Fight Aging!

Startup biotech companies have started to use the publication of preprint scientific papers as a way to enhance their standing with investors; putting out a preprint is considerably faster than formal publication, and requires no review process. Many startups undertake programs of research and development that are novel enough to have little in the way of a foundation of prior scientific literature, and thus this is one area of scientific publication in which more weight than usual should be given to the peer review process. In particular, one should be skeptical regarding claims of very large extension of life span in animal models in preprint papers.

Yes, someone will turn up at some point with a surprising, novel approach to rejuvenation that is impressive in comparison to the past scope of slowed aging and extended life in mice, and perhaps that program will be wrapped in a biotech company, and perhaps they will want the benefits of publishing as soon as possible rather than waiting on review. That future seems inevitable, given the pace of progress in aging research and the trend towards opening and democratizing the peer review process. Nonetheless, extraordinary claims still require extraordinary evidence. The history of claimed extension of life span in mice is littered with failed replication, and particularly so for studies that used small numbers of mice and claimed a large extension of life.

The startup biotech program reported in today's preprint paper is conducted by Sentcell. It is interesting and novel enough for the rest of the world to be skeptical until much more work on the topic is published. The size of the reported extension of life in mice resulting from their novel therapy is very large relative to the best that can be achieved via established approaches; large enough to reduce the credibility of the work, especially given the small numbers of mice used per study group. The researchers claim to have isolated a particular subset of cell communications that induces rejuvenation, which in and of itself is reasonable. Many companies and research groups are indeed exploring how cells might change one another's behavior for the better. Consider that stem cell therapies produce benefits via the signaling of transplanted cells as one example among many. It is the size of gain in mouse life span reported here that calls for a far greater body of supporting evidence in order to be taken at face value, given how very much larger it is than the effects of, e.g. stem cell therapies, exosome therapies, senolytics, and so forth.

CD4+ T cells confer transplantable rejuvenation via Rivers of telomeres

One theory attributes ageing to the accumulation of terminally differentiated or senescent cells in multiple tissues, disrupting homeostasis. A true fountain of youth would need to target senescent cells across organs, be tightly regulated, and transfer youth-promoting activity from a young organism to an old one - as in the original parabiosis studies. One rejuvenation candidate arises from telomere transfer between immune cells. We previously showed that antigen-presenting cells (APCs) donate telomere-containing vesicles to CD4+ T cells during immune synapse formation, extending their telomeres, preventing senescence, and generating long-lived, stem-like memory T cells.

Here we show that, after telomere acquisition, recipient CD4+ T cells undergoing fatty acid oxidation, assemble and release "Rivers" of telomeres into the circulation. These Rivers recycle surplus APC telomeres unused by the T cells and rejuvenate tissues throughout the body, extending lifespan - an unprecedented programme in which CD4+ T cells transmit youth-promoting signals between organisms. While analysing antigen-specific T cell memory responses, we observed that APC telomere transfer was accompanied by abundant extracellular telomeric material. Histology revealed that these extracellular telomeres were not merely tethered to T cells but arranged in vessel-like networks, suggesting release into circulation. The elongated, punctate structures appeared to flow along these networks, evoking miniature streams of genetic material - henceforth referred to as telomere Rivers.

In aged mice, adoptive transfer of young or metabolically reprogrammed CD4+ T cells triggered River production in vivo, and Rivers isolated from these animals could be transplanted into other aged mice to propagate the rejuvenation phenotype independently of T cells. River therapy extended median lifespan by ∼17 months, with several mice surviving to nearly five years. This immune-driven telomere transfer pathway is conserved across kingdoms, including plants, defining the first systemic, transplantable programme of youth.

The chemistry of structural proteins in the lens of the eye changes with age in ways that render the lens less flexible, contributing to vision issues such as presbyopia, and eventually degrade its transparency. Age-related cataracts are the outcome of chemical alterations that cloud the lens and eventually lead to blindness. Better understanding the chemistry involved in this loss of transparency should hopefully lead to ways to replace the problematic molecular structures, or at least help to prevent the early stages of their formation. This is more challenging for the lens of the eye than is the case for most tissues that become damaged with age, as there is at best very limited natural replacement of the structural proteins of the lens. At present, replacement approaches are focused on surgery to replace the lens rather than any sort of nanoscale, chemical intervention that preserves the existing tissue.

The human eye lens plays an essential role in vision by focusing light onto the retina. This transparent tissue consists of densely packed crystallin proteins that exhibit remarkable solubility despite minimal protein turnover. Unlike most proteins, which are continuously recycled, crystallins must remain stable and soluble throughout the human lifespan. Aging causes damage to the lens, primarily via photochemical oxidation. Over time, this causes crystallin aggregation and leads to cataract.

Although understanding oxidative damage is critical to understanding cataract formation and how it can be prevented, it is difficult to study in native biological systems. Here, we use genetic code expansion to introduce an oxidation product, 5-hydroxytryptophan (5HTP), in a key site in human γS-crystallin, enabling it to be specifically investigated under controlled conditions. Replacing a critical tryptophan residue with 5HTP leads to reduced stability and increased aggregation.

Link: https://doi.org/10.1016/j.bpr.2026.100251

Take an aging population and a measure of function, and on average that measure will decline over time. That is degenerative aging in a nutshell, a loss of function, eventually including the very important function of staying alive. Within the environment of an average decline, however, it is possible to find individuals who manage to improve function between time points. Consider that it is well demonstrated that even very old people can improve capacity and reduce mortality risk by undertaking programs of structured exercise and strength training, for example. Few of us are exercising to an optimal level.

A widespread assumption exists among scientists, health care providers, and the public that later life is a time of inevitable and universal cognitive and physical decline. This assumption is likely due to considering older persons who improve to be exceptions, and the reliance on aging-health measures that do not allow for improvement. In contrast, we utilized a measure that allowed for an upward trajectory to occur. Our objective was to examine whether a meaningful number of older persons improve with this measure and, if so, to examine whether a promising modifiable culture-based variable, positive age beliefs, contributes to this improvement.

Individuals 65 years and older, who participated in a nationally representative longitudinal study, had their physical health assessed by walking speed and their cognitive health assessed by a global performance measure. We calculated the percentage of the sample that showed improvement in each domain from baseline to the last measurement up to 12 years later. We also examined whether a positive-age-belief measure predicted this improvement in regression models. It was found that 45.15% of persons improved in cognitive and/or physical function over this period, and positive age beliefs predicted these two types of improvement, both with and without adjusting for relevant covariates.

Link: https://doi.org/10.3390/geriatrics11020028

Species capable of exceptional regeneration also tend to have longer life spans and slowed aging relative to similar species with less proficient regenerative capabilities. Various closely related species of spiny mouse have been studied in the context of mammalian regeneration because of their ability to shed a large amount of skin and supporting tissues as a defensive mechanism, and later regrow that tissue without scarring. This exceptional regenerative capacity extends to at least some internal organs as well. Spiny mice have been used in past studies that pointed to differences in the activity of macrophage cells as one of the important determinants of complete regeneration versus scar formation.

Macrophages are innate immune cells that are deeply involved in ongoing tissue maintenance and regeneration from injury. Finding out exactly how differences in macrophage behavior are regulated in species capable of proficient regeneration, and whether those changes can be introduced into humans as a basis for therapy, remains an ongoing project. Today's open access paper extends this line of research to further link altered macrophage and broader immune behavior in spiny mice to a slowed pace of age-related decline. There is clearly a bigger picture here regarding aging, tissue maintenance, regeneration, and the innate immune system that researchers are in the early stages of assembling, step by step. At the end of the day it seems likely that there will be close ties between how the innate immune system regulates inflammation, its efficiency in certain activities, such as clearance of senescent cells, and both aging and regeneration.

Immunometabolic resistors of aging in long-lived golden spiny mice

One of the key manifestations of aging is a loss of biological resilience, including a slowdown in cell and tissue repair processes due to chronic sterile inflammation and metabolic stress. Long-lived wild rodents closely related to laboratory mice on the evolutionary scale may allow identification of dormant pathways that resist aging. Spiny mice (Acomys) are known for their exceptional regenerative capacity, but their resilience to aging is unknown.

Here, we report that aged golden spiny mice (Acomys russatus), reared in a non-pathogen-free environment, resist functional decline, have a greater repair capacity with reduced senescence in immune-metabolic organs compared to their sister species, eastern spiny mice (Acomys dimidiatus). Compared to A. dimidiatus, A. russatus retained high tissue repair capacity, reduced frailty with lower inflammaging, fibrosis, cellular senescence, and youthful transcriptome even beyond 4 years. Given that our A. russatus cohort was outbred and reared under non-SPF conditions, this model could be especially relevant for the identification of biomedically relevant mechanisms of health and longevity that are typically obscured in standard genetically identical laboratory mice.

Aged A. russatus maintains transcriptional integrity akin to young mice, highlighting experimental checkpoints for inflammation and mortality. A finding of immune system adaptation of A. russatus was the maintenance of functional thymic architecture till 4 years of age. Notably, the thymi of A. russatus were protected from lipoatrophy and involution, similar to naked mole-rat and long-lived fibroblast growth factor 21 (FGF21) transgenic mice that maintain naïve T cell repertoire till advanced age. We further identified that elevated levels of clusterin in A. russatus macrophages restrain inflammaging and enhance health span in aged mice. Thus, A. russatus biology reveals therapeutically actionable targets that may enhance or maintain function during aging.

Some of the organs in the body do not have to be in their current location, nor structured in a single mass of tissue, in order to carry out all of their functions. The liver is one of these organs. Many (not all, but many) of the functions of the liver could be carried out by small amounts of liver tissue distributed throughout the body. Thus the existence of companies like Lygenesis, shepherding clinical trials of liver tissue organoid transplantation into lymph nodes to help restore lost function. Here, researchers report on the early stages of development for an alternative approach that is even less like normal liver tissue, essentially just an injection of cells and hydrogel rather than any production of structured tissue for transplantation, but that nonetheless produces a small volume of pseudo-tissue at the injection site that can carry out many of the functions of the liver.

Liver transplantation remains the standard treatment for end-stage liver failure, yet it is limited by donor scarcity, surgical complexity, and poor accessibility. Cell-based therapies offer an alternative, yet their translation has been hindered by low engraftment, poor localization, and a lack of delivery strategies that are both effective and minimally invasive. To address these challenges, we developed injected, self-assembled, image-guided tissue ensembles (INSITE), an injectable platform composed of primary human hepatocytes (PHHs) and hydrogel microspheres that assemble in situ into supportive, vascularizable scaffolds following image-guided delivery.

Ultrasound-guided delivery into an ectopic site enabled precise graft localization, persistent noninvasive imaging, and vascular integration in vivo. Hepatocytes remained confined within these scaffolds and maintained long-term functional activity. Furthermore, tuning material properties allowed control over scaffold remodeling and vascular recruitment to enhance graft function. By integrating image-guided delivery with a modular scaffold, INSITE establishes a clinically compatible strategy for advancing minimally invasive cell therapies.

Link: https://doi.org/10.1016/j.celbio.2026.100378

Researchers here mount an argument for aging to have evolved due to the interaction between (a) limited nutrient availability in the environment and (b) the options a cell has for generating the vital chemical energy store molecule adenosine triphosphate (ATP). Broadly, ATP can be generated via glycolysis in the cytoplasm or oxidative reactions in mitochondria, at least in eukaryotes such as mammals. Mitochondrial ATP production is slower and more energy-efficient, but both avenues decline with age. Loss of ATP production is harmful to cell and tissue function, most prominently in tissues with high energy needs such as muscle and the brain. Why does ATP production decline with age? The argument advanced here is that this decline evolved in part because it helps the survival of offspring by limiting parental consumption of resources, which borders on being a group selection mechanism. Group selection has long fallen out of favor, but a number of theories of aging, particularly those in the programmed aging category, have considered it to one degree or another.

Why do animals not have an eternal lifespan? Animals possess sophisticated systems that, in many species, appear capable of supporting immortality. Second, why do lifespans vary considerably among species despite similarities in genetic makeup, specifically the central dogma linking DNA, RNA, and protein synthesis, which warrants a molecular explanation? For example, elephants live thirty times as long as mice.

Significant differences between ATP production by glycolysis and oxidative phosphorylation include the quantity produced, production speed, and functional roles. Glycolytic ATP production is approximately 100 times faster than oxidative phosphorylation. ATP from glycolysis supplies rapid energy during acute demands, while oxidative phosphorylation supports basal/homeostatic cellular energy needs. Glycolysis plays important role in cell division and DNA repair. Additionally, the glycolysis activator HIF-1α promotes mitochondria repair through mitophagy. These findings suggest that decreased glycolytic ATP production during aging may underline various age-related symptoms. Immortal cells exhibit a metabolic profile characterized by highly active glycolytic ATP production and HIF-1α activation, even in oxygen-rich conditions.

Populations of species cannot grow infinitely, and one of the major limiting factors in natural world is food supply. The shift from glycolysis to aerobic metabolism increases energy efficiency, benefiting individual survival during food shortages, which can be caused by environmental changes or emergence of competitors for the food. This indicates that reduced glycolytic ATP production with aging can benefit the species by enhancing survival of parent generation at starvation conditions and allocating food to offspring generation in natural world where food supply is limited. Only species that happened to have an optimal rate of reduction in glycolytic ATP production over time were selected and survived through generational changes.

The optimal rate of glycolytic ATP decline for survival varies among species and depends on factors such as environment, competition, maturation time, and body size. This concept clarifies the significant differences in aging rates and lifespans across species despite largely conserved biological components. This is exemplified by the naked mole rat, an exceptionally long-lived species that lives underground where there are few environmental changes and predators, and maintains unrestrained glycolytic flux and ATP supply to adapt to underground life with low oxygen levels.

Link: https://doi.org/10.18632/aging.206356

Mitochondria are the power plants of the cell, vital to cell and tissue function. Mitochondria become damaged and dysfunctional with age, unfortunately, and this is thought to be a major contribution to age-related degeneration. That cells will take up mitochondria from the surrounding environment and put them to use has been established for some years. It is the basis for the development of mitochondrial transplantation therapies as a way to improve cell function in old tissues, delivering youthful mitochondria to augment the activities of native mitochondria that have been impaired by mechanisms of aging. Meanwhile, the research community continues to explore how exactly cells achieve uptake of mitochondria, as greater knowledge of the details may lead to ways to significantly improve on the coming first generation of mitochondrial transplantation therapies.

In today's open access paper, researchers report results from their study of how exactly the processes of endocytosis can be used to ingest mitochondria while preserving their structure and function. As a mitochondrion comes into contact with the exterior of the cell membrane, a region of the membrane wraps around the mitochondrion and then breaks off to bring it inside the cell, wrapped in an endosome. At some point the endosome is removed and the mitochondrion is fully internalized, intact and able to contribute to cell metabolism. This is a very high level description; there are a number of functionally distinct forms of endocytosis, and it appears that different types of endocytosis are used interchangeably for mitochondrial uptake, making it a more robust behavior.

Uptake mechanisms and functions of isolated mitochondria in mesenchymal stromal cells

Mitochondrial transplantation holds great promise as a therapeutic strategy; however, the mechanisms by which recipient cells interact with and internalize isolated mitochondria remain unclear. Therefore, in this study, we isolated functional mitochondria from mesenchymal stromal cells (MSCs) and characterized their biological activities and physicochemical properties. Additionally, effects of isolated mitochondria on MSC functions were evaluated.

Treatment with isolated mitochondria promoted cell proliferation, improved cellular viability under stress conditions, and increased the oxygen consumption rate, indicating enhanced bioenergetic capacity. Uptake of isolated mitochondria by MSCs was visualized via fluorescence imaging and quantitatively assessed over time, showing progressive internalization within 24 hours. To investigate the mechanism of mitochondrial uptake, endocytosis was chemically inhibited, which revealed that endocytic pathways contributed to the internalization of the isolated mitochondria.

These findings suggest that MSCs incorporate isolated mitochondria via active uptake mechanisms and that the internalized mitochondria retain their functional activity. Collectively, our results provide critical evidence of mitochondrial internalization in MSCs and offer insights into the potential applications of mitochondrial therapy for various diseases.

A number of existing classes of drug are suspected to be geroprotective to some degree, altering metabolism in ways that either reduce ongoing cell and tissue damage or help to resist some of the consequences of that damage. We should expect effects on life span at established doses to be modest at best, but there is always the question of how large an effect on human life span can remain hidden because no-one was looking all that hard for it. Here, researchers present evidence for a commonly used PPARα agonist to slow aging in various mouse model. It remains a question as to whether effects in humans are meaningful in comparison to, say, the established benefits of regular exercise.

Aging poses a growing global health burden, creating an urgent need for effective interventions. This study reveals that fenofibrate, a clinically approved drug for hyperlipidemia, exerts significant anti-aging effects by targeting fundamental aging processes. We demonstrated that fenofibrate treatment delays systemic aging in D galactose-induced aging mice, 18-month-old mice, and SAMP8 mice and reverses cellular senescence. Mechanistically, fenofibrate ameliorates age-related lipid accumulation, as evidenced by lipidomic profiling and histological analyses in both cellular and animal models.

Notably, we identify carnitine palmitoyl transferase 1 C (CPT1C) as a crucial mediator of fenofibrate's ability to restore mitochondrial function in senescent cells, as validated by comprehensive metabolic analyses. Fenofibrate is a specific peroxisome proliferator activated receptor α (PPARα) agonist. These effects are mediated through PPARα activation, upregulating downstream metabolic regulators CPT1C. Fenofibrate cannot reverse aging in Pparα knockout mice, establishing that its anti-aging effects are strictly PPARα-dependent.

Our findings demonstrate that fenofibrate delays aging progression of mice and reverses cellular senescence in the PPARα-dependent way. Fenofibrate attenuates lipid accumulation and mitochondrial dysfunction in senescent cells and aged mice by activating the PPARα-CPT1C axis. This research provided the first evidence that pharmacological PPARα activation can directly modulate natural aging through coordinated improvement of lipid metabolism and mitochondrial function. The clinical relevance is underscored by the safety profile and widespread use of fenofibrate, suggesting its immediate potential as a repurposed anti-aging therapeutic. Furthermore, this work establishes PPARα as a master metabolic regulator of aging processes and reveals CPT1C as a novel therapeutic target for age-related metabolic dysfunction.

Link: https://doi.org/10.1016/j.phrs.2026.108154

Periodontitis, the formal name given to inflammatory gum disease, is known to correlate to risk of a range of age-related conditions, including osteoporosis, the loss of bone mass and strength that occurs with age. A number of different mechanisms may be responsible for these correlations, and it remains a matter for debate as to which is most important. In the context of cardiovascular disease, researchers have focused on leakage of oral bacteria and inflammatory metabolites into the circulation via injured gums. Here, in the context of osteoporosis, researchers suggest that the oral bacteria responsible for periodontitis can alter the composition of the gut microbiome in ways that impair bone tissue maintenance, favoring the destruction of bone extracellular matrix by osteoclasts over matrix deposition by osteoblasts.

Epidemiological studies have highlighted an association between periodontitis and osteoporosis. However, the mechanism underlining this association remains unclear. Here, we revealed significant differences in the salivary microbiota between periodontally healthy individuals and periodontitis patients, with periodontitis patients exhibiting increased salivary microbiota diversity and an elevated abundance of pathogenic bacteria.

Using an ovariectomized (OVX) mouse model, we demonstrated that the salivary microbiota from periodontitis patients exacerbated bone destruction by modulating the gut microbiota. Metabolomic analysis revealed that the periodontitis-associated salivary microbiota suppressed tryptophan metabolism. The tryptophan metabolite indole-3-lactic acid (ILA) directly inhibited osteoclast formation and differentiation. In OVX mice treated with periodontitis salivary microbiota, supplementation with ILA effectively suppressed osteoclastogenesis and alleviated the detrimental effects of periodontitis-associated salivary microbiota on systemic bones.

In summary, our data demonstrate that periodontitis can affect systemic bone metabolism via the oral-gut axis and that ILA supplementation serves as a potential therapeutic option to mitigate these adverse effects.

Link: https://doi.org/10.1038/s41368-025-00415-2

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