Fight Aging!

Amyloid is a category, referring to proteins that clump together and precipitate from solution to form solid fibrils or other structures. At least hundreds of different proteins are capable of forming amyloids given suitable alterations to their structure or surrounding conditions, but most of the research attention given to this activity is directed towards toxic, pathological amyloids that form in great excess in the context of neurodegenerative conditions (such as amyloid-β, α-synuclein, and tau), followed by the few amyloids outside the brain that do the same to contribute to severe cardiovascular and other conditions (such as transthyretin or medin).

In today's research materials, researchers provide evidence for a specific type of amyloid formation to be involved in the creation and maintenance of long-term memory. This is very different from the basis for pathological amyloidosis, and involves different proteins, but given the research community focus on that amyloidosis, there has perhaps been a tendency to write off all forms of amyloid as harmful byproducts of cellular metabolism. A brief glance at the history of our understanding of biochemistry suggests that this sort of viewpoint is usually mistaken; if a process exists, evolution will eventually lead to its incorporation into some necessary aspect of cell function.

How Brain May Deliberately Form Amyloids to Turn Experiences Into Memories

The prevailing model of memory hypothesizes that a change in synaptic strength is one of the mechanisms through which information is encoded in neuronal circuits. While changes in synaptic strength require alterations in the synaptic proteome, the mechanisms that initiate and maintain these changes in synaptic proteins remain unclear. Molecular chaperones play a critical role in proteome function, and act as an interface between the environment and the proteome. Chaperones guide proteins to attain the correct folded state. It has long been thought that in the nervous system, chaperones help proteins to either fold correctly or prevent proteins from harmful misfolding and clumping.

A new study found that in Drosophila, one of a family of J-domain protein chaperones, CG10375, which they named "Funes", does something unexpected - it allows proteins to change their shape and form functional amyloids that house long-term memory. "This expands the idea of a protein's capacity to do meaningful things, and suggests there is an unknown universe of chaperone biology that we've long been missing." Thus amyloids are not always harmful unregulated byproducts as previously thought. Amyloids can be carefully controlled - serving as tools the brain uses to store information. Ultimately, the research reveals for the first time a critical step in the process of how long-lasting memories endure.

In fruit flies, a prion-like protein called Orb2 (and its relative protein CPEB in mammals) must undergo self-assembly at the synapses, the gap between two neurons, to maintain a memory. Orb2 belongs to a class of nonpathological amyloids, where amyloid formation enables a protein to acquire a new function. Over time, the researchers began to hypothesize that the difference between a harmful and a helpful amyloid may depend on whether Orb2's assembly process is tightly regulated by other proteins.

The researchers discovered Funes by manipulating the concentrations of 30 different chaperones in the fly's memory centers. Flies with increased levels of Funes showed a remarkable ability to remember an odor-reward link after 24 hours - a standard proxy for long-term memory. But the most surprising discovery came at the molecular level. Researchers engineered Funes variants that could bind Orb2 but could not trigger its transition into amyloid and found the flies' long-term memory failed. This indicated that Funes is an essential component for long-term memory formation.

Diseases of the eye are often the indication of choice for new, advanced forms of medicine, particularly gene therapies. Delivery to the eye is straightforward and proven, effective doses can be very low, and the structures of the interior of the eye are relatively isolated from the rest of the body. All told, the risk to patients is much lower than would be the case for targeting, say, the liver, which makes it a great deal easier to convince investors and regulators to support such a program. Thus we shouldn't be all that surprised to see that the first clinical trial of partial reprogramming to rejuvenate epigenetic control over nuclear DNA structure and gene expression will focus on regeneration of the damaged retina.

The FDA has given the go-ahead for the first ever human trial of a partial epigenetic reprogramming therapy. The FDA's decision clears an investigational new drug application for Life Bioscience's ER-100, a gene therapy designed to rejuvenate damaged retinal cells in people with serious, age-related eye diseases. The biotech is now preparing to commence a Phase 1 first-in-human study to show its therapy can be delivered safely in patients with open-angle glaucoma and non-arteritic anterior ischemic optic neuropathy (NAION).

As a first-in-human trial, Life Bioscience's study is primarily focused on safety and tolerability. Instead of using all four Yamanaka factors, ER-100 employs three of the factors (Oct4, Sox2, and Klf4) delivered transiently to reset age-associated epigenetic markers while keeping cells committed to their original function. By excluding c-Myc, a factor associated with uncontrolled growth, the strategy is intended to lower the risk of tumors that has historically concerned regulators and clinicians. From a safety perspective, the company's preclinical studies in non-human primates demonstrated that ER-100 was well tolerated in NHPs, with no systemic toxicities.

"The therapy uses a doxycycline-inducible system, giving us precise control over when the genes are active and allowing treatment to be paused or stopped if needed. In addition, ER-100 is delivered locally to the eye, limiting systemic exposure. Multiple preclinical animal models have demonstrated controlled gene expression, favorable biodistribution, restoration of epigenetic markers, and improvements in visual function which has collectively provided the foundation for FDA clearance."

Link: https://longevity.technology/news/fda-clears-first-human-trial-of-epigenetic-reprogramming-therapy/

Ferroptosis is a form of programmed cell death associated with iron metabolism. A body of evidence supports a role for excessive ferroptosis in the progression of Alzheimer's disease and other age-related conditions, a maladaptive reaction to forms of age-related damage present in the brain, such as mitochondrial dysfunction, an increased burden of senescent cells, chronic inflammatory signaling, and so forth. Researchers are starting to consider suppression of ferropotosis as an approach to treating neurodegenerative conditions, which leads to papers such as this one, a discussion of the mechanisms by which exercise acts to reduce ferroptosis. That is a step along the road to identifying potential targets for drug development. Attempting to mimic specific outcomes of exercise, calorie restriction, or other environmental effects on metabolism is a widely employed strategy, though it seems unlikely to be capable of more than modestly slowing disease progression or modestly reducing severity.

Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has emerged as a critical link between cellular senescence and Alzheimer's disease (AD). Senescent cells disrupt iron metabolism, promote peroxidation-prone lipid remodeling, and suppress antioxidant defenses, creating a pro-ferroptotic environment that accelerates neuronal degeneration. This review integrates recent mechanistic evidence demonstrating that these senescence-induced changes heighten ferroptotic susceptibility and drive AD pathology through pathways involving protein aggregation, autophagic failure, and inflammatory synaptic loss.

Importantly, physical exercise has emerged as a pleiotropic intervention that counteracts these ferroptotic mechanisms at multiple levels. Exercise restores iron homeostasis, reprograms lipid metabolism to reduce peroxidation risk, reactivates antioxidant systems such as GPX4, enhances mitochondrial and autophagic function, and suppresses chronic neuroinflammation. Moreover, systemic adaptations through muscle, liver, and gut axes coordinate peripheral support for brain health. By targeting ferroptosis driven by cellular senescence, exercise not only halts downstream neurodegenerative cascades but also interrupts key upstream drivers of AD progression.

These findings position ferroptosis as a therapeutic checkpoint linking aging biology to neurodegeneration and establish exercise as a mechanistically grounded strategy for AD prevention and intervention.

Link: https://doi.org/10.3389/fcell.2025.1742209

Autophagy is the name given to a complex collection of processes responsible for identifying and recycling damaged or otherwise unwanted structures in the cell. Typically, a structure flagged for recycling is engulfed by an autophagosome, which is transported to and fuses with a lysosome, and the structure is broken down inside the lysosome by enzymes. An optimal level of autophagy for the maintenance of cell function only occurs in response to stress, including heat, cold, lack of nutrients, toxins, oxidative damage to important molecules, and so forth. Thus mild stresses that inflict relatively little damage to a cell can improve the function of cells, tissues, and organs, leading to a greater resistance to the damage and dysfunction of aging. Most of the well studied interventions shown to modestly slow aging and extend life in animals involve an increased operation of autophagy.

Researchers and the longevity industry continue to work towards the development of drugs capable of upregulating autophagy to produce health benefits in older people. These efforts include examples in the well studied category of mTOR inhibitors, drugs that can mimic some of the beneficial metabolic response to exercise and calorie restriction, as well as a good number of unrelated programs at various stages of preclinical and clinical development. Meanwhile, there is a continued effort to better understand and measure autophagy. One of the challenges is that autophagy consists of many different steps, an assay can only obtain insight into one step, and increased activity in any given step can be a sign of increased function, but it can also be a sign that autophagy is dysfunctional and backed up.

Links between autophagy and healthy aging

Several if not all manifestations of aging can be postponed by a healthy lifestyle involving a balanced diet coupled with regular exercise and sufficient sleep. Similarly, various genetic and pharmacological longevity interventions can exert beneficial effects across species in a conserved manner, extending both lifespan and healthspan. While all these interventions-ranging from genetic perturbations to pharmacological supplementation to lifestyle changes-affect diverse biological processes, a common candidate mechanism underpinning at least some of their benefits is autophagy, a cellular recycling process essential for maintaining cellular homeostasis.

In this review, we summarize how autophagy is affected by various pharmacological and lifestyle factors, with a focus on studies in which autophagy has been shown to play a causal role in promoting healthy aging. Specifically, we review the molecular mechanisms through which pharmacological agents, dietary restriction, exercise, sleep adjustments, as well as temperature modulation affect autophagy to extend lifespan and often also healthspan in model organisms and humans.

Still, major gaps remain in human research due to limited assays to monitor autophagy and the scarcity of longitudinal studies linking autophagy dynamics to health outcomes. Closing this gap is a key challenge in converting discoveries from model organisms into interventions that consistently enhance healthy aging in humans. By summarizing current findings and highlighting remaining uncertainties, this review aims to provide a roadmap for translating insights on autophagy from model organisms into strategies to promote healthy aging in humans.

The best thing that researchers can do with the presently established aging clocks, such as Phenotypic Age, is to gather as much data as possible on the relationship between the clock output and meaningful outcomes such as disease risk and mortality. Hence the existence of studies such as the one reported here. Even now, going on twenty years into the use of aging clocks, it remains unclear as to whether any of the existing, relative well-used clocks will produce a reasonable assessment of the effects of any novel potentially age-slowing or age-reversing therapy. An understanding of the links between what is measured in the clocks and the underlying processes of aging have not been established and will be very challenging to establish, and thus it is impossible to predict whether a clock will overestimate, underestimate, or just fail when it comes to assessing the quality of any given intervention in aging. This is the case even for clocks such as Phenotypic Age that use clinical chemistry rather than omics measures. In this environment, gathering more data is probably the best path forward.

Accelerated biological aging serves as a risk factor for age-related diseases, its role in the prognosis of Parkinson's disease (PD) remains ambiguous. This study investigates the association between biological aging and the mortality in PD patients. Data were sourced from the UK Biobank. Independent prognostic factors for mortality in PD patients were assessed by Cox regression model, and a nomogram was developed to predict the survival of PD patients. A total of 569 PD patients were enrolled in this study.

Phenotypic age (PhenoAge) and PhenoAge acceleration (PhenoAgeAccel) were found to affect the survival in PD patients. Independent risk factors for PD mortality included age, male gender, smoking, underweight, depressive mood, low-density lipoprotein, and higher genetic susceptibility. The nomogram constructed based on PhenoAge showed robust prediction performance for mortality in PD patients. PhenoAge emerges as a pivotal PD mortality predictor, enabling the identification of individuals experiencing accelerated biological aging and implementing targeted interventions.

Link: https://doi.org/10.1038/s41531-026-01268-0

Adult life expectancy has exhibited a slow upward trend over the course of past decades, perhaps a year of increased life expectancy every decade, but the pace varies from year to year, region to region, and between socioeconomic groups. The trend exists as a result of improvements in medicine that impact the pace of aging as a side-effect, as therapies that deliberately target the mechanisms of aging have yet to reach widespread use. The contribution of medical advances is then layered with the effects of lifestyle differences, particularly the prevalence of obesity, public health programs such as efforts to reduce smoking, and other line items that can differ between populations and regions. Researchers here use European data to illustrate this point, and also note differences over time in the life expectancy trend.

This study makes several potential contributions to the ongoing debate on life expectancy trends in high-income countries. Our study examines these trends using data at the level of subnational regions: in total, we cover 450 regions in 13 Western European countries. We believe that addressing life expectancy at a fine geographical level is paramount in understanding the potential to further improve human longevity, as national aggregates mask large differences within countries. For example, in France, there are stark contrasts between laggard regions in the north and vanguard regions in the south and east. The disparities between eastern and western Germany, and northern and southern Belgium are equally pronounced. Together, they tell a compelling story of uneven regional progress.

Our study identified two distinct phases in the evolution of life expectancy gains over the past three decades. The first phase, from 1992 to 2005, was characterized by stable and substantial life expectancy gains in Western Europe (about 2.5 months per year for females and 3.5 months per year for males). Over this period, the pace of gains across regions quickly converged. In contrast, the second phase, from 2005 to 2019, marked a period of declining life expectancy gains. By 2018-2019, annual gains had decreased to about one month per year for females and two months for males.

During the earlier 'golden era', it was laggard regions that made the greatest gains in life expectancy. By contrast, the period 2005-2019 was much less favourable, as laggard regions saw shrinking gains in life expectancy. The driving forces behind this impressive reversal of fortunes can be better understood through the convergence-divergence framework, which explains the mechanisms leading mortality levels across populations to either converge or diverge. According to this theory, major innovations (e.g., drugs that reduce blood pressure) may initially trigger divergence, as some countries or groups are better positioned to benefit from them. Once access broadens, convergence tends to follow.

Link: https://doi.org/10.1038/s41467-026-68828-z

In today's open access paper, researchers review the evidence for exercise to slow the aging of muscle tissue in part because it improves DNA repair mechanisms. How exactly damage to nuclear DNA contributes to aging beyond creating a raised risk of cancer remains a debated topic, despite recent conceptual advances. Nuclear DNA damage occurs constantly, near all of which is repaired. Yet the remaining damage largely occurs in genes that are not used or that are not all that important, and in cells with few replications remaining. Thus the ability to cause harmful alterations to cellular metabolism throughout a tissue was thought to be limited.

The first way in which nuclear DNA damage could meaningfully impact aging is via somatic mosaicism. When mutations occur in stem cells, those mutations spread slowly throughout a tissue over time via the descendants of the somatic daughter cells created by the mutated stem cells. A mosaic of combinations of mutations is established over years and decades, and there is at least some reasonably convincing evidence for this to increase the risk of a few age-related conditions.

More recently, researchers have provided evidence for the repeated repair of DNA double strand breaks, whether successful or not, and wherever the break occurred in the genome, to cause epigenetic changes characteristic of aging. These epigenetic changes alter the structure of nuclear DNA and thus the expression of genes. If support for this mechanism continues to accumulate, it provides a way for random molecular damage to DNA to produce the consistent outcome of harmful age-related epigenetic changes that is observed to occur in all cells.

In this second viewpoint, interventions such as exercise that are thought to slow aging in part by improving the operation of DNA repair mechanisms may not in fact be working as hypothesized. They may indeed be changing the operation of DNA repair, but the primary outcome of interest is to reduce the negative effects of double strand repair on the epigenetic control of nuclear DNA structure and gene expression, rather than improving the efficiency of DNA repair more generally.

Impact of exercise-induced DNA damage repair on age-related muscle weakness and sarcopenia

Sarcopenia, the progressive and generalized loss of skeletal muscle mass, strength, and function with aging, poses a significant public health challenge. A key contributor to sarcopenia is the accumulation of DNA damage, both nuclear and mitochondrial, coupled with a decline in DNA repair efficiency. This genomic instability, exacerbated by chronic oxidative stress and inflammation, impairs critical cellular processes including protein synthesis, mitochondrial function, and satellite cell regenerative capacity, ultimately leading to myofiber atrophy and weakness. Intriguingly, regular physical exercise, while acutely inducing transient DNA damage, concurrently activates and enhances DNA damage repair pathways, serving as a powerful physiological modulator of genomic integrity.

This review comprehensively explores the intricate interplay between exercise, DNA damage, and DNA repair in the context of age-related muscle decline. We delve into the molecular hallmarks of DNA damage (e.g., 8-OHdG, single and double strand breaks) and the major repair mechanisms (base excision repair, nucleotide excision repair, mismatch repair, homologous recombination, non-homologous end joining), detailing how acute exercise modalities (e.g., high-intensity interval training, resistance training) induce specific damage types primarily via reactive oxygen species. Crucially, we synthesize emerging evidence suggesting that chronic exercise training may upregulate the efficiency and capacity of DNA repair enzymes, particularly OGG1 in base excision repair, thereby mitigating the accumulation of deleterious genomic lesions. This exercise-induced enhancement of DNA repair directly contributes to maintaining mitochondrial health, preserving muscle stem cell function, and combating cellular senescence and inflammation, ultimately delaying or ameliorating sarcopenia and improving muscle functional outcomes in older adults.

Researchers have been publishing more data of late from the CALERIE trial of human calorie restriction that took place over the course of a few years. The participants aimed at a 25% reduction in calorie intake, and ended up achieving something more like 12-15%. The trial started nearly 20 years ago at this point. It is often the case that tissue samples and data remain intact and potentially useful long after the study is complete, awaiting greater funding and interest, as well as the existence of more advanced analysis technologies.

Small non-coding RNAs (smRNAs), approximately 20-35 nucleotides in length, represent a diverse class of regulatory molecules that include microRNAs (miRs) and piwi-interacting RNAs (piRs). These nanoscale molecules are key regulators of gene expression, orchestrating complex networks to maintain genome stability and contribute to post-transcriptional gene regulation and cellular homeostasis.

Caloric restriction (CR) extends lifespan and enhances healthspan across species. In humans, the CALERIE Phase 2 trial demonstrated that CR improves inflammation, cardiometabolic health, and molecular aging. To explore underlying mechanisms, we examined CR-induced changes vs. ad libitum (AL) in smRNAs across plasma, muscle, and adipose tissue. Using smRNA sequencing, we analyzed miRs and piRs over 12 and 24 months, comparing CR levels (%CR) and group assignments (CR vs. AL).

We identified 16 smRNAs associated with %CR and 41 with CR vs. AL. Although tissue-specific expression varied, shared pathways emerged, including insulin signaling, circadian rhythm, cell cycle regulation, and stress response. Cross-species analysis revealed 17 miRs altered by CR in both humans and rhesus monkeys. These findings suggest smRNAs are key molecular mediators of CR's effects on aging and longevity, offering insight into biological mechanisms of CR and potential targets for age-related interventions.

Link: https://doi.org/10.1016/j.isci.2025.114514

The immune system is made up of many specialized populations of cells. Even within well recognized categories such as T cells of the adaptive immune system, there are numerous subcategories, defined by surface markers, that exhibit meaningfully different behaviors. The example for today is γδ T cells, known to be involved in the clearance of senescent cells. Unlike other T cells, γδ T cells behave more like innate immune cells, able to attack pathogens and potentially harmful cells without the need for other components of the adaptive immune system to process antigens for recognition. The γδ T cell population is relatively poorly understood, but like the rest of the immune system, it changes with age in ways that are likely in part dysfunctional, in part compensatory.

The transcription factors of the forkhead box O (Foxo) family, particularly Foxo1, play a pivotal role in regulating α/β T-cell key cellular processes. Interestingly, we recently found that the age-related decline in Foxo1 expression in mouse α/β T cells may drive the disruption of their peripheral homeostasis and contribute to the aging of this T-cell compartment. γ/δ T cells form a distinct subset of lymphocytes, differing from NK cells, B cells, and α/β T cells by combining adaptive properties with rapid, innate-like responses. Findings related to Foxo1 in α/β T cells prompted us to investigate how the functional capacities of γ/δ T cells are affected by aging, as well as whether Foxo1 expression could be modulated in this T-cell compartment with age.

In this study, we demonstrate that, as observed for α/β T cells, the homeostasis of the peripheral γ/δ T-cell compartment is markedly altered with age. Indeed, a comparison of the γ/δ T-cell compartment within the secondary lymphoid organs of old (18-month-old) and young (3-month-old) adult mice reveals that aging promotes the expansion of innate-like γ/δ T cells and enhances their capacity to produce IL-17. Notably, we found that these age-related changes were associated with the loss of Foxo1 expression within this T-cell compartment.

Finally, as observed in α/β T cells, our results indicate that the age-related decline in Foxo1 expression in γ/δ T cells is likely driven by a similar T cell-extrinsic factor. In this context, we identify type I IFNs as a key regulator that down-regulates Foxo1 in IL-17-producing γ/δ T cells with age and enhances the capacity of Ly-6C- CD44hi γ/δ T lymphocytes to mount a rapid in vivo response during aging.

Link: https://doi.org/10.1111/acel.70389

Type 2 diabetes is largely a self-inflicted problem, a consequence of becoming overweight. Aging makes it easier to reach the threshold needed for a diagnosis of diabetes, but the condition remains in principle avoidable for the majority of people, were they making better choices about diet and exercise. In recent years, researchers have linked an increased burden of cellular senescence to the pathology of type 2 diabetes; the aberrant diabetic metabolism encourages more cellular senescence, and the presence of lingering senescent cells is in turn inflammatory and disruptive to tissue function.

In today's open access paper, researchers focus on cellular senescence in diabetic kidney disease. In this context the increased burden of senescent cells actively sabotages the function of the kidney. Thus senolytic therapies capable of selectively destroying some fraction of senescent cells can produce measurable improvements in kidney function following a single course of treatment. Given time, and no correction of the lifestyle and physiology that drives diabetes, senescent cells and kidney dysfunction will reemerge, of course. But senolytic drugs nonetheless offer the prospect of meaningfully reducing some of the harms done by aging and obesity.

Senolytics, dasatinib plus quercetin, reduce kidney inflammation, senescent cell abundance, and injury while restoring geroprotective factors in murine diabetic kidney disease

Maladaptive inflammation and cellular senescence contribute to diabetic kidney disease (DKD) pathogenesis and represent important therapeutic targets. Senolytic agents selectively remove senescent cells and reduce inflammation-associated tissue damage. In our pilot clinical trial in patients with DKD, the senolytic combination dasatinib plus quercetin (D + Q) reduced systemic inflammation, senescent cell abundance, and macrophage infiltration in fat. However, D + Q senotherapeutic effects on diabetic kidney injury, senescence, inflammation, and geroprotective factors have not been established.

Diabetes mellitus was induced with intraperitoneal streptozotocin in male C57BL/6J mice, followed by a 5-day oral gavage regimen of either D + Q (5 and 50 mg/kg, respectively) or vehicle. Kidney function and markers of injury, fibrosis, inflammation, cellular senescence, and geroprotective factors were measured. In vitro studies examined reparative effects of D + Q in high glucose-treated human renal tubular epithelial cells (HK2), endothelial cells (HUVECs), and U937-derived macrophages.

D + Q improved kidney function and reduced markers of kidney injury (glomerular and tubular), fibrosis, senescence (p16Ink4a), macrophage- and senescence-associated inflammation (versus diabetic controls) without altering glucose levels. Additionally, geroprotective factors (α-Klotho, Sirtuin-1) increased. D + Q treatment in vitro reduced high glucose-induced senescence and inflammation (NF-κB) in HK2, HUVECs, and macrophages.

The balance of microbial species making up the gut microbiome changes with age. More inflammatory microbes win out over microbes that generate beneficial metabolites, and this contributes to degenerative aging. Restoring a more youthful composition of the gut microbiome has been demonstrated to improve health and extend life in aged animals. Human data for gut microbiome rejuvenation remains very sparse, however. That said, a growing body of observational data from human patients demonstrates that various age-related conditions correlate with an altered, pro-inflammatory gut microbiome. In particular, evidence suggests that Alzheimer's disease - and the mild cognitive impairment that marks its earliest stages - correlate well with specific harmful alterations in the gut microbiome.

The gut microbiome serves a central role in maintaining homeostatic balance or disease pathogenesis, including neurological disorders such as Alzheimer's disease (AD). The mechanisms by which the microbiota and associated metabolites influence the development and/or exacerbation of disease states are multifaceted and multidirectional, involving the central and autonomic nervous systems and neuroimmune, neuroendocrine, and enteroendocrine pathways. This complex interplay involves a bidirectional communication system, often referred to as the microbiota-gut-brain-immune relationship, which connects the brain and gastrointestinal tract through various pathways.

Communication from the brain to the gut occurs via sympathetic and parasympathetic nervous systems and hormones. Conversely, the gut communicates with the brain through pathways such as the vagus nerve, the hypothalamic-pituitary-adrenal (HPA) axis, and a range of microbial products including bacterially synthesized neurotransmitters (e.g., GABA, dopamine, serotonin, noradrenaline), branched-chain amino acids, short-chain fatty acids (SCFAs), aryl hydrocarbon receptor agonists, and bile acids.

This scoping review of gut microbiomes in mild cognitive impairment (MCI) and AD included dietary and probiotic interventions. Our results demonstrated that gut dysbiosis was frequently reported in MCI and AD, including increased Pseudomonadota and Actinomycetota in AD and reduced diversity in some cases. Probiotic and dietary interventions showed promise in modulating cognition and microbiota, but inconsistently. Emerging evidence links dysbiosis to cognitive decline; however, methodological heterogeneity and limited follow-up impede causal inference. Research should prioritize standardized protocols, functional microbiome analysis, and longitudinal human studies to clarify therapeutic potential.

Link: https://doi.org/10.1002/alz.71023

Relative to skin elsewhere on the body, facial skin is less prone to scarring following regeneration from injury. Researchers have identified how this difference is regulated, and here demonstrate that they can influence the relevant mechanisms in order to reduce scarring during regeneration of skin injuries elsewhere on the body. It is also possible that further investigation of this biochemistry may yield approaches to reduce scarring more generally. This is of interest in the context of aging, as tissue maintenance becomes dysfunctional in many organs in ways that lead to excessive formation of disruptive small-scale scar-like structures.

Surgeons have known for decades that facial wounds heal with less scarring than injuries on other parts of the body. This phenomenon makes evolutionary sense: Rapid healing of body wounds prevents death from blood loss, infection or impaired mobility, but healing of the face requires that the skin maintain its ability to function well. Exactly how this discrepancy happens has remained a mystery, although there were some clues.

The face and scalp are developmentally unique. Tissue from the neck up is derived from a type of cell in the early embryo called a neural crest cell. Researchers identified changes in gene expression between facial fibroblasts and those from other parts of the body and followed these clues to identify a signaling pathway involving a protein called ROBO2 that maintains facial fibroblasts in a less-fibrotic state. They also saw something interesting in the genomes of fibroblasts making ROBO2. These fibroblasts more closely resemble their progenitors, the neural crest cells, and they might be more able to become the many cell types required for skin regeneration.

ROBO2 doesn't act alone. It triggers a signaling pathway that results in the inhibition of another protein called EP300 that facilitates gene expression. EP300 plays an important role in some cancers, and clinical trials of a small molecule drug that can inhibit its activity are underway. Researchers found that using this small molecule to block EP300 activity in fibroblasts prone to scarring caused back wounds in mice to heal like facial wounds.

Link: https://med.stanford.edu/news/all-news/2026/01/why-the-face-scars-less-than-the-body.html

The composition of the gut microbiome changes with age. A variety of factors likely contribute, including reduced physical activity, changes in diet, and a decline in the ability of the immune system to keep unwanted microbial populations in check. With age, microbes capable of provoking inflammation grow in number while microbes responsible for generating beneficial metabolites diminish in number. This is not an inevitable fate: the composition of the gut microbiome can be permanently changed by fecal microbiota transplantation. Studies have shown rejuvenation of the aged gut microbiome, improved health, and extended life span following fecal microbiota transplantation from young donor animals to old recipient animals.

In human medicine, fecal microbiota transplantation was up until recently conducted in something of a gray area of regulation, with its use focused on severe cases of bacterial overgrowth and intestinal dysfunction, such as C. difficile infection. A specific approach to sourcing and preparing donor material is now blessed with FDA approval, but this is a fairly recent development. Despite an underground of people conducting fecal microbiota transplantation on their own for various reasons, and suppliers like Human Microbes facilitating this cottage industry, there is little firm human data for the use of fecal microbiota transplantation in the context of aging and age-related disease. This will likely continue to be the case given that is hard to generate strong, defensible intellectual property for fecal microbiota transplantation, and the potential for monopoly granted by intellectual property is required in order to attract the sizable funded needed for regulated clinical development.

One way past this roadblock is for some research group, and later company, to produce a well defined probiotic approach to rejuvenation of the gut microbiome and demonstrate its specific advantages. This would have to involve a sizable advance on present priobiotic use and manufacture, most likely the culturing and quality control of specific combinations of dozens to hundreds of microbial species in order to mimic a youthful gut microbiome in the ways that matter, and thus permanently change a patient's gut microbiome composition following treatment. That seems the most likely outcome, rather than any great expansion of the use of fecal microbiota transplantion, given the incentives placed upon the research and medical industries.

Microbiota from young mice restore the function of aged ISCs

The intestinal epithelium depends on intestinal stem cells (ISCs) for maintaining homeostasis. The intestinal epithelium shows a reduced rate of turnover with age, which is at least in part due to a decline in ISC function. Aged ISCs show a reduced ability to self-renew and differentiate compared to young ISCs. This overall decline in regenerative capacity of ISCs results in slower recovery from damage and, therefore, renders the intestine more vulnerable to injury. The reduced function of aged ISCs is, in part, due to a decline in canonical Wnt signaling within ISCs, driven by lower levels of canonical Wnts in aged ISCs themselves and as well as in aged crypts.

The intestine is an organ that harbors a vast collection of microbiota like bacteria, viruses, fungi, and protozoans. Microbiota protect the host from the invasion of pathogenic microbes and support the maintenance of intestinal epithelium by regulating various signaling mechanisms that influence intestinal epithelial cells directly or indirectly through niche cells. The composition of the intestinal microbiota changes upon aging. In older mice, the diversity of beneficial microbes decreases, while the population of pathogenic microbes increases. In aged humans, microbial diversity is lower compared to young.

We show here that aging-associated changes in microbiota can modulate Ascl2-based canonical Wnt signaling and the regenerative function of ISCs. Fecal microbiota transfer from young to aged mice, resulting in a more young-like microbiota in aged mice, restored Ascl2 and Lgr5 gene expression in crypts and ISCs and enhanced mitotic activity in crypts and the regenerative function of ISCs.

The transfer of an aged microbiota to young mice only marginally affected Wnt signaling and the function of young ISCs. It is a possibility that young crypts are more resistant to acute changes in the relative composition of the microbiota compared to aged crypts. On the other hand, a strong reduction of the overall level of microbiota as in antibiotic-treated animals does significantly affect Wnt signaling and mitotic activity in young crypts. Microbiota-induced changes in signaling in intestine are also not confined to ISCs but are also seen in Paneth cells, the niche cells that secrete Wnt that supports ISC function.

The composition of the intestinal microbiota thus plays a critical role in regulating the function of ISCs. Our data implies potential therapeutic approaches via modulation of the composition of microbiota for aging-associated changes in the function of ISCs.

Some portion of the benefits of exercise and physical fitness arise through effects on the composition and activity of the gut microbiome. Here, for example, researchers provide evidence for exercise to reduce the production of an inflammatory microbial metabolite, TMAO. That the composition of the gut microbiome changes with age in ways that increase the production of inflammatory metabolites is one of many issues that might be corrected via approaches such as fecal microbiota transplantation, flagellin immunization, or the development of much more sophisticated probiotic combinations of microbes than presently exist. Animal studies suggest that significant improvements to later life health can be achieved via rejuvenation of the gut microbiome.

The metabolites produced by the gut microbiota play a role in age-related cognitive decline through the gut-brain axis. Within this axis, trimethylamine N-oxide (TMAO) permeates the intestinal epithelial barrier and enters systemic circulation, triggering inflammation in the central nervous system and ultimately leading to cognitive decline. However, it remains unclear whether exercise training's specific mechanism for delaying age-related cognitive decline is associated with TMAO regulation and inhibition of neuroinflammation.

An aging rat model was established by intraperitoneal injection of D-galactose in Sprague Dawley rats, while simultaneous exercise training and TMAO interventions were conducted. The effects of exercise on cognitive function were evaluated using the new object recognition (NOR) test, the Morris water maze (MWM) test, and the radial arm maze (RAM) test. Additionally, the expression levels of TMAO and NLRP3 inflammasome-related proteins in aging rats were measured.

Exercise training effectively delayed the cognitive dysfunction induced by D-galactose in aging rats, as evidenced by a 22.6% increase in the discrimination index in the NOR test, an 11.2% prolongation of time in the target quadrant and a 50% enhancement in the number of platform crossings in the MWM test, and a 41.8% improvement in working memory in the RAM test. This neuroprotective effect is potentially mediated through the inhibition of the intestinal metabolite TMAO (with plasma TMAO levels reduced by 40.3%) and subsequent modulation of the TXNIP-NLRP3-Caspase-1-GSDMD inflammatory pathway.

Link: https://doi.org/10.1038/s41598-026-36354-z

The first companies working towards mitochondrial transplantation therapies to alleviate age-related mitochondrial dysfunction are primarily focused on logistics, the work needed to establish high quality manufacturing processes capable of producing the very large numbers of mitochondria needed for human subjects. Meanwhile, the research community is engaged in finding novel ways to engineer mitochondria and methods of delivery to improve this approach to therapy. One example is reported here, involving the encapsulation of mitochondria in artificial cell membranes and guidance of their trajectory in the body via magnetic fields.

A major clinical obstacle in the aging population is the significantly reduced regenerative capacity of bone, often resulting in delayed fracture healing or nonunion fractures. Mitochondria, as the central regulators of cellular energy metabolism, are essential for determining cell fate and supporting tissue regeneration. However, age-associated mitochondrial dysfunction critically impairs these processes. While transplanting healthy mitochondria is a promising therapeutic strategy, its efficacy is severely limited by poor targeting efficiency and inherent fragility of mitochondria in circulation.

We constructed artificial cell microspheres (Fmito@ACs) containing mitochondria of fetal mouse mesenchymal stem cells and conducted systematic characterization of them. In vitro experiments evaluated the effects of Fmito@ACs on the functions of primary osteoblasts, and its role in delaying cellular senescence was analyzed through β-galactosidase staining and immunofluorescence analysis of senescence markers (P21 and γH2A.X). Its ability to restore mitochondrial function was assessed by measuring reactive oxygen species, morphology, and energy metabolism. In animal experiments, labeled Fmito@ACs were tracked and their targeted accumulation at fracture sites guided by an external magnetic field was verified.

Fmito@ACs were successfully constructed and characterized, indicating a protective effect on mitochondria. The system ameliorated senescence in aged bone marrow mesenchymal stem cells, promoting osteogenesis by enhancing mitochondrial fusion and aerobic glycolysis. In an aged fracture model, Fmito@ACs showed targeted accumulation and biosafety, significantly improving healing.

Link: https://doi.org/10.3389/fphar.2025.1725973