Fight Aging!

Alzheimer's disease is complex and puzzling, and massively funded, high-profile efforts to find treatments for the condition have been failing for decades. The research community has focused on clearance of amyloid-β, as this protein accumulates and misfolds in Alzheimer's patients. Yet some old individuals exhibit high levels of amyloid-β and do not suffer Alzheimer's, while clearance of extracellular amyloid-β fails to meaningfully improve the condition of patients. It may be that intracellular amyloid-β is the real target, or that amyloid-β accumulation is a side-effect of the real pathological mechanisms.

Of late, more attention is being given to overly active or senescent glial cells in the brain and their contribution to rising levels of inflammation. Chronic inflammation may well turn out to be the most important mechanism in Alzheimer's disease, and thus senolytic therapies to clear senescent cells and their inflammatory secretions may turn out to be quite effective as a treatment. We'll find out whether this is the case in the years ahead.

Today's open access paper delves into post-mortem human brain tissue in order to model the cascade of changing glial cell population characteristics. The data is supportive of a focus on glial cells and their contribution to inflammation. That activation of the immune system may be the cause of increased amounts of amyloid-β in its role as an antimicrobial peptide, a part of the innate immune response. At the end of the day, the only really compelling data in the context of Alzheimer's disease is a narrowly focused treatment that produces a reversal of pathology: that would settle the debate over which of the many possibilities is the most important pathological mechanism.

Cellular dynamics across aged human brains uncover a multicellular cascade leading to Alzheimer's disease

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.

This review paper goes into some detail regarding present thought on the role of senescent cells of different types in idiopathic pulmonary fibrosis. Fibrosis in general is an often age-related dysfunction of normal tissue maintenance and regeneration, in which excessive extracellular matrix is created, leading to scar-like deposits that disrupt normal tissue structure and function. In the lung, this progressively impairs breathing and is ultimately fatal. Idiopathic pulmonary fibrosis was one of the first conditions for which early senolytic drugs to clear senescent cells were tested in humans.

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.

Link: https://doi.org/10.3892/etm.2023.11844

Regeneration following injury is an intricate, coordinated dance between stem cells, various types of somatic cell, and immune cells. Age-related changes in any of those cell populations may contribute to the declining ability to heal injuries observed in later life. Researchers here identify a specific change in the innate immune cells called macrophages that produces a significant impairment in wound healing in mice. This may prove to the basis for therapies to improve regeneration in older people, time will tell.

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."

Link: https://www.eurekalert.org/news-releases/983459

The adaptive immune system depends upon the thymus. Thymocyte cells are generated in the bone marrow and then migrate to the thymus, where they mature into T cells through a complex process of training and selection. The thymus is largest during development, up until the end of childhood. At that point it shrinks dramatically, and then the remainder undergoes a slow atrophy over the rest of a lifespan. In older people, the much reduced volume of active thymic tissue diminishes the supply of new T cells, leading to an adaptive immune system increasingly made up of broken, misconfigured, exhausted, and senescent cells.

Finding ways to regrow the thymus is an ongoing endeavor, a number of companies taking a variety of approaches. Some are looking for small molecules to trigger regulatory genes governing thymic activity; some intend to deliver cells that home to the thymus and encourage new growth; gene therapies have been explored, involving a search for ways to target delivery systems to the thymus; and researchers are investigating the construction of new thymic tissue for transplant. You may be familiar with the work of Lygenesis and associated scientists in building thymus organoids that can be transplanted into lymph nodes.

Today's open access paper is an example of this last sort of work, focused on being able to build thymic organoids from induced pluripotent stem cells. This offers the possibility of universal thymic tissues, built from cell lines engineered to prevent graft rejection, that could be transplanted into any patient. Or the more costly option of patient-matched thymic tissue, grown from their own cells. Clearly there is much more work to be done in order to build an artificial thymus that matches the natural thymus in structure and function, but the progress to date is promising.

Generation of functional thymic organoids from human pluripotent stem cells

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.

Inflammatory signaling may be influential in major depressive disorder. For any condition in which inflammation is important, attention should be given to the possible role of cellular senescence, given the advent of senolytic therapies to clear these cells. Senescent cells grow in number throughout the body with age, and while never a large fraction of all cells, they energetically generate pro-inflammatory signals. Here, researchers discuss the sometimes there, sometimes not correlation between burden of senescent cells and incidence of major depressive disorder in later life.

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.

Link: https://doi.org/10.1038/s44220-023-00033-z

Fibrosis is a feature of the age-related decline of many organs and tissues, notably the heart, kidney, and liver, among others. It is a malfunction of normal tissue maintenance in which excessive extracellular matrix is created, leading to scar-like deposition that is disruptive to tissue structure and function. Chronic inflammation and the presence of senescent cells appear to be important in the development of fibrosis, but as yet the medical community lacks a proven approach to reversal of fibrosis. Much of the research continues to focus on finding regulatory genes that might be targeted in order to disrupt the formation of fibrotic structures, as in the example here, rather than looking at root causes.

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.

Link: https://www.kyushu-u.ac.jp/en/researches/view/253

Autophagy is the name given to a complex, varied set of processes that tag and recycle broken or excess proteins and structures in the cell. The destination for materials to be recycled is the lysosome, a membrane-wrapped collection of enzymes capable of breaking down near all of the proteins and other molecules a cell is likely to encounter. How materials are selected and how exactly they make their way to the lysosome varies considerably. Alongside autophagy, the ubiquitin-proteasome system is another way for cells to identify problem proteins, such as those that misfold into toxic configurations, and then break them down into their component parts for reuse.

In short-lived species, improvement in autophagy or improvement in proteasomal degradation produces a slowing of aging. More effective cellular housekeeping implies a lower burden of damage inside cells, fewer downstream issues resulting from that damage, and thus better cell and tissue function. Today's open access paper is one of many examples of researchers probing the complexities of cell maintenance, asking why some stem cell populations appear to undertake far too little proteasomal activity in order to clear out broken proteins. The authors found that these cells instead rely on a form of autophagy targeting the protein aggregates that can form as a result of misfolding.

All of these housekeeping processes decline in effectiveness with advancing age, and it is possible that ways to at least modestly slow the aging process can be found by improving cellular housekeeping in the stem cell populations responsible for supporting tissues by producing a consistent supply of new somatic cells. As noted here, the details and many possible targets for intervention are likely to be quite different from cell type to cell type. This encourages more holistic approaches such as partial reprogramming rather than going target by target in search of ways to manipulate the regulation of specific aspects of autophagy and proteasomal function.

Hematopoietic stem cells preferentially traffic misfolded proteins to aggresomes and depend on aggrephagy to maintain protein homeostasis

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 provides substantial proteostasis buffering capacity 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.

Semaglutide is probably the best known of the glucagon-like peptide-1 receptor agonists, a class of drug deployed to treat type 2 diabetes and other consequences of obesity. This is one of a number of classes of diabetes drug where there is some suspicion that maybe these small molecules can modestly slow aging through much the same set of mechanisms that help to steer the abnormal metabolism of obesity and diabetes into a modestly less terrible state, e.g. reduced blood glucose and inflammatory signaling. Equally, the data to support that belief is far from compelling, and the effect sizes are small in comparison to, say, those produced by exercise. An equally plausible explanation for observed effects is that drugs that promote weight loss and lower calorie intake operate through the well studied mechanisms of calorie restriction and reduced impact of visceral fat.

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.

Link: https://doi.org/10.1111/acel.13818

It is cheaper and faster to study aging - and potential approaches to treat aging - in short-lived species. The disadvantage is that much of what is learned and achieved will be irrelevant to aging as it occurs in longer-lived species such as our own. The response to calorie restriction, an upregulation of cellular housekeeping mechanisms that lengthens life, fortunately evolved early on in the development of life, and the biochemistry is surprisingly consistent even across widely divergent species. Thus much can be learned of it in lower animals with short life spans. Unfortunately, it turns out that this class of intervention doesn't affect life span in longer-lived species like our own to anywhere near the degree it does in short-lived species. This is the tradeoff of working with short-lived models, in a nutshell: more can be done, but all of that work may turn out to be of very limited utility.

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.

Link: https://www.sens.org/sens-why-not-worms-flies/

The influential hallmarks of aging paper is now nearly ten years old. It has been twenty years since the Strategies for Engineered Negligible Senescence (SENS) categorization of causative mechanisms of aging was first put forward, an effort that inspired the hallmarks. Time moves on relentlessly! Are you feeling old yet? Unlike SENS, the hallmarks of aging made no attempt to be a to-do list of research and development approaches that we should be undertaking in order to effectively treat aging. They are, as it says on the label, hallmarks, observations of old cells and tissues. Nonetheless, a to-do list is somewhat the way in which the hallmarks have been taken in much of the research community, for better or worse. It is good that more of that community is on board with the treatment of aging as a goal to be achieved, but on the other hand some of the hallmarks are clearly far downstream from the root causes of aging, and thus probably poor targets for intervention.

Given the existence and popularity of the hallmarks of aging, far more cited and discussed than SENS ever was, what next? One might hope that today's open access paper illustrates something of the shape of what is next: that researchers talk less about the hallmarks of aging, and instead talk more about the approaches that might reverse aging, producing rejuvenation. The paper is something of a grab bag of presently popular strategies, with epigenetic reprogramming and senescent cell clearance leading the way. It offers only a partial coverage of the field, paying far too little attention to clearance of protein aggregates and lipofuscin, for example. Nonetheless, if more people thought this way, we might see faster progress towards the effective treatment of aging.

Cellular rejuvenation: molecular mechanisms and potential therapeutic interventions for diseases

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 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.

Zebrafish are one of the few vertebrate species capable of repeatedly regenerating major tissue loss without scarring. This ability is impacted by aging, however, as noted here. Researchers find that the age-related loss of angiogenesis capacity impairs regeneration. It is known that capillary density declines with age, hand in hand with impaired angiogenesis, and it is hypothesized that the consequent reduced delivery of oxygen and nutrients is an important contribution to many aspects of aging.

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.

Link: https://doi.org/10.1242/bio.059622

Researchers here delve into the mechanisms by which TDP-43 aggregation contributes to the symptoms of neurodegenerative conditions in which it is involved. It disrupts expression of another gene, stathmin-2, degrading the ability of neurons to maintain axonal connections. This is a feature of ALS, the condition most readily associated with TDP-43 aggregation. The research here points to an approach to therapy: not restoration of appropriate TDP-43 behavior, but rather finding a way to force correct expression of stathmin-2. It remains the case that TDP-43 aggregation may well cause other problems unrelated to this mechanism.

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.

Link: https://doi.org/10.1126/science.abq5622

Chronic, unresolved inflammation in brain tissue is a feature of age-related neurodegenerative conditions, and may even be the most important mechanism in these very complex conditions. The supporting cells of the brain, primarily microglia and astrocytes, become more active and inflammatory in later life. This overlaps with a rising count of senescent cells in these populations. Senescent cells produce an outsized contribution to inflammatory signaling, belying their relatively small numbers compared to non-senescent cells. Active microglia and astrocytes are largely not senescent, however. They are reacting to inflammatory signaling or molecular patterns resulting from cell dysfunction, stress, and death.

Clearing senescent cells from the brain dampens inflammation and pathology in animal models of neurodegeneration. It seems plausible that finding ways to turn off the activation of microglia and astrocytes will be similarly beneficial. In the case of microglia, the entire population can be removed without harm, allowing new non-active microglia to emerge and repopulate the brain. Astrocytes present a harder challenge, however. Given that they make up a sizable fraction of all cell in the brain, clearance really isn't an option. Some form of adjustment or reprogramming of regulatory mechanisms is called for. Fortunately, it may be the case that astrocyte activation is a consequence of microglial activation: further studies of microglial clearance as an approach to therapy may clarify this relationship.

Roles of neuropathology-associated reactive astrocytes: a systematic review

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 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.

Autophagy is the name given to a complex collection of processes that recycle broken and unwanted proteins and cell structures. Autophagy declines in effectiveness with age, while upregulation of autophagy is a feature of many of the approaches shown to slow aging in laboratory species. The ability of calorie restriction to slow aging appears to depend on autophagy, for example. So far, little meaningful progress has been made towards therapies that can greatly improve on the ability of exercise to improve autophagy, though mTOR inhibitors could be argued to be somewhat better than exercise on this front, given their greater effect on longevity in short-lived mammals. As mentioned, autophagy is complicated, and the paper here is an example of that complexity, diving into what is known as non-canonical autophagy, some of the less well explored interactions taking place during cell maintenance.

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.

Link: https://doi.org/10.3389/fcell.2023.1137870

The paper noted here discusses a range of studies assessing the ability of forms of intermittent fasting to improve long-term health and life expectancy. Results are generally positive, but one should expect long-lived mammals to exhibit smaller gains in longevity than are observed in short-lived mammals, following the known outcomes of calorie restriction. Intermittent fasting is not as well studied as the practice of calorie restriction, but does appear to work via a similar set of mechanisms, even when overall calorie intake is not much reduced. Time spent in a state of hunger, and the metabolic changes provoked by hunger, are perhaps the important mechanisms shared by the various forms of dietary restriction.

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.

Link: https://doi.org/10.1155/2023/4038546

When reading about potential mechanistic links between chronic kidney disease and Alzheimer's disease, it is worth considering klotho. Increased expression of klotho has been shown to improve kidney function and better resist the decline of kidney function with age. It also improves cognitive function, though there is some debate over how this is happening. Klotho largely acts in the kidney, and its effects on cognitive function may simply be a compelling demonstration of the point that dysfunction of the kidneys is harmful to organs throughout the body, including the brain.

The mediating mechanisms linking kidney to brain may be the harms done to the cardiovascular system with loss of kidney function, as the brain is sensitive to vascular issues: lowered blood supply; pressure damage due to hypertension; loss of capillary density; leakage of the blood-brain barrier that wraps blood vessels passing through the central nervous system; and so forth. In today's open access paper, researchers discuss how exactly kidney disease may increase the risk and severity of Alzheimer's disease, but the details, particularly those relating to the vasculature, are relevant to other neurodegenerative conditions.

Pathogenesis of Chronic Kidney Disease Is Closely Bound up with Alzheimer's Disease, Especially via the Renin-Angiotensin System

Chronic kidney disease (CKD) is a clinical syndrome secondary to the definitive change in function and structure of the kidney, which is characterized by its irreversibility and slow and progressive evolution. Alzheimer's disease (AD) is characterized by the extracellular accumulation of misfolded β-amyloid (Aβ) proteins into senile plaques and the formation of neurofibrillary tangles (NFTs) containing hyperphosphorylated tau. In the aging population, CKD and AD are growing problems. CKD patients are prone to cognitive decline and AD. However, the connection between CKD and AD is still unclear.

The available evidence suggests that CKD and AD are pathologically related through the renin-angiotensin system (RAS), uremic toxins, and erythropoietin (EPO), which contribute to the occurrence and development of CKD and may aggravate the development of AD. In CKD, excess renin is released and increases circulating angiotensin II (Ang II) levels, resulting in AT1R upregulation and enhancing systemic vascular resistance, increasing blood pressure, and promoting sodium reabsorption in the proximal tubule and (through aldosterone) the collecting duct. In AD animal models, the cerebroventricular infusion of Ang II into aged normal rats increased both tau pathology and amyloid precursor protein (APP) levels, leading to an increase in amyloid-β (Aβ) accumulation. It was also shown that Ang (1-7) expression in the brain increased with disease progression and that there was an inverse correlation between Ang (1-7) level and tau hyperphosphorylation.

In AD model mice, Ang II not only impaired blood-brain barrier (BBB) function in the cerebral microcirculation but also induced inflammatory and thrombotic phenotypes. The binding of Ang II with AT1R damaged the BBB, leading to its leakage and the entry of circulating toxins into the brain. Additionally, AT2R and MasR promoted an M2 anti-inflammatory phenotype in microglia, which is a potential mechanism for alleviating neuronal dysfunction and inflammation and ultimately, for reversing cognition impairment. Based on the current evidence, we propose that the combination of Ang II and AT1R causes BBB leakage and activates microglia to secrete inflammatory factors that lead to apoptosis, neuronal injury, and neurodegeneration, resulting in the aggravation of AD; the activation of the AT2R/MasR axis produces the opposite physiological effect.

It remains unclear whether RAS imbalance in CKD is a cause of AD and vice versa. The following open questions warrant investigation in future studies: (1) Do CKD patients with AD have more severe imbalances in the RAS than those without AD? (2) What are the most significantly altered components of the RAS in CKD patients with AD, and are these components mainly proinflammatory (ACE/AT1R) or anti-inflammatory (ACE2/AT2R/MasR)? (3) Can the use of ACEI/ARB drugs prevent or delay the occurrence of AD? Answering these questions may provide insights that can guide the development of novel treatments for both diseases.

Loss of sensory hair cells in the inner ear, or loss of the connections between these cells and the brain, drive age-related hearing loss. Researchers here focus on the contribution of mitochondrial dysfunction to this condition, alongside the decline of autophagy in older individuals, leading to poor quality control of mitochondria and consequent loss of function. Many pharmacological approaches exist or are under development to improve autophagy to a degree similar to that resulting from structured exercise programs, but compelling evidence for significantly greater improvements are so far lacking. We can reasonably debate whether or not mTOR inhibitors will represent a meaningful step beyond exercise in humans, when it comes to improved autophagy, but even there the size of the effect is not that much greater in the best case.

Hearing loss is mainly considered a sensory disorder in humans. Multiple factors contribute to the pathogenesis of sensorineural hearing loss (SNHL), such as noise exposure, ototoxic drugs, genetic mutations, aging, and chronic conditions. Histopathological changes of SNHL are characterized by mechanosensory hair cell damage, spiral ganglion neuron (SGN) loss, and stria vascularis atrophy. Emerging studies have suggested that mitochondrial DNA damage, reactive oxygen species (ROS) overproduction, and inflammatory mediators activation are associated with subsequent cochlear damage.

Mitochondria ROS could induce inflammasome activation that promotes various disease progression. Moreover, ROS could also induce cellular defense process such as autophagy, a cytoprotective mechanism that delivers damaged organelles to lysosomes for degradation. Current studies reveal autophagy exhibits an antioxidative capacity to protect against hair cell damage and possesses the potential to alleviate noise-induced hearing loss (NIHL). Autophagy not only clears up undesired proteins and damaged mitochondria (mitophagy), but also eliminate excessive ROS. Appropriate enhancement of autophagy can reduce oxidative stress, inhibit cell apoptosis, and protect auditory cells.

Link: https://doi.org/10.3389/fcell.2023.1119773

Researchers here manipulate levels of menin, a regulator of inflammation in the hypothalamus of mice. Menin expression in the hypothalamus diminishes with age, leading to increased inflammation. Upregulation of menin expression improves health and lifespan, while also improving cognitive function. One might take this as one of many examples of the chronic inflammation that is characteristic of later life being harmful to health and disruptive to tissue function. Given the complexity of regulatory systems in cells, there are many possible approaches to suppress chronic inflammation, but the challenge is to find an approach that only reduces the unwanted, excess inflammation, and doesn't sabotage the inflammatory responses necessary in wound healing and defense against pathogens.

The hypothalamus acts as the arbiter that orchestrates systemic aging through neuroinflammatory signaling. Our recent findings revealed that Menin plays important roles in neuroinflammation and brain development. Here, we found that the hypothalamic Menin signaling diminished in aged mice, which correlates with systemic aging and cognitive deficits. Restoring Menin expression in ventromedial nucleus of hypothalamus (VMH) of aged mice extended lifespan, improved learning and memory, and ameliorated aging biomarkers, while inhibiting Menin in VMH of middle-aged mice induced premature aging and accelerated cognitive decline.

We further found that Menin epigenetically regulates neuroinflammatory and metabolic pathways, including D-serine metabolism. Aging-associated Menin reduction led to impaired D-serine release by VMH-hippocampus neural circuit, while D-serine supplement rescued cognitive decline in aged mice. Collectively, VMH Menin serves as a key regulator of systemic aging and aging-related cognitive decline.

Link: https://doi.org/10.1371/journal.pbio.3002033

The biochemistry of the central nervous system is separated from the biochemistry of the rest of the body by the blood-brain barrier, a specialized lining of cells that wrap blood vessels that pass through the brain. Only some molecules and cells are permitted to pass into and out of the brain. Like all bodily systems, the blood-brain barrier breaks down with age, leading to leakage of unwanted molecules and cells into the brain, where they can provoke inflammation and dysfunction. This is thought to provide a significant contribution to the onset and further progression of age-related neurodegenerative conditions, given that blood-brain barrier failure appears somewhat in advance of other aspects of neurodegeneration in humans and animal models.

In today's open access paper, researchers review what is known of blood-brain barrier dysfunction specifically in the context of Alzheimer's disease. Relationships are observed between blood-brain barrier leakage and mechanisms involved in the production and aggregation of amyloid-β. Despite the failures of amyloid-β clearance to produce meaningful benefits in clinical trials, the build up of amyloid-β is still considered a core process in Alzheimer's disease, a foundational pathology that sets the stage for later, more severe pathology involving inflammation and tau aggregation leading to widespread cell death.

Reconsidering the role of blood-brain barrier in Alzheimer's disease: From delivery to target

The blood-brain barrier (BBB) is a dynamic interface that regulates the cellular communication between neural tissues and the blood and its constituents. It acts as a selective semipermeable barrier that controls the transport of substances to and from the central nervous system, serving as a key player in neural homeostasis. The blood is separated from central nervous system (CNS) by brain endothelial cells separated by tight junctions, adherens junctions, and gap junctions; pericytes; the foot processes of astrocytes, and the basement membrane composed of extracellular matrix components. Two main transport pathways occur within BBB: transcellular via endothelial cell used by the vast majority of the molecules which can be active (dependent on energy) or passive; and paracellular via passive diffusion through tight junctions.

The ubiquity and importance of BBB in CNS physiology also translate to how it is also impaired in almost every neurological condition. Such is the case of the most common cause of dementia, Alzheimer's disease (AD). AD affects more than 30 million people worldwide, a number that is expected to increase dramatically in the foreseeable future. To date, intracellular hyper-phosphorylated tau protein accumulation (neurofibrillary tangles) and extracellular amyloid-β (Aβ) deposition (senile plaques) in brain parenchyma is considered the central neuropathological hallmarks of the disease. However, pathogenesis is still not fully understood, and it is unclear whether these protein abnormalities are causative or rather incidental changes in the disease. Nevertheless, it is generally accepted that both proteins play a key role in disease pathogenesis with Aβ acting upstream of tau with other hypotheses building on and extending this to explain other aspects of the disease.

Aβ deposition seems to be a critical pathological trigger in AD and disruption of BBB leads to increased vascular permeability, allowing the entrance and/or hampering the clearance of toxic molecules that can trigger inflammatory and immune responses and, ultimately, neurodegeneration. One such pathologic protein whose normal clearance is dependent on a healthy BBB is the 42 amino acid Aβ peptide (Aβ42), considered the major toxic Aβ in AD. Not surprisingly, BBB dysfunction leads to Aβ deposition by disrupting its transporters. Moreover, there is experimental evidence that a disrupted BBB promotes its production from the amyloid precursor protein (APP) through the activation of the amyloidogenic pathway where APP is cleaved in sequence by β-secretase and γ-secretase.

Several studies have demonstrated BBB breakdown and dysregulation in AD. Whether it is a cause or consequence of the disease has been a matter of debate. Available evidence points to BBB breakdown as an early event preceding AD pathology. These findings have been supporting the vascular hypothesis of AD. First published in 1993 this hypothesis postulates that neurodegeneration is the consequence of a series of pathogenic pathways originating in blood vessels. More recently, others proposed the two-hit vascular hypothesis of AD. According to this hypothesis, impairment of blood vessels leads to BBB dysfunction and initiates a cascade of events leading to neuronal dysfunction (hit one). BBB dysfunction reduces Aβ clearance and increases its production inducing accumulation of this peptide, amplifying neuronal dysfunction, and accelerating neurodegeneration (hit two).

Blood-brain barrier has been emerging as a central hub for AD pathogenesis, presenting as a potential target to treat AD. Understanding its dysfunctional role in AD pathogenesis would be paramount for AD biology clarification and would probably give insights into other brain disorders. In this review, we will detail pathogenic and therapeutic links between AD and BBB offering a comprehensive and integrative view that includes the genetic landscape of AD and anticipates future research and treatment.

Chronic, unresolved, unprovoked inflammation is a feature of aging, a contributing cause of loss of tissue function and all of the common fatal age-related conditions. The biochemistry involved in the regulation of harmful age-related inflammatory signaling is complex, to say the least. There are many contributing causes, such as the signaling of senescent cells, the mislocalization of mitochondrial DNA resulting from mitochondrial dysfunction, and rising levels of other molecular debris from stressed and dying cells. How cells react in detail to inflammatory stimulation is far from fully understood. Researchers are interested in these mechanisms because it is possible that a better understanding might discover targets for intervention that can suppress only unwanted, excess inflammation.

The classic signs of acute inflammation are redness, heat, pain, swelling, and loss of function. Acute inflammation in the absence of infection can also promote wound regeneration or repair, depending on the severity of the tissue damage. In contrast, the chronic, sterile inflammation that results from repeated immune stimulation over time may be the result of the degeneration of a number of receptors that activate the innate immune system in elderly individuals.

A "generic" inflammatory pathway includes Inducers, Sensors, Mediators and Effectors. An example of this pathway in action would be the stimulation of Sensors, such as the Toll-Like Receptors (TLRs) present on macrophages or mast cells by a microbe (Inducer), leading to the production of cytokines (Mediator), which act on target tissues (Effectors) in order to promote the recruitment of pathogen-destroying cells to the affected area. These actions lead to the signs of inflammation through vasodilation, edema, and the presence of pain-promoting prostaglandins in the affected tissue.

Low-grade inflammation is often observed as part of aging. This phenomenon has been termed "inflammaging". In addition to a general decline in function during aging, the nature of the immune system also changes, in a phenomenon known as immunosenescence. This accounts for the reduced ability of the elderly to respond to antigens and correlates with increased susceptibility to infections. The co-ordination of the many processes that contribute to the effective control of the inflammatory response relating to aging is complicated, and the revelation of the mechanisms underlying this control has only recently begun.

It has been found that the production of the correct inflammatory mediator in a timely manner requires exquisite control at the transcriptional level. Importantly, all eukaryotic transcription takes place in the context of the nucleoprotein complex known as chromatin. In this review, we aim to emphasize the roles of chromatin regulation at the intersection between inflammation, aging, and metabolism to deepen our mechanistic understanding of inflammaging while we discuss the possibility of obtaining control over inflammaging and directions for further studies.

Link: https://doi.org/10.3390/ijms221910274

It is hypothesized that degeneration of neuromuscular junctions is an important contributing cause of the characteristic loss of muscle mass and strength that takes place with age, leading to sarcopenia. Researchers here use a gene therapy to upregulate expression of a gene involved in neuromuscular junction maintenance, and find that it improves muscle function in old mice. The paper includes a fairly detailed discussion of the biochemistry involved, and the researchers consider this an approach that works through similar mechanisms to those involved in the effects of exercise.

Sarcopenia is progressive loss of muscle mass and strength, occurring during normal aging with significant consequences on the quality of life for elderly. Neurotrophin 3 (NT-3) is an important autocrine factor supporting Schwann cell survival and differentiation and stimulating axon regeneration and myelination. NT-3 is involved in the maintenance of neuromuscular junction (NMJ) integrity, restoration of impaired radial growth of muscle fibers through activation of the Akt/mTOR pathway.

We tested the efficacy of NT-3 gene transfer therapy in wild type (WT)-aged C57BL/6 mice, a model for natural aging and sarcopenia. In this study, we used a triple muscle-specific creatine kinase (tMCK) promoter to restrict NT-3 expression to the skeletal muscle and self-complimentary adeno-associated virus serotype 1 (scAAV1) as vector. The treatment efficacy was assessed at 6 months post-injection using run to exhaustion and rotarod tests, in vivo muscle contractility assay, and histopathological studies of the peripheral nervous system, including NMJ connectivity and muscle.

NT-3 gene therapy in WT-aged C57BL/6 mice resulted in functional and in vivo muscle physiology improvements, supported by quantitative histology from muscle, peripheral nerves, and NMJ. Hindlimb and forelimb muscles in the untreated cohort showed the presence of a muscle- and sex-dependent remodeling and fiber size decrease with aging, which was normalized toward values obtained from 10 months old WT mice with treatment. Considering the cost and quality of life to the individual, we believe our study has important implications for management of age-related sarcopenia.

Link: https://doi.org/10.18632/aging.204577

Senescent cells accumulate throughout the body with advancing age. Somatic cells become senescent on reaching the Hayflick limit constantly throughout life, then quickly self-destruct or are destroyed by the immune system. As the immune system ages, however, it becomes less able to remove senescent cells in a timely fashion, and their numbers grow. Senescent cells are prolific generators of inflammatory signaling, and this activity is a major contribution to the chronic, unresolved inflammation that characterizes aged tissues. This inflammation is disruptive to tissue structure and function, changing cell behavior for the worse.

Many age-related diseases are characterized by inflammatory signaling and its detrimental effects. Periodontitis, inflammatory gum disease, can occur at any age given sufficient inattention to oral hygiene, but it is more prevalent in older people. One might expect this to be the case, given the increased inflammatory signaling present in an aged body. We might also ask whether the activities of senescent cells are involved in the pathology of gum disease, and in today's open access paper, researchers provide evidence to suggest that this is in fact the case.

Cellular senescence with SASP in periodontal ligament cells triggers inflammation in aging periodontal tissue

Periodontitis is a chronic inflammatory disease characterized by periodontal tissue destruction with loss of tooth-supportive bone. It is thought to be the most common infectious disease and affects more than 40% of people aged over 30 years. Colonization of dental biofilm involving periodontopathic bacteria triggers inflammation and excessive immune responses that exacerbate breakdown of periodontal tissue. In addition to bactericidal pathogens, various environmental factors affect the pathology and progression of periodontal disease. In particular, aging has been recognized as a major risk factor that affects the onset and severity of periodontitis. Thus, understanding the biological mechanisms that regulate periodontal tissue and health by aging is an urgent issue to establish preventive protocols or specialized therapies for elderly persons in the field of periodontal medicine.

Cellular senescence is a major hallmark of senescence in organs and the whole body. Accumulated senescent cells in aged organs and tissues induce senescence of the body. A large number of studies have indicated that senescent cells secrete various proteins such as proinflammatory cytokines, chemokines, growth factors, and metalloproteinases, termed SASP (senescence-associated secretory phenotype). Therefore, understanding cellular senescence is required to develop more effective therapies and prevention protocols for age-dependent, lifestyle-related diseases. However, whether and how cell types within periodontal tissue undergo cellular senescence with SASP have not yet been clarified.

Recently, it has become evident that cellular senescence is a cause of chronic diseases through production of the SASP. In this study, we examined the pathological roles of cellular senescence in periodontitis. We found localization of senescent cells in periodontal tissue, particularly the periodontal ligament (PDL), in aged mice. Senescent human PDL (HPDL) cells showed irreversible cell cycle arrest and SASP-like phenotypes in vitro. Additionally, we observed age-dependent upregulation of miR-34a in HPDL cells. These results suggest that chronic periodontitis is mediated by senescent PDL cells that exacerbate inflammation and destruction of periodontal tissues through production of SASP proteins. Thus, miR-34a and senescent PDL cells might be promising therapeutic targets for periodontitis in elderly people.

In a recent interview, George Church offers opinions on partial reprogramming as an approach to rejuvenation. In the last few years this has moved from popular topic to becoming a sizable fraction of the longevity industry, given the large-scale funding that is now devoted to partial reprogramming groups. Short-term exposure to the Yamanaka factors can be used to reset the epigenetic patterns of a cell in old tissue to be more like those of a cell in young tissue, with corresponding gains in function. There are potentially serious issues to be worked out, such as how to eliminate the possibility of cancer due to the few cells that might fully reprogram into pluripotency in a short time, but this is nonetheless an exciting area of medical science that is now heavily funded. We should expect to see significant progress in the years ahead.

Do we understand how cellular reprogramming improves health and longevity?

There have been two major camps in aging since long ago. One says that aging happens due to damage, to proteins, lipids, RNA, and DNA, and that you have to go in there with your repair kit and fix it as a therapist. The other camp says that it's all epigenetic, and that if you convince the cell that it's young, it will get its own toolkit out and start repairing as much as it can. Some things are beyond repair. If you delete all copies of a tumor suppressor, that's not something a young cell can repair. But most things are fixable with epigenetics - at least, that's how the second hypothesis goes.

I believe in a hybrid model. I think most of the work can be done epigenetically. A surprising amount of it can be done via the bloodstream, but probably not all of it. Then, there's a residual amount that you can fix with the Yamanaka factors and another residual amount that you can fix by restoring genes. Since we do the epigenetic reprogramming by adding in genes, it's not that fundamental a difference between adding in genes that will go into the blood, adding genes that will reprogram the nucleus, and adding genes that are missing, like tumor suppressors. In a certain sense, they are all addressable by multiplex gene therapy. That's why being able to either use multiple rounds of dosing or to have bigger vectors will become increasingly important.

Given the rising popularity of partial reprogramming, what is its overall place in the longevity landscape?

I think there are subtle but important differences between anti-aging drugs and drugs that improve biomarkers in the way that statins improve cholesterol. That doesn't mean such drugs increase longevity, just that they improve this one biochemical. It could actually hurt you; for instance, it could improve cardiovascular chances for some subset of the population, but for another subset, it could hasten muscle pain. So, affecting biomarkers is one thing. Reversing diseases of aging is different. You could do it just by addressing that particular disease, or you could do it more broadly, affecting multiple diseases. You might get FDA approval for one of them, but it's actually affecting multiple ones, and maybe acting preventatively. Say, there might be a cure for muscle wasting that helps prevent a variety of diseases. Finally, you're really at the core of aging when you reprogram shared elements - with good feedback systems that already exist in the body or with feedback systems that you introduce as part of the therapy.

Are you bullish about longevity biotech?

I think the whole field is very healthy economically and scientifically. We have passed through multiple "valleys of death". We're now in the solid science phase, and this field is going to be very impactful, maybe more impactful than any other pharmaceuticals in history, including even antibiotics, because our very ability to fight off diseases is age-related. Almost every single form of human morbidity and mortality has an age-related component to it. If you want to have a pleiotropic effect on many different diseases, this is the way to go.

Link: https://www.lifespan.io/news/prof-george-church-on-cellular-reprogramming-and-longevity/

The end of life is not pretty. The body is a failing machine of many complex essential parts, and the failures cascade and feed into one another as it breaks down. There is pain, loss of capacity, loss of the self as the brain runs down. There is a tendency to paper over the ugly reality in public discussion, to not talk about the facts of the matter, even when we all know people who have suffered a slow and painful decline. That the slow progression towards death by aging is an ugly reality, a horrible experience in its final stages, just adds to the reasons why far more effort should go towards the development of rejuvenation therapies capable of preventing the age-related failure of our bodies and brains.

The prevalence of heart failure is increasing in aging populations. Furthermore, dementia is more prevalent in patients with heart failure. Dementia is detected 10 years earlier in patients with heart failure in Asian countries, particularly low-income countries, than in Western countries. Heart failure and dementia share similar cardiovascular risk factors, such as age, hypertension, diabetes, dyslipidemia, and increased arterial stiffness, which explains their overlap in elderly patients.

In a large database of patients with heart failure (mean age 75.3 years), 11.0% developed dementia during an average follow-up period of 4.1 years. Heart failure patients with dementia were at a 4.5-fold higher risk of all-cause mortality, 5.4-fold higher risk of cardiovascular death, and 3.8-fold higher risk of noncardiovascular death. An analysis of a longitudinal dataset indicated a causal relationship between decreased cardiac function and cognitive decline.

Heart failure patients with dementia often have sarcopenia and cachexia. Nutritional changes caused by hypoperfusion and edema in skeletal muscles, the intestines, and visceral organs may contribute to the risk of cardiovascular and noncardiovascular mortality. Autonomic nerve dysregulation has been detected in some patients with dementia, particularly those with Lewy body disease. Elderly patients with heart failure are also more susceptible to infections owing to a decreased lymphocyte count.

Heart failure patients that develop dementia enter a vicious cycle of heart failure, dementia, malnutrition, sarcopenia, and cachexia, which is associated with an increased risk of all-cause mortality. Therefore, the prevention of cognitive decline is important in elderly patients with heart failure.

Link: https://doi.org/10.1016/j.jacasi.2022.10.009

Use of senolytics to clear a sizable fraction of senescent cells in the tissues of aged mice results in a reversal of many aspects of aging, including muscle aging. Muscle tissue provides a good example of the present state of play regarding the detailed understanding of senescent cells in specific tissues, in that it remains challenging to definitively identify the senescent populations in muscle. This is particularly the case following injury, when a transient, short-lived population of senescent cells are expected to arise to aid in the regenerative process, but common markers such as senescence-associated β-galactosidase are shared with the innate immune cells that also participate in regeneration.

In older individuals, the lingering senescent cells present prior to injury, and the reduced ability of the immune system to rapidly remove senescent cells created in response to injury, once their job is done, results in impaired wound healing. Senolytic drugs can improve this situation, and it seems more than clear that there is enough evidence to run clinical trials targeting frailty, non-healing wounds, and to improve healing in the elderly. The present regulatory system makes it harder to proceed in absence of a complete mechanistic understanding of the processes taking place in response to therapy, however. Thus given the demonstrated effectiveness of senolytic therapies in animal studies, there is considerable interest in better understanding exactly what is going on. Given progress on that front, expect to see a sizable expansion of senolytic research and development programs beyond those already underway.

Senolytics improve muscle adaptation in old mice

Recently, our lab and others have utilized senolytics to examine the contribution of senescent cells to impaired muscle adaptability with age, including regeneration following injury and the anabolic response to mechanical overload, as well as any potential role in sarcopenia. There is little evidence that senescent cells are present in aged muscle causing sarcopenia, but they appear to contribute to the impaired ability of muscle to adapt to exogenous stimuli. Even so, systemic deletion of senescent cells improves physical function and has been implicated in slowing sarcopenia. This apparent disconnect between a lack of senescent cells in muscle and improvements in age-associated conditions could be due to various technical or biological reasons.

Work from our lab shows that seven days following muscle injury, there are approximately 250 times more senescence-associated β-galactosidase positive (SA β-Gal+) cells in injured muscle compared to uninjured in both young and old mice. In young mice, these numbers return close to baseline after 28 days, however, the senescent cell burden remains elevated in old mice. Treating mice with a senolytic cocktail of dasatinib and quercetin (D+Q) lowers the senescence burden in old mice, while subsequently reducing the inflammatory profile of the muscle and improving the regenerative response.

β-Gal+ cells appear to transition to senescence in muscle from old mice, developing a senescence-associated secretory phenotype (SASP) relative to cells isolated from young mice 14 days post injury. Some of these findings were recently confirmed by other researchers, who show a greater abundance of senescent cells early in the regenerative process that is reduced over time and greater in old versus young mice. They also show a reduction in senescent cell abundance in response to D+Q treatment following injury, associated with improved regeneration and improvements in muscle force production.

It is important to note that our work shows young mice treated with D+Q display an attenuated regenerative response, whereas others shows an improvement in the regenerative response of young mice as early as 7 days post injury. Considering senescence has been shown to be required for the full regenerative response in skeletal muscle, the large overlap in phenotype between β-Gal+ non-senescent macrophages and bona fide senescent cells likely contributes to the confusion and warrants further investigation.

In a model of muscle hypertrophy, old mice display a blunted hypertrophic response relative to young mice, which is accompanied by a greater senescent cell burden. Treatment with D+Q improves the hypertrophic response in old mice, in addition to lowering the abundance of senescent cells. In this model, we did not observe any change in many of the SASP genes, although genes that are crucial for extracellular matrix reorganization, along with genes that negatively regulate myostatin, were elevated. In summary, senolytics effectively lower the protracted senescent cell burden that accompanies a regenerative or hypertrophic stimulus in muscle from aged mice, resulting in increased muscle fiber size.

The lingering senescent cells characteristic of old tissues contribute to the pathology of osteoathritis via their constant disruptive inflammatory signaling, the senescence-associated secretory phenotype (SASP). Researchers recently reported that the use of antioxidant ceria nanoparticles can reduce the SASP in joint tissue, acting on important regulators that control the generation of the SASP. In this context, it is worth noting that both human and animal evidence suggests that local clearance of senescent cells or local inhibition of SASP in the joint is not sufficient to turn back osteoathritis. Senescent cells elsewhere in the body may be more distant, but there are a lot more of them, and they all generate pro-inflammatory signaling that impacts the joint environment.

Accumulation of senescent cells is the prominent risk factor for osteoarthritis (OA), accelerating the progression of OA through a senescence-associated secretory phenotype (SASP). Recent studies emphasized the existence of senescent synoviocytes in OA and the therapeutic effect of removing senescent synoviocytes. Ceria nanoparticles (CeNP) have exhibited therapeutic effects in multiple age-related diseases due to their unique capability of reactive oxygen species (ROS) scavenging. However, the role of CeNP in OA remains unknown.

Our results revealed that CeNP could inhibit the expression of senescence and SASP biomarkers in multiple passaged and hydrogen-peroxide-treated synoviocytes by removing ROS. In vivo, the concentration of ROS in the synovial tissue was remarkably suppressed after the intra-articular injection of CeNP. Likewise, CeNP reduced the expression of senescence and SASP biomarkers as determined by immunohistochemistry analysis. The mechanistic study showed that CeNP inactivated the NFκB pathway in senescent synoviocytes. Finally, safranin O-fast green staining showed milder destruction of articular cartilage in the CeNP-treated group compared with the OA group.

Overall, our study suggested that CeNP attenuated senescence and protected cartilage from degeneration via scavenging ROS and inactivating the NFκB signaling pathway. This study has potentially significant implications in the field of OA as it provides a novel strategy for OA treatment.

Link: https://doi.org/10.3390/ijms24055056

The signaling produced by transplanted mesenchymal stem cells is well known to reduce the chronic inflammation that accompanies aging. This is a temporary effect, as the transplanted cells near all die rather than engraft, but it can lead to lasting improvement should the respite allow tissues to better maintain themselves for a time. Chronic inflammation is highly disruptive to tissue function, and drives the onset and progression of many age-related conditions. It is thus an important target for interventions aiming to reduce the burden of aging. Here, researchers show that mesenchymal stem cell therapy can improve neurogenesis and cognitive function in old mice, a good example of the way in which inflammation is relevant to degenerative aging.

Age-related decline in cognitive functions is associated with reduced hippocampal neurogenesis caused by changes in the systemic inflammatory milieu. Mesenchymal stem cells (MSC) are known for their immunomodulatory properties. Accordingly, MSC are a leading candidate for cell therapy and can be applied to alleviate inflammatory diseases as well as aging frailty via systemic delivery.

Akin to immune cells, MSC can also polarize into pro-inflammatory MSC (MSC1) and anti-inflammatory MSC (MSC2) following activation of Toll-like receptor 4 (TLR4) and TLR3, respectively. In the present study, we apply pituitary adenylate cyclase-activating peptide (PACAP) to polarize bone-marrow-derived MSC towards an MSC2 phenotype. Indeed, we found that polarized anti-inflammatory MSC were able to reduce the plasma levels of aging related chemokines in aged mice (18-months old) and increased hippocampal neurogenesis following systemic administration.

Similarly, aged mice treated with polarized MSC displayed improved cognitive function in the Morris water maze and Y-maze assays compared with vehicle- and naïve-MSC-treated mice. Changes in neurogenesis and Y-maze performance were negatively and significantly correlated with sICAM, CCL2, and CCL12 serum levels. We conclude that polarized PACAP-treated MSC present anti-inflammatory properties that can mitigate age-related changes in the systemic inflammatory milieu and, as a result, ameliorate age related cognitive decline.

Link: https://doi.org/10.3390/ijms24054490

Somatic mosaicism arises from random mutational damage to stem cells and progenitor cells. Daughter somatic cells resulting from mutated cells also bear these mutations, and so a pattern of differently mutated somatic cell populations spreads throughout a tissue over years and decades. This is thought to be a mechanism by which nuclear DNA damage can give rise to some meaningful degree of dysfunction beyond cancer risk. Otherwise, one must accept that near all mutations (a) affect few cells, as somatic cells are limited in their ability to replicate, and (b) occur in cells that will be destroyed on some timescale, as they hit the Hayflick limit. Further, the vast majority of somatic cell mutations occur in unused areas of DNA, and should not change cell behavior via altered or missing proteins.

Recently, researchers have suggested that some forms of nuclear DNA damage cause characteristic age-related changes in gene expression regardless of where they occur and whether they are successfully repaired, which may turn out to be the more important issue deriving from DNA damage. With regard to changes that do affect cell function and then spread from stem cells into a sizable fraction of cells in a tissue, evidence is sparse when it comes to clear connections between this somatic mosaicism and specific issues in aging, however. That said, clonal hematopoiesis of indeterminate potential (CHIP) is a form of somatic mosaicism specific to the immune system, and one of the few types of somatic mosaicism for which data does exists to link the process to detrimental consequences in later life. Thus researchers are interested in expanding this foothold, to better determine when CHIP can be problematic versus benign.

Defining clonal hematopoiesis of indeterminate potential: evolutionary dynamics and detection under aging and inflammation

Clonal hematopoiesis (CH), where hematopoietic stem and progenitor cell (HSPC) clones and their progeny expand in the circulating blood cell population, occurs following the acquisition of somatic driver mutations. Individuals diagnosed with clonal hematopoiesis of indeterminate potential (CHIP) carry somatic mutations in hematological malignancy-associated driver genes, historically at or above a variant allele frequency of 2%, but do not exhibit abnormal blood cell counts or any other symptoms of hematologic disease. However, CHIP is associated with moderately increased risk of hematological cancer, and a greater likelihood of cardiovascular disease and pulmonary disease.

Recent advances in the resolution of high-throughput sequencing experiments suggest CHIP is much more prevalent in the population than once thought, particularly among those aged 60 and over. While CHIP does elevate the risk of eventual hematological malignancy, only one in ten individuals with CHIP will receive such a diagnosis; the problem lies in the continued difficulty in accurately separating the 10% of CHIP patients who are most likely to be in a pre-malignant state from those who are not, given the heterogeneity of this condition and the etiology of the associated hematological cancers. Concerns over the risk of eventual malignancies must be balanced with growing recognition of CH as common age-dependent occurrence, and efforts to better characterize and differentiate oncogenic clonal expansion from that which is much more benign.

In this review, we discuss evolutionary dynamics of CH and CHIP, the relationship of CH to aging and inflammation, and the role of the epigenome in promoting potentially pathogenic or benign cellular trajectories. We outline molecular mechanisms that may contribute to heterogeneity in the etiology of CHIP and incidence of malignant disease among individuals. Finally, we discuss epigenetic markers and modifications for CHIP detection and monitoring with potential for translational applications and clinical utility in the near future.

One of the more important reasons not to carry excess fat tissue is that it becomes ever more inflammatory with age, particularly visceral fat. Chronic, unresolved inflammation is a feature of aging that accelerates the onset and progress of all of the common fatal age-related conditions. To the degree that excess fat tissue contributes to this inflammation, one might argue that it is accelerating aging. The contribution of fat to this form of immune system dysfunction is a two-way street, as noted here. In part, the contribution of fat to inflammation becomes worse with age because of harmful changes in the immune system itself.

Adipose tissue is essential for age-related dysfunction such as metabolic diseases, while aging can also generate multiple effects on adipose tissue, including redistribution of deposits and composition, adipose tissue plasticity reduction, senescent cell accumulation and inflammaging. Among them, adipose tissue inflammation is the most important. This chronic inflammation is usually promoted by senescent cell/dead cell accumulation, adipocyte hypertrophy, free fatty acids (FFAs) and lipopolysaccharide (LPS), and immune cell dysregulation.

Various cellular and molecular mechanisms regulate adipose tissue inflammaging. Immune cells are recruited to adipose tissue by different chemokines, and undergo tremendous changes in both their numbers and characteristics during aging. Proinflammatory signaling pathways, including the JAK/STAT, Wnt/β-catenin, NF-κB, and MAPK signaling pathways, control the process of adipose tissue inflammaging in different way. Indeed, Increased inflammaging in aging impacts adipose tissue, leading to adipose tissue dysfunction and ectopic lipid accumulation, further impacting the overall health status.

Systemic diseases, such as type II diabetes, cardiovascular disease, and cancer, are somewhat caused by adipose tissue inflammation. Since adipose tissue inflammaging plays pivotal roles, emerging anti-aging interventions have recently been developed targeting adipose tissue. In this review, we summarize the latest approaches that can extend healthy lifespan and delay the onset of age-related diseases including caloric restriction, senotherapeutics, immune therapies, and other strategies targeting adipose tissue inflammaging related signaling pathways. Further research may need to focus on whether suppressing the inflammatory response in adipose tissue can reverse the senescent phenotype, an approach that may identify new targets to relieve aging-associated complications.

Link: https://doi.org/10.3389/fimmu.2023.1125395

It has been a few years since researchers suggested a role for senescent cells in mediating the damage done by excess fat tissue in the context of type 2 diabetes. Senescent cells accumulate with age, but accumulate significantly faster in people who are meaningfully overweight or obese. The inflammatory signaling produced by lingering senescent cells is disruptive of tissue structure and function throughout the body, and that includes problems in the insulin-generating regions of the pancreas that take place in diabetes patients. Interestingly, senescent cells may also be important in type 1 diabetes, a completely different path to pathology, but perhaps all roads involve cellular senescence in this condition.

Over the past decade, clinical trials have reported the efficacy of drugs that target cellular senescence and their potential use in the treatment of age-related chronic diseases, such as type 2 diabetes mellitus (T2DM). When normal cells are subjected to severe DNA damage, they either die by apoptosis or undergo irreversible cell proliferation arrest by induction of cellular senescence. These biological defense mechanisms prevent the proliferation of abnormal cells that have suffered DNA damage. Cellular senescence is the state in which cells irreversibly stop proliferating while retaining their metabolic activity and can be induced by external stressors such as aging, obesity, and radiation due to DNA damage, telomere shortening, and mitochondrial dysfunction.

A unique characteristic of senescent cells is the secretion of senescence-associated secretory phenotype (SASP), which induces chronic inflammation through the secretion of inflammatory proteins. The SASP has been involved in the pathogenesis of several age-related diseases, including cancer. Chronic insulin exposure, which occurs in T2DM, has been shown to cause senescence in hepatocytes, pancreatic β-cells, and adipose tissue. Hyperglycemia, pathognomonic of T2DM, can also contribute to senescence through several pathways, and animal studies have shown that removal of senescent cells improves blood glucose levels and decreases diabetic complications.

However, at least two barriers need to be overcome before these therapies can be translated to the clinic: (1) differences between senescent cells in different tissues are unknown, and (2) the specific effects of removing senescent cells in each organ remain to be determined. Therefore, this review focuses on the mechanisms of cellular senescence and its SASP in four key organs for the regulation of blood glucose levels: pancreas, liver, skeletal muscle, and adipocytes, and summarizes ongoing efforts to therapeutically target cellular senescence in them.

Link: https://doi.org/10.4093/dmj.2022.0416

Insulin metabolism is one of the better studied areas of biochemistry in connection with aging, and one of the earliest areas of focus for the aging research community. Dysfunction of insulin metabolism, meaning loss of insulin sensitivity, is characteristic of obesity and the slide into type 2 diabetes, and the manifestations of diabetes in some ways resemble accelerated aging. While one should not consider high levels of a single form of dysfunction to be accelerated aging, since normal aging is a specific mix of various forms of damage and dysfunction, it can be worth bearing in mind that there are mechanistic overlaps between diseases and aging.

In today's open access paper, researchers connect insulin sensitivity with better function of the innate immune cells known as macrophages. Better insulin sensitivity ensures that macrophages change their behavior to be more ready to clear molecular waste and damaged cells from tissues, while suppressing inflammatory signaling. The researchers suggest that this could be enough to explain the link between insulin metabolism and life expectancy. Since insulin metabolism touches on near every other aspect of cellular behavior, that is a challenging hypothesis to prove, but it is something to think on. The function and inflammatory state of the immune system is clearly important in aging.

Enhanced insulin-regulated phagocytic activities support extreme health span and longevity in multiple populations

The immune system plays a central role in many processes of age-related non-communicable diseases such as cardiovascular diseases, type 2 diabetes, and dementia. Activated immune functions, which frequently describe as inflammation, has been recognized as part of their pathophysiologies. However, accumulating evidence challenges this assumption and suggests that the immune system may instead get mounting adaptive responses to chronic stressors, prolonging the chances of survival of an organism. To address this argument, one possible way is to investigate the immune signatures in long-lived individuals (LLIs; mean age of greater than 95 years old) and centenarians, the "aging champions" who achieved successful human aging and exhibited medical histories with remarkably low incidences of common age-related disorders. Since inflammaging and immunosenescence is a common feature of chronological aging in ordinary people contributing to enhances risks of mortality at advanced age; this proposes that a better functioning immune system, with stronger pro-survival and stress handling abilities, are likely at play in shaping extreme longevity.

The immune system can be schematically seen as two divisions. The ancestral/innate arm is mainly represented by monocytes, natural killer (NK) and dendritic cells (DC); whereas the adaptive arm is represented by the B lymphocytes and T lymphocytes. As if a functioning immune system requires a homeostatic balance between the two, gene expression profiles of circulating immune cells would likely reveal important clues that are crucial for achieving healthy aging. A recent single-cell transcriptomic study reported that expansion of cytotoxic CD4 T cells is a unique immune signature among supercentenarians; whereas previous bulk transcriptome studies proposed that shift in lymphocyte to myeloid cell ratio, enhanced autophagy-lysosomal function; reduction in ribosomal biosynthesis, or upregulated apoptotic Bcl-xL is however crucial to successful aging. It remains unclear if any common immune features unique to extreme longevity exist among LLIs regardless to their origins; and whether the associated molecular signatures can provide insights for practical translations.

By harnessing the wealth of single-cell and bulk transcriptome datasets available in the public repositories; we uncovered that significant induction of innate immune monocytes with enhanced lysosomal and phagocytic activity is a previously unrecognized, common, and unique immune signature among LLIs from various geographical origins and ethnicities. The life cycle of these monocytes in LLIs is enhanced and primed to a M2-like macrophage phenotype. Monocytes are the major immune cells that express insulin receptor (INSR). Functional characterization revealed an insulin-signaling centric immunometabolism network which supports multiple aspects of phagocytosis. Such reprogramming is associated to a skewed trend of DNA demethylation, particularly at the promoter regions of multiple phagocytic genes, so as a direct transcriptional effect induced by the nuclear INSR. Together, these findings highlighted that preservation of insulin sensitivity hence an active innate monocyte-driven phagocytic activity is a defense mechanism in safeguarding healthy lifespan and extended longevity.

Alzheimer's disease, and other forms of neurodegenerative condition, are characterized by chronic inflammation in brain tissue. Unresolved inflammatory signaling is disruptive of tissue structure and function. Here, researchers provide evidence for T cells to become involved in this process. Normally T cells of the adaptive immune system do not enter the brain in any great numbers, but those numbers are greater in Alzheimer's patients. Researchers here show that eliminating these T cells slows the progression of neurodegeneration in animal models, suggesting that this approach may be worth trying in human clinical trials.

Many of the immunity-focused Alzheimer's drugs under development are aimed at microglia, the brain's resident immune cells, which can injure brain tissue if they're activated at the wrong time or in the wrong way. A new study indicates that microglia partner with another type of immune cell - T cells - to cause neurodegeneration. Studying mice with Alzheimer's-like damage in their brains due to the protein tau, the researchers discovered that microglia attract powerful cell-killing T cells into the brain, and that most of the neurodegeneration could be avoided by blocking the T cells' entry or activation. The findings suggest that targeting T cells is an alternative route to preventing neurodegeneration and treating Alzheimer's disease and related diseases involving tau, collectively known as tauopathies.

"This could really change the way we think about developing treatments for Alzheimer's disease and related conditions. Before this study, we knew that T cells were increased in the brains of people with Alzheimer's disease and other tauopathies, but we didn't know for sure that they caused neurodegeneration. These findings open up exciting new therapeutic approaches. Some widely used drugs target T cells. Fingolomid, for example, is commonly used to treat multiple sclerosis, which is an autoimmune disease of the brain and spinal cord. It's likely that some drugs that act on T cells could be moved into clinical trials for Alzheimer's disease and other tauopathies if these drugs are protective in animal models."

Link: https://medicine.wustl.edu/news/discovery-of-t-cells-role-in-alzheimers-and-related-diseases-suggests-new-treatment-strategy/

Researchers here show that reprogramming of mesenchymal cells present in wounded skin produces a population of epithelial progenitor cells that induce the creation of new hair follicles and sweat glands during the healing process. Mammalian skin does not normally regenerate these features, an issue that many research groups have sought to address. This is an interesting advance, to be added to some of the other approaches that are claimed to more completely regenerate injured skin.

Mammalian skin appendages, such as hair follicles and sweat glands, are complex mini-organs formed during skin development. As wounds heal, the resulting scar tissue lacks skin appendages. The clinical regeneration of skin appendages is an ongoing challenge. Skin epithelial tissues have been regenerated in vivo by cellular reprogramming, but the de novo generation of skin appendages has not previously been achieved.

Here, we show that transplantation of a type of epithelial cell and two types of mesenchymal cells, reprogrammed from adult mouse subcutaneous mesenchymal cells to mimic developing skin cells, resulted in the generation of skin-appendage-like structures. After recent advances in cellular reprogramming we have developed a method to generate skin epithelial tissues by in vivo reprogramming of wound-resident mesenchymal cells with four transcription factors (DNP63A, GRHL2, TFAP2A, and cMYC), resulting in cells with the ability to form stratified epithelia.

With the development of a new AAV serotype, in vivo reprogramming of wound-resident cells with the same reprogramming factors generates skin with de novo appendages in adult mice. These findings may provide new therapeutic avenues for skin regeneration and frequent aging-associated skin appendage disorders, such as hair loss and dry skin, and may extend to other tissues and organs. This study also provides the potential for de novo generation of complex organs in vivo.

Link: https://doi.org/10.1101/2023.03.05.531138

Senolytic drugs are those that selectively force senescent cells into programmed cell death. Senescent cells accumulate with age throughout the body, and their pro-inflammatory signaling is disruptive to tissue structure and function when maintained over the long term. Clearance of senescent cells has produced sizable, rapid reversal of age-related disease and improvement in health in mice. There are numerous classes of senolytic small molecule drugs, each class attacking the biochemistry of senescent cells from a different direction in order to force programmed cell death. The well-studied senolytic drug dasatinib is a tyrosine kinase inhibitor, and there is evidence for another tyrosine kinase inhibitor, nintedanib, to also be senolytic.

Today's open access paper concerns ongoing clinical trials of masinitib, another tyrosine kinase inhibitor, as a treatment for Alzheimer's disease. Cellular senescence in brain cells, particularly the supporting cells of the brain such as astrocytes and microglia, is implicated in the progression of Alzheimer's disease. The use of tyrosine kinase inhibitors in this context predates a growing understanding of their relevance to cellular senescence in aging, and so the paper here focuses reducing inflammatory activation of brain cells rather than putting this in terms of cellular senescence. It is unclear as to whether masinitib is in fact senolytic, but it would not be that surprising to find that it is. It is also worth noting that the dasatinib and quercetin senolytic combination is presently in early trials to treat Alzheimer's disease.

Masitinib for mild-to-moderate Alzheimer's disease: results from a randomized, placebo-controlled, phase 3, clinical trial

Masitinib is an oral tyrosine kinase inhibitor that has demonstrated neuroprotective action in neurodegenerative diseases via inhibition of mast cell and microglia/macrophage activity, and which is capable of accumulating within the central nervous system (CNS) at a therapeutically relevant concentration. There is a growing body of evidence implicating mast cells and microglia (types of innate immune cells that are present in the central nervous system), with the pathophysiology of Alzheimer's disease (AD). Masitinib has been shown to restore normal spatial learning performance and promote recovery of synaptic markers in a mouse model of AD, with its synapto-protective action being directly linked to mast cell inhibition. Previously, a small phase 2 trial showed that masitinib slows progression in mild-to-moderate AD patients. Here, we report findings from the first large randomized trial targeting activated neuroimmune cells for treatment of mild-to-moderate AD.

Masitinib was administered as an adjunct therapy to standard of care in 182 patients with mild to moderate dementia due to probable AD. After 24 weeks of treatment, masitinib (4.5 mg/kg/day) significantly slowed cognitive deterioration (as measured by the primary endpoint of ADAS-cog), with acceptable safety. Masitinib (4.5 mg/kg/day) showed significant benefit over placebo according to the primary endpoint of ADAS-cog, -1.46 (representing an overall improvement in cognition) versus 0.69 (representing increased cognitive deterioration), respectively, with a significant between-group difference of -2.15. For the ADCS-ADL primary endpoint, the between-group difference was 1.82, i.e. 1.01 (representing an overall functional improvement) versus -0.81 (representing increased functional deterioration), respectively. Safety was consistent with masitinib's known profile (maculo-papular rash, neutropenia, hypoalbuminemia).

Multiple approved drug treatments and dosages for AD have demonstrated a similar change in ADAS-Cog (approximately 2-point) to that reported for masitinib (4.5 mg/kg/day) and this value is also consistent with published recommendations. The observed improvement in ADAS-Cog for masitinib (4.5 mg/kg/day) relative to control is therefore clinically meaningful. Conversely, results from the masitinib 6.0 mg/kg/day parallel group did not demonstrate any treatment effect. One explanation of this divergent result is that the 6.0 mg/kg/day parallel group placebo arm showed an atypical improvement over 24 weeks, as exemplified by the positive change from baseline in ADCS-ADL score

Retro Biosciences is one of the better funded ventures focused on the treatment of aging to have emerged from the Bay Area centered science, advocacy, and venture communities. The story of how Retro Biosciences came to exist is illustrative of that community, and the way in which a strong interest in human longevity on the part of a few high net worth individuals has shifted in its focus over the past decade. Interested parties have expanded their activities from philanthropic funding of research, initially the only viable approach to make progress, to the addition of much larger investments in startup companies, growing as the biotechnology of treating aging advanced to the point at which it became possible to generate an industry around it.

When a startup called Retro Biosciences led by Joe Betts-LaCroix eased out of stealth mode in mid-2022, it announced it had secured $180 million to bankroll an audacious mission: to add 10 years to the average human life span. It had set up its headquarters in a raw warehouse space near San Francisco just the year before, bolting shipping containers to the concrete floor to quickly make lab space for the scientists who had been enticed to join the company. The entire sum was put up by Sam Altman, the 37-year-old startup guru and investor who is CEO of OpenAI. He says he's emptied his bank account to fund two other very different but equally ambitious goals: limitless energy and extended life span.

Altman's investment in Retro is among the largest ever by an individual into a startup pursuing human longevity. Altman has long been a prominent figure in the Silicon Valley scene, where he previously ran the startup incubator Y Combinator in San Francisco. Altman says he has been placing bets in areas where underlying trends make him think technologies that look impossible today might actually work relatively soon.

About eight years ago, Altman became interested in so-called "young blood" research. These were studies in which scientists sewed young and old mice together so that they shared one blood system. The surprise: the old mice seemed to be partly rejuvenated. In 2018, Y Combinator launched a special course for biotech companies, inviting those with "radical anti-aging schemes" to apply, but before long, Altman moved away from Y Combinator to focus on his growing role at OpenAI.

Then, in 2020, researchers in California showed they could achieve an effect similar to young blood by replacing the plasma of old mice with salt water and albumin. "Sam called me up and said 'Holy moly, did you see this plasma intervention paper?'" recalls Betts-LaCroix, who had once been the part-time biotech partner at Y Combinator and still leads a meetup for longevity enthusiasts. Betts-LaCroix agreed that it was cool and some company should pursue it. "How about I fund you to do it?" Altman said. But Betts-LaCroix was already working on a different longevity-related idea, cellular reprogramming. Altman's response: "Why don't you do all those things?" Betts-LaCroix recalls saying. "I'll do it. I'll build a multi-program company around aging biology, and that is the big play. He was like, 'Great - let's go for it.'"

Link: https://www.technologyreview.com/2023/03/08/1069523/sam-altman-investment-180-million-retro-biosciences-longevity-death/

Researchers here note an approach to extending life by 50% in nematode worms that functions by lowering levels of glycerol and glyceraldehyde in tissues. Lower animals such as nematodes have a far greater plasticity of life span in response to interventions than is the case for mammals. Thus this research is worth taking note of, a suggestion that this area of metabolism is worthy of more attention, but implementing something similar in mammalian species should not be expected to do more than modestly slow aging.

Glycerol and glyceraldehyde are harmful by-products of fat that naturally accumulate over time. Prior aging research in worms, mice, and human cells made researchers in the field suspect that the key to extending lifespan was to activate autophagy, a process that renews broken and old parts in our cells. But researchers were surprised to find that wasn't necessary - the scientists improved worm health and lifespan by 50% with no increase in autophagy at all. They did this by increasing expression a particular gene, adh-1. Doing so prompted the gene to produce more of an enzyme, alcohol dehydrogenase, that prevented the toxicity caused by glycerol and, indirectly, glyceraldehyde. The result was that the worms lived longer, healthier lives.

Findings in lab models such as worms and mice don't always hold true in people, of course. So the researchers took several more steps to see if their lead was as promising as it appeared. First, they confirmed that the enzyme had similar beneficial effects on lifespan in another lab model, yeast. Then they scoured through research looking at gene activity in creatures, including humans, who had undergone fasting or calorie restriction because both fasting and calorie restriction are known to extend healthspan and lifespan. Sure enough, the scientists found increased levels of the anti-aging enzymes in all the mammals tested, including in humans.

The scientists suspect that our levels of glycerol and glyceraldehyde naturally increase over time because they are toxic byproducts of fat, which we store more of as we age. Thus, this approach may offer a way to head off the fat-derived toxicity, extend the number of years we live in good health, and maybe help us shed some extra pounds, too.

Link: https://www.eurekalert.org/news-releases/982125

Molecular waste builds up in the lysosomes of long-lived cells such as neurons, and in cells like microglia that ingest extracellular debris in order to clear it from the brain. Lysosomes are the destination for all cellular waste, where materials are broken down to be recycled. While lysosomes are capable of breaking down near every type of biological molecule that they will encounter, some persistent metabolic byproducts pose a problem. Old tissues are characterized by the presence of what is known as lipofuscin, a toxic mix of the various forms of metabolic waste that the lysosome struggles with. When lysosomes become packed with this waste, cells suffer, as the quality control and clearance processes required for optimal function falter.

In today's research materials, scientists provide evidence for lipofuscin in microglia, the innate immune cells of the brain, to be problematic. This presence of lipofuscin increases with age, and appears to meaningfully contribute to the observed age-related dysfunctions of these cells. Relatedly, activation and inflammatory signaling of microglia is implicated in the onset and progression of neurodegenerative conditions. When researchers clear microglia from the brain, there are improvements - this has been demonstrated numerous times in recent years. Since all microglia are cleared, however, it is hard to claim that benefits result from removal of lipofuscin-bearing microglia versus other subpopulations of these cells.

Fresh understanding of ageing in the brain offers hope for treating neurological diseases

"As the brain ages, fat molecules, cholesterol crystals, metals, and misfolded proteins build up inside autofluorescent microglia, which increase their autofluorescence as a result. Unfortunately, this accumulation of cellular debris also makes it harder for the microglia to perform their essential garbage collection tasks in the brain and to prevent neurological injury and neurodegenerative disease."

"In this study we found - in aged animals - that these microglia adopt a unique, dysfunctional state, which has a number of problematic impacts. For example, there is an increase in cellular stress and damage, an accumulation of fats and iron, alterations to metabolic processes and an increase in production of molecules that overstimulate the immune response. Increasing evidence now suggests that the accumulation of autofluorescent microglia contributes to diseases of ageing and neurodegeneration. If these sub-populations of microglia are highly inflammatory and damaging to the brain, then targeting them could be a new strategy for treating aging-related diseases."

Brain injury accelerates the onset of a reversible age-related microglial phenotype associated with inflammatory neurodegeneration

Lipofuscin is an autofluorescent (AF) pigment formed by lipids and misfolded proteins, which accumulates in postmitotic cells with advanced age. Here, we immunophenotyped microglia in the brain of old C57BL/6 mice (older than 18 months) and demonstrate that in comparison to young mice, one-third of old microglia are AF, characterized by profound changes in lipid and iron content, phagocytic activity, and oxidative stress. Pharmacological depletion of microglia in old mice eliminated the AF microglia following repopulation and reversed microglial dysfunction.

Age-related neurological deficits and neurodegeneration after traumatic brain injury (TBI) were attenuated in old mice lacking AF microglia. Furthermore, increased phagocytic activity, lysosomal burden, and lipid accumulation in microglia persisted for up to 1 year after TBI, were modified by APOE4 genotype, and chronically driven by phagocyte-mediated oxidative stress. Thus, AF may reflect a pathological state in aging microglia associated with increased phagocytosis of neurons and myelin and inflammatory neurodegeneration that can be further accelerated by TBI.

Novel immunotherapies for Alzheimer's disease have in recent years finally succeeded in clearing toxic extracellular amyloid-β aggregates from the brain in human clinical trials. Nonetheless, this advance has failed to meaningfully improve patient outcomes. This outcome has led to renewed theorizing on the mechanisms of Alzheimer's disease, in search of an explanation as to how amyloid-β can be so clearly associated with the condition, but fail as a target for therapy.

Some researchers focus on chronic inflammation as the primary mechanism of disease progression, seeing amyloid-β aggregation as a side-effect at best, while others suggest that amyloid-β is critically important, but inside cells rather than outside cells. Here, researchers discuss a possible role for age-related dysfunctions in the cellular maintenance process of autophagy, specifically focusing on the capability of lysosomes to break down the molecular waste that accumulates within them. Impaired autophagy and accumulation of waste in the lysosome harms cells, and is suggested to produce amyloid-β aggregation outside cells as a side-effect of those harms.

The amyloid precursor protein (APP) is infamous for its putatively critical role in the pathogenesis of Alzheimer's disease (AD). However a recent study found that autolysosome acidification declines in neurons with advancing age more than 4 months before amyloid β-protein (Aβ) is deposited extracellularly. Endolysosome de-acidification increases intraneuronal and secreted levels of Aβ. On the other hand, autolysosome acidification increases the degradation of accumulated Aβ in autophagic vacuoles and promotes glial clearance of oligomeric amyloid-β. Therefore, autolysosome acidification declines directly result in Aβ aggregation.

APP accumulates selectively within enlarged and de-acidified lysosomes. In more compromised yet still intact neurons, profuse Aβ-positive autophagic vacuoles pack into large membrane tubules. Then lysosomal membrane permeabilization, cathepsin release, and lysosomal-mediated cell death occur, accompanied by microglial invasion. Thus, Aβ accumulation may be the "result" rather than the "cause". The finding prompts rethinking of the conventionally accepted sequence of AD plaque formation and may help explain the inefficiency of Aβ/amyloid vaccines and Aβ/amyloid-targeted therapies.

Link: https://doi.org/10.3389/fnagi.2023.1130658

Researchers here find that both reduced phosphate in the diet and use of a phosphate binding drug slow age-related loss of muscle mass in mice. It is an interesting result given the size of the effect. It has been proposed that high levels of phosphates observed in later life are relatively important in the constellation of many contributing mechanisms implicated in the onset of sarcopenia, the name given to this characteristic decline of muscle mass and strength. The data noted here seems a compelling demonstration of the point.

Sarcopenia is defined by the progressive and generalized loss of muscle mass and function associated with aging. We have previously proposed that aging-related hyperphosphataemia is linked with the appearance of sarcopenia signs. Because there are not effective treatments to prevent sarcopenia, except for resistance exercise, we propose here to analyse whether the dietary restriction of phosphate could be a useful strategy to improve muscle function and structure in an animal model of aging.

Five-month-old (young), 24-month-old (old) and 28-month-old (geriatric) male C57BL6 mice were used. Old and geriatric mice were divided into two groups, one fed with a standard diet (0.6% phosphate) and the other fed with a low-phosphate (low-P) diet (0.2% phosphate) for 3 or 7 months, respectively. A phosphate binder, Velphoro, was also supplemented in a group of old mice, mixed with a standard milled diet for 3 months.

Old mice fed with low-P diet showed reduced serum phosphate concentration (16.46 ± 0.77 mg/dL young; 21.24 ± 0.95 mg/dL old; 17.46 ± 0.82 mg/dL low-P diet). Old mice fed with low-P diet displayed 44% more mass in gastrocnemius muscles with respect to old mice. NMRI revealed a significant reduction in T2 relaxation time and increased magnetization transfer and mean diffusivity in low-P diet-treated mice compared with their age-matched controls. The low-phosphate diet increased the fibre size and reduced the fibrotic area by 52% in gastrocnemius muscle with respect to old mice. Twitch force and tetanic force were significantly increased in old mice fed with the low phosphate diet. Physical performance was also improved, increasing gait speed by 30% and reducing transition time in the static rod by 55%. Similar results were found when diet was supplemented with Velphoro.

Link: https://doi.org/10.1002/jcsm.13194

You might recall that in 2011, researchers observed a five year gain in life expectancy versus the general population in a study of 121 older people with osteoporosis who were treated with bisphosphonates. This is a large effect size, at the upper end of what is typically observed in studies of exercise and physical fitness. Other, larger trials have observed reduced mortality with bisphosphonate treatment. A modest degree of effort has gone into attempting to understand the mechanisms that might be involved.

One possible candidate mechanism is the clearance of senescent cells and suppression of the harmful inflammatory signaling produced by lingering senescent cells present in old tissues. Selective destruction of senescent cells via senolytic drugs has been shown to produce impressive degrees of rejuvenation in aged mice. With this in mind, in today's open access paper researchers demonstrate that the bisphosphonate drug zoledronate is in fact either senolytic to a meaningful degree, or acts in other ways to reduce the generation of inflammatory signaling by senescent cells. This is quite interesting.

In vitro and in vivo effects of zoledronate on senescence and senescence-associated secretory phenotype markers

In addition to reducing fracture risk, zoledronate has been found in some studies to decrease mortality in humans and extend lifespan and healthspan in animals. Because senescent cells accumulate with aging and contribute to multiple co-morbidities, the non-skeletal actions of zoledronate could be due to senolytic (killing of senescent cells) or senomorphic (inhibition of the secretion of the senescence-associated secretory phenotype [SASP]) actions.

To test this, we first performed in vitro senescence assays using human lung fibroblasts and DNA repair-deficient mouse embryonic fibroblasts, which demonstrated that zoledronate killed senescent cells with minimal effects on non-senescent cells. Next, in aged mice treated with zoledronate or vehicle for 8 weeks, zoledronate significantly reduced circulating SASP factors, including CCL7, IL-1β, TNFRSF1A, and TGFβ1 and improved grip strength. Analysis of publicly available RNAseq data from CD115+ pre-osteoclastic cells isolated from mice treated with zoledronate demonstrated a significant downregulation of senescence/SASP genes. To establish that these cells are potential senolytic/senomorphic targets of zoledronate, we used single cell proteomic analysis and demonstrated that zoledronate significantly reduced the number of pre-osteoclastic cells and decreased protein levels of p16, p21, and SASP markers in these cells without affecting other immune cell populations.

Collectively, our findings demonstrate that zoledronate has senolytic effects in vitro and modulates senescence/SASP biomarkers in vivo. These data point to the need for additional studies testing zoledronate and/or other bisphosphonate derivatives for senotherapeutic efficacy.

The brain-resident innate immune cells known as microglia are thought to play an important part in the age-related decline of cognitive function, and rising dysfunction in brain tissue. In the broader population of microglia in mice and humans, an increase in inflammatory behavior is observed, and likely a major cause of issues in the aging brain. Here, however, researchers focus on a subpopulation of microglia in the fly brain called ensheathing glia that become dysfunctional and decline in number with age. These cells act as a sheath for axons, and thus their loss is understandably problematic. Preventing this loss is shown here to improve brain function and longevity in aging flies. Whether analogous processes are important in the equivalent mammalian microglial cells remains to be determined.

Glia have an emergent role in brain aging and disease. In the Drosophila melanogaster brain, ensheathing glia function as phagocytic cells and respond to acute neuronal damage, analogous to mammalian microglia. We previously reported changes in glia composition over the life of ants and fruit flies, including a decline in the relative proportion of ensheathing glia with time. How these changes influence brain health and life expectancy is unknown.

Here, we show that ensheathing glia but not astrocytes decrease in number during Drosophila melanogaster brain aging. The remaining ensheathing glia display dysregulated expression of genes involved in lipid metabolism and apoptosis, which may lead to lipid droplet accumulation, cellular dysfunction, and death. Inhibition of apoptosis rescued the decline of ensheathing glia with age, improved the neuromotor performance of aged flies, and extended lifespan. Furthermore, an expanded ensheathing glia population prevented amyloid-beta accumulation in a fly model of Alzheimer's disease and delayed the premature death of the diseased animals. These findings suggest that ensheathing glia play a vital role in regulating brain health and animal longevity.

Link: https://doi.org/10.1111/acel.13803

Aspects of the sense of smell are some of the earlier casualties of central nervous system aging. Assessments of age-related olfactory dysfunction can provide some insight into the road to neurodegenerative conditions, as the same underlying mechanisms are at work. Researchers here assessed different aspects of olfaction in aging mice, finding that odor discrimination is first loss. Given the data provided to show that upregulation of NAD+ can slow this loss, we might think that mitochondrial dysfunction is an important contributing mechanism in this form of neurodegeneration.

Olfactory dysfunction is a prevalent symptom and an early marker of age-related neurodegenerative diseases in humans, including Alzheimer's and Parkinson's diseases. However, as olfactory dysfunction is also a common symptom of normal aging, it is important to identify associated behavioral and mechanistic changes that underlie olfactory dysfunction in nonpathological aging. In the present study, we systematically investigated age-related behavioral changes in four specific domains of olfaction and the molecular basis in C57BL/6J mice.

Our results showed that selective loss of odor discrimination was the earliest smelling behavioral change with aging, followed by a decline in odor sensitivity and detection while odor habituation remained in old mice. Compared to behavioral changes related with cognitive and motor functions, smelling loss was among the earliest biomarkers of aging. During aging, metabolites related with oxidative stress, osmolytes, and infection became dysregulated in the olfactory bulb, and G protein coupled receptor-related signaling was significantly down regulated in olfactory bulbs of aged mice. Poly ADP-ribosylation levels, protein expression of DNA damage markers, and inflammation increased significantly in the olfactory bulb of older mice.

Lower NAD+ levels were also detected. Supplementation of NAD+ through nicotinamide riboside in water improved longevity and partially enhanced olfaction in aged mice. Our studies provide mechanistic and biological insights into the olfaction decline during aging and highlight the role of NAD+ for preserving smelling function and general health.

Link: https://doi.org/10.1111/acel.13793

Today's research materials describe a clever approach to cancer immunotherapy, focused on the goal of enabling the immune system to better identify cancerous cells. In the past, researchers have made some inroads in training the immune system to attack specific target molecules characteristic of cancerous cells, but this is a slow and expensive process when progressing from single target to single target. Further, any given cancer might be capable of evolving to function without exhibiting any one specific target molecule, and only some cancers of a particular type will exhibit that specific signature molecule to start with.

How might one dramatically improve on the number of targets presented to the immune system? Here, researchers report on reprogramming cancer cells into antigen presenting cells, such as macrophages. Antigen presenting cells, as the name suggests, inform T cells of the adaptive immune system as to targets that they might engage. A macrophage normally ingests potential antigens, fragments them, and then presents the fragments as a part of its distinctive cell surface. These converted cancer cells contain all of the characteristic biochemistry of the cancer, but also act as macrophages, fragmenting and displaying those molecules to educate the adaptive immune system as to the full range of targets it might use to identify and kill the other cells of that cancer.

Scientists transform cancer cells into weapons against cancer

Some of the most promising cancer treatments use the patient's own immune system to attack the cancer, often by taking the brakes off immune responses to cancer or by teaching the immune system to recognize and attack the cancer more vigorously. A better approach would be to train T cells to recognize cancer via processes that more closely mimic the way things naturally occur in the body - like the way a vaccine teaches the immune system to recognize pathogens. T cells learn to recognize pathogens because special antigen presenting cells (APCs) gather pieces of the pathogen and show them to the T cells in a way that tells the T cells, "Here is what the pathogen looks like - go get it."

Something similar in cancer would be for APCs to gather up the many antigens that characterize a cancer cell. That way, instead of T cells being programmed to attack one or a few antigens, they are trained to recognize many cancer antigens and are more likely to wage a multipronged attack on the cancer. Now that researchers have become adept at transforming one kind of cell into another, researchers had a hunch that if they turned cancer cells into a type of APC called macrophages, they would be naturally adept at teaching T cells what to attack.

In the current study, the researchers programmed mouse leukemia cells so that some of them could be induced to transform themselves into APCs. When they tested their cancer vaccine strategy on the mouse immune system, the mice successfully cleared the cancer. Other experiments showed that the cells created from cancer cells were indeed acting as antigen-presenting cells that sensitized T cells to the cancer. "What's more, we showed that the immune system remembered what these cells taught them. When we reintroduced cancer to these mice over 100 days after the initial tumor inoculation, they still had a strong immunological response that protected them."

Reprogramming Cancer into Antigen Presenting Cells as a Novel Immunotherapy

Therapeutic cancer vaccination seeks to elicit activation of tumor-reactive T cells capable of recognizing tumor-associated antigens (TAAs) and eradicating malignant cells. Here, we present a cancer vaccination approach utilizing myeloid lineage reprogramming to directly convert cancer cells into tumor reprogrammed-antigen presenting cells (TR-APCs). Using syngeneic murine leukemia models, we demonstrate that TR-APCs acquire both myeloid phenotype and function, process and present endogenous TAAs, and potently stimulate TAA-specific CD4+ and CD8+ T cells.

In vivo TR-APC induction elicits clonal expansion of cancer-specific T cells, establishes cancer-specific immune memory, and ultimately promotes leukemia eradication. We further show that both hematologic cancers and solid tumors, including sarcomas and carcinomas, are amenable to myeloid-lineage reprogramming into TR-APCs. Finally, we demonstrate the clinical applicability of this approach by generating TR-APCs from primary clinical specimens and stimulating autologous patient-derived T cells. Thus, TR-APCs represent a cancer vaccination therapeutic strategy with broad implications for clinical immuno-oncology.

As a companion piece to a recent article questioning whether transcriptional noise actually exists as envisaged, this review paper covers what is known and unknown in this part of the field. Transcriptional noise is random variation in the first stage of gene expression, and it is thought to increase with age. It seems likely to be a consequence of the broad variety of changes and dysfunctions that occur in cellular biochemistry in old tissues, an accompaniment to faltering quality control of protein synthesis and altered epigenetics. While easily defined at the high level, transcriptional noise is challenging to measure in a defensible way, and hence there is a good deal of debate over quite fundamental questions relating to this topic.

Increasing stochasticity is a key feature in the aging process. At the molecular level, in addition to genome instability, a well-recognized hallmark of aging, cell-to-cell variation in gene expression was first identified in mouse hearts. With the technological breakthrough in single-cell RNA sequencing, most studies performed in recent years have demonstrated a positive correlation between cell-to-cell variation and age in human pancreatic cells, as well as mouse lymphocytes, lung cells, and muscle stem cells during senescence in vitro. This phenomenon is known as the "transcriptional noise" of aging.

In addition to the increasing evidence in experimental observations, progress also has been made to better define transcriptional noise. Traditionally, transcriptional noise is measured using simple statistical measurements, such as the coefficient of variation, Fano factor, and correlation coefficient. Recently, multiple novel methods have been proposed, e.g., global coordination level analysis, to define transcriptional noise based on network analysis of gene-to-gene coordination. However, remaining challenges include a limited number of wet-lab observations, technical noise in single-cell RNA sequencing, and the lack of a standard and/or optimal data analytical measurement of transcriptional noise. Here, we review the recent technological progress, current knowledge, and challenges to better understand transcriptional noise in aging.

Link: https://doi.org/10.3390/ijms24043701

Atherosclerosis is a condition of macrophage dysfunction. Macrophages are responsible for clearing the excess and oxidized cholesterol that finds its way into blood vessel walls, but they falter at this task with advancing age. In part this is due to the inflammatory environment, which induces changes in the behavior of macrophages, tipping the balance of activities away from repair and towards further amplication of inflammatory signaling. The research noted here demonstrates the relevance of chronic inflammation to the progression of atherosclerosis in a population of patients on statins, looking at risk of subsequent cardiovascular mortality based on inflammatory status.

Once a patient is on statin therapy, cardiologists typically describe two conditions: "residual cholesterol risk" which can be further reduced with additional lipid-lowering therapy, and "residual inflammatory risk" which can be further reduced with certain drugs that impact vascular inflammation. Whether clinicians should choose to focus on further lowering cholesterol or inflammation has been uncertain and controversial.

Researchers examined data from three recently conducted clinical trials (PROMINENT, REDUCE-IT and STRENGTH) of patients with or at high risk for atherosclerotic disease to understand the relative importance of "residual inflammatory risk" as compared to "residual cholesterol risk" among contemporary statin-treated patients. All patients were receiving aggressive guideline directed medical care including statins, usually at high doses. But cardiovascular event rates in all three trials approached 10 percent at five years. In all three trials, blood levels of high-sensitivity C-reactive protein (hs-CRP, a measure of vascular inflammation) were significantly associated with major adverse cardiovascular events (MACE), cardiovascular mortality, and all-cause mortality.

Moreover, the researchers report that hs-CRP was a more potent predictor of future cardiovascular risk than LDL-cholesterol. For example, among aggressively treated patients already on higher intensity statins, the risks of cardiovascular death and all-cause mortality were more than twice as high among those with the highest levels of CRP when compared to those with the highest levels of cholesterol, differences that were highly statistically significant. Treatments that aggressively lower vascular inflammation need to be incorporated into daily practice if doctors are to maximize patient outcomes.

Link: https://www.eurekalert.org/news-releases/981794

In order to function correctly, proteins must form a specific folded structure after assembly from amino acids in a ribosome. This folding doesn't always work as it should, and there is naturally some rate of error for processes taking place in the crowded, organized chaos of a cell interior. Protein misfolding leads to non-functional, sometimes toxic molecules. In the worst case scenario, with only a handful of proteins in the body being capable of this, a misfolded protein can encourage other molecules of the same protein to also misfold, and join into solid aggregates. Beyond this, a given error rate in folding across all proteins produced by a cell puts stress on that cell, and is addressed by a variety of quality control and housekeeping mechanisms that flag and recycle such mistakes when they occur.

To what degree is the burden of misfolded proteins an important mechanism of aging? The handful of well-known misfolded proteins that can spread from cell to cell and form solid aggregates, such as amyloid-β and α-synuclein, are a characteristic feature and likely important contributing cause of age-related neurodegenerative conditions. But beyond these few types of protein, is there a background of diverse misfolded proteins that builds up with age to cause broad cellular dysfunction, particularly in long-lived cells such as neurons? In today's open access paper, researchers argue that this is likely the case, based on data from a range of species. They identify a few hundred different proteins in which the presence of misfolded molecules appears to increase with age.

Extensive accumulation of misfolded protein aggregates during natural aging and senescence

The biological activity of cells and organisms depends on the proper function of many different proteins involved in key cellular signaling pathways. To remain biologically active, proteins need to preserve their native three-dimensional structure and solubility. Any alterations to these parameters challenge their ability to perform their normal biological function, with devastating consequences for the cell and the organism. Previously reported evidence showed a transition to insolubility of several proteins during aging in different models. Interestingly, many of these proteins are predicted to have high propensity to misfold and aggregate, similarly to protein misfolding disorders (PMDs). Based on these observations, we hypothesized that during aging several different proteins undergo progressive misfolding and aggregation to form structures similar to those found in age-related PMDs, causing widespread and chronic cellular dysfunction, which is the hallmark feature of aging.

In this study, we report the extensive and progressive accumulation of misfolded proteins during natural aging/senescence in different models, in the absence of disease. We coined the term age-ggregates to refer to this subset of proteins. Our findings demonstrate that age-ggregates exhibit the main characteristics of misfolded protein aggregates implicated in PMDs, including insolubility in detergents, protease-resistance, and staining with dyes specific for misfolded aggregates. Misfolded protein aggregates with these characteristics are thought to be implicated in some of today most prevalent diseases, including Alzheimer's disease and related forms of dementia, Parkinson's disease, Amyotrophic Lateral Sclerosis, type 2 diabetes, and even cancer. The strongest risk factor for all these diseases is aging, supporting our concept that advanced age is associated with increased accumulation of misfolded protein aggregates.

We found intracellular age-ggregation in the aged brain, where misfolded proteins are sequestered into aggresomes. Aggresomes have been studied in the context of neurodegenerative diseases, where they act as a general defense mechanism against high levels of accumulation of toxic misfolded proteins. Our results indicate that the aged brain contains relatively large amounts of misfolded species, whose soluble versions participate in cellular pathways that play fundamental roles in preserving basic functions, such as protein quality control, synapsis, and metabolism. By comparison with PMD, it is likely that the aging-associated misfolded protein will be non-functional or acquire a toxic activity. Therefore, we speculate that age-related protein misfolding may play a key role in the decline of those processes. Alternatively, the formation of misfolded aggregates might be a consequence of a dysfunctional proteasomal and other degradation pathways. The reproducibility of our results using various different techniques, methodologies, and model systems (invertebrates, cellular models, and rodents) indicate that protein misfolding during aging is not a stochastic phenomenon, but rather that a specific subset of proteins are prone to misfold with age.

It seems there is ever more enthusiasm for regenerating the thymus these days, which is welcome. A number of companies are out there pursuing widely divergent scientific programs to achieve this goal, at varying stages of progress towards the clinic. At some point, someone will figure out an optimal path past the various challenges presented by the location and biology of the thymus to produce a large regrowth of this organ in older individuals. The company noted here, Thymmune Therapeutics, is taking the cell therapy approach, which I think to be one of the more viable options, given that a few cell types have been shown to home to the thymus. Still, they are not initially focused on aging, which will likely slow any application to aging of the specific approach that they choose to pursue.

The thymus gland is a small organ tucked beneath the breastbone. Its primary function is to produce T cells, which help the body ward off infections and diseases and mount an immune response to vaccines. The thymus grows weaker with age and is less capable of producing naïve T cells, leading to immune dysfunction and various chronic conditions.

Thymmune Therapeutics debuted recently with $7 million in seed financing. Thymmune aims to reverse thymic atrophy by combining machine learning with cellular engineering to mass produce thymic cells derived from induced pluripotent stem cells. With this approach, the start-up intends to create off-the-shelf cell therapies that can restore immune function minimally invasively.

The small team will first test their platform against athymia, a rare and congenital immune disorder wherein an infant is born without a thymus. Babies with athymia cannot produce T cells and are at a high risk of infection. Left untreated, athymic infants typically die by age two or three. The company is also looking at testing its platform to treat several autoimmune diseases and address organ transplant tolerance. In the future, Thymmune's platform could also boost immune function and address the biology of aging.

Link: https://www.biospace.com/article/george-church-backed-thymmune-launches-to-target-overlooked-organ/

Stem cells spend much of their time quiescent, only intermittently activating to produce daughter somatic cells. Some well studied populations of stem cells are known to become increasingly quiescent with age, a response to some mix of internal damage and altered signaling environment that arises due to chronic inflammation and other age-related issues. Researchers here report on a way to force neural stem cells back into greater activity, increasing the pace at which new neurons are generated. Since this process of neurogenesis declines with age, contributing to loss of cognitive function, there is considerable interest in finding ways to increase neurogenesis in the aged brain.

Cellular metabolism is important for adult neural stem/progenitor cell (NSPC) behavior. However, its role in the transition from quiescence to proliferation is not fully understood. We here show that the mitochondrial pyruvate carrier (MPC) plays a crucial and unexpected part in this process. MPC transports pyruvate into mitochondria, linking cytosolic glycolysis to mitochondrial tricarboxylic acid cycle and oxidative phosphorylation. Despite its metabolic key function, the role of MPC in NSPCs has not been addressed.

We show that quiescent NSPCs have an active mitochondrial metabolism and express high levels of MPC. Pharmacological MPC inhibition increases aspartate and triggers NSPC activation. Furthermore, genetic Mpc1 ablation in vitro and in vivo also activates NSPCs, which differentiate into mature neurons, leading to overall increased hippocampal neurogenesis in adult and aged mice. These findings highlight the importance of metabolism for NSPC regulation and identify an important pathway through which mitochondrial pyruvate import controls NSPC quiescence and activation.

Link: https://doi.org/10.1126/sciadv.add5220

Proteins are made up of amino acids. It is known that reducing only protein in the diet, while maintaining the same calorie intake, produces a modest slowing of aging. Some of the beneficial effects of reduced calorie intake, such as upregulation of autophagy and improved cell maintenance, are triggered by sensing protein levels rather than other components of diet. The sensor mechanisms are more specific than simply protein as a whole, however, and can be triggered by reducing levels of individual essential amino acids, meaning amino acids that are required for protein synthesis in cells, but must be consumed because they are not manufactured in the body. A good deal of work has gone into assessing the effects of lower levels of the essential amino acid methionine in the diet, for example, finding that this captures a sizable fraction of the benefits of reduced calorie intake.

In today's open access paper, researchers compare overall protein restriction (all dietary amino acids) with restriction of only the essential amino acid isoleucine, in both cases maintaining an overall calorie intake equivalent to that of a non-restricted diet. Old mice are given these different diets, and the researchers present a great deal of data on the outcomes. Restriction in older individuals doesn't help with muscle loss and frailty, which is interesting given that long-term calorie restriction does slow the progression of age-related loss of muscle mass and strength. Restricting only isoleucine produces greater benefits by some metrics, but doesn't reduce cellular senescence in tissues, unlike protein restriction. Overall, it is an interesting data set, though as ever we should remember that evidence strongly suggests that calorie restriction and its equivalents are much less effective at extending life span in long-lived mammals than in short-lived mammals.

Restricting dietary protein or dietary isoleucine improves metabolic health in aged mice

An appealing alternative to reducing calories may be manipulating dietary macronutrients. Contrary to the conventional wisdom that calories from different sources are equivalent, a number of retrospective and prospective clinical trials have found that eating diets with lower levels of protein is associated with lower rates of age-related diseases including cancer and diabetes, and an overall reduction of mortality in those under age 55. While the effect of long-term protein restriction (PR) on human aging has not been tested in a randomized clinical trial (RCT), short-term RCTs in overweight or diabetic humans has found that protein restriction (PR) promotes metabolic health. Finally, PR diets have been repeatedly shown to increase the healthspan and lifespan of model organisms, including flies and rodents.

We and others have shown that much like calorie restriction (CR), restriction of specific nutrients, including total protein, the three branched-chain amino acids leucine, isoleucine, and valine, or isoleucine alone, can promote lifespan and metabolic health in animal models. While CR is less efficacious when starting in late life, the effects of interventions restricting amino acids in late life on healthy aging is unknown. Here, we investigate the metabolic, molecular, and physiological effects of consuming diets with a 67% reduction of either all amino acids (Low AA) or of isoleucine alone (Low Ile) in male and female C57BL/6J.Nia mice starting at 20 months of age.

We find that both diets reduce adiposity in aged mice; however, these diets decreased lean mass, and did not show significant improvements in frailty or fitness. The glucose tolerance of both male and female mice consuming Low Ile and Low AA diets were improved. We also observed a moderate increase in energy expenditure and respiratory exchange ratio induced by the two dietary interventions. In the hearts of aged female mice, Low Ile reversed age-associated changes in heart rate and stroke volume, returning cardiac function to similar levels as observed in young mice. We found that both Low AA and Low Ile diets promoted a more youthful molecular cardiac profile, preventing age-dependent increases in phosphatidylglycerols. These results demonstrate that Low AA and Low Ile diets can improve aspects of metabolic health in aged mice of both sexes, and has positive effects on cardiac health in aged females, suggesting that these dietary interventions are translationally promising for promoting healthy aging even in older people.

The review paper here might be compared with a very similar paper noted a few days ago. Any discussion of extracellular vesicles is essentially a discussion of cell signaling in general. Extracellular vesicles are membrane wrapped packages of signaling molecules that carry a sizable fraction of all of the varied signaling molecules that pass between cells. Cell signaling changes with age because cell behavior changes with age, and thus this is a vast topic, and hard to do more than touch on summary points in a single paper. It is perhaps the case that more attention is being given to extracellular vesicles these days because they can be harvested from cell cultures and used in therapies. This initially offers a logistically less complicated alternative to stem cell transplants, but potentially more interesting and more engineered therapies in the future.

Extracellular vesicles (EVs) are membrane-enclosed particles secreted by cells and circulating in body fluids. Initially considered as a tool to dispose of unnecessary material, they are now considered an additional method to transmit cell signals. EV alteration with aging suggests that the modulation of EV release, in terms of number and content, could represent a target to slow aging and for the therapy of age-related diseases.

First, the evaluation of EV features associated with aging (i.e., number, size, specific markers, genetic and/or biochemical content) could represent a possible biomarker of aging, useful to evaluate a variety of age-delaying therapeutic approaches. Second, the decrease of EVs number, via the removal of senescent cells which are known to release a higher number of EVs, could represent a rejuvenating tool associated with treatment with senolytic drugs. Third, the administration of EVs including key components showing anti-aging effects could be an effective rejuvenating strategy, potentially safer than the administration of whole cells.

Nonetheless, these studies are still preliminary and key issues have still to be elucidated. These challenges require further studies assessing the specific content of aging-associated EVs, as well as the development of methods and tools to produce EVs containing rejuvenating factors in a safe and abundant manner. In cell models, there is agreement that cell senescence is associated with an increased release of EVs, but the functional role of these EVs is less clear, as a few studies have reported pro-senescent and pro-apoptotic effects, whereas others have described a pro-tumorigenic role.

As for body fluid EVs, further studies are needed to assess whether aging is associated with an increased or decreased number of EVs, and the main biochemical features of EVs circulating in old versus young individuals, both in humans and in animal models, need to be further elucidated. Indeed, it must be considered that these samples are subjected to mechanical, chemical, and thermal stress during sampling and processing. This may notably change the shape, size, and composition of EVs in a manner that could be possibly influenced by age-related factors. However, there is converging evidence that EVs from young subjects have a rejuvenating effect and vice versa.

Link: https://doi.org/10.3390/cells12040527

Cyclarity is taking a fast path to the clinic for clearance of 7-ketocholesterol, a toxic altered form of cholesterol that contributes to the dysfunction of macrophage cells that lies at the root of atherosclerosis. To the degree that macrophage cells can be rescued from the local excess of cholesterol and altered cholesterol present in an atherosclerotic plaque, they will work to dismantle that plaque. The question is whether removing only 7-ketocholesterol will produce a bigger effect on established atherosclerotic plaque than the presently established approach of lowering LDL-cholesterol in the bloodstream. This is a low bar, as even greatly lowered LDL-cholesterol, while slowing the progression of the condition, actually does very little to reverse existing plaque.

Our lead drug candidate is a cyclodextrin that targets an oxidized cholesterol called 7-ketocholesterol that accumulates in various cells and tissues with age, and the main type of tissue that we are looking at is in the artery where, as I'm sure everyone knows, cholesterol is considered the bad guy that accumulates and causes plaque, the buildup inside of your arteries. What a lot of people don't know is that the most toxic and the most atherogenic is the oxidized cholesterol form. Atherosclerosis is the buildup of plaque inside of your arteries, which is formed by the accumulation of this oxidized cholesterol form. Additionally, unlike cholesterol, which you absolutely need to survive, you don't need any of this oxidized form. And so that's our target. Our lead drug candidate can go into cells and tissues and even penetrate plaque and grab onto that oxidized cholesterol, pull it out and then float away with it, so you can safely excrete it.

We studied all the cyclodextrins in the chemical catalog, and then we did all this computational modeling, and we figured out that the best way to grab onto our target was to dimerize it to basically take two cyclodextrin molecules, stick them together in the right configuration, and then modify it chemically in particular ways to give it the right shape in the binding cavity. Then what it does is, it grabs it and then it eats a single molecule of its target, a bit like Pac-Man, then wraps around it, and the inside cavity forms a shape around the target that fits it. It can then bind it with extremely high affinity and specificity and float away with the 7-ketocholesterol.

We're well into the process of preparing for clinical trials. We've brought on board a noted expert in developing cardiovascular drugs, and are building a team to plan, initiate, and run the clinical trials. Importantly, this is going to start in months, not years. We're going to start clinical trials in 2023, and.we're well along the path of getting ready for that. There's a certain number of things that you need to do with a drug candidate to be ready for that, and you can put them into two basic categories. First is safety testing your drug and the other is in the manufacturing process, and so we're in the final stages of doing the safety testing. Then we need to manufacture the actual version of the drug that will go into people. We're making several kilograms of the final drug product right now, and that's already begun. Then, all the data on both the manufacturing of the drug and the safety testing will be submitted to the regulatory body, at which point we ask for permission to initiate clinical trials.

Link: https://www.lifespan.io/news/ending-atherosclerosis-cyclarity-and-dr-matthew-oconnor/

A sizable portion of the chronic inflammation of aging is produced by the growing presence of senescent cells in tissues throughout the body. Senescent cells secrete a mix of pro-growth, pro-inflammatory signals (the senescence-associated secretory phenotype, SASP), useful when present in the short-term in the context of wound healing and suppression of cancer risk resulting from cell damage. When sustained over the long-term, however, this signaling becomes highly disruptive to tissue structure and function. The inflammatory mechanisms inside senescent cells that produce pro-inflammatory components of the SASP include the same mechanisms that operate in normal cells in response to inflammatory stimuli. It is therefore possible that targeted inhibition of regulatory genes and proteins could reduce the SASP.

Today's open access paper is one example of many lines of work that aim to understand how exactly the inflammatory component of the SASP arises. The authors identify the NLRP1 inflammasome as important, as inhibition diminishes the SASP. When it comes to new approaches to suppress inflammation, a great many groups are looking at inflammasomes in cells as a potential point of intervention. It is an open question as to whether this is going to be any better in practice than existing approaches (such as TNF inhibitors) that target important pro-inflammatory signal molecules. The problem with suppressing a target of this nature is that it disrupts desirable, short-term inflammation, needed for the normal immune response to operate, in addition to the undesirable chronic inflammation.

NLRP1 inflammasome modulates senescence and senescence-associated secretory phenotype

Aging generates specific changes associated with a process called cellular senescence. This permanent state of cell cycle arrest promotes tissue remodelling during development but leads to the declined tissue regenerative potential and function after injury, and activates inflammation and tumorigenesis in aged organisms. Senescence promotes the production of cytokines, chemokines, proteases, and growth factors some of which are known as senescence-associated secretory phenotype (SASP). Recent studies demonstrates that chromatin is instrumental in regulating SASP and inflammation through the innate immune cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) which can be activated upon DNA sensing.

Inflammasomes are intracellular protein complexes involved in almost all human aging-associated complications such as cancer, cardiovascular, metabolic, and neurodegenerative diseases through the production of interleukin-1β (IL-1β) and IL-18. These protein platforms comprise sensing proteins of the NOD-like receptor (NLR) family, the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC), and procaspase-1. Upon sensing of pathogen-associated molecular patterns (PAMPS) or damage-associated molecular patterns (DAMPS), some NLRs such as NLRP3 and NLRP1 to some extent associate with ASC, a response that leads to the recruitment and activation of the cysteine protease, caspase-1. Active caspase-1 cleaves pro-IL-1β, pro-IL-18, and GSDMD, thereby facilitating the secretion of IL-1β and IL-18 through plasma membrane pores formed by the N-terminal fragments of GSDMD. These pores can also release IL-1α and cause pyroptosis. Despite scientific advances in the biology of the NLRP1 and NLRP3 inflammasomes, the role that these proteins play in senescence remain controversial.

Irradiation of cells or tissues is a widely used model of stress-induced senescence, which we used to determine the role of the NLRP1 and NLRP3 inflammasomes in this process. We found that irradiation induced the expression of NLRP1, NLRP3, and SASP. Notably, inhibition of the NLRP1 inflammasome but not NLRP3 inflammasome attenuated the expression of senescence markers, responses that were GSDMD- and cGAS-dependent.

Targeted protein degradation is a term that covers a range of possible approaches to more selectively removing specific modified proteins from cells than has traditionally been possible. Researchers here provide an example of this type of work, targeting a modification of p38 in the context of Alzheimer's disease. This is a good illustration of the capabilities of this class of therapy, but probably not the best illustration of a good target: this still seems like a matter of messing with metabolism made dysfunctional by damage rather than targeting the underlying damage itself for repair.

Recent progress in the field of targeted protein degradation (TPD) has proven its immense potential as a novel therapeutic modality in drug discovery. In 2015, researchers devised a phthalimide-based small molecule that promotes degradation of transcriptional coactivator BRD4 by hijacking the Cereblon (CRBN) E3 ubiquitin ligase complex. In the same year, others also reported a TPD technology recruiting the von Hippel-Lindau (VHL) E3 ligase complex, commonly referred to as proteolysis-targeting chimeras (PROTACs). These technologies feature bifunctional small molecules that bring the proteins of interest into proximity with the E3 ubiquitin ligase complexes for ubiquitination and subsequent proteasomal degradation.

Such TPD-based small molecules have several advantages over traditional small molecule inhibitors in that they eliminate the target protein instead of modulating its function. TPD technology thus can complement nucleic acid-based gene knockdown in removing unwanted intracellular proteins. In addition, the TPD technique can target a plethora of proteins in various compartments of the cell, including disease-causing proteins that have previously been considered undruggable with the conventional small-molecule approach. Recently, several strategies have been suggested to potentiate therapeutic efficacy of TPD technology. In particular, TPD molecules that recognize and bind to the protein with specific post-translational modifications (PTMs), such as phosphorylation, may be a novel strategy to induce selective degradation of pathological proteins attributed to aberrant PTMs. However, a TPD molecule specifically targeting post-translationally modified proteins has not been reported yet.

It has been reported that phosphorylated p38 (p-p38) is significantly upregulated under pathological conditions, such as chronic inflammation, thus triggering downstream signal transduction and leading to pathological deterioration. P38 dysfunction has been implicated in a variety of medical disorders, such as neuroinflammation, ischemia, and cognitive impairment. Our previous study showed that enzymatic inhibition of p38 alleviated pathological symptoms of Alzheimer′s disease (AD), particularly neuroinflammation and accumulation of beta-amyloid (Aβ) and tau proteins. The therapeutic potential of inhibiting p38 in neurodegeneration has been investigated in several clinical trials, but there has been no success yet partly due to off-target effects and insufficient efficacy.

In this study, we use targeted protein degradation as a strategy to induce selective degradation of p-p38. Based on the phosphorylation-dependent conformational difference in p38, we rationally designed and synthesized a series of p-p38-degrading small molecules, consisting of a p-p38 ligand and pomalidomide that can recruit the CRBN E3 ubiquitin ligase complex. We found that one candidate molecule induced selective in vivo degradation of p-p38 and ameliorated neurodegenerative symptoms including neuroinflammation, Aβ deposition, and memory loss. Overall, this study highlights selective targeting of p38 bearing a specific PTM for proteasomal degradation, providing a novel therapeutic approach for the treatment of AD.

Link: https://doi.org/10.1021/acscentsci.2c01369

Extracellular vesicles of varying size classes carry a sizable fraction of all cell signaling. These are membrane-wrapped collections of molecules, generated in various ways and under various circumstances by sources cells. When researchers discuss extracellular vesicles in the context of aging, this is really a discussion of cell signaling in general. In the context of aging, vesicles are perhaps a more interesting topic than cell signaling in general because they are readily harvested and delivered as a therapy. Initially, this is being used to recapitulate the effects of stem cell transplants, delivering vesicles harvested from stem cells in culture, but it is likely that there will be further, more engineered and specific vesicle-based therapies in the future.

In recent decades, the concept of extracellular vesicles (EVs) has changed. When they were initially discovered, EVs were cellular dust; therefore, they did not have any functions; with time, this concept has changed and will probably continue being updated. Nowadays, EVs are considered critical mediators in physiological and pathophysiological processes. Therefore, this review summarizes the current knowledge on EVs from their discovery as cellular dust to their recognition as "very important particles" (VIPs) that mediate cell-cell communication and the current and newest isolation methods. Moreover, we describe the role of EVs in aging and age-related diseases and their potential use in the clinic as biomarkers for early diagnosis and as therapeutic agents for disease treatment.

EVs display several features that provide them with invaluable abilities for their application in regenerative medicine. First, the EV content mimics their parental cells. Thus, isolation of EVs from body fluids with a specific cargo is very useful as a biomarker in disease development for early diagnosis. Second, EVs have a specific set of surface proteins that indicates their target cells. This characteristic also has a valuable potential for their use as drug-delivery carriers to target cells. To date, EVs are VIPs because they act as mediators in physiological and pathological processes. Particularly, as shown in this review, EVs mediate biological aging and premature aging by their content and number released by senescent cells.

Research is still needed in the EV therapeutic field, in particular, focusing on the development of autologous EVs that would enable personalized treatment for each specific disease. Regarding the research on EV-mediated mechanisms of aging, efforts should be performed to establish a time- and cargo-dependent correlation between EVs and the incidence of age-related diseases so that EVs become a very early biomarker. It is also necessary to elucidate the exact molecular mechanisms involved in the change in EV content during aging; this understanding would help us to develop new cell-free treatments to reverse age-related diseases in the future. However, it should be mentioned that before starting antiaging therapies with EVs, safety, sensitivity, and specificity must be precisely verified. Additionally, administration, dosages, treatment intervals, and duration must be strictly certified.

Link: https://doi.org/10.3390/ijms24044250

For those who believe that only governments get things done, it is frustrating to see the lack of interest in human longevity in politics, a mirror of the relative lack of interest in society at large. The past few decades have seen a number of political initiatives, largely the formation of lobbying campaigns and organizations, aimed at diverting more public funding into aging research. Little has been achieved to date as a result, but these efforts are now growing alongside the new longevity industry.

Politicians pay attention to the movement of money in the world, for the obvious reasons; they are nothing if not self-interested. Thus, as recently noted, the US Congress now has a longevity caucus. A cynic might believe that the timing of such a thing has a lot to do with the high-profile, large investments into rejuvenation biotechnology made in the past year, such as the $3 billion for Altos Labs. Politicians taking a stance in public, in effect announcing themselves to be the destination for campaign donations from those interested in further lobbying on this topic, tends to happen in the wake of sizable flows of funding in industry. We might see it as the next step along the long road to changing priorities in public funding of science.

Personally, I see lobbying as a waste of funds and time that might have used in more productive endeavors. Governments are the last to the table in any new field, and most of what they do when they do arrive is wasted, funding siphoned off by the politically connected into work that bears little resemblance to the original goal. The actually important work of building new therapies occurs as a result of philanthropy to fund the research, and venture capital to fund development: that is the way matters have progressed for therapies to slow or reverse aging, in any case.

Pushin' The Envelope: The First Longevity Caucus Launches

Although investments from the private sector are at all-time highs and foundations such as Hevolution and Impetus Grants are committing millions of dollars to aging research every year, the amount of funding that longevity and other preventative healthcare organizations receive is still a far cry from the more traditional fields of medicine. For context, when picking apart the 2023 Presidential Budget Request, a rough measure showing how much government capital is provided to the National Institutes of Health (NIH), and more specifically to the National Institute of Aging (NIA), we found that only 0.54% of the entire NIH annual budget request was dedicated towards Aging Biology.

This week, A4LI, a 501c4 non-profit proudly announced the launch of the Longevity Science Caucus - an initiative, years in the making, to help educate members of Congress about the growing field of longevity biotech and promote initiatives aimed at increasing the healthy average lifespan of all Americans. While there are numerous ways Congress can help propel this industry forward, such as making an easier FDA approval process specifically for longevity medicines, the newly launched caucus will primarily focus on increasing funding efforts to start.

Bilirakis and Tonko Kick Off Longevity Science Caucus

Congressman Gus Bilirakis (R-FL) and Congressman Paul Tonko (D-NY) are proud to announce the formation of the Congressional Caucus for Longevity Science. The "Longevity Science Caucus" aims to educate Members about the growing field of aging and longevity biotechnology, and promote initiatives aimed at increasing the healthy average lifespan of all Americans. Along with Bilirakis and Tonko, Representatives Dan Crenshaw (R-TX), Michael Burgess (R-TX) and Anna Eshoo (D-CA) are founding members of the newly created caucus. "Increasing life expectancy and promoting positive health outcomes are important priorities, and the formation of this caucus is an important step toward achieving those goals. I believe in promoting individual responsibility and supporting innovation in the pursuit of scientific discoveries that will enable Americans to live happier and longer lives. I am honored to co-chair this bipartisan effort with my colleague, Congressman Tonko. We will work with our colleagues in an effort to make a significant impact on the future health and wellness for our constituents."

Senescent cells act to suppress risk of cancer its very earliest stage. The pro-inflammatory secretions of cells made senescent as a result of mutational damage and the response of tumor suppressor genes attract the immune system to places in which damaged cells may give rise to a tumor. When senescent cells are present in larger numbers, and linger over time, as is the case in aged tissues, they actively encourage tumor growth, however. Here, researchers produce a compelling demonstration of this harmful consequence of cellular senescence, categorizing and eliminating senescent cells present in glioblastoma tumors in mice to slow tumor growth, and demonstrating similar characteristics in human glioblastoma cells.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, yet it remains refractory to systemic therapy. Elimination of senescent cells has emerged as a promising new treatment approach against cancer. Here, we investigated the contribution of senescent cells to GBM progression. Senescent cells are identified in patient and mouse GBMs.

Partial removal of p16Ink4a-expressing malignant senescent cells, which make up less than 7 % of the tumor, modifies the tumor ecosystem and improves the survival of GBM-bearing female mice. By combining single cell and bulk RNA sequencing, immunohistochemistry, and genetic knockdowns, we identify the NRF2 transcription factor as a determinant of the senescent phenotype. Remarkably, our mouse senescent transcriptional signature and underlying mechanisms of senescence are conserved in patient GBMs, in whom higher senescence scores correlate with shorter survival times. These findings suggest that senolytic drug therapy may be a beneficial adjuvant therapy for patients with GBM.

Link: https://doi.org/10.1038/s41467-023-36124-9

The more obvious manifestations of Parkinson's disease stem from the the loss of a small population of dopamine-generating neurons. These cells are more sensitive to the underlying pathology of α-synuclein protein aggregation that drives the condition. Researchers have been working towards cell therapies that deliver new neurons for a long time now. A variety of clinical trials are underway, using a variety of cell sources; here, one of those programs has advanced to the stage of a first treated patient. None of these programs have yet emerged into widespread clinical practice. Is replacing cells the best way forward in this condition? It seems likely that ways to remove the toxic protein aggregates would be more beneficial, given that (a) they are causing other harms, and (b) transplanted cells will likely succumb to the same environmental issues caused by the aggregates.

There are around eight million people living with Parkinson's disease globally; a disease which involves loss of dopamine nerve cells deep in the brain, leading to problems in controlling movement. The standard treatment for Parkinson's disease are medications that replace the lost dopamine, but over time these medications often become less effective and cause side effects. As of today, there are no treatments that can repair the damaged structures within the brain or that can replace the nerve cells that are lost.

The STEM-PD trial is now testing a new investigational therapy aimed at replacing the lost dopamine cells with healthy ones manufactured from stem cells. The cell product that is being used has been subjected to rigorous pre-clinical tests. After being transplanted, the cells are expected to mature into new and healthy dopamine producing nerve cells within the brain. On 13th of February 2023, a transplant of stem cell-derived nerve cells was administered to a person with Parkinson's. The product is being tested in patients for the first time. The transplantation product is generated from embryonic stem cells and functions to replace the dopamine nerve cells which are lost in the parkinsonian brain.

This patient was the first of eight with Parkinson's disease who will receive the transplant. The patients in the trial were diagnosed with Parkinson's at least ten years ago and are at a moderate stage of their disease. The researchers will follow these patients closely and assessments of cell survival and potential effects will be conducted over the coming years.

Link: https://www.medicine.lu.se/article/first-patient-receives-milestone-stem-cell-based-transplant-parkinsons-disease

Aging is caused by a number of independent issues, forms of damage and dysfunction that arise as a consequence of the normal operation of a youthful and undamaged metabolism. If these processes remained independent, aging would be a far less challenging field of study than is the case, but unfortunately, everything interacts with everything else in cellular biology. Processes of damage encourage one another, and combine in complex ways to produce shared consequences. Those consequences can in turn interact with the underlying mechanisms of damage to alter and accelerate their effects.

In today's open access paper, researchers discuss some of the interactions between cellular senescence and mitochondrial dysfunction, two quite different mechanisms of aging. Mitochondrial dysfunction is known to promote inflammatory signaling, such as via the mislocalization of mitochondrial DNA to places in which it will trigger an innate immune response. Evidence suggests that this sort of mechanism likely drives some fraction of the harmful inflammatory signaling that is produced by senescent cells. This raises interesting questions, such as whether or not strategies intended to reverse mitochondrial dysfunction will, as a side-effect, also reduce the contribution of senescent cells to degenerative aging.

Targeting Mitochondria to Control Ageing and Senescence

Ageing is associated with increased inflammation and activation of the innate immune system. This condition is known as "inflamm-ageing" and is characterised by chronic activation of JAK-STAT signalling in the circulating immune cells of elderly patients, activation of the NLRP3 inflammasome, and higher circulating levels of inflammatory mediators such as C-reactive protein, IL-6, and fibrinogen. A leading hypothesis for the origin of "inflamm-ageing" is the build-up of senescent cells with ageing, and the consequent production of a systemic senescence-associated secretory phenotype (SASP). An important support for this hypothesis comes from experiments in which aged mouse blood is transferred to young animals, which results in features of accelerated ageing. Interestingly, previous treatment of the old donors with senolytic agents reduced "inflamm-ageing" after blood exchange, and the old blood lost its pro-ageing activity. In humans, senolytic treatments also reduce the "inflamm-ageing" of patients suffering from lung fibrosis or chronic kidney disease.

Importantly, mitochondria of senescent cells are known to play a key role in triggering the SASP. In particular, depriving senescent cells of mitochondrial DNA or mitochondria altogether seriously compromises the SASP. The detailed mechanisms connecting the mitochondria of senescent cells with the SASP are still unknown. We speculate that they could be similar to the mechanisms connecting dysfunctional mitochondria with inflammation. These may include the release of cytosolic and/or extracellular mitochondrial DNA (mtDNA), mitochondrial double-stranded RNA, N-formyl peptides (a sub-product of mitochondrial protein translation), and phospholipid species such as cardiolipin, enriched in the inner mitochondrial membrane . The most studied of these components is mtDNA.

Taken together, the evidence presented in this review shows that mitochondria dysfunctions have a close relationship with ageing and cellular senescence. Several mitochondrial pathways have already been taken into consideration as potential therapeutic targets for ageing-associated diseases, and promising compounds have been developed. Future research will have to answer numerous open questions including: is it possible to completely restore mitochondrial function in senescent and aged cells? Which age- or senescence-associated aspects are the primary drivers of mitochondrial dysfunction and vice-versa? Which ones are targetable therapeutically? Answering some of these questions could get us closer to healthy ageing, with countless medical, social and economic benefits.

Dementia risk for individuals has decreased in recent decades, even as the population grows and ages to the point at which overall number of cases expands. Since individual risk of suffering cardiovascular disease has also decreased over the same period of time, it is reasonable to ask whether reduced dementia risk is a direct consequence of improvements in long term vascular health. Researchers here provide evidence to suggest that this is the case, noting that levels of amyloid-β aggregates in post-mortem brains are much the same across recent decades, while vascular health improves. Misfolding and aggregation of amyloid-β is still broadly thought to be the mechanism that produces Alzheimer's disease, though there is now considerable debate given the failure of amyloid-clearing immunotherapies to help patients. Is amyloid-β actually a meaningful cause, or is it only relevant in the early stages of Alzheimer's? The situation is complicated by the fact that a sizable fraction of Alzheimer's patients also exhibit clear signs of vascular dementia.

In Europe and the U.S., proportionately fewer people are developing dementia now than in the past. Is this driven by less-prevalent Alzheimer's disease (AD) pathology? No, say researchers, who reported that among 1,550 older Americans born over a 25-year period, all had similar amounts of amyloid plaques at death, which came at an average of 90 years. If less pathology does not explain falling dementia incidence, then what does? People born in the 1920s had healthier blood vessels in their brains when they died than did those born in the 1900s, the authors found. They think better cardiovascular health among people born in more recent decades may make them more resilient to AD pathology.

Dementia incidence has steadily fallen by 20 to 25 percent over the past three decades in the U.S., U.K., Sweden, and the Netherlands. Researchers suspect that this drop was due to better overall health - especially improvements in cardiovascular health - and higher levels of education . Might these factors stave off amyloid plaques and neurofibrillary tangles? To find out, researchers quantified the extent of amyloid plaques, neurofibrillary tangles, Lewy bodies, TDP-43 aggregates, infarcts, and the severity of atherosclerosis and arteriosclerosis in cortical tissue from 1,554 participants in the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP) cohort. About one-quarter were born in each of four periods: 1905 to 1914, 1915 to 1919, 1920 to 1924, and 1925 to 1930. All died between 1997 and 2022.

The prevalence of postmortem AD diagnoses hovered between 64 and 68 percent in each birth epoch. The amount of Lewy bodies and TDP-43 inclusions remained the same across birth cohorts, as well. Notably, people born later had higher densities of neurofibrillary tangles than those born earlier. However, the extent of blood vessel damage, be it through atherosclerosis or arteriosclerosis, had decreased dramatically in participants born in the later cohorts. About half of those born from 1905 to 1914 had moderate to severe atherosclerosis, while only 22 percent of people born in the late 1920s did. All told, the researchers think that the declining prevalence of clinically diagnosed AD may be due to people having more cognitive reserve, which might be a product of better cardiovascular health and more education.

Link: https://www.alzforum.org/news/research-news/those-declining-dementia-rates-its-not-plaques-and-tangles

Transcription is the first step in gene expression, the production of RNA from sequences in the genome. Transcriptional noise describes an age-related increase in the raggedness of transcription, differences in amounts of proteins produced as individual cells become affected by the damage of aging to different degrees, and in different ways. Does this in fact happen as presently thought, however? It is certainly the case that epigenetic changes occur with age, and protein levels also alter with age. How much of this is noise versus other reactions to a changing tissue environment, such as alterations in the balance of different cell types? There is room for debate, it seems.

Aging is often associated with a loss of cell type identity that results in an increase in transcriptional noise in aged tissues. If this phenomenon reflects a fundamental property of aging remains an open question. Transcriptional changes at the cellular level are best detected by single-cell RNA sequencing (scRNAseq). However, the diverse computational methods used for the quantification of age-related loss of cellular identity have prevented reaching meaningful conclusions by direct comparison of existing scRNAseq datasets.

To address these issues we created Decibel, a Python toolkit that implements side-to-side four commonly used methods for the quantification of age-related transcriptional noise in scRNAseq data. Additionally, we developed Scallop, a novel computational method for the quantification of membership of single cells to their assigned cell type cluster. Cells with a greater Scallop membership score are transcriptionally more stable. Application of these computational tools to seven aging datasets showed large variability between tissues and datasets, suggesting that increased transcriptional noise is not a universal hallmark of aging.

To understand the source of apparent loss of cell type identity associated with aging, we analyzed cell type-specific changes in transcriptional noise and the changes in cell type composition of the mammalian lung. No robust pattern of cell type-specific transcriptional noise alteration was found across aging lung datasets. In contrast, age-associated changes in cell type composition of the lung were consistently found, particularly of immune cells. These results suggest that claims of increased transcriptional noise of aged tissues should be reformulated.

Link: https://doi.org/10.7554/eLife.80380

It has long been suspected that removing senescent cells locally is insufficient to treat age-related conditions in which the pro-inflammatory signaling produced by senescent cells contributes to pathology. These signals enter the bloodstream and are carried widely about the body. While the effect of a distant senescent cell on local pathology is more dilute than that of a local senescent cell, there are a lot more distant senescent cells than there are local senescent cells. This issue is likely why Unity Biotechnology's initial clinical trial of localized removal of senescent cells in osteoarthritic knee joints failed to produce sufficiently large beneficial effects in patients to proceed.

In today's open access paper, researchers demonstrate this issue in mice, in the context of the age-related loss of bone density that leads to osteoporosis. Bone tissue is constantly remodeled through the actions of osteoblast cells, depositing extracellular matrix, and osteoclast cells, breaking down extracellular matrix. Chronic inflammatory signaling generated by senescent cells helps to tip the balance away from osteoblast activity, leading to a steady loss in bone density over time. At least in mice, clearing senescent cells locally doesn't help to prevent this issue to anywhere near as great a degree as clearing senescent cells globally.

Local senolysis in aged mice only partially replicates the benefits of systemic senolysis

Clearance of senescent cells (SnCs) can prevent several age-related pathologies, including bone loss. However, the local versus systemic roles of SnCs in mediating tissue dysfunction remain unclear. Thus, we developed a mouse model (p16-LOX-ATTAC) that allows for inducible SnC elimination (senolysis) in a cell-specific manner and compared the effects of local versus systemic senolysis during aging using bone as a prototype tissue. Specific removal of Sn osteocytes prevented age-related bone loss at the spine, but not the femur, by improving bone formation without affecting osteoclasts or marrow adipocytes.

By contrast, systemic senolysis prevented bone loss at the spine and femur and not only improved bone formation, but also reduced osteoclasts and marrow adipocytes. Transplantation of SnCs into the peritoneal cavity of young mice caused bone loss and also induced senescence in distant host osteocytes. Collectively, our findings provide the first proof-of-concept evidence that local senolysis has health benefits in the context of aging, but importantly, local senolysis only partially replicates the benefits of systemic senolysis. Further, we establish that SnCs, through their senescence-associated secretory phenotype (SASP), lead to senescence in distant cells. Therefore, our study indicates that optimizing senolytic drugs may require systemic instead of local SnC targeting to extend healthy aging.

There is evidence for mitochondrial DNA mutations to spread throughout a tissue, though the degree to which each of the possible mechanisms contribute to this outcome is unknown. Mitochondrial DNA mutations in stem cells will spread in the same way as nuclear DNA mutation, producing mosaicism. Cells can also transfer mitochondria, however. Further, mitochondria are subject to selection effects based on their continued replication and removal by quality control mechanisms. Thus it is far from clear as to exactly how any observed snapshot of mitochondrial mutations came about. Researchers have taken a swing at this challenge, as noted here, but pay much more attention to substitutions than to deletions that completely disable mitochondrial genes. We might expect that deletions are the more important form of mutation. Nonetheless, the researchers find some evidence for quality control to bias the spread of substitution mutations in favor of those that are less harmful to mitochondrial function.

Accumulation of somatic mutations in the mitochondrial genome (mtDNA) has long been proposed as a possible mechanism of mitochondrial and tissue dysfunction that occurs during aging. A thorough characterization of age-associated mtDNA somatic mutations has been hampered by the limited ability to detect low frequency mutations. Here, we used Duplex Sequencing on eight tissues of an aged mouse cohort to detect more than 89,000 independent somatic mtDNA mutations and show significant tissue-specific increases during aging across all tissues examined which did not correlate with mitochondrial content and tissue function.

G→A/C→T substitutions, indicative of replication errors and/or cytidine deamination, were the predominant mutation type across all tissues and increased with age, whereas G→T/C→A substitutions, indicative of oxidative damage, were the second most common mutation type, but did not increase with age regardless of tissue. We also show that clonal expansions of mtDNA mutations with age is tissue and mutation type dependent. Unexpectedly, mutations associated with oxidative damage rarely formed clones in any tissue and were significantly reduced in the hearts and kidneys of aged mice treated at late age with Elamipretide or nicotinamide mononucleotide. Thus, the lack of accumulation of oxidative damage-linked mutations with age suggests a life-long dynamic clearance of either the oxidative lesions or mtDNA genomes harboring oxidative damage.

Link: https://doi.org/10.7554/eLife.83395

Proteostasis is the normal maintenance of protein levels and protein structure in a cell. This is disrupted with age, the result of failing quality control, epigenetic change, and other issues. Loss of proteostasis is a hallmark of aging, but has the look of a consequence of aging, not a cause to be addressed. It is also highly complex, and thus progress towards practical therapies is probably better served by a focus on causes of aging rather than the fine details of age-related changes in the cell. Fix the causes, see how well those repair efforts improve long-term health, and then worry about the fine details of the biochemistry of aging.

Proteostasis is the sum of reactions and signalling pathways related to the synthesis, folding, trafficking, disaggregation, and degradation of proteins. One of the hallmarks of aging is a decline in proteostasis. Unsurprisingly, defects in all major steps of proteostasis are related to the accumulation of toxic aggregates and misfolded proteins, a key feature of neurodegenerative diseases. Throughout evolution, a range of protein quality-control mechanisms have emerged, some of which are specialised in monitoring the proteome within specific subcellular compartments. Examples are the cytosolic heat-shock response (HSR), the mitochondrial unfolded protein response (UPRmt), and the unfolded protein response of the endoplasmic reticulum (UPRER). The mechanisms underlying age-related proteostasis collapse are still not completely understood, but studies using Caenorhabditis elegans and mice suggest that it initiates during early adulthood preceding the emergence of age-related diseases.

A fundamental question in biogerontology is why animals lose the ability to maintain proteostasis with aging. A new study observed that an age-related increase in ribosome pausing occurs driven by a reduced activity of the ribosome quality control (RQC) pathway. Another provocative study, in mice, argued that error-prone translation caused by ribosomal ambiguity mutations induces phenotypes that more closely match the progression of Alzheimer's disease than amyloid-β overexpression models do. Their findings suggest that the accumulation of random mutations in DNA over time may induce increased protein misfolding, sequestering away key components of the proteostasis maintenance machinery, such as chaperones, ultimately causing a collapse in proteostasis.

Link: https://doi.org/10.1101/2023.02.06.527311

Neurogenesis occurs throughout life to support the changes in neural structure inherent in learning and memory. It also provides some resilience to brain injury, when it comes to maintaining and restoring function. In the process of neurogenesis, new daughter neurons are generated by neural stem cells, and then mature and integrate into existing neural networks in brain tissue. This is all largely studied in mice, due to the difficulties inherent in obtaining access to living human brains, but despite some debate it is reasonable to assume that learning and memory in our species are similarly supported by ongoing neurogenesis throughout life.

Unfortunately, stem cell populations decline in activity with advancing age. This is in part the result of intrinsic damage to the cells themselves, but also a response to altered signaling and dysfunction in stem cell niches. The chronic inflammation of aging, for example, appears to have a strongly negative impact on stem cell function. Thus the pace of neurogenesis is much reduced in old individuals, and experiments in mice indicate that this is an important part of the loss of memory function that occurs with aging. Given this, there is some interest in finding ways to boost neurogenesis, to override the reaction of stem cells to the aged tissue environment, and reduce age-related memory dysfunction. Today's open access paper is one example of this sort of research.

MiR-181a-5p promotes neural stem cell proliferation and enhances the learning and memory of aged mice

The hippocampus is a brain region closely related to spatial learning and memory. Adult neural stem cells (NSCs), which are located in the subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus, play important roles in the function of the hippocampus. NSCs have the ability to proliferate, either generating two NSCs to maintain NSC pools through symmetric division or generating one NSC and one neural progenitor cell (NPC) through asymmetric division. NPCs then further differentiate into particular cell types, such as neurons or astrocytes. Studies on rodents have shown that proliferation and neurogenesis of NSCs persist throughout the lifespan; however, adult neurogenesis decreases with age, and this decrease is involved in cognitive and memory declines, indicating that abnormalities in hippocampal NSCs are one of the main causes of age-related deterioration in hippocampus-dependent cognition.

Proliferation and neurogenesis of NSCs are exquisitely regulated by extrinsic and intrinsic factors, including secreted molecules, neurotransmitters, transcription factors, and epigenetic regulators. Among these, miRNAs, which are enriched in the brain, have been shown to be widely involved in the regulation of NSC proliferation and differentiation. In the current study, we found that the expression level of miR-181a-5p was decreased in the hippocampal NSCs of aged mice and that exogenous overexpression of miR-181a-5p promoted NSC proliferation without affecting NSC differentiation into neurons and astrocytes.

The mechanistic study revealed that phosphatase and tensin homolog (PTEN), a negative regulator of the AKT signaling pathway, was the target of miR-181a-5p and knockdown of PTEN could rescue the impairment of NSC proliferation caused by low miR-181a-5p levels. Moreover, overexpression of miR-181a-5p in the dentate gyrus enhanced the proliferation of NSCs and ameliorated learning and memory impairments in aged mice. Taken together, our findings indicated that miR-181a-5p played a functional role in NSC proliferation and aging-related, hippocampus-dependent learning and memory impairments.

The biggest challenge in tissue printing is the achievement of sufficient control over small scale structure to produce a vasculature that can supply the tissue as it develops. Without that capacity, tissue growth is limited to thin sheets and tiny organoids. Advances have been made in recent years, such as the work of Volumetric, but there is still a way to go before large tissue sections are regularly generated for use in medicine. This is in large part why work on decellularization continues to proceed apace, taking donor tissue and stripping the cells from it to leave the extracellular matrix structure, with all of its fine-scale detail and chemical cues to guide new, patient-matched cells into the correct locations and development activities.

Bioprinting is based on 3D-printing technology, using cells and biopolymer to create biological structures and tissues. One of the most promising types of 3D-bioprinting is called digital light processing (DLP) bioprinting. Within this branch of 3D-bioprinting, progress has been impeded by practical and technical impediments. It has proven difficult to print tissues with high cell densities and finely resolved structures.

DLP-based 3D bioprinting uses a digital micromirror device (DMD) to project a 2D cross-section of the 3D model to the photo-crosslinkable bioink. When exposed to light, the photocrosslinkable bioink, which can be either synthetic or natural, solidifies. Then, a motorized stage lifts up the bioink by a few tens microns to 200 microns, which allows uncured bioink to refill the gap. When the next cross-section is projected to the bioink, a new layer solidifies and the process repeats.

When all goes well, a newly formed layer precisely matches the shape of the projected cross-section. However, with existing methods, the incorporation of cells in the bioink can cause severe light scattering, which blurs the projected light in the bioink. As a result, the newly formed layers cannot replicate the fine details of the projected cross-sections. The researchers reduced this light-scattering effect by tenfold, allowing them to print with high cell densities and high resolution thanks to the contrast agent iodixanol, a new ingredient in the bioink.

Tuning the refractive index of the bioink minimizes the scattering effect and significantly improves the fabrication. The new research shows that a ~50 µm feature size can be achieved in a refractive-index-matched gelatin methacrylate (GelMA) bioink with a cell density as high as 0.1 billion/mL. This approach introduces a few novel technical innovations, including a hollow organic vascular network embedded in a cell-laden thick tissue, enabling it for perfused and long-term culture, and a snow-flake and spoke shape to showcase the high resolution for both positive and negative features.

Link: https://today.ucsd.edu/story/a-new-technique-creates-greater-fidelity-in-bioprinting-functional-human-tissues

Atherosclerosis leading to heart attack is one of the more amenable issues in aging to control through lifestyle choice and available medications. A very rigorous commitment to diet, exercise, and lowering LDL cholesterol will greatly reduce the odds of developing atherosclerotic plaque sufficient to produce heart attack or stroke. A combination of better treatment and better lifestyle choices has led to a sizable reduction in mortality due to heart attack in recent decades. Eliminating atherosclerosis entirely is going to require new developments in medical science, however, as lowering LDL cholesterol doesn't do much to help those people who have already developed significant atherosclerotic plaque.

New findings, based on an analysis of data from the Centers for Disease Control and Prevention (CDC) from 1999-2020, indicate that age-adjusted rates of death attributed to acute myocardial infarction (the medical term for heart attack) fell by an average of over 4% per year across all racial groups over the two-decade period. "Researchers often highlight the bad news, but people should know that even if we're not there yet, we're making progress in the right direction. I think the reasons are multifactorial, spanning all the way from health-promoting and prevention activities through treatment during and after a heart attack."

Researchers found the overall rate of death from heart attack, adjusted for age, fell from about 87 deaths per 100,000 people in 1999 to about 38 deaths per 100,000 people in 2020. It is difficult to definitively determine whether the decline is the result of fewer heart attacks occurring or better rates of survival when they do occur because of new diagnostic strategies and treatment options, researchers said. For example, hospitals now frequently test for troponin in the blood when a heart attack is suspected, which can help clinicians diagnose a heart attack at an earlier stage than was possible with previous diagnostic strategies. This change has led to earlier and more sensitive heart attack detection but also makes it challenging to compare data on heart attacks over time.

On the prevention side, the public has become more aware of the need to reduce cardiovascular risk factors through steps such as quitting smoking and managing cholesterol. Clinicians also have a better understanding of the signs of a heart attack and improved tools to quickly diagnose and treat them when they occur. More hospitals are also equipped with mechanical support devices to assist with heart attack treatment and new medications such as potent antiplatelet drugs have become available, which may have improved survival rates and reduced the likelihood of a second heart attack.

Link: https://www.acc.org/About-ACC/Press-Releases/2023/02/22/21/30/Heart-Attack-Deaths-Drop-Over-Past-Two-Decades

FOXN1 is the master regulator of thymic growth and activity; the thymus is an unusually straightforward organ in this respect. One can make it grow and perform to a greater degree just by dialing up expression of this one gene in thymic tissue. Thymic regrowth is a desirable goal for the elderly, given that thymic atrophy occurs in everyone, and limits the production of T cells. It is a major contribution to immune aging.

One of the approaches that has been taken to achieve this goal of thymic regrowth is the delivery of a FOXN1 recombinant protein attached to the TAT domain derived from the HIV-1 virus, allowing it to enter the cell. Researchers published a study some years back in which intrathymic injection was used, an approach that is probably too risky to serve as a basis for human therapies. Without direct injection, one can't get enough of the protein into the thymus to be worth the effort.

Today's open access paper discusses an advance on that earlier work by the same team. The researchers further attach an additional binding domain to the FOXN1-TAT fusion protein to optimize uptake in thymic tissue, and inject the protein intravenously instead of directly into the thymus. This necessarily requires higher doses (and recombinant proteins remain expensive), but the team reports good results. This is an approach that could in principle be developed for human use, setting aside the more conservative concerns one might encounter regarding the use of TAT versus the adoption of other options for cell entry.

Recombinant FOXN1 fusion protein increases T cell generation in aged mice

The thymus is a specified immune organ that provides an inductive environment for the generation of T cells that play a critical role in the adaptive immune system. Although the thymus continues to export T cells throughout life, it undergoes a profound atrophy with age, a process termed thymic involution, resulting in decreased numbers and functional capacity of T cells in the older adult, which has direct etiological linkages with many diseases. Furthermore, T cell immune deficiency in the older adult is exacerbated when the immune system is insulted by chemotherapy, radiotherapy, infections (e.g. HIV), and preparative regimens for foreign tissue or organ transplants. Therefore, restoring thymus function in the older adult has important implications.

We have previously reported that intrathymic injection (i.t.) of a recombinant (r) protein containing FOXN1 and a protein transduction domain embedded in the HIV transactivator of transcription (TAT) protein increases the number of thymic epithelial cells (TECs) in mice that have undergone hematopoietic stem cell transplantation. Consequently, these mice had enhanced thymopoiesis, an improved thymic output and an increased number of naïve T cells in the periphery. However, i.t. injection may not be an ideal choice for clinical applications. 

It has been reported that chemokine CCL25 is highly expressed in thymic tissue, especially thymic stroma. CCR9 is the receptor for CCL25. Unlike other CC chemokine receptors, CCR9 shows a strict specificity for its ligand CCL25. It has been shown intramural injection of a fusion protein containing the N-terminal of CCR9 and IL-7 increased the content of IL-7 in the thymus as compared to injection of IL-7 alone.

In this study, we develop a rFOXN1 fusion protein that contains the N-terminal of CCR9, FOXN1, and TAT. We show here that, when injected intravenously (i.v.) into aged mice, the rFOXN1 fusion protein can migrate into the thymus and enhance T cell generation in the thymus, resulting in increased number of peripheral T cells. Our results suggest that the rFOXN1 fusion protein has the potential to be used in preventing and treating T cell immunodeficiency in the older adult. 

Nicotinamide adenine dinucleotide (NAD) is involved in mitochondrial function, but levels decline with age for reasons that are not fully understood, alongside a loss of mitochondrial function. Thus there is some interest in delivering NAD precursor molecules, largely derived from vitamin B3, that can increase NAD levels. One might compare this trial of nicotinamide mononucleotide (NMN) with a similar trial of nicotinamide riboside (NR) a few years ago, which produced a better outcome, but still nothing to write home about. People who advocate for upregulation of NAD in mitochondria might say that the dosing is too low, but equally the long history of trying to increase NAD levels, accompanied by dozens of clinical trials, has little to show for it in terms of effect sizes that are any better than those produced by exercise. A good exercise program does still outperform NAD precursor supplementation, at least in clinical trial data.

Many animal studies have shown that oral administration of the nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide mononucleotide (NMN) prevents the reduction of NAD+ levels in organs and tissues, helping alleviate aging-related diseases. However, there are very few clinical reports of NMN supplementation in humans. Thus, this study aimed to investigate the influence of a 12-week NMN oral supplementation on biochemical and metabolic health parameters.

A 12-week randomized, double-blind, placebo-controlled, parallel-group clinical trial was conducted. A total of 36 healthy middle-aged participants received one capsule of either 125 mg NMN or placebo twice a day. Among the NAD+ metabolites, the levels of nicotinamide in the serum were significantly higher in the NMN intake group than in the placebo group. Pulse wave velocity values indicating arterial stiffness tended to decrease in the NMN intake group. However, no significant difference was found between the two groups. Long-term NMN supplementation at 250 mg/day was well tolerated and did not cause adverse events. NMN safely and effectively elevated NAD+ metabolism in healthy middle-aged adults. Additionally, NMN supplementation showed potential in alleviating arterial stiffness.

Link: https://doi.org/10.1038/s41598-023-29787-3

Researchers here look at epidemiological data on physical activity and brain function in old age. While the presence of any period of life in which physical activity was a regular occurrence correlates with improved late life brain health, the best option is to remain active throughout life. When it comes to established human data, the effects of exercise and calorie restriction remain the bar to beat for any attempt to improve healthspan and longevity across a broad population of varied individuals. We might hope that at least the use of senolytics to clear senescent cells will improve on this, as well as some of the following biotechnologies aimed at other fundamental mechanisms of aging.

Using data from the population-based 1946 British birth cohort, which has followed people born in the same week of 1946, previous studies have demonstrated beneficial effects of midlife physical activity on midlife verbal memory and search speed decline. Here, we extend this work by taking a life course approach to evaluate the effects of physical activity timing, frequency and maintenance, spanning over 30 years, with later-life cognitive function. We assess three measures of later-life cognitive function including a measure of cognitive state, verbal memory, and processing speed. We further aim to investigate to what extent, these effects are explained by pathways including earlier-life influences, cardiovascular health, and mental health.

To investigate the effect of timing of physical activity, we investigated the strength of associations between a range of cognitive tests at age 69 with participation in physical activity at the ages of 36, 43, 53, 60 and 69. We then investigated whether any associations observed are best explained by physical activity in specific 'sensitive' periods across the life course, or being physically active across multiple time periods.

Being physically active, at all assessments in adulthood, was associated with higher cognition at age 69. For cognitive state and verbal memory, the effect sizes were similar across all adult ages, and between those who were moderately and most physically active. The strongest association was between sustained cumulative physical activity and later-life cognitive state, in a dose-response manner. Thus being physically active at any time in adulthood, and to any extent, is linked with higher later-life cognitive state, but lifelong maintenance of physical activity was most optimal.

Link: https://doi.org/10.1136/jnnp-2022-329955