Fight Aging!

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

Every cell contains hundreds of mitochondria, the distant descendants of ancient symbiotic bacteria that still contain a remnant circular genome, the mitochondrial DNA. The most important task undertaken by mitochondria is the production of the chemical energy store molecule adenosine triphosphate (ATP). A constant supply of ATP is needed to power the functions of the cell, and mitochondria are thus essential to cell function. Mitochondrial dysfunction is a feature of aging, arising in part from damage to mitochondrial DNA, and in part due to epigenetic changes that impair the operation of mitochondria and mitochondrial quality control processes. This dysfunction is particularly impactful in tissues with high energy demands, and the brain is at the top of that list.

Today's open access paper reviews present thought on mitochondrial dysfunction as a contributing (or even central) cause of Alzheimer's disease. While the authors focus on Alzheimer's disease specifically, mitochondrial dysfunction in the aging brain is broadly relevant to all neurodegenerative conditions. If it is central in any one condition, it is probably central to all. The fastest way to assess whether or not this is the case is to run clinical trials of therapies capable of greatly restoring lost mitochondrial function and observe the results.

In the near term, mitochondrial transplantation is the approach closest to realization that could in principle achieve dramatic improvement in mitochondrial function. Mitochondrial transplantation involves the delivery of large numbers of functional mitochondria harvested from cell cultures. In the context of improving the function of the aging brain, transplanted mitochondria may need to be delivered intrathecally into the cerebrospinal fluid rather than intravenously into the bloodstream, but otherwise the approach is the same. Animal studies suggest that a sizable improvement lasting for at least months is an achievable goal in human patients. The one caveat is that mitochondrial dysfunction in the brain is not just the result of the cellular mechanisms of aging, but also results from a reduced supply of oxygen and nutrients. The cardiovascular system declines with age, and thus improvement to its function may also be needed to realize the full benefits of mitochondrial transplantation into the brain.

Aging and Alzheimer's: the critical role of mitochondrial dysfunction and synaptic alterations

Alzheimer's disease (AD) is a degenerative brain disorder that is characterized by memory loss and the accumulation of two insoluble protein clumps, i.e., amyloid beta (Aβ) plaques and tau neurofibrillary tangles (NFTs). Multiple years of research have indicated that mitochondrial respiratory complex dysfunction has long been associated with the aetiology of neurodegenerative diseases such as AD. The finding of impaired oxygen and glucose transport in the brains of AD patients is the most significant indirect evidence supporting mitochondrial participation in the disease. According to the mitochondrial cascade theory, the other clinical symptoms of AD should be considered side effects, as mitochondrial malfunction is the primary cause in the majority of instances.

Electron microscope scans of the brains of AD patients have revealed altered mitochondrial morphology, including smaller mitochondria, altered and broken cristae, accumulation of osmophilic components, lipofuscin vacuoles, and elongated connected organelles. Numerous studies have been undertaken to evaluate the relationship between alterations in mitochondria (mtDNA) and AD, which have demonstrated that mtDNA levels in the brain cells and cerebrospinal fluid of AD patients have been reduced

Oxidative phosphorylation (OXPHOS) in mitochondria, which serves as the cell's energy source, produces the majority of the adenosine triphosphate (ATP). Neurons are the most ATP-consuming cell type. The primary reason for this is the requirement to maintain the ionic gradients required for ongoing neurotransmission, electrophysiological activity, and transient synaptic plasticity. In addition to being significant sources of free radical generation, defective mitochondria can trigger apoptosis by releasing cytosolic cytochrome C (cyt). Consequently, neuronal damage could result from even a little reduction in mitochondrial function.

The pathogenesis of AD has been explained through several competing and overlapping models, including the amyloid cascade, tau-first, and mitochondrial cascade hypotheses. While the amyloid and tau models emphasize extracellular plaque and cytoskeletal pathology, respectively, accumulating evidence suggests that mitochondrial dysfunction may act as an upstream trigger influencing both Aβ aggregation and tau hyperphosphorylation.

Why is it that some people exhibit only a minimal loss of cognitive function in later life? Here researchers suggest that mechanisms relating to APOE variant are relevant. Largely researched in the context of Alzheimer's disease, but more broadly applicable to other manifestations of age-related neurodegeneration, the APOE-ε4 variant may increase disease risk by promoting greater inflammation and dysfunction in microglia, among other mechanisms. In comparison people with the APOE-ε2 exhibit a lower risk of disease. The degree to which APOE variants contribute to later life inflammation and dysfunction seems likely to impact cognitive function, but is only one of a number of influences. Lifestyle choices, such as those that impact weight and fitness, affect the burden of inflammation and are thus also likely important in determining whether cognitive function is sustained in later life.

"SuperAgers" is a term used to describe oldest-old (ages 80+) adults with episodic memory performance most closely resembling adults in their 50s to mid-60s. Apolipoprotein E (APOE)-ε4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), while APOE-ε2 is in comparison the protective APOE allele.

The present study aims to explore APOE-ε4 and -ε2 allele frequency in SuperAgers compared to AD dementia cases and controls in a large, harmonized multicohort dataset from the Alzheimer's Disease Sequencing Project Phenotype Harmonization Consortium (ADSP-PHC). Using harmonized clinical diagnoses and cognitive domain scores (e.g., memory, executive function, language), we classified non-Hispanic Black (NHB) and non-Hispanic White (NHW) middle-aged, old, and oldest-old adults as cases, controls, or SuperAgers, and compared APOE-ε4 and -ε2 allele frequency of SuperAgers to cases and controls.

NHW SuperAgers had significantly lower frequency of APOE-ε4 alleles and higher frequency of APOE-ε2 alleles compared to all cases and controls, including oldest-old controls. Similar patterns were found in a small yet substantial sample of NHB SuperAgers; however, not all comparisons with controls reached significance. Thus we demonstrated strong evidence that APOE allele frequency relates to SuperAger status.

Link: https://doi.org/10.1002/alz.71024

By far the largest single cause of human mortality is atherosclerosis, the growth of fatty plaques that narrow and weaken blood vessels. Atherosclerosis is a universal phenomenon, occurring in every older person to some degree. Absent other causes of mortality, everyone would ultimately be killed by one of the consequences of the presence of severe atherosclerosis; reduced blood flow, heart failure, or rupture of an unstable plaque leading to heart attack or stroke. A sizable industry is focused on the development of new therapies for atherosclerosis, but no approach that can reliably regress existing plaques has yet to reach clinical development. It remains a largely irreversible condition, one that can only be slowed to some degree.

Heart disease remains the leading cause of death in the U.S. and stroke has moved up to the #4 spot. Together, heart disease and stroke accounted for more than a quarter of all deaths in the U.S. in 2023, the most recent year for which data is available. Cardiovascular diseases, including all types of heart disease and stroke, claim more lives in the U.S. each year than all forms of cancer and accidental deaths - the #2 and #3 causes of death - combined.

"The good news is that, overall, fewer people are dying from any cause, and death rates are improving as life expectancy continues to rebound after the COVID-19 pandemic. However, about half of all U.S. adults continue to have some form of cardiovascular disease. Those rates are still higher than they were before the pandemic and persistent increases in common conditions like high blood pressure, diabetes, and obesity continue to drive the risk."

These health factors not only contribute to heart disease and stroke, they also lead to other complications. Because of the interconnectivity of these conditions, for the first time this year's American Heart Association's Heart Disease and Stroke Statistics Update includes a chapter on cardiovascular-kidney-metabolic (CKM) syndrome, a health disorder made up of connections between heart disease, kidney disease, diabetes, and obesity, leading to poor health outcomes.

A review of 59 studies from 2010 to 2022 found that people who had ideal cardiovascular health as measured by Life's Essential 8 had a 74% lower risk of cardiovascular events compared with those who had poor cardiovascular health. In the United States, optimal Life's Essential 8 scores could prevent up to 40% of annual all-cause and cardiovascular disease deaths among adults. Better cardiovascular health was also associated with better brain health including younger brain age, less subclinical vascular disease, slower cognitive decline, and reduced dementia risk.

Link: https://newsroom.heart.org/news/heart-disease-stroke-deaths-down-yet-still-kill-more-in-u-s-than-any-other-cause

The therapies developed by Immunis represent the less well trodden path when it comes to the ongoing but still early stages in the replacement of stem cell therapies. This replacement is possible because the benefits provided by presently widespread forms of stem cell therapy result from the signals secreted by those cells in the short period of time before they die. Few such therapies have demonstrated any meaningful degree of long-term engraftment and survival of transplanted cells. Benefits are thus a matter of signals from the stem cells favorably adjusting the behavior of native cells for some extended period of time. The most reliable beneficial outcome of such therapies is a reduction in chronic inflammation.

Most efforts to replace stem cell therapies with a logistically simpler approach have focused on harvesting extracellular vesicles from stem cell cultures. Much of the signaling between cells is carried in these vesicles, and in animal studies the delivery of vesicles instead of stem cells has produced broadly similar benefits. Extracellular vesicles are more easily stored and transported than is the case for cells, and their use offers the vision of a future industry in which the challenging and expensive parts of the manufacturing process, meaning the establishment, maintenance, and quality control of stem cell lines, can be centralized.

Instead of extracellular vesicles, Immunis focuses on harvesting soluble molecules secreted by stem cells - the rest of the panoply of intracellular communication. This is an important difference, but, downstream of the fork in the road that is the choice of soluble molecules or extracellular vesicles, all of the consequent logistical benefits appear similar. The therapeutic product becomes more easily stored and transported, while the thorny challenges inherent in managing a high quality production process that relies upon the incompletely understood, highly complex biochemistry of living cells can be centralized.

Interim Phase 2 IMM01-STEM data pioneers a class of cell-free multi-active secretomes, showing clinically significant improvements in a key vital sign of health

Immunis, a clinical-stage biotech company pioneering multi-active secretome-based biologics, today announced positive topline interim results from STEM-META, a double-blind placebo-controlled study of the IMM01-STEM secretome in overweight seniors experiencing muscle loss and metabolic dysfunction. The study offers some of the first Phase 2 data on a class of drugs known as "secretome-based biologics." Secretomes, like IMM01-STEM, are derived from secreted stem cell factors that have the natural ingredients known to stimulate various cell signaling pathways simultaneously, influencing immune regulation and promoting healing. A strong body of preclinical and Phase 1 evidence shows these "cell-free cell therapies" deliver the therapeutic benefits of stem cell molecules without the risk of administering stem cells, and has contributed to high demand in the class.

In the study of 47 obese seniors with loss of muscle functionality, IMM01-STEM demonstrated clinically relevant improvements to functionality, including the walking speed (gait speed), one of the most well-documented, validated indicators of muscle function and overall health. IMM01-STEM improved gait speed by 26% compared to placebo controls. Gait speed, or the average speed at which an individual walks, is a measure of mobility, and a summary measure of physiologic reserve across multiple systems.

Immunis' Phase 2 data follows preclinical placebo-controlled studies of muscle and metabolism, demonstrating IMM01-STEM increased whole-body lean mass, reduced fat mass and decreased muscle fat while increasing muscle fiber area and the number of muscle stem cells, and enhancing collagen turnover, grip strength, and overall physical activity in mice. Together, these data provide a basis for future clinical research studies of IMM01-STEM.

It is well established that the age of the male parent can impact a range of health issues in offspring. Separately, of late researchers have noted that aging produces changes in RNA processing that depend on RNA length. Longer RNA transcripts exhibit greater changes in abundance, for example, which could be characterized as a systemic downregulation biased towards longer RNAs. The work on RNA in aged sperm noted here falls into this line of research, as the data indicates subtly detrimental changes that depend on RNA length. This is again indicative of age-related changes in RNA processing machinery.

Sperm aging impacts male fertility and offspring health, highlighting the need for reliable aging biomarkers to guide reproductive decisions. However, the molecular determinants of sperm fitness during aging remain ill-defined. Here, we profiled sperm small non-coding RNAs (sncRNAs) using PANDORA-seq, which overcomes RNA modification-induced detection bias to capture previously undetectable sncRNA species associated with mouse and human spermatozoa throughout the lifespan. We identified an "aging cliff" in mouse sperm RNA profiles - a sharp age-specific transition marked by significant shifts in genomic and mitochondrial transfer RNA (tRNA)-derived small RNAs (tsRNAs) and ribosomal RNA (rRNA)-derived small RNAs (rsRNAs).

Notably, rsRNAs in mouse sperm heads exhibited a transformative length shift, with longer rsRNAs increasing and shorter ones decreasing with age, suggesting altered biogenesis or processing with age. Remarkably, this sperm head-specific shift in rsRNA length was consistently observed in two independent human aging cohorts. Moreover, transfecting a combination of tsRNAs and rsRNAs resembling the RNA species in aged sperm was able to induce transcriptomic changes in mouse embryonic stem cells, impacting metabolism and neurodegeneration pathways, mirroring the phenotypes observed in offspring fathered by aged sperm. These findings provide novel insights into longitudinal dynamics of sncRNAs during sperm aging, highlighting an rsRNA length shift conserved in mice and humans.

Link: https://doi.org/10.1038/s44318-025-00687-8

Vaccination status correlates with better health outcomes and lower risk of a range of age-related disease unrelated to the target of the vaccine. One possible contribution to this outcome is that people who make the effort to be vaccinated also tend to be more conscientious about other health practices. Another involves the trained immunity effect, in that many vaccinations have been demonstrated to both reduce maladaptive age-related inflammation and increase immune capabilities against a variety of unrelated targets. The data reported here argues more for the trained immunity effect, in that researchers note reduced inflammation as an outcome correlated with shingles vaccination status.

Using data from the nationally representative U.S. Health and Retirement Study, researchers examined how shingles vaccination affected several aspects of biological aging in more than 3,800 study participants who were age 70 and older in 2016. Even when controlling for other sociodemographic and health variables, those who received the shingles vaccine showed slower overall biological aging on average in comparison to unvaccinated individuals.

Researchers measured seven aspects of biological aging: inflammation; innate immunity (the body's general defenses against infection); adaptive immunity (responses to specific pathogens after exposure or vaccination); cardiovascular hemodynamics (blood flow); neurodegeneration; epigenetic aging (changes in how genes are turned "off" or "on"); transcriptomic aging (changes in how genes are transcribed into RNA used to create proteins). The team also used the measures collectively to record a composite biological aging score.

On average, vaccinated individuals had significantly lower inflammation measurements, slower epigenetic and transcriptomic aging, and lower composite biological aging scores. The results provide more insight into the possible mechanisms underlying how immune system health interacts with the aging process. Chronic, low-level inflammation is a well-known contributor to many age-related conditions, including heart disease, frailty, and cognitive decline. These potential benefits could also be persistent. Participants who received their vaccine four or more years prior to providing their blood sample still exhibited slower epigenetic, transcriptomic, and overall biological aging on average versus unvaccinated participants.

Link: https://gero.usc.edu/2026/01/19/shingles-vaccine-slower-biological-aging/

Angiopoietin-2 (ANGPT2) is not to be mistaken for angiopoietin-like protein 2 (ANGPTL2), but both appear problematic in similar contexts. Angiopoietins are in the vascular growth factor family, and angiopoietin-like proteins are, as the name suggests, somewhat similar. They are involved in the inflammatory response to damage that resolves into regeneration in the vascular system. Unfortunately, as in the rest of the body, the mechanisms involved in this response to damage run awry with advancing age and contribute to dysfunction rather than helping to address it. So, to pick a few examples, the presence of ANGPTL2 is a marker of cellular senescence and contributes to inflammatory heart disease. Meanwhile, ANGPT2 is known to be involved in the maladaptive reaction to ischemic injuries such as a heart attack, inducing excessive inflammation and further loss of function.

The vasculature extends into the brain, of course, and the aging of the cardiovascular system is known to influence the aging of the brain, an energy-hungry organ that operates at the edge of maximum metabolic capacity at the best of times. The brain is also a distinct microenvironment from the rest of the body; where blood vessels pass through the brain, they are wrapped by the structures of the blood-brain barrier. The blood-brain barrier restricts the passage of cells and molecules to and from the brain. Unfortunately, vascular dysfunction also implies blood-brain barrier dysfunction, and thus leakage of unwanted molecules and cells into the brain where they can induce damage and inflammation. In today's open access paper, researchers extend what is known of the issues induced by ANGPT2 expression in the aging vasculature to include harmful effects on the blood-brain barrier, and thus a contribution to the onset and progression of neurodegenerative conditions.

Angiopoietin-2 aggravates Alzheimer's disease by promoting blood-brain barrier dysfunction and neuroinflammation

Alzheimer's disease (AD) is a fatal neurodegenerative disorder. Emerging evidence highlights neuroinflammation as a crucial factor in AD pathogenesis and progression, with the disruption of the blood-brain barrier (BBB) significantly contributing to this process. The BBB constitutes a pivotal aspect of the neurovascular unit (NVU), a distinct structural and functional complex formed by endothelial cells, pericytes, and astrocytes within the central nervous system (CNS), specialized for tightly regulated interactions among vascular cells, glial cells, and neurons. NVU cell interactions are crucial for maintaining brain homeostasis, modulating immune responses, and facilitating neural communication. BBB disruption is closely linked to NVU dysfunction, which contributes to neuroinflammation and cognitive impairment in many neurological disorders, including AD.

In this study, we identified ANGPT2 as a key vascular determinant upregulated in human AD brains, as demonstrated by transcriptomic analyses and validated in postmortem tissues. To investigate its role in AD pathogenesis, we utilized the 5xFAD transgenic mouse model, which harbors five familial AD mutations that accelerate β-amyloid deposition.

Endothelial-specific deletion of ANGPT2 reduced β-amyloid accumulation, whereas ANGPT2 overexpression via adeno-associated viral (AAV) delivery exacerbated β-amyloid deposition. Mechanistically, ANGPT2 inhibition of TIE2 signaling compromised BBB integrity and amplified microglial activation and neuroinflammation, ultimately exacerbating cognitive dysfunction. Furthermore, single-nucleus RNA sequencing (snRNA-seq) from AD mice revealed ANGPT2-driven transcriptional changes consistent with microglial dysfunction and neuronal impairment. Collectively, these findings demonstrate that ANGPT2 promotes BBB dysfunction and neuroinflammation, thereby serving as a critical driver of AD pathology and progression.

Astrocytes make up a sizable fraction of the cells in brain tissue, responsible for supporting the functions of neurons and the microenvironment of the brain. Cellular senescence in these supporting populations grows with age and is thought to provide an important contribution to the aging of the brain and onset of neurodegenerative conditions. Lingering senescent cells secrete inflammatory signals, disrupting the function and structure of tissue in proportion to their numbers. The research community continues to investigate the biochemistry of the senescent state and how cells become senescent, details that may differ meaningfully from cell population to cell population, in search of novel approaches that might lead to drugs that can prevent senescence, destroy senescent cells, or even reverse the normally irreversible senescent state.

Astrocytes are the primary source of circulating high mobility group box-1 (HMGB1) which is intimately associated with aging and related disease in central nervous system (CNS). However, the multi-localization and multifunctional characteristics of HMGB1 indicate that it may regulate brain aging through various pathways and mechanisms which are not yet clearly defined. In this study, we find that the expression of HMGB1 decreases with aging in both human and mouse astrocytes. Conditional knockout of Hmgb1 in astrocytes induces the exacerbation of mice aging.

Physiologically, HMGB1 locates in the nucleus and acts as a DNA binding protein to modulate gene expression and DNA repair. During cell activation, injury or death, HMGB1 can also translocate to the extracellular microenvironment and serve as a damage-associated molecular pattern (DAMP) to activate immune responses. The roles of HMGB1 in cellular senescence are complicated. Some studies have observed that HMGB1 functions as a core senescence-associated secretory phenotype (SASP) component, being extracellularly released to drive inflammaging. Conversely, emerging evidence suggests that nuclear HMGB1 exhibits a protective role in cellular senescence by maintaining telomerase activity and telomere function.

By establishing a nuclear HMGB1 depletion model and interfering in the interactions of extracellular HMGB1, we find that nuclear HMGB1 is anti-senescent whereas extracellular HMGB1 is pro-senescent. Inhibiting HMGB1 nuclear export to enhance its nuclear retention effectively alleviates astrocyte senescence. Thus promoting the nuclear retention of HMGB1 is a new strategy for attenuating brain aging and related disorders.

Link: https://doi.org/10.1186/s12974-025-03684-0

Hemoglobin is the primary carrier for oxygen found in red blood cells. It preferentially binds oxygen in relatively high oxygen environments, such as lung tissue, and releases it in relatively low oxygen environments as it moves about the body. As is true of near all proteins, hemoglobin has many roles. Independently of its role in oxygen transport, it also interacts with a range of proteins involved in the regulation of inflammation, for example. Here find a discussion of the ways in which hemoglobin might be involved in the relationship between oxidative stress, inflammation, and the progression of degenerative aging. Oxidative stress is excessive alterations to cellular proteins caused by oxidative reactions; these take place constantly, and cells employ antioxidants and repair mechanisms to reduce their impact. Increased oxidative damage is a feature of aged tissues, however, and well known to associate with increased inflammation, disruptive to tissue structure and function.

Hemoglobin's significance extends beyond basic physiology; its levels and functional integrity are closely linked to health outcomes across the human lifespan. In elderly populations, deviations in hemoglobin levels - particularly anemia - are strongly associated with frailty, cognitive impairment, increased hospitalization, and mortality. On the other hand, abnormally high levels may predispose individuals to thrombosis and vascular complications. These observations suggest that hemoglobin serves as more than just a biomarker of oxygenation; it may be a critical regulator of longevity itself.

Moreover, the regulatory networks that govern hemoglobin synthesis are closely tied to adaptive mechanisms implicated in longevity. Hypoxia-inducible factors (HIFs), which regulate erythropoietin expression and hemoglobin production under low-oxygen conditions, are also known to modulate genes involved in angiogenesis, glucose metabolism, and cellular survival. Interventions that mildly activate HIF signaling - such as intermittent hypoxia, exercise, and pharmacological stabilizers - have demonstrated protective effects against aging-related degeneration, positioning HIF-hemoglobin pathways as promising targets in longevity research

Oxidative stress presents another dimension through which hemoglobin may influence lifespan. As hemoglobin undergoes auto-oxidation, it produces reactive oxygen species (ROS), which, in excess, can damage DNA, proteins, and lipids, triggering pro-aging processes. Aging tissues typically show reduced antioxidant capacity, making them more vulnerable to ROS-mediated injury. Maintaining redox balance through antioxidant defense systems and preserving the functional integrity of hemoglobin is therefore crucial to cellular longevity.

In addition to its role in oxygen transport, hemoglobin may also interact with various signaling pathways that influence inflammation, immune function, and vascular health. Chronic inflammation and immunosenescence are hallmarks of aging, and studies have shown that dysfunctional hemoglobin and heme overload can trigger pro-inflammatory cascades. Conversely, stabilizing hemoglobin structure and minimizing heme release may help modulate these pathways and contribute to healthier aging.

Link: https://doi.org/10.1097/MS9.0000000000004508