human motor neurons depleted of TDP-43 was achieved with steric binding antisense oligonucleotides (ASOs). We identified RNA-targeted CRISPR effectors and ASOs that restored STMN2 levels despite reduced TDP-43. ASO injection into cerebral spinal fluid, an approach feasible for human therapy, rescued stathmin-2 protein levels in the central nervous system of mice with chronically misprocessed Stmn2 pre-mRNAs.

Impaired wound healing is associated with aging and has significant effects on human health on an individual level, but also the whole health care sector. Deficient angiogenesis appears to be involved in the process, but the underlying biology is still poorly understood. This is at least partially being explained by complexity and costs in using mammalian aging models.

To understand aging-related vascular biology of impaired wound healing, we have utilized zebrafish and turquoise killifish fin regeneration models. The regeneration of caudal fin after resection was significantly reduced in old individuals in both species. Age-related changes in angiogenesis, vascular density, and expression levels of angiogenesis biomarker VEGF-A were observed. Furthermore, an anti-angiogenic drug, vascular endothelial growth factor receptor blocking inhibitor SU5416, reduced regeneration indicating a key role for angiogenesis in the regeneration of aging caudal fin despite aging-related changes in vasculature.

Taken together, our data indicates that these fish fin regeneration models are suitable for studying aging-related decline in wound healing and associated alterations in aging vasculature.

Wouldn't it actually accelerate progress if we instead did most testing in far shorter-lived animals, like the roundworm C. elegans or the fruit fly Drosophila? On its face, that's a totally reasonable question: time is ticking for all of us, and we want to get longevity therapeutics into people's hands as quickly as possible! And certainly these short-lived animals have taught us a lot about the roles of different biological signaling pathways.

Some interventions that work in C. elegans act by altering the worms' early developmental processes, which isn't terribly helpful to those of us who "have the misfortune of already being alive." That's also becoming increasingly evident in mice. We've known for about twenty years now that mutations that block IGF-1/growth hormone signaling in mice slow down their aging and extend lifespan. But those mutations dampen down signaling through these pathways throughout the animals' entire lives. To take advantage of that discovery and develop a longevity therapeutic that would work in middle-aged and older adults, a large part of the anti-aging effect would have to be due to the hormone still being low during adulthood. Instead, studies have shown that almost all the benefit of IGF-1 signaling inhibition goes away if growth hormone production is brought back to normal during the very earliest period of life.

The preceding examples apply to studies based on trying to usurp the regulation of metabolism to slow the aging process down. SENS Research Foundation is instead grounded in the direct "damage-repair" strategy of SENS. If we're going to use an organism as a test animal for rejuvenation biotechnology, it has to accumulate similar kinds of aging damage as we do, and it must do so in similar tissues and with similar pathological results. And here C. elegans and Drosophila just aren't qualified for the job. For instance, C. elegans don't live long enough to accumulate cells overtaken by mitochondrial DNA deletions, and there is no clear link between other kinds of mitochondrial DNA damage and the rate of aging in these worms. C. elegans also have no bones, so no osteoarthritis or osteoporosis either. And they lack any of the cells dedicated to the immune system.

Increased age is associated with frailty and diseases of varying severities, and for many, the hope of a long and healthy lifespan therefore becomes elusive. Nevertheless, overall life expectancy has increased markedly during the past decades, owing to a large extent to the introduction of medicines such as statins and anti-hypertensives. These and newer-generation drugs have resulted in a lower prevalence and severity of age-related illnesses such as cardiovascular disease (CVD). To sustain and reinforce this positive trend and help ensure a prolonged healthspan for more people across the world, novel pharmacotherapeutics and optimal use of existing options are arguably needed.

Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are an example of a drug class with proven or potential benefits across a range of prevalent age-related conditions and complications. Originally developed to manage blood glucose levels in type 2 diabetes (T2D), GLP-1 RAs have subsequently been confirmed to have marked benefits on body weight and CVD risk. Furthermore, evidence from research and clinical use of the drug class has led to the initiation of clinical trials with GLP-1 RAs in other prominent aging-related diseases, including chronic kidney disease (CKD) and Alzheimer's disease. In sum, GLP-1 RAs are positioned as one of the pharmacotherapeutic options that can contribute to addressing the high unmet medical need characterising several prevalent aging-related diseases, potentially helping more people enjoy a prolonged healthy lifespan.

When an injury is on your skin, it shows up as a visible scar, but what happens when vital organs like your heart or liver are damaged and hardens? If left unchecked, it can lead to loss of mechanics and dangerous consequences. These changes in tissues are attributed to the extracellular matrix. The extracellular matrix is a web of proteins found in every cell in the body, and acts both like wires on a circuit that allow cells to communicate with each other, and the beams in a building, giving the organs its structure. Too much extracellular matrix makes the cell, and by extension the organ, tough and inflexible, a condition known as fibrosis. In simple terms, fibrosis is a stiffening of cells and tissue. Its health implications are profound, as it can lead to poor pumping by the heart or cirrhosis in the liver.

"Myofibroblasts are a group of cells that produce collagen, a common extracellular matrix protein. In diseased organs they are seen overproducing collagen. Once myofibroblasts appear in diseased organs, fibrosis proceeds in a snowball fashion. At the same time, myofibroblasts are responsible for proper wound healing."

To understand how myofibroblasts turn pathological, researchers looked at how different physical stimuli changes the expression of genes in these cells. They found consistent changes in the expression of one gene: VGLL3. Their study showed that after a heart attack, myofibroblasts in both mouse and human hearts express more VGLL3 protein which led to the production of collagen. VGLL3 was also expressed more in fibrotic mouse liver, suggesting it contributes to fibrosis in multiple organs. Conversely, preventing VGLL3 activation in mice led to far less fibrosis in these organs. The study further showed that the relationship between matrix stiffness and VGLL3 activation becomes a pathological positive feedback loop, in that a stiffer matrix triggers more VGLL3 activation, which triggers the cell to produce more collagen.

Previous studies suggested the role of cellular senescence in late-life depression (LLD). However, it is unclear how this finding relates to common features of LLD, such as medical and cognitive problems. We applied factor analyses to an extensive battery of clinical variables in 426 individuals with LLD. Here we tested the relationship between these factors, age and sex, with an index of cellular senescence based on 22 senescence-associated secretory phenotype (SASP) proteins.

We found four factors: 'depression and anxiety severity', 'cognitive functioning', 'cardiovascular and cardiometabolic health' and 'blood pressure'. A higher senescence-associated secretory phenotype index was associated with poorer 'cognitive functioning' and 'cardiovascular and cardiometabolic health' but not with 'depression and anxiety severity'.

When interpreting this finding, it is critical to note that it does not contradict our previous studies that have consistently demonstrated an increased SASP index in individuals with a major depressive disorder compared with non-depressed older adults. However, it suggests that the SASP index is more closely associated with physical health and cognitive functioning than with the severity of depression and anxiety symptoms within individuals with LLD. The question of how depressive symptoms interact with the pathophysiology of major depression is fiercely discussed.

Our findings highlight the interactive effect between LLD and physical burden. Previous research has demonstrated that depression frequently occurs in individuals with chronic illness and amplifies the disability and disablement associated with co-occurring physical illness and cognitive impairment. In addition, depression undermines adherence to co-prescribed pharmacotherapy for medical diseases and reduces healthy lifestyle choices. Therefore, evidence-based treatment of depression may also reduce mortality risk secondary to physical illness, such as cancer. On the other hand, co-occurring physical burden moderates the long-term response to antidepressant treatment and renders the individual's response more brittle.

As our organism ages, the muscles lose the capacity to regenerate. Researchers have found a protein that regulates the function of a subset of immune cells, macrophages, by promoting their ability to clear residues in the regenerating muscle. The behavior of macrophages is altered in aged mice. Macrophages are a type of immune cells that are capable of phagocytosis, the process of ingestion and elimination of particles inside cells. During regeneration the macrophages are responsible for clearing the dead cells from the muscle after injury, which is a normal step of the process of muscle regeneration.

The researchers found that macrophages in aged mice have reduced levels of a protein, called MANF, that is crucial for this process. "In fact, this protein is so important in this process that if we decrease MANF levels in the macrophages in younger mice, their ability to regenerate muscle is also impaired. On the other hand, increasing the levels of the protein MANF in aged muscle is sufficient to recover muscle's regenerative capacity."

"A central promise of regenerative medicine is the ability to repair aged or diseased organs using stem cells. This approach will likely become an effective strategy for organ rejuvenation, holding the potential to increase human health span by delaying age-related diseases. Our study shows that immune aging is an important obstacle to the regenerative capacity of aged muscle."

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease of unknown origin. Histologically, IPF is characterized by massive accumulation of fibroblasts, myofibroblasts, alveolar epithelial cells (AECs), and macrophages and a significant deposition of extracellular matrix (ECM). A previous review showed that AECs, as the main source of pro-fibrogenic cytokines in IPF, express a variety of cytokines and growth factors, which can promote the migration, proliferation, and accumulation of extracellular matrix of fibroblasts; these are key events of cell dysfunction in PF.

AECs are damaged by pathogenic microorganisms, dust, drugs, chemicals, and oxygen free radicals which, when coupled with risk factors such as aging and genetics, may decrease the ability of alveolar epithelial type II (ATII) cells and lung fibroblasts (LFs) to repair damage to the lung. LFs proliferate locally, migrate to the injury site and differentiate into myofibroblasts, which produce a large amount of ECM and exhibit contractile function. These myofibroblasts typically vanish after successful repair; dysregulation of the normal repair process can lead to persistent myofibroblast activation.

PF is an aging-associated lung disease in which LF and AEC senescence play a complex role in pathogenesis. Numerous studies have revealed that ATII cell senescence and apoptosis are associated with endoplasmic reticulum stress and autophagy, telomere damage, mitochondrial dysfunction, and epigenetic changes, leading to development of pulmonary fibrosis. The activation of LF and deposition of ECM proteins are key steps in the development of IPF. Epigenetic changes and reduced activation of autophagy promote myofibroblast differentiation, ultimately leading to pulmonary fibrosis. Aging AECs promote LF activation by increasing expression of the senescence-associated secretory phenotype (SASP), thereby increasing occurrence and development of pulmonary fibrosis. In short, cellular senescence is an important mechanism of IPF pathogenesis.