Fight Aging!

RANKL is best studied in the context of bone remodeling. Its activity, binding to the cell surface receptor RANK, is necessary for the function of the osteoclast cells that break down bone extracellular matrix. Bone tissue is in a constant state of remodeling, built up by osteoblast cells and broken down by osteoclast cells. The loss of bone mineral density that leads to osteoporosis arises from a growing age-related imbalance between osteoblast and osteoclast activity, favoring the osteoclasts. The various established therapies used to slow the progression of osteoporosis attempt to tilt that balance away from loss of bone mineral density, such as via monoclonal antibodies targeting RANKL to suppress osteoclast activity.

In today's open access paper, researchers note that RANKL inhibition extends life in progeroid mice. The details are interesting, adding to other data suggesting that RANKL has roles in aging that go beyond issues with bone tissue, such as influence on muscle aging. One would want to see a study in normally aged mice to confirm that this is the case, of course. In the broader context, it might be worth noting that another class of drug that inhibits osteoclast activity in a different way, bisphosphonates, may also act to slow aging. There is evidence for bisphosphonates to be senolytic, for example, and human data showing a survival advantage of five years in people using bisphosphonates versus the general population.

Targeting RANKL Prevents Bone Loss, Improves Muscle Function and Extends Lifespan in Progeroid Mice

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by the early development of pathological features associated with aging, ultimately leading to premature death. HGPS primarily affects tissues of mesenchymal origin, as evidenced by the clinical manifestations characteristic of this premature aging disorder, including, but not limited to, osteoporosis, muscle wasting, lipodystrophy, and cardiovascular disease.

In this study, we used preclinical mouse models and both genetic and translational approaches to investigate whether an antiresorptive strategy, based on RANKL targeting, ameliorated the bone loss phenotype of progeroid mice. Here we show that osteocyte-derived RANKL deletion in the Zmpste24-/- mouse model of HGPS reverted bone loss in both long bones and vertebrae. These mice also exhibited increased grip strength and improved endurance capacity. Furthermore, Zmpste24-/- mice showed increased survival upon osteocyte-specific RANKL deletion. Notably, the use of a translational approach based on the administration of a neutralizing antibody against RANKL also restored bone mass, reduced muscle fibrosis, and extended the lifespan of Zmpste24-/- mice.

Altogether, these findings support that targeting RANKL exerts a beneficial effect on both osseous and extra-osseous phenotypes of HGPS, suggesting the potential of this therapeutic approach to explore in the treatment of this disease.

In recent years, an increasing level of attention has been given to microglia as an important contribution to neurodegeneration in the aging brain. Microglia are innate immune cells resident in the central nervous system, analogous to the macrophages found elsewhere in the body. They are deeply involved in the complex processes of normal tissue function and maintenance, not just a defense against pathogens and malfunctioning cells. With age, microglia become more inflammatory at the expense of tissue function. Here, researchers look at this harmful change in the behavior of microglia through the lens of cellular metabolism: what are the alterations in metabolism that accompany and perhaps cause unwanted inflammatory activities in this cell population? Finding ways to adjust the behavior of microglia is becoming a priority in the development of therapies to treat neurodegenerative conditions, and a greater understanding of how these cells change with age is a first step on that path.

Microglia, the resident macrophages of the central nervous system (CNS), are key players in maintaining brain and spinal cord homeostasis and protecting the CNS from damage and disease. During aging, the brain undergoes profound changes-including chronic low-grade inflammation, synaptic dysfunction, and increased vulnerability to neurodegenerative diseases - all of which are closely related to alterations in microglial function. One emerging theme is that microglial metabolism is a crucial determinant of their immune and homeostatic activity.

In this mini-review, we explore how metabolic programs shape brain microglial behavior and how these processes change during aging and in neurodegenerative diseases. We first highlight the link between specific metabolic pathways and key microglial functions, including phagocytosis, cytokine production, and the oxidative stress response. We then discuss how microglial metabolism is reprogrammed during healthy aging and in Alzheimer's disease and Parkinson's disease, including sex-specific differences. Finally, we examine regulators that influence microglial metabolic states and discuss how these pathways contribute to disease susceptibility and progression.

Collectively, recent findings highlight the central role of metabolic reprogramming in shaping microglial responses during aging and in neurodegenerative diseases. We emphasize the need for integrative studies that consider microglial subsets, sex differences, disease context, and upstream molecular regulators to better understand how microglial metabolism contributes to brain health and pathology. A deeper understanding of these pathways may offer new opportunities for therapeutic strategies aimed at restoring microglial homeostasis and mitigating harmful neuroinflammatory processes.

Link: https://doi.org/10.1111/acel.70660

Researchers here review the present state of research and use of metformin as a geroprotective drug, intended to modestly slow aging. They are largely on point, if somewhat too accepting of the quality of the existing human data. While effective as a treatment for metabolic syndrome and type 2 diabetes, metformin is nowhere near as good a choice as rapamycin if forced to pick a geroprotective drug with modest effects on aging. For one, the animal data for effects on aging is very mixed, and there are sizeable methodological and other concerns regarding the human clinical trial evidence for reduced mortality and increased life expectancy. More recent human data tends to show little to no effect on that front.

Metformin is a biguanide and first line drug for type 2 diabetes (T2D) mellitus that is being recognized as a geroprotective agent capable of influencing important hallmarks of aging. Apart from its primary role in lowering blood glucose levels, metformin has been shown to have several effects at the molecular level. It acts by activating the AMPK, which leads to a cascade of downstream events such as the inhibition of mTOR, increased mitochondrial biogenesis, and autophagy, as well as epigenetic modifications. Current findings also showed its capacity to alter the gut microbiota by increasing short-chain fatty acid producing bacteria, indicating the involvement of other systemic pathways that aid in lowering inflammation, increasing metabolic fitness, and keeping epigenetic stability.

The Targeting Aging with Metformin (TAME) trial represents a landmark effort to evaluate metformin's efficacy in delaying the onset of chronic age-related diseases in non-diabetic individuals [28]. Designed as a multi-center, randomized, placebo-controlled trial, TAME seeks to enroll 3,000 individuals between the ages of 65 and 79 years and follow them for four years. By assessing biomarkers of aging and clinical endpoints across multiple age-related conditions such as cardiovascular events, cancer, cognitive decline, and all-cause mortality, TAME aims to validate metformin as a gerotherapeutic. However, since its start in 2017, no results have been published yet which make many to speculate that the trial may be on hold due to financial issues. In a 2025 interview, Dr. Nir Barzilai clarified that TAME is now handled by ARPA-H and could lead to two major trials with similar design but focused on GLP-1 agonist drugs.

The Metformin and Dietary Restriction to Prevent Age-Related Morbid Events in People with Metabolic Syndrome (MeMeMe) trial on the other hand evaluated the effects of metformin with or without dietary restriction on the development of major age-related diseases in over 1,400 participants aged 50-79 with metabolic syndromes. The trial found that 1700 mg/day of metformin was effective in preventing diabetes in people with metabolic syndromes. They reported an 80% and 92% reduction of type two diabetes in the metformin and the metformin and Mediterranean diet groups compared to the placebo group. However, no preventive effect was seen for cancer, cardiovascular diseases, and mortality.

Link: https://doi.org/10.18632/aging.206407

Most forms of air pollution (with a particular focus on fine particles) are now well established to contribute to age-related conditions at the level of exposure that is experienced in much of the industrialized world. Typically matters are worse in less wealthy regions, particularly those using solid fuel for domestic cooking and heating. Nonetheless, there is enough of a contribution even in wealthier regions for studies to show meaningful differences to health depending on varying levels of exposure. A study in the Puget Sound region, for example, found that greater exposure increased dementia risk.

The specific mechanisms by which air pollution accelerates the onset and progression of common age-related conditions are largely linked to chronic inflammation. Unresolved inflammatory signaling is disruptive to tissue structure and function, and the interaction of pollutants with cells in the lungs and airways promotes inflammatory signaling that affects the whole body.

Today's open access paper reviews what is known of these mechanisms in the context of a specific condition, Parkinson's disease. This neurodegenerative condition has a strong connection to the aging of the gut microbiome and intestines, as that is where the misfolded α-synuclein that drives the condition can originate. It then spreads through the nervous system to the brain, where it produces the first evident symptoms of Parkinson's disease, and eventually dementia and death. The greater the burden of inflammation placed upon body and brain, the faster this will happen.

Air Pollution and Parkinson's Disease Pathology: Clinical Evidence and the Molecular Mechanisms Linking Airborne Toxicants to Neuroinflammation and Neurodegeneration

Studies have reported positive correlations between exposure to particulate matter (PM), nitrogen oxide (NOx), ozone (O3), and an increased risk of Parkinson's disease (PD). Beyond the incidence of PD, studies have examined the linkage between long-term air pollution contact and the risk of hospitalization, mortality, and disease progression among PD patients, suggesting that air pollution may not only lead to the development of PD but also aggravate the clinical course and outcomes of the disorder.

Several pathways have been proposed to involve the biological processes underpinning the connection between air pollution and PD. Extensive research in animal models and human studies has reported that PD is interrelated with significant modifications in gut microbial structure, including the reduction of anti-inflammatory short-chain fatty acid (SCFA)-producing bacteria and the enrichment of opportunistic pathogens. Exposure to air pollution has been shown to disrupt the gut microbiome, potentially resulting in increased gut permeability, the propagation of pathogenic processes, and inflammation that may contribute to the development and progression of PD.

It has been demonstrated that interaction with air pollutants can also motivate α-synuclein to misfold and accumulate, as well as the impairment of other key proteins involved in neuronal function and homeostasis. Air pollution has been linked to oxidative stress and neuroinflammation, which can lead to the induction of multiple transcription factors, NRF2, NF-κB, and MAPK, forcing dopaminergic neurons to malfunction and degenerate. Furthermore, the incorporation of ultrafine PM in the brain, particularly in the olfactory bulb and other vulnerable zones, has been associated with excitotoxicity, mitochondrial dysfunction, and the propagation of neuroinflammatory processes that may be responsible for the pathophysiology of PD.

Despite progress in investigating the association between air pollution and PD, findings remain inconsistent. Some studies have recognized positive links between exposure to pollutants such as PM, NOx, and O3 and an increased risk of PD, whereas other studies have not found statistically important associations. These discrepancies underscore the complexity of the interactions between environmental exposures, genetic predisposition, and any other modifiable risk factors in the pathogenesis of PD. Mechanistic studies have offered useful insights into the biological pathways linking air pollution to PD. However, the precise mediators and dose-response relationships remain unclear. Furthermore, regional differences in pollution levels, exposure assessment methods, and population characteristics may contribute to the variability in findings across epidemiological studies. There is a growing need for well-designed, large-scale longitudinal studies with standardized exposure assessment methods to more accurately quantify the long-term effects of specific air pollutants on PD risk and progression.

The state of the cardiovascular system has a strong impact on the aging of the brain. The brain requires an sizable supply of energy, delivered via the bloodflow, and suffers when that supply is reduced. With age, the vascular system loses smaller vessels, while larger vessels become damaged. Loss of physical fitness also reduces blood supply. Additionally, damaged blood vessels allow leakage of unwanted cells and molecules into the brain to produce inflammation, while blood vessel walls can be a source of inflammatory signaling themselves. Increased blood pressure can be avoided or controlled, but where hypertension is present, it is harmful to vessels in the brain, causing a toll of small ruptures that damage brain tissue over time. All of this adds up. The study here is one of many to link vascular health with cognitive decline leading to dementia.

Midlife vascular risk factors are associated with both dementia and premature death; however, their combined association with dementia-free survival years remains unclear. We conducted a prospective cohort study (Atherosclerosis Risk in Communities study) with participants from 4 US communities. Participants were alive and dementia-free at age 55 years and had visit 2 (1990-1992) measurements of diabetes (self-report, medication use, or HbA1c ≥ 6.5%), hypertension (blood pressure ≥ 140/90 mm Hg or medication use), and current smoking. Vascular risk burden was defined as the count of these risk factors (0-3).

Among 12,409 participants (mean age 56.2 ± 5.2 years), over a median follow-up of 26.3 years, 3,008 developed dementia and 5,238 died dementia-free. Compared with 0 risk factors, 3 risk factors were associated with higher hazards of dementia (hazard ratio [HR] 2.69) and death without dementia (HR 5.61). Higher vascular burden was associated with fewer dementia-free survival years, declining from 30.1 years for 0 risk factors to 17.5 years for 3 risk factors. In conclusion, maintaining optimal midlife vascular health was associated with up to 12.6 additional dementia-free survival years, reflecting both higher dementia hazard and markedly higher competing mortality.

Link: https://doi.org/10.1212/WN9.0000000000000152

From one perspective, the XPRIZE Healthspan research prize is a way to encourage what should be happening to a far greater extent in the development of means to treat aging as a medical condition, which is to assess which approaches are better than others. The field spends too much time on approaches that cannot improve on lifestyle choices, for example. Ideally this competitive assessment requires some useful consensus definition of aging and age-related degeneration to work against - which is presently lacking; aging clocks are a step in that direction, but cannot be trusted to provide useful results for any given novel intervention targeting mechanisms of aging. Thus the XPRIZE Healthspan leadership chose to go with benchmarking competing approaches against narrow definitions of function in a few areas where fairly standardized methodologies exist: muscle, cognition, immune capacity.

Launched in 2023, the seven-year, $101 million XPRIZE Healthspan competition is the first incentive health competition of its kind dedicated to accelerating the development and clinical testing of proactive, accessible interventions that target the biology of aging itself. Rather than treating age-related diseases after they occur, the competition challenges teams to restore muscle, cognitive, and immune function by at least 10 years - with an ambitious target of 20 years - in adults ages 50 to 90, all within one year or less of treatment. If successful, these breakthroughs have the potential to help millions of people live longer, healthier, and more independent lives.

Today, XPRIZE announced the 20 Finalist teams advancing to the next stage of the competition, marking a major milestone in the global race to transform how we age. Among the finalists, 10 teams from the United States, South Korea, Japan, and China were selected as Milestone 2 awardees and will each receive a $1 million award, totaling $10 million in milestone funding, to accelerate the development and clinical testing of innovative therapies designed to extend healthy years of life. In addition to funding, the teams will gain access to key clinical testing resources to support the next phase of their work.

Together, the finalist teams represent a diverse range of approaches targeting the biology of aging, including: novel medicines and biologics designed to improve metabolism, reduce inflammation, protect neurons, and repair damaged cells; regenerative approaches, including stem cell and gene-based therapies, that support cellular repair, energy production, and tissue health; extracellular vesicles and other next-generation delivery technologies that harness the body's natural processes to promote rejuvenation; AI-enabled precision health and personalized care models that combine data, existing medicines, nutraceuticals, and lifestyle interventions to optimize healthy aging.

Link: https://www.xprize.org/news/20-healthspan-finalist-teams-advance-in-the-race-to-extend-healthy-aging

The composition of the gut microbiome is influential on long term health and the progression of aging. Unfortunately, this composition changes with age for a range of reasons yet to be fully explored, but which include the decline of the immune system and growing leakage of the intestinal barrier. With age, populations of inflammatory microbial species grow at the expense of microbial species that produce metabolites necessary for tissue function. Studies in short-lived animals suggest that the composition of the gut microbiome is at least as important as lifestyle choices such as level of physical activity when it comes to pace of aging and level of dysfunction in later life.

The means available to manipulate the composition of the gut microbiome are largely not that effective in the grand scheme of things. We know the scope of benefits that arise from a better diet and otherwise better lifestyle choices. Like probiotics, dietary choice can only produce lasting changes in the gut microbiome to some degree, and only if kept up over time. There are one-time treatments that can produce a lasting change in the gut microbiome, however. Flagellin immunization has been explored in animal studies, and provokes the immune system into a lasting campaign to eliminate exactly the sort of undesirable microbial species that increase in number with age. Fecal microbiota transplantation from a young donor into an old recipient resets the composition of the gut microbiome, and in animal studies this improves health and extends life.

In both of these one-time treatments, it is hard to predict exact outcomes. This hinders the development of these therapies for a more widespread use as treatments to reduce the impact of aging by resetting the gut microbiome. More attention is given to fecal microbiota transplantation, with clinical trials accumulating and planned. Nonetheless, the challenges in terms of controlling the inputs and the outcomes of this therapy make it likely that the path ahead will involved the development of artificial gut microbiomes that can be completely controlled and specified. These will form the basis for the next generation of probiotic therapy, capable of replicating some fraction of the effects of fecal microbiota transplantation, and in particular to be capable of producing lasting change in composition.

Gut Microbiota and Ageing: Mechanisms, Age-Related Diseases, and Therapeutic Perspectives

This narrative review synthesised a substantial body of peer-reviewed evidence demonstrating that the gut microbiota undergoes progressive, context-dependent remodelling with advancing age, characterised by reduced taxonomic and functional diversity, depletion of short-chain fatty acid (SCFA)-producing taxa, and relative expansion of pathobionts. These changes are increasingly recognised as likely contributors to inflammaging and several hallmarks of ageing, although causal relationships remain incompletely established in humans and likely promote or exacerbate prevalent age-related diseases including neurodegenerative disorders, cardiovascular disease, type 2 diabetes, sarcopenia, osteoporosis, and frailty. Conversely, the distinct microbial configurations observed in centenarians and individuals exhibiting healthy ageing trajectories suggest that maintenance of specific metabolic functionalities (particularly robust SCFA and secondary bile acid pathways) may constitute a feature of successful longevity rather than mere survival bias.

Evidence-based strategies targeting the microbiota, ranging from Mediterranean-style dietary patterns and exercise to precision probiotics, synbiotics, postbiotics, and carefully screened fecal microbiota transplantation (FMT), show genuine potential to restore microbial homeostasis, attenuate inflammaging, improve clinical phenotypes, and extend healthspan. Nevertheless, substantial methodological, causal, and translational gaps remain. Overcoming these will require concerted investment in longitudinal multi-omics cohorts, rigorously designed personalised intervention trials, advanced experimental models, and equitable implementation frameworks.

Ultimately, the gut microbiota should be viewed not as a separate entity but as an integral component of the ageing human superorganism. By nurturing microbial ecology throughout life and deploying targeted restoration strategies in later decades, it may become possible to compress morbidity, preserve functional independence, and enable more individuals to reach extreme old age in good health. While the journey from associative observation to causal, personalised, clinically validated interventions remains incomplete, the trajectory is clear: microbiome research represents one of the most promising and rapidly evolving areas within contemporary geroscience. Realising its full potential for human longevity will demand the same rigorous, collaborative, and innovative spirit that has characterised the field's rapid evolution since the advent of high-throughput sequencing.

The next generation of geroscience will increasingly depend on integrating microbial ecology with complementary molecular regulatory systems governing the ageing process, including epigenetic, metabolic, immunological, and post-transcriptional mechanisms. Such multidimensional approaches have the potential to transform microbiome research from a predominantly associative discipline into a mechanistically grounded framework capable of supporting personalised interventions for healthy ageing and longevity.

Senescent cells accumulate with age, and actively secrete pro-inflammatory signals. The present understanding of senescent cell biochemistry and animal studies of senescent cell clearance strongly suggest that senescent cells in aged tissues provide a major contribution to the characteristic chronic inflammation of old age, disruptive to tissue structure and function. As researchers here note, finding biomarkers to quantify this contribution in a usefully robust and specific way is a work in progress, however. While one might think that the medical field could forge ahead with therapies targeting senescent cells for clearance, based on being able to evidently reverse age-related pathology in animal studies, in practice regulators place a strong emphasis on the availability of simple biomarkers that can measure the direct engagement of a drug with its target, not just indirect outcomes. Drugs that lack such biomarkers will struggle to progress though the regulatory system, and thus creating these biomarkers is a major concern for researchers and companies.

Cellular senescence is the process in which cells lose their ability to proliferate irreversibly. While the process is needed for performing different functions, accumulation of senescent cells over time leads to the secretion of senescence-associated secretory phenotype (SASP). Senescence and SASP have now been known, defined and quantified in the last couple of decades. Both senescence and inflammaging are known to contribute towards several age-related diseases (ARDs), with inflammaging being a more recent concept than the former. They appear bi-directional in their cause and effects with respect to ARDs, resulting in immunosenescence, which is the age-related decline in the functioning of the immune system, but senescence is currently more quantifiable due to specific markers and known senescent cellular features.

With the increasing interest in the field, several scientists and research groups have contributed to the growing body of evidence towards cellular senescence and inflammaging in ARDs. Existing evidence indicates that senescence might be the key to tracking diseases (and thus targeting senescence for treatment), healthy aging and longevity; however, this knowledge is yet to be translated to the 'bedside' for clinical applications. This review aims to outline and simplify our current understanding of the complex links between aging, senescence and inflammaging in ARDs, classify and list the biomarkers of aging, and discuss the knowns and the unknowns of the field.

Link: https://doi.org/10.3390/biomedicines14071486

It is well established that physical fitness (and the level of activity and other lifestyle choices required to sustain it) correlate with a lower risk of mortality and longer life expectancy. Human data largely cannot provide evidence for causation, but that greater activity and fitness slow aging and extend life is robustly demonstrated in animal studies. Many large epidemiological studies have quantified the reduction in mortality risk provided by exercise or physical fitness, usually with a specific focus on some narrow aspect of the relationship, and here find yet another example of the type. The data in this study shows that old people at the low end of the range of fitness experience something like twice the late life mortality risk of those at the high end of fitness.

Regular physical activity promotes healthy aging, yet clinical risk stratification in older adults relies largely on comorbidity burden, often overlooking functional capacity. Objective fitness assessment may serve as a clinically relevant indicator of physiological reserve, but evidence from large cohorts evaluating multiple fitness domains remains limited. This nationwide cohort study included community-dwelling adults aged 65 years or older who completed standardized fitness assessments in Taiwan between January 11, 2015, and November 25, 2016. Participant data were linked to National Health Insurance records, with follow-up through December 31, 2022. The main outcome was all-cause mortality.

Of 13,423 participants (mean age, 72.9 ± 6.1] years;), 1,631 (12.2%) died during a median follow-up of 7.0 years. Compared with the lowest performance quintile, participants in the highest performance quintile had lower all-cause mortality across 4 physical fitness assessments: 8-foot up-and-go (adjusted hazard ratio, AHR, 0.41), 1-leg stance (AHR 0.50), 30-second chair stand (AHR 0.55), and 2-minute step test (AHR 0.58). The composite fitness index showed the lowest risk of all-cause mortality (AHR 0.39).

To conclude, in this cohort study of older adults, objectively measured physical fitness - particularly balance and agility, lower-body strength, and cardiorespiratory fitness - was associated with lower all-cause mortality in a graded manner.

Link: https://doi.org/10.1001/jamanetworkopen.2026.28227

Rehabilitation following a stroke that causes significant loss of function is a slow, painful, and uncertain process. The concept underlying these efforts is that the brain will attempt to rebuild neural connections given sufficient efforts to use lost and diminished function. This does happen to some degree, but far less so in aged patients. Changes in brain circuitry require neuroplasticity: the creation of new neurons that integrate into existing neural networks, and the creation of new synaptic connections between neurons. Neuroplasticity is well demonstrated to decline with age, though there is some debate over which of the contributing factors are more versus less important. Stem cells decline in their activity, and the aged tissue environment is more inflammatory and less conducive to regeneration.

In today's open access paper, researchers report on a demonstration of improved rehabilitation in mice following stroke via reprogramming. Reprogramming involves exposing cells to some or all of the Yamanaka factors; if kept up for long enough, cells undergo rejuvenation of their patterns of gene expression and a change of state into pluripotent stem cells. Ideally in a therapeutic use, the exposure lasts long enough to produce epigenetic rejuvenation but not so long as to produce change in cell state. It is worth noting that for the purposes of a mouse study, in which the mice will be sacrificed and examined at the end of the assessment, it isn't necessary to be as careful about crossing the line into the creation of pluripotent stem cells that can generate cancers as one would have to be in human medicine.

Here, researchers used a viral vector to introduce plasmids encoding the Yamanaka factors Oct4, Sox2, and Klf4 into neurons in the corticospinal tract of mice, which links the cortex to the spinal cord and carries the signaling necessary for control of limbs. Expression of the Yamanaka factors was transiently induced by treatment with doxycycline, a necessary limit on the process of reprogramming. After inducing a stroke in the animals, those mice with reprogrammed neurons exhibited greater neuroplasticity and functional recovery. This is one of a number of interesting demonstrations of the capabilities of cellular reprogramming, but questions on safety, and how to ensure it in various different therapeutic contexts, will no doubt slow down the field for some years yet.

Rejuvenation of corticospinal neurons enhances rehabilitation-associated corticospinal tract axon sprouting and functional recovery post photothrombotic ischemic stroke in mice

Rehabilitative training is widely adopted in the clinic to achieve functional recovery following stroke. The rationale of rehabilitative training is based on the Hebb theory, which predicts simultaneous pre- and post-synaptic activities that will facilitate synaptogenesis and ultimately lead to the formation of new circuits. However, the effectiveness of rehabilitative training is highly dependent on the level of neuroplasticity and, consequently, is limited in aged patients. Thus, a logical strategy to improve outcomes of rehabilitative training is to identify avenues that are capable of rejuvenating adult neurons in the central nervous system (CNS).

Epigenetic changes are well recognized as hallmarks of ageing. The transcription factor-based cellular reprogramming can refresh the epigenetic landscape and thus presents an innovative method for the rejuvenation of aging cells. Recent studies have shown that overexpression of Oct4, Sox2, and Klf4 (referred to as OSKTFs) reverses epigenetic changes in aged retinal ganglion cells and enables them to regrow their injured axons, a process typically absent in the mature mammalian CNS.

In the current study, we first showed that unilateral photothrombotic stroke ablated corticospinal neurons, leading to severe impairments in skilled but not gross motor function. We further demonstrated that expression of OSKTFs in corticospinal neurons partially rescued the developmental decline of major epigenetic regulators. Ectopic expression of OSKTFs in corticospinal neurons had minimal impact on corticospinal tract (CST) axons' spinal termination and function in intact animals but moderately promoted the collateral outgrowth of the CST axons in the cervical spinal cord and skilled motor recovery in animals with photothrombotic stroke.

OSKTFs expression synergized with rehabilitative training through enhanced mTOR activity, producing additive benefits on CST collateral sprouting and skilled locomotion recovery. Mechanistically, the observed axon sprouting and functional recovery depend on mTOR activation and are driven by newly formed CST collaterals. Taken together, our study revealed an effective avenue to rejuvenate corticospinal neurons, thereby providing new thoughts to optimize the otherwise modest effects of rehabilitative training that is widely used for treating patients with traumatic CNS injuries.

Cells become senescent constantly throughout life, in response to damage, stress, or reaching the Hayflick limit on replication. A senescent cell ceases to replicate, grows in size, and begins to secrete a potent mix of pro-inflammatory signals. In youth, the immune system efficiently clears senescent cells. Clearance falters in later life, however, and this failure of the immune system to keep up with the pace at which senescent cells are created enables the steady accumulation of senescent cells over time. The inflammatory signaling becomes increasingly disruptive to tissue structure and function, an important contribution to degenerative aging. A number of research groups and companies are focused on ways to restore the ability of the aged immune system to clear senescent cells, and time will tell as to whether this sort of approach becomes favored versus senolytic small molecule drugs that selectively stress senescent cells to cause programmed cell death.

Aging involves molecular changes that can give rise to different cell fates, one of those being cellular senescence. Senescent cells stably arrest in the cell cycle and play important roles in physiological processes and can act in a tumor-suppressive manner. However, senescent cells accumulate throughout the body with both chronological and biological aging, promoting chronic inflammation and tissue dysfunction. One of the features of senescent cells is their ability to adopt a secretory phenotype, which can act as a chemotactic gradient to attract immune cells. These infiltrating immune cells are capable of recognizing senescent cells and targeting them for destruction, thus maintaining a balance between senescent cell generation and elimination.

Unfortunately, with age, the immune system undergoes changes that alter functional capacity, referred to as immunosenescence. Immunosenescence impacts both innate and adaptive immune cells, impairing their protective functions, like immunosurveillance, or causing them to adopt a hyperinflammatory phenotype, which may further enhance senescent cell burden. These age-related changes in immune function can compromise immunosurveillance, further exacerbating senescent cell burden and its effects. Additionally, senescent cells themselves can modulate markers on their cell surface that make detection by immune cells more difficult and allow them to escape immune clearance. The role of the immune system in limiting senescent cell burden to maintain homeostasis and how immunosurveillance is compromised with age is explored. Furthermore, mechanisms by which senescent cells evade immunosurveillance and potential strategies to restore age-related deficits in immune cell-mediated clearance of senescent cells are also discussed.

Link: https://doi.org/10.3389/fgene.2026.1882818

First generation stem cell therapies that use a variety of cell sources and protocols are widely used in the medical tourism industry. A more limited set of such therapies are used in more regulated medical systems. The aspirational goal in the field of stem cell medicine is to induce regeneration of aged and damaged tissues to improve function, but this outcome remains unreliable. Stem cell therapies can fairly reliably produce a reduction in chronic inflammation for a period of months, however. Even so, results vary widely from patient to patient and clinic to clinic; standardization remains a challenge, perhaps in large part due to the sensitivity of cells to small differences in how they are cultured. The degree to which stem cells in culture become senescent, and thus detrimental to the treatment, can vary widely.

Stem cell therapy has emerged as one of the most promising strategies in regenerative medicine due to its potential to repair, replace, or regenerate damaged tissues and organs. Over the past several decades, advances in stem cell biology, biomaterials, and translational medicine have significantly expanded the therapeutic landscape, enabling applications across a wide range of diseases, including neurological, cardiovascular, ophthalmological, orthopedic, and oncological conditions

Despite substantial progress in stem cell biology, biomaterials, and regenerative medicine, several important clinical challenges continue to limit the successful translation of stem cell-based therapies into routine medical practice. Although numerous preclinical studies have demonstrated encouraging therapeutic outcomes, reproducibility across clinical studies remains inconsistent. Differences in patient populations, disease stage, genetic background, age, and underlying pathological conditions may contribute to substantial variability in treatment responses.

Link: https://doi.org/10.3390/biomedicines14071443

Myesthenia gravis is a rare autoimmune condition in which a specific receptor needed for nerve impulses to pass through the neuromuscular junction to active muscle fibers is blocked or destroyed by immune activity. This leads to muscle weakness that varies over time, and can progress to be life-threatening in a minority of cases. The prognosis is good for the majority of patients, however. While distressing, the condition affects only parts of the body, and doesn't cause pathology (such as chronic inflammation) that directly contributes to other conditions or the pace of aging. The existing therapies are helpful for most patients, and are improving over time. If forced to choose one presently incurable neuromuscular autoimmune condition to suffer, this would be strong contender. The others tend towards being much worse.

A very interesting paper was published recently. Researchers set out to compare the epidemiology of patients with myesthenia gravis and multiple sclerosis using data in four US state databases. Both are incurable autoimmune conditions that affect muscle function, the second being far worse than the first in terms of loss of vital function and patient outcomes. Along the way, the researchers made the unexpected discovery that myesthenia gravis patients live five years longer than the general population, noting that "this observation should be interpreted as hypothesis-generating." Meaning that there is no obvious reason as to why this would be the case.

How long can sizable differences in life expectancy between groups hide from the attention of those who seek to understand why exactly it happens? There are analogous examples, such as the clinical trial showing a five year survival advantage over the general population in osteoporosis patients who took bisphosphonate drugs, for example. It later turned out that those drugs may be senolytic, reducing the burden of senescent cells, but the topic is by no means closed, nor even really all that widely known or eagerly investigated.

But on with the hypothesizing on the matter of myesthenia gravis related longevity. Firstly, we might propose that there was some form of error on the part of one or more groups within the chain that leads from gathering to warehousing to analysis of epidemiological data. This seems unlikely, given the incentives of those involved, and the effort to use distinct sources of data, but this is why replication is necessary: someone will have to repeat the analysis using databases for another population.

Secondly, we might think that one or more of the common treatments used by the majority of myesthenia gravis patients have a positive effect on late life mortality risk. These treatments are acetylcholinesterase inhibitors and various immunosuppressive therapies. It would be surprising to find that any immunosuppressive therapy reduces mortality risk in late life in any scenario other than inflammatory autoimmune disease; the consensus is that suppression of necessary immune functions is harmful, and only an acceptable trade-off for conditions such as rheumatoid arthritis and worse autoimmunities. As noted above, myesthenia gravis isn't an inflammatory condition. Acetylcholinesterase inhibition is a more interesting thread to pull on; acetylcholine is an important neurotransmitter, these drugs block its degradation, and are primarily used in Alzheimer's patients where they are shown to slow cognitive decline. Do they produce other meaningful benefits that start in the brain and percolate out into the body or that result directly from actions outside the brain? The answer to that question seems largely unclear, but there are supportive studies in aged mice, such as one showing improved lung function.

Thirdly, myesthenia gravis patients, once diagnosed, tend to have a close relationship with physicians and are quite actively monitored, as is the case for many rare diseases. One outcome of this is that patients are strongly encouraged to exercise and improve their lifestyle. Does this five year difference in life expectancy result from being closely monitored by physicians, and thus other age-related issues are identified earlier and treated more effectively as a result, combined with being constantly encouraged and motivated to improve lifestyle choices? One has to imagine that the threat of severe muscle weakness should the condition advance, to the point of needing mechanical ventilation, is quite motivating, even setting aside the effects of a great deal more support and direction from the medical community than most people receive.

Unexpected longevity in myasthenia gravis: a multi-state population-based comparison with multiple sclerosis and the U.S. population

We examined death records from four US states in the years 2000, 2005, 2010, and 2015. We compared the age at death for people with myasthenia gravis (MG) and multiple sclerosis (MS) to life expectancy in the general US population. During this period, many of today's newer high-efficacy treatments were not yet available, which allowed us to examine mortality patterns before the introduction of more recent therapies. MS is widely known to shorten life expectancy, but less is understood about long-term survival in MG. In clinical practice, we observed that many patients with MG were living into their 80s and 90s, while this was uncommon in MS. Understanding whether these observations reflect broader patterns can help clinicians, patients, and researchers better understand the long-term impact of these conditions.

This population-based analysis across four U.S. states demonstrates a consistent and substantial difference in age at death between individuals with MG and those with MS. Age at death of MS patients was significantly lower than the general population (-12.4 years). In contrast, MG patients showed a higher mean age at time of death compared with the general population (+4.8 years) and died significantly later than MS patients (+15.5 years, adjusted for sex and year). These patterns were consistent across datasets. Despite a higher reported burden of age-related comorbidities in MG populations, MG patients demonstrated higher mean age at death than both MS patients and the general population.

Differences in disease biology are also likely relevant. MS is characterized by chronic neuroinflammation, demyelination, and progressive neurodegeneration, leading to loss of neurological reserve and increasing vulnerability to systemic complications. These downstream effects extend beyond the central nervous system and contribute to long-term morbidity. MG, by contrast, affects neuromuscular transmission without causing structural neurodegeneration. Although MG can produce severe weakness and life-threatening crises, many patients experience meaningful functional recovery with treatment. The absence of a progressive neurodegenerative component may help explain the more favorable long-term outcomes observed in this analysis.

An additional complexity is the apparent mismatch between comorbidity burden and survival. Prior studies suggest that MG populations, particularly those with late-onset disease, often carry a higher burden of age-related comorbidities, including hypertension, diabetes, and pulmonary disease. In contrast, MS populations may have fewer traditional comorbidities but higher rates of psychiatric and cardiovascular conditions. Despite this, MG patients in the present analysis demonstrated higher age at death than both MS patients and the general population. This finding is difficult to reconcile and suggests that factors beyond comorbidity burden alone are influencing outcomes. At present, this observation should be interpreted as hypothesis-generating.

Tauopathies emerge in the aging brain, a pathological level of phosphorylation of the tau protein that is disruptive to cell function. Evidence suggests a feedback loop between tau phosphorylation and consequent aggregation into neurofibrillary tangles on the one hand and chronic inflammation in brain tissue on the other, ultimately leading to the widespread death of neurons. Here, researchers show that another feedback loop exists between pathologically altered tau and mitochondrial dysfunction in brain cells. Since it is well established that mitochondrial dysfunction promotes inflammatory signaling via a range of mechanisms, such as maladaptive reactions to mitochondrial DNA fragments released into the cell cytoplasm, this new discovery fleshes out the bigger picture considerably.

Tau molecules spend some of their time sitting on microtubules. But tau molecules spend even more of their time detached from their seats on microtubules. During this downtime, a free-floating tau molecule becomes especially prone to confrontations such as the stapling of a chemical cap onto its exposed parts by neighborhood enzymes. These modifications predispose tau molecules to clumping with one another, potentially aggregating into neurofibrillary tangles. A single tau molecule can acquire numerous chemical caps along its length, all the more pumping up its potential for mischief. More often than not, the chemical cap that gets attached is what chemists call a phosphate group. A single tau molecule can accommodate as many as 80 separate phosphate-group additions, or phosphorylations. Tau "hyperphosphorylation" is a uniting feature linking all tauopathies.

The newly discovered pathological pathway is entirely independent of both neurofibrillary-tangle formation and microtubule instability. Instead, it involves a switch in the directionality of mitochondria's energy-production line, with a resulting disruption of mitochondria's primary function: the conversion of calories from glucose or fat to energy by what's known as the electron-transport chain. This multiple-component complex passes electrons, conveyor-belt-style, from one to the next of its components, the last of which converts a precursor molecule into ATP, our cells' universal energy currency. The new study shows that when the hyperphosphorylated tau molecule interacts with a key mitochondrial component, it jams up the conveyor belt, causing electrons to flow backward. Aptly named "reverse electron transport," this snarl produces large amounts of highly reactive, noxious chemicals, with accompanying inflammation and damage to proteins.

The researchers proved that reverse electron transport was occurring in animal models of tauopathy as well as in tauopathy-afflicted human brain tissues. Healthy nerve cells, largely spared of hyperphosphorylated tau's malevolent presence, showed no sign of reverse electron transport or its downside effects. Next, they showed how reverse electron transport is activated: Tau molecules enter mitochondria - although only when they're phosphorylated. There, they can bind to a component of the electron-transport chain called NDUSF3, warping that protein's shape. When this happens, electrons drop off the conveyor belt and start flowing backward. Genetically or pharmacologically depleting tau halted this defection. Reverse electron transport is a textbook example of a vicious circle. The massive release of highly reactive chemicals dramatically boosts the odds that individual tau molecules will get hyperphosphorylated, leading to additional activation of reverse electron transport. Once started, this can self-perpetuate.

An experimental drug called CPT prevented hyperphosphorylated tau from binding to NDUSF3, blocking reverse electron transport without impairing normal electron flow. In fly and mouse models of tauopathy, CPT treatment rescues behavioral deficits, reduces neuroinflammation and mitigates neurodegeneration. Cerapeut, Inc. is developing CPT as a therapeutic drug for the treatment of neurodegenerative diseases.

Link: https://med.stanford.edu/news/all-news/2026/08/tau-alzheimers.html

Muscle tissue is metabolically active. In response to use during physical activity, muscle cells secrete a range of signals, as a class now called myokines or exerkines. These signals produce overall beneficial effects on cell behavior and tissue function throughout the body. The precise details of this process are still under investigation, and only the major signals are fairly well mapped - a great deal remains to be discovered in terms of exactly how exercise improves function. Here, researchers review what is presently known of this connection between exercise and a slowing of the progression of age-related neurodegeneration. The research community is quite interested in producing exercise mimetic therapies of various sorts, and one approach to that goal is the identification of specific signals or responses to those signals that can be manipulated.

Parkinson's disease (PD) is a progressive neurodegenerative disorder with motor and non-motor symptoms, driven by dopaminergic loss and α-synuclein accumulation. Beyond neurodegeneration, growing evidence highlights skeletal muscle health as a key determinant of prognosis, with sarcopenia and frailty contributing to greater disability, fall risk, and reduced quality of life. This narrative review synthesizes current evidence on the interplay among exercise, muscle status, and exerkine signaling in PD, emphasizing their potential roles in neuroprotection and functional outcomes.

Sarcopenia and reduced muscle strength are highly prevalent in PD and independently associated with disease severity, frailty, and falls, while grip strength has emerged as a simple biomarker of progression. Clinical trials consistently show that aerobic, resistance, and multimodal exercise programs improve gait, balance, mood, cognition, and quality of life, with progressive resistance and balance training yielding the greatest motor benefits.

At a mechanistic level, skeletal muscle functions as an active endocrine organ, releasing a variety of exercise-induced signaling molecules known as exerkines. These include brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), irisin, cathepsin B, myostatin, and growth/differentiation factor 15 (GDF15). Together, these exerkines facilitate muscle-brain crosstalk and are thought to contribute to the neuroprotective effects of exercise in PD. Through anti-inflammatory, antioxidant, and mitochondrial regulatory pathways, they support dopaminergic neuron survival and promote synaptic plasticity and neuronal resilience.

Link: https://doi.org/10.1002/nep3.70032