Fight Aging!

The peptide industry has been growing for some years now, becoming more vocal and visible. It occupies a similar space to the supplement industry, and seems likely to provoke many of the same battles with regulators such as the FDA. Peptide use is characterized by the same lack of rigorous supporting data that attends supplement use, and for many of the same reasons. The lines in the sand dividing peptide from drug are just as arbitrary as those dividing supplement and drug, and just as driven by funding and the high cost of regulatory compliance. Peptides that can be effectively monopolized via intellectual property become drug candidates, as only with that monopoly is it possible to raise enough funding to engage with regulators and run clinical trials. Peptides that cannot remain on the outside, without the robust human data needed to support greater interest.

Against the background of this broader context of a growing market for the use of peptides, you might recall that the peptide FOXO4-DRI was one of the early potential senolytic therapies to be validated in animal studies, back in the mid-2010s. FOXO4-DRI interferes in the interaction between FOXO4 and p53 that normally inhibits apoptosis of senescent cells, and thus results in the selective destruction of senescent cells with very little impact on other cells. Clearance of senescent cells is well demonstrated to improve health in aged animal models, but only relatively small clinical trials of a few senolytic small molecules have yet taken place to validate use in humans.

A company, Cleara Biotech, was formed to commercialize the early academic work on FOXO4-DRI, and appears to still be a going preclinical concern focused more on the FOXO4-p53 interaction than on FOXO4-DRI per se. Other groups have since become involved, such as Numeric Biotech, and it has long been the case that anyone so minded can just up and buy FOXO4-DRI for personal use from any number of peptide sellers. It is unclear as how many people are choosing to do that, and certainly we'll never see any sort of useful data resulting from that use. Meanwhile, academic research groups continue to work with FOXO4-DRI as a tool to explore the FOXO4-p53 interaction in the context of cellular senescence as a driver of degenerative aging.

FOXO4-DRI regulates endothelial cell senescence via the P53 signaling pathway

Endothelial cell dysfunction during aging is a key driver of vascular aging and related diseases; however, effective strategies to selectively eliminate senescent endothelial cells and restore vascular function remain lacking. FOXO4-DRI, a novel peptide-based intervention, specifically disrupts the interaction between FOXO4 and P53, thereby inducing apoptosis in senescent cells. This study innovatively focuses on the mechanism by which FOXO4-DRI induces apoptosis in senescent endothelial cells, demonstrating that it functions by activating the p53/BCL-2/Caspase-3 signaling pathway to promote selective apoptosis of these cells. FOXO4-DRI significantly improves vascular function and delays vascular aging.

This study aims to analyze the vascular function and aging status of the aorta in naturally aged mice and progeroid model mice following FOXO4-DRI injection. Additionally, it investigates changes in endothelial cell function in senescent endothelial cells induced by oxygen-glucose deprivation (OGD), as well as the protein expression and interaction in the FOXO4-P53 signaling pathway. To assess the impact of FOXO4-DRI on endothelial cell senescence, the senescent endothelial cells were treated with FOXO4-DRI, followed by immunofluorescence and Western blotting experiments.

Injection of FOXO4-DRI in both naturally aged and induced aging mice effectively suppressed aortic aging and improved aortic function. Additionally, we found that FOXO4-DRI alleviates endothelial cell senescence induced by OGD, thereby enhancing endothelial cell function. Through co-immunoprecipitation (CO-IP) experiments, we discovered that FOXO4-DRI prevents the binding of FOXO4 to P53, facilitating the phosphorylated P53 nuclear exclusion, which subsequently trigger BAX and cleaved caspase-3, leading to the apoptosis of senescent cells. Ultimately, this mechanism achieves the goal of inhibiting vascular aging.

There are so many detrimental age-related changes in gene expression that it will always be possible to pick out any one gene exhibiting altered expression and spend years on research and development aimed at fixing this one specific issue. Restoring youthful expression of any one gene in any one tissue is an achievable goal for present day medical research and development, though costs and regulatory hurdles remain challenging. Expression can be increased via gene therapy vectors, or reduced via various approaches, such as small interfering RNA, that attack some part of the process of gene expression. The most productive future will not be one of picking through thousands of changes one by one, however, but instead a matter of attempts to restore youthful gene expression more generally, for most or all genes, through some form of reprogramming. Still, the one by one approach remains the primary focus of the research community, as this example illustrates, though at least researchers now tend to favor regulatory genes that influence the expression of large numbers of other genes.

O-GlcNAc Transferase (OGT) is responsible for the addition of β-O-linked N-acetyl-D-glucosamine (O-GlcNAc) to serine and threonine residues, thereby regulating more than 8000 human proteins through O-GlcNAcylation. In the brain, reduced O-GlcNAc levels, which can arise from insufficient OGT activity, have been increasingly linked to aging-related neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis.

While current strategies focus on restoring O-GlcNAc levels via O-GlcNAcase (OGA) inhibition, recent discoveries highlight transcript-level regulation of OGT as a direct and promising therapeutic target. This concept article explores the role of intron detention and decoy exon-mediated splicing repression in limiting OGT pre-mRNA maturation and proposes the use of antisense oligonucleotides or selective splicing factor degraders to promote productive splicing and nuclear export of OGT mRNA. By enhancing OGT expression independently of O-GlcNAc feedback, these approaches aim to restore proteostasis and improve resilience to neurodegeneration, offering a novel therapeutic approach for aging-related neurodegenerative diseases.

Link: https://doi.org/10.1002/cbic.202500774

Researchers here provide evidence for glycogen produced by the gut microbiome to contribute to age-related neurodegeneration. A mutation associated with amyotrophic lateral sclerosis and frontotemporal dementia appears to make the inflammatory consequences of microbiome-derived glycogen worse, thus potentially explaining its relevance to disease. But the prevalence of the microbes involved in the production of glycogen in the gut microbiome of patients with these conditions suggests that every older person is impacted by this mechanism to some degree, with that degree being dependent on the exact composition of the gut microbiome. This is one of a range of studies showing at least some correlation between gut microbiome composition and specific age-related conditions, and as illustrated here, researchers are starting to move beyond correlation to explore the mechanisms responsible.

Gut dysbiosis and neural inflammation occur in patients with amyotrophic lateral sclerosis (ALS), including those with a causal mutation in chromosome 9 open reading frame 72 (C9ORF72). How gut commensals interact with common ALS genotypes to impart risk of neural degeneration remains unclear. Here, we identify 10 phylogenetically diverse bacterial strains that promote cytokine release in a C9orf72-dependent manner. Metatranscriptomics implicated the glycogen biosynthesis pathway as a driver of inflammation.

Colonization of germ-free C9orf72-deficient mice with Parabacteroides merdae that produced inflammatory glycogen enhanced monocytosis, blood-brain barrier breakdown, and T cell infiltration into the central nervous system. Enzymatic digestion of glycogen in the gut promoted survival of C9orf72-deficient mice and dampened microglial reactivity in the brain.

A survey of human fecal samples demonstrated that inflammatory forms of glycogen were present in gut contents from 15/22 patients with ALS, 1/1 patient with C9ORF72 frontotemporal dementia (FTD), and 4/12 healthy controls. Together, the results of this work identify bacterial glycogen as a modifiable mediator of immune homeostasis in the gut and brain.

Link: https://doi.org/10.1016/j.celrep.2025.116906

The composition of the gut microbiome, the relative sizes of the various microbial populations, changes with age in ways that promote chronic inflammation and dysfunction throughout the body. The production of beneficial metabolites decreases, while microbes capable of provoking a constant inflammatory reaction increase in number. Studies of fecal microbiota transplantation have demonstrated that the unfavorable composition of the gut microbiome in old animals can be rejuvenated via the introduction of donor material from young animals. One treatment produces lasting rejuvenation, though presumably the processes of aging will slowly degrade the gut microbiome over time, just as they did before. Health is improved and life span increased.

Fecal microbiota transplantation sees enough use in medicine for researchers and clinicians to broadly understand the safety profile of the treatment, and for a body of work to have evolved regarding best practices for sourcing, screening, storing, and using donor material. But the most common use case, to treat C. difficile infections in which hostile bacteria have overrun the intestine, is not focused on older people, and donors do not necessarily tend to be younger people. Clinical trials that do provide evidence specifically for the use of young donor material to treat old patients are thin on the ground. So it is good to see that at least one group is making the effort to run such a trial; we might expect to see results in a few years.

Aging Resilience Through Microbiota Optimization and Regulation (ARMOR)

It has been proposed that changes in the gut microbiota in aging individuals, known as gut dysbiosis, contribute to sarcopenia. Species diversity decreases, and bacterial representation is altered, which could impair muscle function through various pathways, such as mitochondrial dysfunction, chronic inflammation, and disruption of protein synthesis. Muscle function loss is strongly associated with cognitive and metabolic impairment in older adults.

Recently, it has been demonstrated that fecal microbiota transplantation (FMT) is an effective procedure for modulating gut microbiota and has proven highly effective in managing cases of Clostridium difficile-associated chronic diarrhea. The main objective of this project is to carry out FMT from young, physically active donors to a cohort of older adults to evaluate its effect on muscle, cognitive, and metabolic function.

Why donors who exercise? There is growing evidence that gut microbiota diversity is increased in young, physically active individuals. The FMT is planned to be administered through lyophilized microbiota capsules. By restoring microbial diversity, it is expected to improve the quality and function of skeletal muscles, leading to greater cognitive and metabolic resilience.

Randomized, double-blind, placebo-controlled trial of fecal microbiota transplantation from young physically active donors to promote resilient aging: clinical trial protocol (ARMOR study)

Sarcopenia, characterized by the progressive loss of skeletal muscle mass and strength in older adults, is a key determinant of frailty and functional decline. Affecting up to 15% of individuals aged 65-80 years and more than 50% of those over 80, sarcopenia not only compromises physical autonomy but also increases the risk of metabolic dysfunction and cognitive decline. Emerging evidence suggests that age-related gut microbiota dysbiosis contributes to these impairments by reducing microbial diversity and altering host metabolic signaling, leading to chronic inflammation and mitochondrial dysfunction. The present study aims to evaluate the safety, tolerability, and preliminary efficacy of oral fecal microbiota transplantation derived from young, physically active donors administered to older adults, focusing on outcomes related to functional autonomy, muscle performance, metabolism and cognition.

This is a double-blind, randomized, placebo-controlled clinical trial involving community-dwelling adults aged 65-84 years. Participants will be randomized 1:1 to receive either FMT capsules or placebo following a short course of oral rifaximin (or placebo). Assessments will be performed at baseline and at 4, 8, and 20 weeks post-intervention. The primary outcomes are safety and tolerability, as well as changes in the Global Index of Functional Autonomy (GDLAM battery) and muscle strength. Secondary outcomes include gait speed, body composition (DXA), metabolic biomarkers, gut microbiota composition (shotgun metagenomics), cognitive performance, and psychological well-being.

By restoring microbial diversity and function, FMT from young, active donors may enhance muscle quality, cognitive resilience, and metabolic health in older adults. This study introduces a novel, non-invasive therapeutic approach based on lyophilized and encapsulated microbiota, offering a feasible and scalable strategy to promote healthy aging.

Aging is by far the greatest cause of human suffering and mortality. Yet is it in human nature to resist every change whether or not it is beneficial. It is also in human nature to accept what is. So the development of means to treat aging in order to prevent the present toll of suffering and death will be resisted, and then these means will come into being, exist, and be accepted. Along the way, a lot of ink will be spilled on why we should or should not make the world a better place in this way. Such is the way of things. Ignoring the debate to focus on building rejuvenation biotechnologies is probably the fastest way to create (a) therapies for aging that most people will choose to use and (b) a world in which most people accept this state of affairs as a good thing.

Humanity has long sought to mitigate the challenges of ageing and extend the span of healthy life. But for centuries, a story of resignation shaped the moral imagination: ageing and death were inevitable, so ethics concerned how best to accept them. This narrative is crumbling. Over the past few decades, biogerontology has revealed that ageing is not immutable. Lifespan has been extended by tenfold in nematodes and by 50% in mice. Cellular reprogramming, senolytic drugs, and genetic insights suggest that at least parts of the ageing process can be modified.

Due to the profound implications of such progress, ethical debate has followed close behind. However, most discussions have been dominated by consequentialist framings: balancing hoped-for benefits (e.g., reduced healthcare costs, productivity gains) against feared harms (e.g., overpopulation, inequality, loss of meaning). Both critics and advocates tend to treat longevity as a matter of projected outcomes, reducing the ethical question to a contest of demographic forecasts. What remains underexplored is a deeper foundation: whether anti-ageing research is justified independent of its consequences, rooted instead in duties, autonomy, and the intrinsic value of life itself.

We seek to further this discussion by grounding the case for longevity research not only in outcomes but also in respect for autonomy, self-ownership, and the intrinsic value of life itself. On this basis, we address three kinds of critiques: philosophical appeals to "naturalness", societal concerns about resources, justice, and stagnation, and individual worries about meaning and boredom, showing that none provide decisive objections. Beyond rebuttal, we highlight neglected benefits: longevity research drives technological integration like the Apollo program, affirms the priority of existing persons over abstractions, and liberates individuals from rigid age-based expectations. The moral baseline must flip: the burden now falls on defenders of forced ageing to explain why preventable suffering should continue.

Link: https://doi.org/10.1016/j.arr.2026.103054

The supporting cells of the brain are collectively known as glia. This category includes astrocytes, microglia, and oligodendrocytes, among others, cells that are responsible for maintenance of an environment in which neurons can function, or directly aiding neuron function in various ways. Researchers here discuss how age-related changes in the interactions between neurons and glia may both arise from neurodegeneration and drive neurodegeneration. Manipulating some of these interactions can slow aging and extend life span in flies.

Aging is often discussed as something that happens inside cells: DNA is damaged, mitochondria stop working, and proteins are misfolded. But aging also changes how cells communicate with each other. For example, neurons in the brain rely on neighboring cells, called glia, for nutrients, waste handling, and local repair. Dysregulation of the interactions between neuron and glia is considered a hallmark of brain aging, but the consequences of disrupting neuron-glia communications are still being uncovered.

Researchers compared glial cell-surface proteomes in young (5 day) and old (50 day) flies to examine how signaling molecules are regulated in the aging brain, and identified a set of 872 proteins that exhibited age-specific differences in abundance. Proteins that became more abundant with age were enriched for functions related to localization and transport, which supports the idea that older brains may need stronger homeostasis and trafficking control. In contrast, many proteins that became less abundant with age were associated with synapse organization, axon guidance, and related processes.

The researchers chose 48 genes that exhibited the greatest changes between the glial surface proteomes of young and old flies, and tested whether manipulating these genes in adult glia altered lifespan. One candidate from the screen, a cell adhesion protein called DIP-β, was found to extend lifespan in both males and females when overexpressed in glia. Older flies with higher levels of DIP-β in their glia also climbed better than controls, suggesting improved late-life function in addition to longer lifespan. Analysis suggested that DIP-β overexpression was associated with increased signaling between glia and neurons, and between glia and fat cells, with prominent shifts in a number of signaling pathways (such as the TGF-beta, Wnt, FGFR, and EGFR pathways). This is an appealing model because it connects a surface protein found in glia to broader tissue coordination during aging.

Link: https://doi.org/10.7554/eLife.110158

Nuclear DNA is surrounded by transcriptional machinery, protein structures that will attempt to transcribe any gene sequence they encounter. Where DNA is compacted into regions of heterochromatin by being spooled onto histones, genes are silenced because their sequences are hidden from transcriptional machinery. Whether a given stretch of DNA is compacted or not is determined by epigenetic mechanisms, largely decorations (such as methyl groups) attached to DNA and histones that alter their structural behavior. A general feature of aging is a loss of heterochromatin and increasing expression of genes and other sequences that are usually silenced in youth. This leads to, for example, the expression of transposons that can drive DNA damage and inflammation, but also disruption and change in normal cell function.

Some time ago, researchers established a way to visualize whether or not a given region of DNA is compacted into heterochromatin. Flies can be genetically engineered with suitably placed genes that change the color of some of their features, such as eye segments, depending on whether or not they are expressed. Thus just by looking at the fly, researchers will know whether or not the region of DNA containing the inserted gene is compacted. A number of different fly lineages have been constructed over the years, as researchers needed a solution for one region or another. This approach is called position effect variegation.

Today's open acccess paper is a discussion of position effect variegation as a tool to inspect changes in DNA compaction into heterochromatin that occur with age and their correlation with high level outcomes such as mortality risk and longevity. Since increased loss of heretochromatin appears to correlate with longevity in flies, position effect variegation could be used to build aging clocks (in flies at least) that primarily reflect alterations to DNA structure rather than other mechanisms.

Position effect variegation (PEV) as an aging clock: visualization of age-dependent loss of heterochromatin and longevity associated with enhanced heterochromatin

The heterochromatin loss model of aging suggests there is an age-dependent reduction in epigenetic factors that form and maintain the heterochromatin state of chromosomes. Position Effect Variegation (PEV) can visually report phenotypes of heterochromatin mediated silencing in Drosophila Melanogaster eyes and we use PEV to examine the association between heterochromatin state changes and aging.

Pericentric inserts causing PEV showed suppressed variegation phenotypes in old age compared to young age and were confirmed to be associated with progressively increasing transcription, indicating loss of heterochromatin mediated silencing. Within a single population, animals with enhanced PEV phenotypes live longer than those with more suppressed PEV phenotypes, suggesting that small differences in environmental or genetic factors within this population could be responsible for differences in heterochromatin and lifespan.

Environmental factors could enhance heterochromatin, reduced nutrient diet and lower temperature coincided with enhanced heterochromatin and longer life. Furthermore, genetic variants associated with long life, including chico mutants, lead to increased heterochromatin and enhanced PEV phenotypes. Therefore, aging can be linked to heterochromatin loss and developmental increases in heterochromatin are associated with longevity. Thus, PEV reporters act as aging clocks demonstrating loss of heterochromatin that progresses with age and epigenetic alterations that can promote longevity.

The addition and removal of methyl groups from specific locations on the genome is one of the epigenetic mechanisms used to control the structure of DNA in the cell nucleus, such as which sequences are hidden via compaction into heterochromatin and which remain accessible to allow the expression of genes. That the pattern of DNA methylation changes with age in characteristic ways is what allows the existence of epigenetic clocks, the use of DNA methylation status to assess biological age. That epigenetic control over gene expression changes with age also makes it a potential target for the development of therapies to treat aging, particularly now that partial reprogramming studies have amply demonstrated that reversing age-related epigenetic changes is possible in principle.

As individuals age, the precise regulation of DNA methylation gradually deteriorates, leading to widespread epigenetic drift. This loss of control results in both global hypomethylation and site-specific hypermethylation, disrupting normal gene expression patterns. Global hypomethylation can lead to genomic instability, activation of transposable elements, and oncogene expression, while localized hypermethylation may silence tumor suppressor genes or genes critical for immune regulation and metabolic function. These changes are increasingly recognized as contributors to the development of chronic diseases. For example, aberrant DNA methylation patterns have been implicated in cancer, cardiovascular disease, type 2 diabetes, and neurodegenerative disorders such as Alzheimer's disease.

One of the most promising trends is the integration of DNA methylation data with other layers of biological information, such as transcriptomics, proteomics, metabolomics, and microbiomics. This multi-omics approach offers a holistic view of aging by capturing complex molecular interactions/network that DNA methylation alone cannot fully explain. Combining these datasets can refine biological age estimates, identify novel aging biomarkers, and uncover mechanisms driving age-related functional decline.

Parallel to these analytical advances, there is growing interest in interventions targeting epigenetic aging. Lifestyle modifications, including diet, exercise, and stress management, have demonstrated potential to modulate DNA methylation patterns and slow epigenetic age acceleration. Pharmacological approaches, such as senolytics, epigenetic modulators, and novel small molecules, are under investigation for their ability to reverse or delay methylation-based biological aging. Clinical trials integrating methylation clocks as endpoints are beginning to evaluate the efficacy of these interventions, potentially enabling real-time monitoring of biological age and intervention impact.

Link: https://doi.org/10.3389/fmolb.2025.1734464

Rapamycin is the most well studied of the mTOR inhibitors. It produces immunosuppression at high doses, and has been used in this context in the clinic for more than twenty years. At lower doses it mimics aspects of the beneficial metabolic response to calorie restriction, om particular an increased operation of the cellular maintenance processes of autophagy. In animal studies this has been demonstrated to slow aging and extend healthy life. Human clinical trial data for this lower dose anti-aging usage remains relatively sparse, unfortunately, but the results that do exist are interesting.

Rapamycin is one of the most intensively studied compounds with potential effects on longevity. Available experimental data indicate that inhibition of the mTOR pathway and activation of autophagy lead to improved cellular homeostasis, reduced oxidative stress, and a slowing of aging processes across multiple model organisms.

Current clinical studies in humans, although limited in number and involving small populations, suggest that low doses of rapamycin may enhance immune function, reduce visible signs of skin aging, and positively influence well-being and metabolic parameters.

Despite these promising findings, knowledge regarding the long-term safety, efficacy, and optimal dosing regimens of rapamycin remains limited. Further, multicenter, randomized clinical trials are needed to determine whether modulation of the mTOR pathway can represent an effective and safe strategy to support healthy human aging.

Link: https://doi.org/10.7759/cureus.98514

Rapamycin and other mTOR inhibitors mimic some of the mechanisms making up the response to calorie restriction. Their most interesting effect is to increase the operation of autophagy in cells. Autophagy is a collection of processes responsible for recycling damaged or unwanted proteins and structures in the cell. A large proportion of the approaches shown to modestly slow aging in yeast, worms, flies, and mice are characterized by increased or more efficient autophagy; it is a universal response to stress of any sort placed upon a cell. Too much autophagy can be a bad thing, but a modest increase improves health in the context of the dysfunctional, damaged environment of aged tissues.

Another feature of mTOR inhibitors, and the age-slowing interventions that are characterized by upregulated autophagy, is that the burden of harmful, inflammatory senescent cells that linger in aged tissues is reduced. The present thinking on this topic is that this reduction does not occur because senescent cells are destroyed by the intervention, but rather that the pace at which cells become senescent is reduced. This seems sensible: more autophagy allows cells to better maintain function and resist damage, and thus fewer cells will be tipped over the line into senescence in response to damage.

Here, however, researchers argue that, at least in immune cells, the effects of mTOR inhibition on cellular senescence do not emerge from autophagy. Instead, there is a direct effect on the burden of DNA damage in these cells, and it is that reduced DNA damage that leads to a reduced number of cells becoming senescent. Further work will have to be conducted in order to fully understand how exactly mTOR inhibition produces this outcome.

Rapamycin Exerts Its Geroprotective Effects in the Ageing Human Immune System by Enhancing Resilience Against DNA Damage

mTOR inhibitors such as rapamycin are among the most robust life-extending interventions known, yet the mechanisms underlying their geroprotective effects in humans remain incompletely understood. At non-immunosuppressive doses, these drugs are senomorphic, that is, they mitigate cellular senescence, but whether they protect genome stability itself has been unclear. Given that DNA damage is a major driver of immune ageing, and immune decline accelerates whole-organism ageing, we tested whether mTOR inhibition enhances genome stability.

In human T cells exposed to acute genotoxic stress, we found that rapamycin and other mTOR inhibitors suppressed senescence not by slowing protein synthesis, halting cell division, or stimulating autophagy, but by directly reducing DNA lesional burden and improving cell survival. Ex vivo analysis of aged immune cells from healthy donors revealed a stark enrichment of markers for DNA damage, senescence, and mTORC hyperactivation, suggesting that human immune ageing may be amenable to intervention by low-dose mTOR inhibition.

To test this in vivo, we conducted a placebo-controlled experimental medicine study in older adults administered with low-dose rapamycin. p21, a marker of DNA damage-induced senescence, was significantly reduced in immune cells from the rapamycin compared to placebo group. These findings reveal a previously unrecognised role for mTOR inhibition: direct genoprotection. This mechanism may help explain rapamycin's exceptional geroprotective profile and opens new avenues for its use in contexts where genome instability drives pathology, ranging from healthy ageing, clinical radiation exposure and even the hazards of cosmic radiation in space travel.

Structures of the endoplasmic reticulum are where the folding of newly synthesized proteins takes place in the cell. The endoplasmic reticulum is also involved in a range of other activities relevant to the manufacture of proteins and other molecules, such as quality control and recycling of misfolded proteins. Researchers here describe how the endoplasmic reticulum changes in structure with age, and link this to changes in the recycling of endoplasmic reticulum structures via autophagy. They suggest that these changes are compensatory, but become maladaptive in later life.

The morphological dynamics of the endoplasmic reticulum (ER) have received little attention in the context of ageing. Here we established tools in C. elegans for high-resolution live imaging of ER networks in ageing metazoans, which revealed profound shifts in ER network morphology that are driven by autophagy of ER components (ER-phagy). Across a variety of tissues, we consistently found a decrease in ER protein levels and cellular ER volume, and a structural shift from densely packed sheets to diffuse tubular networks. The ER content also declined in yeast and mammalian systems, and proteomic atlases of the ageing process in worms and mammals showed that age-onset collapse in ER proteostasis function is a broadly conserved aspect of the ageing process

We found that Atg8-dependent ER-phagy is the key mechanism driving turnover and remodelling of the ER network during ageing. A targeted screen for mediators in C. elegans revealed that the physiological triggers of ER-phagy in an ageing metazoan model are cell-type specific. Tissue-specific roles of ER-phagy receptors may help to explain why the ubiquitous macroautophagy machinery seems to be a universal requirement for longevity assurance in metazoan genetic studies, whereas the importance of selective ER-phagy mediators has been slower to emerge. Subsequently, we demonstrate that the two pathways capable of blocking age-associated ER-phagy, TMEM-131 and IRE-1-XBP-1, are required for mTOR-dependent lifespan extension in C. elegans.

Importantly, not all changes that occur during ageing reflect pathogenesis. The earliest remodelling events are likely to be adaptive responses to the cessation of developmental programmes and rising metabolic and cellular damage. We propose a model where age-dependent ER remodelling serves as an adaptive step in the ageing process associated with reprogramming of the proteostasis network. However, although data indicate that the net effect of ER-phagy on lifespan is positive, we speculate that early pronounced remodelling of ER structures is likely to trigger pleiotropic trade-offs later, especially in longer-lived cells and animals.

Link: https://doi.org/10.1038/s41556-025-01860-1

In recent years, researchers have established that a great many proteins can aggregate to some degree in cells of the aging brain, and that this likely contributes to loss of function. This issue is distinct from the few well-known proteins such as amyloid-β that aggregate to a very large degree in the context of neurodegenerative conditions. Here, researchers provide evidence for this generalized aggregation across more than a thousand proteins to contribute to impaired maintenance of synapses in the aging brain.

Neurodegenerative diseases affect 1 in 12 people globally and remain incurable. Central to their pathogenesis is a loss of neuronal protein maintenance and the accumulation of protein aggregates with ageing. Here we engineered tools that enabled us to tag the nascent neuronal proteome and study its turnover with ageing, its propensity to aggregate and its interaction with microglia. We show that neuronal protein half-life approximately doubles on average between 4-month-old and 24-month-old mice, with the stability of individual proteins differing among brain regions. Furthermore, we describe the aged neuronal 'aggregome', which encompasses 1,726 proteins, nearly half of which show reduced degradation with age.

The aggregome includes well-known proteins linked to diseases and numerous proteins previously not associated with neurodegeneration. Notably, we demonstrate that neuronal proteins accumulate in aged microglia, with 54% also displaying reduced degradation and/or aggregation with age. Among these proteins, synaptic proteins are highly enriched, which suggests that there is a cascade of events that emerge from impaired synaptic protein turnover and aggregation to the disposal of these proteins, possibly through microglial engulfment of synapses. These findings reveal the substantial loss of neuronal proteome maintenance with ageing, which could be causal for age-related synapse loss and cognitive decline.

Link: https://doi.org/10.1038/s41586-025-09987-9

Cryonics refers to the low-temperature storage of the body (or at least the brain) at death to offer the chance that a more technologically capable future can restore that individual to life. It is an unknown chance, possibly a small and unknown chance, but cryonics is certainly a better option that the other end of life alternatives facing someone who is going to age to death before rejuvenation biotechnology and the medical control of aging becomes a reality. Cryonics remains a very good idea that should be far more widely used, significantly supported, and undergoing aggressive technological development to improve capabilities. But it is very far from being widely used and suffers from the same situation that afflicted the aging research community thirty years ago: a minority field with too little financial and popular support to generate the desired degree of progress.

Newfound enthusiasm for the development of means to treat aging has led to a vast (if very unevenly distributed) investment in the field, hundreds of companies working on all sorts of approaches. A tiny fraction of that enthusiasm for doing something to address age-related disease and mortality has spilled over into support for cryonics. Even that tiny fraction is proving to be transformative. I pick on Alcor as the example because I am signed up with Alcor, and therefore do pay more attention to what is going on there, but the field as a whole is showing progress. Europe has its own modern cryopreservation organization these days, Tomorrow.bio, their focus on customer service raising the bar for the community. Meanwhile Until Labs is working on making reversible vitrification of organs a commercial possibility, a best foot forward to generate further capital and legitimacy for cryonics.

After years of little visible progress and too little funding to improve on that situation, Alcor has of late acquired what is for a non-profit a sizable influx of capital. Enough to not just establish new research programs with new equipment, but to address look and feel and customer service priorities, such as a modernization of the website and creating a portal and modern relationship management system for their customers - and no doubt more under the hood than that. Alcor comes to the table with the DNA of decades of year to year struggle as a small non-profit serving a small community. Shedding some of those historical habits and culture will be necessary in order for a commercial industry of cryopreservation to emerge.

In a better world, this could have happened decades ago, driven by a broad popularist realization that cryopreservation to travel into a potentially far better future is the best of all options, turning an end into a hiatus. But it didn't. At least the first increments of such a sea change are happening now. A few excepts from a recent Alcor newsletter follow, for those who don't keep tabs on how this industry is modernizing.

Fundraising & Endowment: 2025 closed out as one of the stronger fundraising years in Alcor's history, including a major gift from the Rothblatt family - one of the largest individual donations Alcor has ever received. About 75% of donations came from people who hadn't given at that level before. The goal is to build an operational endowment similar to what exists for the Patient Care Trust, which is very healthy. The operations and administrative side, however, has historically struggled to keep pace. A comparable endowment would allow Alcor to focus on growth rather than making ends meet. Expect a significant fundraising initiative announcement in the near future.

First-Ever In-House Whole Body CT Scan: The team performed Alcor's first-ever in-house whole body CT scan. The scan itself went smoothly: they used the new ceiling trolley and hoist to transfer the patient from the perfusion table directly onto a radiotranslucent scanning tray, completed the scan in just a few minutes, transferred the patient back, and proceeded directly to cooldown. That patient is now in long-term storage. After everything it took to get here, it was well worth the wait. Being able to validate cryoprotectant distribution in-house and in real time opens up a lot of doors for quality assessment and research.

CT Scanning for Vitrification Assessment: we are putting the CT scanner to good use and have already started producing valuable data. Pre- and post-cooling scans show clear differences between frozen kidneys and vitrified kidneys. The next step: quantifying exactly how much ice forms in different regions using a newly purchased differential scanning calorimeter. This will let the team precisely correlate CT images with ice content - a tool that could become standard for assessing cryopreservation quality in organs and patients alike

Organ Cryopreservation: The team continues refining porcine kidney cryopreservation protocols. About 40% of kidneys show excellent vitrification with minimal ice formation. The other 60% show small ice crystals in the inner medulla - the part of the kidney that's hardest to perfuse.

Brain Slice Cultures: we are developing long-term brain slice cultures that can survive 2-3 weeks in a CO2 incubator. Using assays to measure metabolic activity, they've established a baseline comparing fresh tissue versus straight-frozen tissue. The goal: cryopreserve brain slices, rewarm them, and show maintained viability and functionality over time. This would be a significant contribution to the literature - evidence that brain tissue can remain alive and functional after proper cryopreservation. Additional human brain tissue experiments are also in the works, with a neurosurgery partnership nearly finalized.

New Project: Antifreeze Protein Gene Integration: A particularly exciting update is that we are developing a project to integrate antifreeze protein genes directly into cells via gene therapy. The idea is that if cells can produce their own antifreeze proteins internally, they might survive freezing and thawing better without needing external cryoprotectants. This is early-stage - they're still screening candidate proteins from fish, beetles, and other organisms. Potential applications include improving CAR-T cell therapy, which could be relevant for both cryonics and mainstream medicine.

The protein BDNF is known to encourage neuroplasticity in the brain and otherwise assist in protecting the health and function of neurons. Numerous studies have demonstrated upregulation of BDNF to improve cognitive function in the context of aging and neurodegenerative conditions. Much of this work focuses on very indirect paths to the upregulation of BDNF, such as manipulation of the gut microbiome, but here researchers take the direct approach of a viral gene therapy introduced into brain tissue via stereotactic injection. They show that this can improve cognitive function in mouse models of Alzheimer's disease

Brain-derived neurotrophic factor (BDNF) can protect neurons from apoptosis and maintain normal synaptic structures, indicating a significant potential for Alzheimer's disease (AD) treatment. However, the method of in vivo BDNF delivery requires further optimization, and the therapeutic efficacy of BDNF in AD animal models needs to be further evaluated. Here, we demonstrated that a newly engineered adeno-associated virus (AAV) serotype termed AAVT42 showed better tropism for neurons than AAV9 in the central nervous system (CNS).

We analyzed the therapeutic potentials of AAVT42-delivered BDNF in three AD mouse models: amyloid precursor protein/presenilin-1 (APP/PS1), rTg4510, and 3xTg. Long-term BDNF expression in the hippocampus mitigated neuronal degeneration or loss in these AD mice, and alleviated their cognitive impairment, with no discernible effect on amyloid-β deposition or tau phosphorylation. Furthermore, transcriptomic analysis in 3xTg mice revealed that BDNF orchestrated the up-regulation of genes associated with neuronal structural organization and synaptic transmissions, such as Neuropeptide Y (Npy), Corticotropin-releasing hormone (Crh), Tachykinin precursor 1 (Tac1), and the down-regulation of Bone morphogenetic proteins (Bmps).

Our study highlighted the efficacy of AAVT42 in gene delivery to CNS and validated the therapeutic benefits of BDNF in treating AD, which will be useful for future translational research on AD treatment using an AAV delivery system.

Link: https://doi.org/10.1016/j.gendis.2025.101649

Cancer diagnosis and treatment tends to involve the removal of lymph nodes, leading to impaired flow in the lymphatic system and either transient or permanent lymphedema. In aging, lymph nodes become fibrotic and structural disorganized, impairing the ability of immune cells to use the lymphatic system to coordinate a response to infection. One possible approach to these problems is the generation of artificial lymph nodes, or at least suitable arrangements of cells that will form themselves into a functional lymph node and connect to the lymphatic system once implanted into the body. A number of different groups have made progress towards this goal, to the point of demonstrating the creation of partially functional lymph nodes in animal studies; the research program noted here is the most recent.

The increase in cancer incidence has accelerated the need for secondary lymphedema treatments after lymphadenectomy because lymph nodes cannot be regenerated. Recently, many attempts have been made to treat secondary lymphedema by forming lymphatic vessels using three-dimensional cellular structures. Of these, three-dimensional cellular structures composed of lymphatic endothelial cells (LECs) and fibroblasts fabricated using a cell stacking technique by coating functional proteins on the cell surface were reported to form a lymphatic network inside the structures, demonstrating the formation of a lymphatic lumen structure after transplantation in mice. Unfortunately this cellular structure has not been effective for the treatment of secondary lymphedema. Therefore, lymph node regeneration or reconstruction using therapeutic cells has not been achieved, and the development of a better therapeutic method is desired.

This study aims to develop a bioengineered three-dimensional tissue composed of LECs and mesenchymal stem/stromal cells (MSCs), which has immunomodulatory functions and can prolong the survival of transplants for lymph node reconstruction. To fabricate the bioengineered tissue simply, we establish a centrifugal cell stacking technique with no additives. This bioengineered tissue, termed "centrifuge-based bioengineered lymphatic tissue" (CeLyT), forms a lymphatic network inside the tissue during culture for several days. CeLyTs induce the formation of lymph node-like structures, with characteristics similar to lymph nodes, after transplantation into mice, and the formation of this lymph node-like structure suppress edema following lymphadenectomy in mice. Therefore, CeLyTs composed of LECs and MSCs might be a cell-based therapeutic strategy for secondary lymphedema.

Link: https://doi.org/10.1038/s41467-025-65121-3