Fight Aging!

Neurogenesis is the creation of new neurons from stem cell populations, followed by the integration of these newly created cells into existing neural networks. Neurogenesis is required for memory and learning to take place in the adult brain, and is thought to provide an important contribution to what limited capacity for regeneration exists in brain tissue. If researchers could induce a greater degree of neurogenesis, this could be a path to greater repair of an injured brain, and restoration of lost function in an aged brain.

This high level view of neurogenesis skates over a great deal of complexity, much of which has yet to be mapped. For example, which cell populations are responsible for generating new neurons? What are their regulating mechanisms? Why does activity decline with age? Neurogenesis does not emerge from one single cell population; it isn't just neural stem cells, and even that label covers a great many distinct varieties and locations of cell within the brain. Some sources of neurons are even found outside the brain - nearby, but not within brain tissue.

Today's open access paper gives a sense of the work needed to pin down just one of the many cell populations that can act as sources of new neurons for the adult brain. Here, the cells are resident in bone marrow of the skull. The authors summarize their findings to present both the distinct subpopulation of mesenchymal stem cells that generates neurons and a way to beneficially manipulate its activity via increased expression of the ANKRD1 gene. A viral gene therapy delivered systemically, but where the ANKRD1 expression is constrained by promoter, increases neurogenesis in aged mice to improve cognitive function.

ANKRD1 sustains a neurogenic BMSC niche and counters cognitive aging

Craniofacial bone marrow mesenchymal stromal cells (BMSCs) derived from neural crest stem cells (NCSCs), which represent a transient embryonic progenitor population endowed with diverse lineages, including peripheral neurons and glia. Emerging evidence suggests adult BMSCs retain traces of their NCSCs heritage, exhibiting latent neurogenic plasticity that could be harnessed for neural repair. Despite progress in characterizing BMSCs multipotency, the transcriptional circuits preserving their neural competence during aging and the mechanisms by which they deteriorate remain unresolved.

In this study, through scRNA-seq of human BMSCs, we discovered a discrete subpopulation exhibiting molecular signatures of neurogenic potential. Gene enrichment analysis identified ANKRD1 as a top-scoring candidate, and subsequent validation studies confirmed its role as a key regulator of this neurogenic phenotype. We propose that ANKRD1 may sustain neurogenic competence in undifferentiated BMSCs, a capacity that is progressively eroded by aging or differentiation-associated transcriptional reprogramming. Mechanistically, protein-DNA interaction profiling revealed that ANKRD1 directly engages with enhancer elements of SOX2 and NESTIN, thereby preserving their expression and reinforcing neural-lineage characteristics.

Critically, neuron-targeted ANKRD1 delivery rescues spatial memory deficits in aged mice. These findings establish ANKRD1 as a therapeutically tractable regulator that sustains neurogenic chromatin reservoirs to support neurocognitive resilience, opening avenues to counter cognitive aging.

Researchers have demonstrated that many forms of mild, repeated stresses can improve cell function and slow aging. Lack of nutrients, lack of oxygen, heat, cold, oxidative damage, and others have been demonstrated to be beneficial in animal studies. Here, researchers discuss what is known of the response to hypoxia specifically, but note that many of the mechanisms involved are the same as those involved in other forms of stress response. The cell increases maintenance activities, for example, such as the processes of autophagy responsible for recycling damaged proteins and structures. This in turn helps to reduce the risk of cells becoming senescent. A fair amount of effort has been devoting to finding ways to trigger increased autophagy and other beneficial responses to mild stress using small molecule drugs, which has given rise to work on mTOR inhibitors and a range of other classes of compound.

Hypoxia is a physiologically relevant microenvironment in both normal and diseased tissues and has emerged as a potent modulator of cellular senescence and organismal longevity. This review synthesizes evidence that hypoxia delays senescence across diverse experimental systems and species, and highlights mechanisms by which hypoxia rewires chromatin states during senescence-associated transitions. We focus on oxygen- and α-ketoglutarate-dependent epigenetic regulators, particularly histone lysine demethylases, whose catalytic activities are limited under hypoxia. Consequently, histone methylation increases and higher-order chromatin organization is stabilized.

Using oncogene-induced senescence as an experimentally tractable framework, we discuss recent findings showing that hypoxia suppresses senescence-associated histone clipping, preserves nuclear lamina integrity, and restrains large-scale heterochromatin reorganization while leaving canonical cell-cycle arrest largely intact. We further consider emerging links among DNA damage, epigenetic instability, and aging phenotypes, and propose that senescence can be viewed as a breakdown of coordinated epigenetic homeostasis. By integrating these concepts, we position hypoxia and hypoxia-mimetic interventions as promising strategies to modulate aging-associated cellular states and to explore therapeutic opportunities in age-related pathologies.

Link: https://doi.org/10.4062/biomolther.2026.014

The study of aging is an ongoing project, as is the study of cellular metabolism. The research community remains some way from a complete understanding, and as such there is a great deal of ongoing empirical discovery. Popular areas of study exist because someone demonstrated that a particular approach to therapy produced a slowing or reversal of measurable aspects of aging. Others then join in to try to understand how it works. None of these existing approaches are yet fully understood, in part because they produce complex changes in complex systems. Layered atop considerations of aging in laboratory mice and humans is the point that the world contains thousands of species that researchers might plausibly study, many of which exhibit quite different patterns of aging or specific aspects of aging biology. There is more complexity than can be engaged with in any reasonable amount of time, but discoveries made in recent decades suggest that there is the potential to find useful new approaches to the treatment of aging by comparing different species. It just won't happen quickly.

Despite still being an emerging field of research, biogerontology has made remarkable progress in identifying molecular principles of cellular aging over the last two decades. The categorization of these principles into "hallmarks of aging" has proven useful, as experimental modulation of these hallmarks in various model organisms can alter aging trajectories. In nature, we encounter remarkable variation in lifespan and demographic aging across individuals, species, populations, and space. Why has this variability evolved? Do the same "hallmarks of aging" identified as important in laboratory animals explain this variation? How do the molecular processes shaping aging vary across species and environmental conditions? What role do developmental processes and conditions play in shaping the onset and rate of aging across species? These fundamental questions remain largely unanswered. Yet, they are critical not only for advancing the biology of aging but also for designing interventions to mitigate age-related decline.

Understanding why particular pathways or hallmarks matter in specific taxa, and how developmental processes interact with environmental constraints to shape aging, requires synthesizing and comparing mechanisms identified in classical model organisms with those discovered in non-model species spanning broad phylogenetic and ecological contexts. Many evolutionary theories of aging were proposed well before the discovery of the molecular mechanisms involved, and they remain largely theoretical. Moreover, the growing number of model organisms and the expanding array of experimental and theoretical approaches used to study aging have often remained compartmentalized. As a result, integrating these diverse insights into a unified framework has become increasingly important. As a step toward this goal, this field perspective outlines general biological mechanisms that help explain the variability in aging patterns and longevity across the animal kingdom.

Link: https://doi.org/10.1038/s44318-026-00725-z

The immune system changes with age, a mix of damage and reactions to that damage. Some of those reactions make things better and some are maladaptive, making things worse. Immune cell populations change in size, and immune cells themselves carry burdens of dysfunction, the usual forms of damage and change one might expect from the Strategies for Engineered Negligible Senescence (SENS) view of cellular aging. Immune cell behaviors change in response to both internal shifts and the altered environment they find themselves in, a change in the signaling produced by all of the other cells in the body. Much of this is a matter of chronic inflammation, a sustained activation of the primary triggers that cause the immune system to react in defense of the body. In old age these triggers become constantly active, a maladaptive response to damage and dysfunction in cells through the body.

The complement system is a major component of the innate immune system, a well-mapped collection of circulating signal molecules and their cell surface receptors that acts to call the immune system to action against forms of infection and damage. But one should also consider that the innate immune system is actively involved in tissue maintenance and function beyond defense, and thus any aspect of the immune system likely affects normal tissue function as well. The complement system is in one sense easy to measure, just assess the levels of the various signals. In another sense it is hard to measure; what do specific alterations in signaling actually mean for system-level functions, or functions in the tissues supported by innate immune cells? This has been fairly well studied, as complement dysfunction is implicated in a range of autoimmune conditions, and in aging itself, but firm answers remain challenging here, just as is the case elsewhere in our biochemistry.

Within this context, the authors of today's open access paper show a distinct pattern of differences in complement signaling between older individuals who do and do not go on to develop Alzheimer's disease. This fits with much of the research into the relationship between the innate immune system, particular its inflammatory behavior, and the development of neurodegenerative conditions. To a large degree, the innate immune system of the central nervous system is not the same innate immune system of the rest of the body; the two sides communicate with one another, but the brain has microglia where the rest of the body has macrophages and other cell types. Microglia are similar to macrophages, but with important additions to their portfolio of duties that relate to the maintenance of connections between neurons. A growing body of work implicates the dysfunction and inflammatory behavior of microglia in the onset and progression of neurodegenerative conditions.

Systemic complement factors in aging, Alzheimer's disease and other dementias: a longitudinal study over 10 years

The complement system, an essential component of innate immunity, contributes to pathogen clearance, removal of apoptotic cells, and elimination of misfolded proteins. Within the central nervous system (CNS), circulating complement factors are actively involved in neuronal development, synaptic remodeling, and immune surveillance. However, aberrant complement activation is increasingly associated with neuroinflammatory pathologies, including Alzheimer's disease (AD).

We conducted a study involving two cohorts: a longitudinal cohort (n = 235; all cognitively normal at baseline) and a cross-sectional cohort (n = 323; including 53 with AD, 54 with vascular dementia, 51 with Parkinson's disease dementia, 56 with behavioral variant frontotemporal dementia, and 52 with dementia with Lewy bodies). Plasma levels of 14 complement factors were assessed every 2 years over a 10-year follow-up period in the longitudinal cohort and once in the cross-sectional cohort.

In this 10-year follow-up study, complement factors C4, C4b, Factor I, Factor D and Properdin showed progressive deviations from normative aging trajectories exclusively in individuals who later converted to AD. These alterations correlated robustly with established cerebrospinal fluid (CSF) biomarkers, indicating that peripheral complement remodeling reflects AD-specific pathophysiology rather than age-related change. Collectively, these findings establish complement dysregulation as a systemic hallmark of Pre-AD and identify a discrete panel of proteins with potential for early detection and treatment.

Bioprinting even small sections of replacement tissue faces a range of challenges relating to recapturing the small-scale structure of natural tissues. The formation of blood vessels is a particularly thorny issue that can be bypassed in some circumstances, such as rebuilding muscle following injury. A sufficient vasculature will be established in newly bioprinted constructs as they integrate with neighboring existing tissue, provided that the constructs are not too large. In muscle, alignment of muscle fibers is another structural challenge. Muscle tissue functions because its myocytes are aligned with one another. Here researchers report on solving this alignment challenge by using an electric field, demonstrating that the resulting bioprinted muscle can restore function in injured rats.

Bioprinting provides an unparalleled tool for engineering living tissue constructs that mimic the structural organization of native skeletal muscles. However, it remains a challenge for existing bioprinting strategies to recapitulate the highly aligned cellular architectures inside skeletal muscles, primarily due to low printing resolution and limited capability for in situ microenvironmental regulation. Here, we propose to employ the electrical force during the electrohydrodynamic (EHD) bioprinting process to induce the in situ orientation of cell-laden fibrin-alginate hydrogel, which provides nanostructural guidance to the encapsulated cells for the formation of highly aligned skeletal muscle constructs.

It was observed that the randomly distributed fibrin protofibril aggregates gradually elongated into uniformly aligned nanofibers at the Taylor cone stage as the applied voltage increased to 3 kV. The oriented fibrin nanofibers further direct in situ cellular alignment along the EHD bioprinting trajectory, facilitating the freeform fabrication of parallelly or circumferentially aligned muscle tissue constructs in vitro. The addition of conductive polymers into the fibrin-alginate hydrogel endows the EHD-bioprinted living constructs with muscle-specific conductivity and cellular organization, which promote myotube differentiation and maturation.

The resultant aligned and conductive muscle constructs promoted in situ muscle regeneration in a rat injury model and restored lost muscle functions at the defect regions. The presented EHD bioprinting strategy for fibrin-alginate hydrogel provides a versatile and simple platform to freely fabricate conductive, living tissue constructs with designer cellular alignments.

Link: https://doi.org/10.1088/2631-7990/ae3923

Perhaps the most useful way to think of atherosclerosis, the ultimately fatal growth of fatty plaques in blood vessel walls, is as a condition driven by macrophage dysfunction. Macrophages are innate immune cells responsible for repair and maintenance in blood vessel walls. Where blood vessels are damaged, native macrophages are joined by monocytes from the circulation that transform into macrophages. These cells attempt repair of outright damage but also ingest any harmful excess of lipids (such as cholesterol) in the blood vessel wall, returning those lipids to the circulation for delivery to the liver. When macrophages efficiently carry out this work, atherosclerosis is prevented or even reversed. Atherosclerosis progresses when macrophages become dysfunctional, which can be caused by excess lipids, systemic inflammation, the molecular damage of aging, or other environmental factors. All of the contributing factors and risk profiles associated with atherosclerosis can be viewed through the lens of how they impair macrophage function in the regions of the blood vessel walls that are most affected by damage and excess lipid accumulation.

Atherosclerosis is a chronic inflammatory disease driven by pathological processes such as macrophage foam cell formation. Semaphorin 7A (SEMA7A) is an immunoregulatory signaling molecule known to modulate immune responses and cellular adhesion. However, the contribution of macrophage-derived SEMA7A to atherogenesis has yet to be fully elucidated. In this study, we analyzed gene expression profiles of human mononuclear cells from the Gene Expression Omnibus (GEO) database and revealed highly expressed SEMA7A and its receptor integrin β1 in macrophages. The upregulation of SEMA7A and integrin β1 was also observed during the differentiation of THP-1 monocytes into macrophages.

Mice with macrophage-specific deletion of Sema7a showed a 57.2% reduction in atherosclerotic lesion size and improved plaque stability in atherosclerosis mouse model compared to control mice. Mechanistically, macrophage SEMA7A promoted the expression of macrophage scavenger receptor 1 (MSR1) and lipid uptake mediated by integrin β1 and downstream JNK signaling pathway in macrophages. Notably, pharmacological inhibition of integrin β1 with integrin receptor antagonist GLPG0187 effectively suppressed atherosclerosis progression. These findings identify macrophage-derived SEMA7A as a key driver of atherosclerosis through a novel integrin β1/JNK/MSR1 axis, providing potential targets for the prevention and treatment of atherosclerosis.

Link: https://journal.hep.com.cn/fmd/EN/10.1007/s11684-025-1181-z

The human body hosts countless viruses in addition to the other forms of microbe such as bacteria and fungi. Most of these viruses are commensal species, most likely harmless throughout much or all of the life span, playing their parts in the microbial ecosystems that exist within and around the body. At the present time there is considerable enthusiasm for the study of the gut microbiome, and this is one avenue of research in which viruses are being cataloged and their activities considered by researchers. Another avenue is the study of persistent infectious viruses, primarily herpesviruses, and their effects of health over the course of aging. Persistent viruses may contribute meaningfully to age-related immune dysfunction and various age-related diseases. Consider what is known of the effects of cytomegalovirus on the immune system, or the evidence for other herpesvirus species to contribute to the onset and progression of Alzheimer's disease.

In today's open access paper, researchers review what is known of the human virome and its impact on health and aging. At the high level, the theme is that much is yet to be mapped and discovered. Despite considerable progress in gathering data, particularly in recent years, the research community's understanding of the role of viruses in human aging still contains large dark areas and many unknowns. We might think that this is in part the case because we lack a good way to clear viral infections. Given tools that can selectively destroy specific viruses, such as the DRACO system still somewhere in the development process, it would become much easier to determine the activities of various species and their effects on health.

The gut and circulating virome: emerging players in aging and longevity

A growing body of evidence indicates that the human virome, comprising both the gut and circulating viral communities, plays a critical role in shaping host physiology across the lifespan. In the context of aging, this complex viral ecosystem is increasingly recognized as a key modulator of immune function, inflammation, and metabolic balance, with direct implications for healthspan and longevity. While much attention has traditionally focused on bacterial components of the microbiota, recent advances in metagenomics have uncovered age-related shifts in the composition and function of the virome, including expansion of specific bacteriophage families, reactivation of latent viruses, and the persistence of commensal viral pathobionts.

These changes are tightly linked to immunosenescence, chronic inflammation, and neurodegeneration, hallmarks of unhealthy aging. Notably, centenarians appear to harbor a unique virome signature marked by increased viral diversity, enhanced lytic activity, and the enrichment of phage-encoded metabolic functions, suggesting a potential protective role in extreme longevity. Despite these insights, significant challenges remain in virome profiling, including technical biases, database limitations, and the vast proportion of taxonomically unassigned sequences known as "viral dark matter". This review highlights emerging data on the aging virome, underscores its relevance within the Geroscience framework, and discusses current barriers and future directions for translating virome research into clinical aging studies.

Research into the biochemistry of longevity does not proceed at a rapid pace, even now that the field has become popular. Much of this research takes the form of first discovering longevity-enhancing mutations in short-lived species and then painstakingly tracing chains of cause and effect from protein to protein and interaction to interaction. Since cellular metabolism is by no means fully understood, even in the extremely well studied nematode worm C. elegans, this takes a long time. For example, we can see that is has taken thirty years or so to move from the first C. elegans longevity-enhancing mutation to the discovery of many more, and now here finding that some of these mutations converge on the activity of the FMO-2 gene. This slow pace of increased understanding is one of the reasons why manipulating the operation of cellular metabolism to slow the pace of aging seems a poor choice of primary goal for research and development, versus the alternative approach of finding specific forms of damage and attempting to repair them.

A mild impairment of mitochondrial function activates the hypoxia inducible factor (HIF-1)-mediated hypoxia stress response pathway leading to a HIF-1-dependent increase in lifespan. Lifespan extension resulting from HIF-1 stabilization is dependent on activation of flavin-containing monooxygenase-2 (FMO-2). In this work, we explored the role of fmo-2 in the long lifespan of genetic mitochondrial mutants in C. elegans. We found that fmo-2, but not other fmo genes, are specifically upregulated in the long-lived mitochondrial mutants clk-1, isp-1, and nuo-6. Disruption of fmo-2 through RNA interference or genetic mutation shortens the lifespan of these mitochondrial mutants indicating that fmo-2 is required for lifespan extension in these worms.

Moreover, signaling molecules that have been shown to be involved in upregulation of fmo-2 are also required for the long life of clk-1, isp-1, and nuo-6 mutants including HLH-30, NHR-49, and MDT-15. Finally, we examined the effect of multiple lifespan-promoting pathways in clk-1 mutants on the expression of fmo-2. We found that in all cases, genes required for clk-1 longevity are also required for the upregulation of fmo-2 in clk-1 worms. These genes included DAF-16, PMK-1, SKN-1, CEH-23, AAK-2, HIF-1 and ELT-2. Combined, this work advances our understanding of the molecular mechanisms contributing to longevity in the long-lived mitochondrial mutants and identifies FMO-2 as a common downstream effector of multiple pathways that modulate longevity.

Link: https://doi.org/10.64898/2026.02.10.705198

That new neurons are generated in the adult brain and integrate into existing neural networks was first established in mice in the 1990s, but considerable debate has taken place since then as to whether this adult neurogenesis also occurs in humans. Working with human brain tissue has always been logistically difficult, and this combined with methological challenges in the quantification of neurogenesis allowed uncertainty to continue. At this point, the balance of evidence and scientific consensus is that adult neurogenesis does occur in our species, and further is necessary to the operation of memory and learning. Here, in addition to providing further confirming data for human adult neurogenesis, researchers suggest that differences in neurogenesis could contribute to sustained cognitive function in older individuals who exhibit relatively little cognitive aging.

The existence of human hippocampal neurogenesis has long been disputed and its relevance in cognition remains unknown. Recent studies have established the presence of proliferating progenitors and immature neurons and a reduction in the latter in Alzheimer's disease (AD). However, their origin and the molecular networks that regulate neurogenesis and function are poorly understood. Here we studied human post-mortem hippocampi obtained from different cohorts: young adults with intact memory, aged adults with no cognitive impairments, aged adults with extraordinary memory capacity (SuperAgers), adults with preclinical intermediate pathology or adults with AD.

Using multiomic single-cell sequencing (single-nucleus RNA sequencing and single-nuclei assay for transposase-accessible chromatin with sequencing), we analysed the profiles of 355,997 nuclei isolated from the hippocampus samples and identified neural stem cells, neuroblasts and immature granule neurons.

Dysregulated neurogenesis was largely associated with changes in chromatin accessibility. Analyses of transcription factors and target gene signatures that distinguished each of the groups revealed early alterations in chromatin accessibility of neurogenic cells from individuals with preclinical AD, and such changes were even more evident in samples from individuals with AD. We identified a distinct profile of neurogenesis in SuperAgers that may reflect a 'resilience signature'. Finally, alterations in the profile of astrocytes and CA1 neurons govern cognitive function in the ageing hippocampus. Together, our study points to a multiomic molecular signature of the hippocampus that distinguishes cognitive resilience and deterioration with ageing.

Link: https://doi.org/10.1038/s41586-026-10169-4

The composition of the gut microbiome changes with age. Microbial species capable of provoking inflammation, by infiltrating tissues or via production of harmful metabolites, grow in number. This occurs at the expense of populations that produce beneficial metabolites, such as butyrate, known to promote function in a number of different tissues. The reasons for this shift of composition are not fully understood, especially since meaningful change starts to occur relatively early in adult life. Immune dysfunction likely plays a significant role, however, as the immune system is responsible for gardening the gut microbiome, keeping harmful species to a minimum.

Rejuvenation of the aged gut microbiome via fecal microbiota transplantation from a young donor has been shown to improve health and extend life in animal studies. To what degree are these benefits a restoration of youthful microbial metabolite production versus a removal of inflammatory species, however? Today's open access paper provides evidence to suggest that it is mostly a matter of reducing the production of harmful metabolites. The researchers did not rejuvenate the aged microbiome in old mice, but instead used high dose antibiotic treatment to greatly reduce all microbial populations in the gut. This allowed the assessment of health and physiology in an environment in which the production of harmful microbial metabolites was also greatly reduced.

The result reported in the paper is a significant improvement in aspects of brain health. Removing the gut microbiome in this way is not a viable approach to therapy for the population at large, but the results reported here suggest that benefits will arise from any approach that successfully reverses the increase in numbers of harmful microbes that is characteristic of the aged gut microbiome. Restoring the youthful population sizes of helpful microbes is good, but likely less important to the benefits demonstrated in animal studies of gut microbiome rejuvenation via fecal microbiota transplantation.

Microbiome depletion rejuvenates the aging brain

Aging is associated with cognitive decline and increased vulnerability to neurodegeneration driven by an array of molecular and cellular changes like impaired vascular integrity, demyelination, reduced neurogenesis, and chronic inflammation. Recent studies implicate the gut microbiome as a modulator of brain aging, but the underlying mechanisms remain elusive. Here, we show that depleting the gut microbiome by administering antibiotics to aged mice induces widespread molecular and structural rejuvenation in the brain.

Our transcriptomic analyses by single-nucleus RNA sequencing revealed pronounced transcriptional shifts across multiple brain cell types. We confirmed that antibiotic treatment improves vascular density, promotes myelination, enhances neurogenesis, and reduces microglial reactivity. Functionally, microbiome-depleted mice showed improved hippocampal memory performance. Analyses of brain and plasma cytokine levels showed a decrease in several pro-inflammatory factors post-treatment and identified candidate factors, including the chemokine eotaxin-1. Inhibiting eotaxin-1 alone can reverse several aspects of brain aging.

Our findings demonstrate that age-associated microbial inflammation contributes to brain aging and that its attenuation can restore youthful features at the molecular, cellular, and functional levels. Targeting the gut microbiome or its circulating mediators may therefore represent a non-invasive approach to promote brain health and cognitive resilience in aging.

Some gene sequences can give rise to circular RNAs when transcribed. As a class, circular RNAs are not as well studied as other classes of molecule in the cell, but it is becoming apparent that, as for just about everything one might find in a cell, some circular RNAs become relevant in the context of aging. Here, researchers discuss findings relating to circular RNAs generated from mitochondrial genes. In particular circular RNAs for MT-RNR2 appear to meaningfully affect mitochondrial function, and lower levels of MT-RNR2 in older individuals may be involved in the age-related decline of mitochondrial function. The best way forward to a greater understanding is to manipulate MT-RNR2 expression and see what happens as a result. In general, improved mitochondrial function should be a good path to the production of therapies that improve health, but the question is always how great an improvement can be achieved, and that remains to be seen in this case.

During mammalian aging, there are changes in abundance of noncoding RNAs including microRNAs, long noncoding RNAs, and circular RNAs. Although global profiles of the human transcriptome and epitranscriptome during the aging process are available, the existence and function of mitochondrial circular RNAs originating from the mitochondrial genome are poorly studied. Here, we report profiles of circular RNAs annotated to the mitochondrial chromosome in young and old cohorts.

The most abundant circular RNA junctions are found in MT-RNR2, whose level is depleted in old cohorts and senescent fibroblasts. The mitochondria-localized RNA-binding protein GRSF1 binds various mitochondrial transcripts, including linear and circular MT-RNR2, with a distinct RNA motif. Linear and circular MT-RNR2 bind a subset of TCA cycle enzymes, suggesting their possible function in regulating glucose metabolism in mitochondria to preserve proliferating status in young cohorts. In human fibroblasts, depletion of GRSF1 reduced levels of circMT-RNR2 and fumarate/succinate, concomitantly accelerating cellular senescence and mitochondrial dysfunction.

Taken together, our findings demonstrate the existence and possible function of circular MT-RNR2 during human aging and senescence, implicating its role in promoting the TCA cycle. Future mechanistic studies will reveal how these mitochondrial circular RNAs are produced by trans-splicing, possibly, and how the circular RNAs accelerate the TCA cycle to preserve the proliferation status and suppress senescence as well as aging.

Link: https://doi.org/10.18632/aging.206354

The brain requires a great deal of energy to function. That energy is provided by mitochondria, hundreds of these organelles in every cell producing the chemical energy store molecule adenosine triphosphate (ATP), that activity reliant on the nutrients and oxygen delivered via the vascular system. The brain operates at the limit of its metabolic capacity even in youth, as demonstrated by the fact that exercise and the consequent increased supply of blood to the brain transiently increases cognitive function. Mitochondrial function declines with age, and this has consequences. But as researchers show here, improving the capacity of mitochondria to provide the cell with energy can enhance cognitive function at any age.

Expensive energy usage in neurons must be limited to avoid unnecessary overconsumption of fuels in the brain that could otherwise be useful for survival. During neuronal activity, synapses synthesize the exact levels of energy that are consumed during each firing event, without underproducing or overproducing ATP. While the work of several laboratories has identified how mitochondrial metabolism is upregulated on demand in activated neurons to preserve the metabolic integrity of synapses, the importance and the molecular identity of mechanisms slowing down mitochondrial metabolism after firing have remained elusive.

From insects to mammals, essential brain functions, such as forming long-term memories (LTMs), increase metabolic activity in stimulated neurons to meet the energetic demand associated with brain activation. However, while impairing neuronal metabolism limits brain performance, whether expanding the metabolic capacity of neurons boosts brain function remains poorly understood. Here, we show that LTM formation of flies and mice can be enhanced by increasing mitochondrial metabolism in central memory circuits.

By knocking down the mitochondrial Ca2+ exporter Letm1, we favour Ca2+ retention in the mitochondrial matrix of neurons due to reduction of mitochondrial H+/Ca2+ exchange. The resulting increase in mitochondrial Ca2+ over-activates mitochondrial metabolism in neurons of central memory circuits, leading to improved LTM storage in training paradigms in which wild-type counterparts of both species fail to remember. Our findings unveil an evolutionarily conserved mechanism that controls mitochondrial metabolism in neurons and indicate its involvement in shaping higher brain functions, such as LTM.

Link: https://doi.org/10.1038/s42255-026-01451-w

The longevity industry will at some point diffuse into the broader pharmaceutical and biotech industries. It will cease to be so distinct in culture, technology, and regulation as to merit the drawing of firm lines. Treating aging as a medical condition is no longer looked upon as strange by the powers that be, even though the public at large has yet to catch up entirely to this new viewpoint. This relatively new environment of approval means that sizable funding is available, and indeed deployed in large amounts to advance the cause, both by private and public sources.

One of the US government programs in which program managers have become very sympathetic to the cause of treating aging is ARPA-H, portions of which one might think of as spiritual successors to the attitudes and aims of DARPA, except that the focus is progress in medical technology specifically. That clinical trials are so enormously expensive to prepare for and run is the fault of government regulatory bodies, a mess created over decades. Now another arm of government will feed public funds into that process to enable more groups to make progress in passing the financial hurdle that regulators created. As is usually the case, however, it is largely the already well funded, high-profile initiatives that receive that assistance; if one is connected enough to have a large chance of obtaining major government funding, one is connected enough to be able to raise just as much from private sources, and have probably already done so.

Regardless, medicine is a highly regulated industry, and this is how the game is played in any industry in which government appointees exert such a large degree of control over what does and does not happen. In these years in which the first therapies that might slow aging (or in a few cases selectively reverse aging) are making their way into clinical trials, most groups are indeed trying to play the game as it exists, with all of its flaws, as in the bigger picture it is vital to demonstrate to the world at large that the treatment of aging can be real. An increasing number of companies are looking for alternative paths, however, such as those setting up their initial clinical trials in much less costly locations, and intending to initially prove their worth and provide access via medical tourism. From a very high level perspective, the most important outcome for the next decade or two is that therapies for aging, as many different approaches as possible, are meaningfully tested in humans - however that outcome is achieved. Even a few successes will give rise to a massively larger industry, with enough weight behind it to meaningfully change the way in which medical development takes place.

ARPA-H pours millions into healthspan-focused human trials

The US Government, via its Advanced Research Projects Agency for Health (ARPA-H) initiative, is putting up to $144 million into multiple projects aimed at extending healthspan - the years people live in good health. Through its PROSPR program, ARPA-H is funding seven research teams working to treat aging as a tractable biological process, and proving, in humans, that intervening earlier can help people stay healthier for longer.

Short for "Proactive Solutions for Prolonging Resilience," PROSPR's goal is to overcome one of the key challenges that has limited clinical development in geroscience: aging is slow, and its associated diseases and conditions can take years or decades to emerge, making conventional trials unwieldy and expensive. The initiative aims to use longitudinal human data to identify early, actionable biomarkers that respond before late-stage outcomes appear. Those biomarkers are intended to serve as surrogate endpoints that can show, within one to three years, whether an intervention is plausibly shifting an individual's trajectory toward better function, resilience, and quality of life.

Longevity biotech Cambrian has been awarded up to $30.8 million to support human trials of a daily, oral, next-generation rapamycin analog intended to selectively inhibit mTORC1. The company views dysregulated mTORC1 signaling as a key driver of the metabolic decline that accumulates with age, and it is tying its program to "intrinsic capacity," a composite measure of physical and metabolic resilience that declines over time.

Linnaeus has been awarded up to $22 million to advance a drug targeting the G protein-coupled estrogen receptor (GPER) into human trials for healthspan preservation. Interestingly, the company is building on its work in oncology, where more than 100 cancer patients have been treated with its drug (LNS8801) in early human trials and signals observed in those patients suggested potential translation into aging-related benefits.

TDP-43 is a protein only relatively recently discovered to undergo pathological modification and aggregation in the aging brain. Much like amyloid-β, α-synuclein, and tau, this aggregation is thought important in the progression of specific neurodegenerative conditions. Here, researchers present evidence for TDP-43 aggregation to contribute to lost function in vascular dementia. Vascular dementia arises from a reduced blood supply to the brain, or other issues in the vasculature supplying brain tissue with the oxygen and nutrients it needs. The brain operates at the edge of metabolic capacity at the best of times, and as that supply diminishes with age, function suffers. Can some of the consequent damage done to the brain be prevented? Obviously it would be ideal to maintain a healthy vasculature instead of trying to compensate for vascular aging, but the research community does spend a lot of time looking at possible compensatory approaches, ways to sabotage at least some of the maladaptive reactions to the damage and dysfunction of aging.

Vascular dementia (VaD) ranks as the second most common cause of dementia worldwide and is linked to the highest mortality rate among dementia subtypes. A key driver of VaD pathogenesis is chronic cerebral hypoperfusion (CCH), a state of persistently reduced blood flow to the brain stemming from cerebrovascular compromise. A hallmark of VaD, CCH can diminish cerebral blood flow by as much as 40%, triggering hypoxia-induced cellular stress. This includes oxidative damage, mitochondrial failure, and heightened neuroinflammation, which collectively impair blood-brain barrier integrity and promote white matter lesion (WML) formation.

Recent evidence points to Tar DNA-binding protein 43 (TDP-43) as a potential mediator in this cascade. While TDP-43′s pathological role is well-established in amyotrophic lateral sclerosis (ALS), frontotemporal dementia, and Alzheimer's disease (AD), its involvement in VaD is poorly understood. In healthy neurons, TDP-43 is crucial for synaptic function and stress response. Under pathological conditions, however, it undergoes detrimental modifications, including hyperphosphorylation, nuclear-to-cytoplasmic mislocalization, and aggregation that are common processes across neurodegenerative diseases. These aberrant forms of TDP-43 lose their normal function and can acquire toxic properties, potentially exacerbating neuroinflammation. While TDP-43 pathology is a well-established feature of several neurodegenerative diseases, its potential role in the context of cerebrovascular injury remains largely unexplored.

This study demonstrates that CCH, a key feature of VaD, triggers pathological TDP-43 changes, namely cytoplasmic mislocalisation and hyperphosphorylation, in both in vivo and in vitro models. In a mouse model of VaD, time-dependent cytoplasmic accumulation of TDP-43 and pTDP-43 was observed in cortical and hippocampal neurons, with elevated pTDP-43 despite stable total TDP-43 levels, implicating phosphorylation in its aberrant redistribution. These results mirror hallmark features of TDP-43 proteinopathies in neurodegenerative diseases, such as ALS and AD, and suggest that similar mechanisms may be triggered by vascular insults.

Link: https://doi.org/10.1002/alz.71196

Researchers here report an association between late life survival and levels of specific piwi-interacting RNAs. This subcategory of non-coding RNAs, meaning RNA molecules that are not translated into proteins, has attracted more interest of late in the context of aging and age-related changes to the regulation of gene expression. The understanding of the role of non-coding RNAs in metabolism lags behind the still incomplete understanding of proteins. The life science community is slowly filling in an enormous map of interactions, a map that will contain many large dark areas for a long time yet. There are only so many researchers, and developing a reasonably complete understanding of how even a single protein or RNA contributes to cell metabolism requires years of work in the best of circumstances.

To investigate the relevance of small RNAs to human longevity, we pursued three goals: (a) to validate epigenetic (small RNA) factors underlying survival of older adults, (b) to develop and validate prediction models of survival for potential clinical application, and (c) to identify plausible druggable targets prolonging longevity. We evaluated 828 small non-coding RNAs - 687 microRNAs (miRNAs) and 141 piwi-interacting RNAs (piRNAs) - in baseline plasma from 1271 community-dwelling older adults (≥ 71 years) in the EPESE study. Our predictive model incorporating small RNAs, clinical variables (demographics, lifestyle, mood, physical function, standard clinical laboratory tests, NMR-derived lipids and metabolites, and medical conditions) and age achieved strong performance, with cross-validated area under the curve (AUC) values of 0.92 for 2-year survival in Discovery and 0.87 in external Validation.

Nine piRNAs, all reduced in longer-lived individuals, were identified as potential therapeutic targets. Under the assumption of causal sufficiency, these data provide causal evidence linking circulating small RNAs with survival outcomes in humans. While such inference does not replace experimental validation, it complements mechanistic studies by identifying candidate molecular drivers most relevant to human longevity. Supporting biological plausibility, reduced piRNA biogenesis has been shown to double lifespan in C elegans. Together, our findings identify circulating piRNAs and miRNAs as promising biomarkers and potential therapeutic targets to advance human longevity.

Link: https://doi.org/10.1111/acel.70403