Fight Aging!

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

In order to produce an airtight answer to the question of whether obesity accelerates aging, versus merely being very bad for one's health, one has to have an airtight definition of aging. It is always possible to fall back to the oldest and least useful definition of aging, which is a rise in risk of mortality over time driven by intrinsic causes. Arguably the effects of obesity fit that definition, but then replace the introduction of excess calories with the introduction of infectious viral particles, and suddenly someone will say that if obesity accelerates aging as judged by mortality risk, then a few weeks of influenza infection also accelerates aging by the same measure. Or ingesting outright toxins (dramatically) accelerates aging. This is unsatisfying.

Thus any reasonable discussion of whether obesity accelerates aging has involve a tour of what obesity does to cellular biochemistry, and also has to involve judgement calls on which of those changes are versus are not aging. Everything changes with age. Some of that is cause, some of it consequence. Natural aging is a certain balance of certain harmful mechanisms; if we observe what looks like accelerated aging, and under the hood we see that it is just one or just two of those mechanisms running amok, then is it really accelerated aging? Or is it just poor health resulting from the accumulation of cell and tissue damage? Obesity certainly accelerates the age-related accumulation of senescent cells. But harmful levels of irradiation achieve that outcome as well! A great many things can superficially look like accelerated aging: inefficient DNA repair; slow poisoning; malnutrition; and of course obesity. There is a great deal of room to argue over whether they are in fact accelerated aging or not, but all that debate hinges on how exactly one defines aging.

There is one way in these considerations can be useful, and that is managing expectations as to whether therapies that treat aging are going to be more versus less useful as treatments for various forms of what appear to be accelerated aging. For a therapy to be useful, mechanisms have to align. We know that the apparently dramatically accelerated aging of Hutchinson-Gilford progeroid syndrome (HGPS) is driven by mutation that harmfully alters a critical protein involved in the structure of the cell nucleus. Those protein alterations occur in normal aging to only a small degree. Treatments for aging are thus unlikely to be useful in HGPS and vice versa. Obesity, however, is clearly correlated with an increased burden of senescent cells. Senotherapeutics developed for use in the treatment of aging may well be beneficial for obese individuals even at younger ages.

Obesity accelerates aging: Mechanisms and therapeutic implications

To explore how to delay aging effectively, scientists have summarized twelve aging characteristics that may be slowed, stopped, or reversed through intervention: genomic instability, telomere depletion, epigenetic changes, loss of protein balance, loss of autophagy, deregulated nutrient sensing, mitochondrial dysfunction, cellular aging, stem cell depletion, changes in intercellular communication, chronic inflammation, and dysbiosis. The accumulation of these characteristics is associated with an increased prevalence of various age-related diseases. Research indicates that interventions aimed at slowing the aging process can postpone the onset and progression of various diseases in numerous rodent models.

There are intricate and multifaceted connections between obesity and aging. Obesity is associated with a variety of chronic and degenerative diseases, such as type 2 diabetes, osteoarthritis, cancer, and cardiovascular and renal dysfunction, and may lead to premature aging. A large amount of research evidence suggests that obesity can affect the accumulation of various aging biomarkers, including telomere shortening, epigenetic changes, disruptions in protein homeostasis, mitochondrial dysfunction, cellular senescence, stem cell depletion, and alterations in intercellular communication. Meanwhile, interventions aimed at extending health and lifespan, such as calorie restriction and exercise, are associated with reducing obesity.

Undoubtedly, obesity is an accelerator of aging and aging-related diseases, and its intervention directly impacts the development of aging. However, the overlapping characteristics mentioned above merely indicate potential mechanisms by which obesity promotes aging, with the specific molecular mechanisms involved remaining unclear. These findings suggest that future efforts should focus on further exploring these mechanisms and validating them through targeted biological markers to advance precision medicine development.

A sizable body of evidence points to a meaningful role for the accumulation of senescent cells in the onset and development of age-related pulmonary conditions such as idiopathic pulmonary fibrosis. These are conditions characterized by chronic inflammation and harmful structural remodeling in lung tissue. Animal studies suggest that senolytic therapies to clear senescent cells can turn back the course of disease. An initial small academic human trial of senolytic treatment in patients with idiopathic pulmonary fibrosis produced promising results, but little to no follow up has occurred. This is the standard problem for generic drugs and otherwise low-cost therapies: since little profit can be made, no-one can raise sufficient capital to pay for the high costs of clinical trials.

Aging is the primary risk factor for most chronic diseases and is accompanied by the progressive accumulation of senescent cells within tissues. While cellular senescence initially serves as a protective mechanism that limits the proliferation of damaged cells, its persistent presence contributes to tissue dysfunction through the secretion of a broad spectrum of inflammatory and profibrotic mediators. The resulting chronic low-grade inflammation, oxidative stress, immune dysregulation, and impaired regenerative capacity are increasingly recognized as hallmarks of age-related pathology. Chronic pulmonary diseases, including chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis, increase markedly with age and are increasingly regarded as manifestations of accelerated lung aging. Their development and progression are further exacerbated by obesity and type 2 diabetes mellitus, two highly prevalent metabolic disorders characterized by chronic metabolic stress, mitochondrial dysfunction, systemic inflammation, and enhanced accumulation of senescent cells.

Emerging evidence suggests that cellular senescence represents a common biological denominator linking metabolic and pulmonary disease. Through persistent inflammatory and profibrotic signaling, senescent cells establish a self-perpetuating cycle of chronic inflammation, extracellular matrix remodeling, fibrosis, endothelial dysfunction, and impaired tissue repair, thereby driving progressive deterioration of both metabolic and pulmonary function. The recognition of cellular senescence as one of the important drivers of both chronic pulmonary and metabolic diseases has stimulated growing interest in therapeutic strategies aimed at reducing senescent-cell burden or attenuating its detrimental effects. Current approaches include both novel senotherapies specifically targeting cellular senescence, as well as established therapies used in metabolic diseases that have recently been shown to exert senescence-modulating effects. Although clinical evidence remains limited, targeting cellular senescence offers a unique opportunity to address the underlying biology of aging rather than individual disease manifestations.

Link: https://doi.org/10.3389/fragi.2026.1812724

There are now scores of aging clocks in the literature, most of which have come and gone and see little adoption. Most research is focused on gathering more data for handful of mainstream clocks, but these clocks are intended to capture a measure of aging generally across the whole body, keyed to outcomes such as mortality risk. Evidence suggests that different organs and tissues can age at different rates, however. Thus there remains a need for the development and validation of tissue-specific aging clocks. Here, researchers review the present state of development for clocks intended to measure aging in the brain specifically.

Brain aging represents a critical risk factor for neurodegenerative diseases and cognitive decline, yet the measurement of biological brain age remains challenging. Brain aging clocks, which quantify the discrepancy between predicted brain age and chronological age, have emerged as powerful tools for assessing brain health and predicting disease outcomes. Recent advances have transformed these clocks from simple global metrics to sophisticated, multi-modal approaches that capture regional heterogeneity, measure the pace of aging, and achieve cellular resolution.

This review examines the methodological evolution of brain aging clocks, including the development of regional brain age gradients, pace-of-aging measurements, and multi-modal integration strategies. We then explore the cellular and molecular mechanisms underlying accelerated brain aging, with particular emphasis on cellular senescence, cell-type-specific aging patterns, vascular dysfunction and blood-brain barrier breakdown, mitochondrial decline, proteostasis failure, synaptic loss, and the accumulation of senescent cells in neurodegenerative conditions. Epigenetic clocks and emerging plasma biomarkers (neurofilament light, GFAP, phosphorylated tau), particularly DNA methylation-based approaches, are discussed in the context of their relationship with neuroimaging markers and cognitive outcomes.

Clinical applications are reviewed, including the prediction of neurodegenerative disease, the impact of socioeconomic and geographic disparities on brain aging, and emerging senotherapeutic interventions. Finally, we address current challenges in biomarker standardization, the need for longitudinal validation, and future directions toward precision aging medicine. Together, these advances position brain aging clocks as essential tools for understanding neural aging mechanisms and developing targeted interventions to promote healthy brain aging.

Link: https://doi.org/10.1016/j.exger.2026.113260

The major divide in theories of aging lies between the mainstream camp of damage accumulation and antagonistic pleiotropy on the one hand, and the minority camp of programmed aging theories on the other. The damage accumulation camp sees aging as a side-effect of the focus of evolutionary mechanisms on early life reproductive success, favoring the development of biological systems that are front-loaded for early life success, with little investment in maintenance over time. Programmed aging purists view aging as a process that is under active natural selection, however, not a side-effect at all. Why degenerative aging would be selected for is debated, but group selection to reduce the risk of runaway population growth has been argued, as well as the winnowing effect of environmental change on non-aging species, as aging allows for faster adaptation to that change, out-competing non-aging competitor species.

The relatively recently developed hyperfunction theories of aging have a foot in each camp, and might crudely be thought of as a compromise position, though that isn't why they emerged. It has been a difficult area of the field to follow, as it wasn't always clear that everyone involved had the same view of the definition of hyperfunction. Today's open access paper provides a good summary of the consensus hyperfunction view, insofar as such a thing now exists: biological programs that determine early life growth and development continue to operate in adult life in maladaptive ways, and become overtly harmful over time, giving rise to aging. This is roughly a direct conceptual fusion of the concepts of antagonistic pleiotropy and programmed aging. Does any of this theorizing matter? To the degree that it determines research priorities for the development of therapies to treat aging, it probably does.

A brief history of the hyperfunction theory of aging and future directions

Understanding the mechanisms underlying aging processes is crucial for biogerontology and for developing translational approaches. There is much debate, however, regarding the fundamental nature and drivers of aging. The idea that aging arises from genetically encoded processes has gained traction in recent years, the so-called "programmatic theories". It is important not to conflate programmatic and programmed theories, as the latter view aging itself as an evolved adaptation serving a function, while in programmatic theories late-life decline is driven by developmental programs that run-on without aging being adaptive.

In past decades, the idea that aging results from a program or from continued developmental processes became less popular. The evolutionary theory of aging argued against a programmed (i.e., adaptive) aging process, predicting that such a program would be selected against. The dominant view was that aging arises from the declining force of natural selection with age, the so-called "selection shadow". In this model, both genetic variants with detrimental late-life effects, or variants beneficial early in life but harmful later, can become fixed in populations, contributing to aging; here, aging is not an adaptation and, in that sense, not programmed.

The increasing emphasis on molecular damage in aging research was likely driven, at least in part, by advances in molecular biology and biochemistry. The explosion of molecular discoveries in the second half of the 20th century revealed a vast and intricate number of cellular components and biological processes, which in turn led to a proliferation of theories linking aging to defects in each of these many processes. Because virtually any important biochemical or molecular process can malfunction and become harmful to cells, it is easy to conceive new damage-based theories of aging. This abundance of molecular detail reinforced the perception that aging is driven by stochastic damage and led to many theories and frameworks positing damage accumulation as the root cause of aging. It was against this trend that a new wave of programmatic theories emerged at the start of the 21st century.

In 2006, a seminal conceptual paper proposed the quasi-programmed theory of aging, introducing the term hyperfunction. It proposed "a quasi-program for aging, a continuation of the developmental program that is not turned off, is constantly on, becoming hyper-functional and damaging, causing diseases of aging." While acknowledging that damage occurs with age, it was argued that such damage plays a negligible role in determining lifespan. Instead, quasi-programs are the principal drivers of aging and limiting human lifespan.

Although programmatic theories, such as hyperfunction, provide powerful conceptual frameworks for understanding the aging process, much work remains to be done. They are still outside the dominant geroscience paradigms, such as the "hallmarks" and "pillars" of aging. The unfortunate consequence - I would argue - is that most aging studies focus exclusively on adult life, hindering efforts to connect aging to developmental processes. If aging processes follow trajectories set early in life, then studying the whole life course is imperative to elucidate aging mechanisms. Besides, if repair and maintenance mechanisms are downregulated during development, then studying early development may prove valuable for identifying rejuvenation therapies, as already demonstrated in partial reprogramming.

Iron metabolism is strongly connected to oxidative stress, the excessive production of reactive oxygen species and other oxidative molecules that outpaces the ability of cells to avoid, resist, or repair the consequent damage. It can lead to a form of programmed cell death called ferroptosis. Here, researchers describe how iron metabolism and ferroptosis are seen to contribute to the development of atherosclerosis. This isn't a very well developed area of research into cardiovascular disease, in that while one can paint an interesting mechanistic picture at the high level, much of the detail remains to be filled in, and robust forms of therapy based on manipulation of iron metabolism or ferroptosis have yet to emerge.

Disturbances in iron homeostasis have a bidirectional impact on the development of atherosclerosis. The classic "iron hypothesis" states that systemic iron overload increases the risk of cardiovascular diseases (CVDs), while controlling iron deficiency can protect blood vessels. Histopathological studies have confirmed that atherosclerotic plaques have a higher iron deposition compared to healthy blood vessels, and this phenomenon can be observed from the early stages of atherosclerosis. Macrophages recycle iron from senescent red blood cells, and intra-plaque hemorrhage exacerbates the phagocytosis of red blood cells, which is considered a key mechanism for iron deposition.

An increase in intracellular iron concentration enhances the uptake of oxidized low-density lipoprotein (ox-LDL), hinders cholesterol efflux, and accelerates the formation of foam cells in the plaque environment. This process leads to a decrease in GPX4 expression, an excessive production of reactive oxygen species (ROS), and an exacerbation of lipid peroxidation - all three together exacerbate intracellular oxidative stress, directly aggravating endothelial dysfunction and ultimately increasing plaque instability.

Despite the promising therapeutic potential of targeting ferroptosis discussed throughout this manuscript, several important limitations must be acknowledged. First, the disease specificity of ferroptosis-driven pathology remains incompletely defined; not all conditions involving cell death or oxidative stress may benefit from ferroptosis inhibition, and the contribution of ferroptosis varies substantially across different diseases and even across stages of the same disease. Second, the optimal timing of intervention is challenging to determine, as ferroptosis may play divergent roles in early versus late disease phases, and premature or delayed intervention could be ineffective or even detrimental. Third, systemic modulation of iron metabolism carries risks of off-target effects on other organs, including potential hepatotoxicity, cardiotoxicity, and disruption of normal iron homeostasis in tissues with high iron turnover. Fourth, while natural compounds are often proposed as ferroptosis modulators, they have pharmacological limitations such as poor solubility, low bioavailability, off-target bioactivity, and unknown long-term safety profiles.

Link: https://doi.org/10.1016/j.redox.2026.104330

That we cannot accurately and robustly measure biological age is a major impediment to the development of rejuvenation therapies. Without the ability to quickly focus on approaches with the largest effects on biological age, the field spends far too much time on marginal classes of therapy, and optimization of any given approach is challenging, haphazard, and slow. The development of aging clocks in recent years is a step in the right direction, but clock data is not trustworthy in the matter of assessing the effects of any given intervention until they are fully calibrated to that intervention via life span studies - which defeats the point of having a fast clock measure. That this is a problem is widely appreciated in the field of aging research, so we might hope that we will see meaningful progress towards reliably and accurate measurement of biological age in the years ahead.

Aging is a major risk factor for numerous chronic diseases and a leading contributor to global mortality. Slowing the rate of aging would have revolutionary implications for health and longevity. A fundamental barrier to achieving this goal, however, is the difficulty of accurately measuring the effects of rejuvenating interventions. The development of precise gerontometric methods, therefore, is a priority for both science and preventive medicine.

metabolomics. Although metabolomic approaches have limited accuracy in determining biological age, the described approach, which averages multiple metabolites from a large metabolomic signature of aging, circumvents this limitation. It allows for measurement of biological age change with an accuracy of approximately one month. Such precision gerontometry enables accelerated testing of candidate anti-aging interventions, helping to eliminate ineffective ones, speed the development of effective ones, and ultimately extend the duration of healthy human life, with profound social and humanitarian benefits.

Link: https://doi.org/10.3390/metabo16070463

Alzheimer's disease, and the other common age-related neurodegenerative conditions, are characterized by chronic inflammation in brain tissue. Aging in general is characterized by an increased level of constant inflammatory signaling. Numerous different mechanisms contribute to this constant inflammation, such as maladaptive reactions to mitochondrial DNA fragments released into the cytoplasm as a result of age-related mitochondrial dysfunction, and a growing burden of senescent cells that actively secrete pro-inflammatory signals. The gut microbiome changes in ways that provoke inflammation as well, and the intestinal barrier becomes leaky with age, allowing more unwanted bacteria and bacterial metabolites into the body. In the brain, clearance of metabolic waste is achieved in large part by circulation of cerebrospinal fluid and its drainage into the body via channels that atrophy or become dysfunctional with age. Reduced flow allows metabolic waste to build up in brain tissue, including the protein aggregates associated with neurodegenerative conditions - and all of this increases maladaptive inflammatory responses on the part of immune cells in the brain.

Any reasonably complete list of contributions to age-related inflammation is much longer than the few high points noted above. Comprehensively dealing with the inflammation of old age is a task that will require more than one therapy, if the objective is to remove the causes. This is perhaps why much of medical research tends to favor sabotaging inflammatory signaling or aspects of immune cell function rather than addressing causes. It is a bad long term strategy from the point of view of achieving radically better human health, but it works in the short term to get drugs approved and investors their profits. The therapy that is the subject of today's open access report on its initial clinical trial results is an example of the dominant class of approach to chronic inflammation - find a central mechanism involved in coordinating the inflammatory response, and sabotage it. Unfortunately the initial data suggests that this particular anti-inflammatory therapy may not work as well in humans as it does in mouse models of inflammatory neurodegeneration.

Immunotherapy with a short-lived anti-PD-L1 antibody in Alzheimer's disease: a phase 1b, randomized, double-blind trial

While Alzheimer's disease (AD) is initiated by amyloid plaque accumulation, its progression involves local neuroinflammation that the brain cannot resolve when age-related dysfunction of the systemic immune system limits peripheral immune support. Preclinical studies using rodent models showed that transient systemic blockade of programmed death-ligand 1 is associated with reduced neuroinflammation, neuroprotection and attenuation of disease progression. Based on the underlying mechanism, a new short-lived anti-programmed death-ligand 1 antibody with fragment crystallizable (Fc) region-effector silencing and reduced neonatal fragment crystallizable receptor (FcRn) binding (IBC-Ab002) was engineered.

Here, we report a randomized, double-blind, phase 1b first-in-human trial in early AD, with safety and tolerability as the primary endpoint. Forty participants were enrolled across five ascending dose cohorts (1 mg/kg to 30 mg/kg), with dosing administered four times at 3-month intervals. Treatment was well tolerated, with no treatment-related serious adverse events or evidence of amyloid-related imaging abnormalities. Exploratory analyses at week 48 showed directional changes in cerebrospinal fluid biomarkers of neuronal and synaptic damage favoring the 30 mg/kg dose, although no doses reached statistical significance given the limited sample size. The safety and tolerability profile supports further clinical development of systemic, intermittently administered IBC-Ab002 in early AD.

Mitochondrial transplantation is a promising approach to treating age-related mitochondrial dysfunction. Cells readily take up mitochondria from their surroundings. The major challenge in the development of practical mitochondrial transplantation therapies is the robust production of the large numbers of mitochondria needed for a human therapy. Ways to improve the survival and uptake of mitochondria are thus helpful because they reduce the manufacturing burden, lowering the number of mitochondria needed for a successful treatment. Researchers here upon tools used in lipid nanoparticle therapies and gene therapies and demonstrate that they can be used to improve the delivery and uptake of mitochondria into cells in tissues.

Mitochondrial transplantation has emerged as a promising strategy for modulating cellular bioenergetics in mitochondrial dysfunction. However, isolated mitochondria suffer from poor stability and limited cellular uptake, restricting their therapeutic application. To address these limitations, we developed a surface engineering strategy that stabilizes isolated mitochondria while enabling interactions with target cells, providing a platform for selective organ- and cell-targeting. Polyethylene glycol (PEG) with lipid/carbon chains was introduced to mitochondria-associated membrane structures, forming a protective hydration layer on the mitochondrial surface. This PEG layer also serves as a modular platform for functionalization with biomolecules, such as peptides and antibodies, thereby broadening its biomedical applications.

In this study, we examined whether mitochondrial function in target cells can be modulated using PEG-shielded mitochondria functionalized with a cell-penetrating peptide (CPP) via a maleimide linkage. Our results suggest that CPP-PEG-modified mitochondria exhibit efficient cellular internalization and are associated with increased mitochondrial respiratory activity, consistent with intracellular bioenergetic modulation. These findings suggest that spatially controlled presentation of CPP at the terminus of a PEG layer may provide an effective approach for stabilizing isolated mitochondria while modulating intracellular dynamics and functional responses. This surface engineering strategy offers a proof-of-concept design framework for mitochondria-associated engineering and future bioenergetic strategies.

Link: https://doi.org/10.1002/admi.70583

The bacterial species P. gingivalis is a cause of periodontitis, a common form of inflammatory gum disease that in addition to damaging gums, teeth, and bone in the mouth, also contributes to the development of inflammatory age-related conditions elsewhere in the body. Here researchers report on a novel approach to selectively removing P. gingivalis from the mouse, using a combination of a photosensitive dye conjugated to an antibody that binds to surface features on this species of bacteria. When irradiated with near infrared light, this kills the targeted cells. Treating a mouse model of periodontitis in this way successfully reduced inflammation and resolved the condition.

Traditionally, periodontitis was viewed as a simple infection; however, it is now recognized as a complex polymicrobial disease driven by synergistic interactions within the oral microbiota and a subsequent aberrant host immune response. Periodontitis is typically initiated by a shift from symbiotic to dysbiotic microbial communities. In this process, 'keystone pathogens' such as Porphyromonas gingivalis, even at low abundance, can remodel the surrounding commensal bacteria into a highly inflammatory state.

Recently, a new cancer-targeted therapy called near-infrared photoimmunotherapy (NIR-PIT), which combines antibody-dye conjugates and near-infrared light, has emerged. The cell death mechanism of NIR-PIT is unique. Specifically, when the conjugate is irradiated with near-infrared light in the presence of sufficient electron donors, the hydrophilic side chain (silanol) of the IR700 molecule dissociates through a photochemical ligand reaction, and the remaining structure, including the antibody, rapidly becomes hydrophobic and aggregates. At the same time, the antibodies bound to the surface antigens also aggregate on the tumor cell membrane. The aggregation reaction of IR700 causes physical stress on the antigen-antibody complex and selectively destroys the target cells

We recently developed NIR photoantimicrobial-targeted therapy (NIR-PAT2) to treat infectious diseases. For NIR-PAT2, as targeting molecules, we exploit immunoglobulin Y (IgY). NIR-PAT2 with IgY could be used for body surface and lumens, such as skin, hair, eye, digestive tract. The aim of this study was to develop a bacteria-targeted therapeutic modality using NIR-PAT2. While we acknowledge the inherent limitations of single-pathogen targeting in a complex polymicrobial disease, we hypothesized that selectively eliminating a keystone species would disrupt the synergistic drivers of dysbiosis. We define this approach as a precision-modulating therapy, designed to selectively ablate P. gingivalis while preserving the ecological integrity of the oral community. Here, we demonstrate that NIR-PAT2 successfully modulates oral dysbiosis, leading to the resolution of periodontitis and the restoration of a healthy-associated microbial profile in a murine model.

Link: https://doi.org/10.1186/s12967-026-08336-2

Telomeres are repeated DNA sequences found at the ends of chromosomes. A little telomere length is lost with each cell division, and short telomeres trigger cell senescence or programmed cell death. It is a part of the system ensuring the Hayflick limit on the replication of somatic cells. The stem cells that create replacement somatic cells can lengthen their own telomeres, but there are very few stem cells in comparison to the number of somatic cells making up the majority of tissue. This is how evolution reduces cancer to an acceptable level, by dramatically restricting the number of cells capable of unfettered replication, and thus reducing the odds of a malfunction leading to runaway replication.

With age stem cell function declines, reducing the pace at which stem cells deliver replacement somatic cells with long telomeres. As a result, average telomere length falls and the proportion of cells with very short telomeres increases in tissues throughout the body. This has a meaningful negative effect on health, a driver of chronic inflammation, increased numbers of senescent cells, and impaired tissue function. In today's open access paper, researchers report on their efforts to specifically sabotage the cascade of mechanisms that emerge in response to short telomeres in a cell, showing that it improves health in aged mice, at least in the short term. The flip side of the coin, not investigated here, is that this could increase cancer risk by promoting damage to DNA via the continued operation of damaged cells, usually avoided because cells with very short telomeres are destroyed on some timescale.

Therapeutic inhibition of telomeric DNA damage response rescues hematopoietic dysfunction driven by telomere shortening and aging

Telomeres progressively shorten and accumulate damage with aging, and this contributes to cellular senescence and hematopoietic dysfunction. When critically short, telomere ends are detected as DNA damage and trigger a telomeric DNA damage response (tDDR), a signaling cascade involving posttranslational protein modifications, such as phosphorylation of histone H2AX at serine 139 (known as γH2AX), which promotes recruitment of DDR factors including phosphorylated KRAB-associated protein 1 (pKAP1) at damaged sites. Persistent tDDR drives cellular senescence and cell death. The inability of senescent cells to proliferate impairs tissue regeneration, and their secretion of proinflammatory factors, collectively known as the senescence-associated secretory phenotype, promotes chronic, low-grade inflammation, disrupting the local microenvironment and eventually causing systemic frailty.

Whether the tDDR causally impairs hematopoiesis remained unclear. Here we show in telomerase-deficient Telomerase RNA component (TERC) knockout mice, which recapitulate telomere-driven hematopoietic dysfunction and aging, that targeting telomeric noncoding RNAs with telomeric antisense oligonucleotides (tASO) suppresses tDDR in hematopoietic organs, reduces senescence and inflammation, alleviates hematopoietic dysfunction, and enhances hematopoietic stem cell fitness and repopulating potential in vivo. Similar observations were recapitulated in aged wild-type mice, and ex vivo treatment with tASO improved the function of human hematopoietic stem cells from aged donors.

Taken together, our results identify tDDR as a pathogenic driver of hematopoietic decline and support tASO-mediated tDDR inhibition as a potential therapeutic strategy for telomere biology disorders and age-associated hematopoietic aging.

Technically, even very small effects can be classed as rejuvenation if they move the right markers, if they in some way reduce the burden of damage and dysfunction of aging. Exercise probably rejuvenates to some degree, by any reasonable definition. Yet we know the bounds of the possible when it comes to exercise and other widely used interventions, and the outcomes are nowhere near as large as we would like. Fit people are still aging to death, and end up frail in the later stages of life.

In the matter of restoring lost function to the hematopoietic stem cell populations of the bone marrow that are responsible for generating the cells that make up the immune system, there are a number of interventions that have been shown to outperform the effects of exercise in mice. One of the more interesting examples is the results of a single treatment of CASIN, which improves stem cell function globally, improves immune function, and extends life. Restored immune function is an important goal in the treatment of aging, given the sizable influence the immune system has over the course of aging.

Aged hematopoietic stem cells (HSCs) are characterized by increased phenotypic number, decreased self-renewal and long-term reconstitution capacity, myeloid-biased differentiation, and clonal hematopoiesis. In this review, we summarize the life cycle of HSCs, integrate recent advances in understanding the cell-intrinsic and extrinsic mechanisms that drive HSC aging, and highlight innovative rejuvenation strategies that could be harnessed to delay HSC and systemic aging.

Exercise enhances systemic health through improved circulation and metabolism. However, it was found that exercise has little effect on rejuvenating HSCs. It is plausible that exercise preferentially accelerates lymphopoiesis via niche remodeling rather than directly rejuvenates aged HSCs. Dietary restriction (DR) modulates HSC function through multiple nutrient-sensing pathways. Pharmacological approaches targeting the same metabolic pathways also show rejuvenation effects on HSCs. Nicotinamide riboside (NR) enhances mitochondrial function and restores the metabolic competence and regenerative capacity of aged HSCs. Similarly, mTOR inhibition with rapamycin reverses age-related functional decline of HSCs, improving self-renewal, reconstitution potential, and antiviral immunity in aged mice.

Sirt3 is a mammalian deacetylase that exhibits age-dependent expression decline in HSCs. Sirt3 knockout in aged mice impairs HSC self-renewal capacity, while its overexpression enhances regenerative potential. Sirt7 deletion induces premature activation, lymphoid differentiation bias, and functional exhaustion of HSCs. In contrast, Sirt7 overexpression reverses these aging hallmarks, and restores balanced lineage output and reconstitution capacity in geriatric murine models. Transient expression of Yamanaka factors (e.g., Oct4, Sox2, Klf4, and c-Myc) showed systemic rejuvenation effects and extended life span in mice, whether it can reverse HSC aging remains to be tested.

A marked increase in non-polarized cells is observed among aged HSCs, attributed to elevated Rho-GTPase activity of Cdc42 during aging. Casin, a small-molecule Cdc42 inhibitor, restored the proportion of polarized HSCs in aged mice and moderately enhanced their long-term reconstitution potential. In vivo Casin treatment significantly extended the lifespan of aged mice and reduced systemic inflammatory cytokines. Aged HSCs exhibit MMP reduction and pronounced mitochondrial heterogeneity, with low-activity subpopulations displaying characteristic aging phenotypes. Mito-Q treatment in aged mice partially restored MMP and augmented transcriptional activity in HSCs.

Oral administration of the senolytic drug ABT263, an inhibitor of the anti-apoptotic proteins BCL-2 and BCL-xL, effectively cleared senescent HSCs, ameliorated irradiation-induced premature hematopoietic aging, and partially restored the regenerative ability of HSCs.

Link: https://doi.org/10.1186/s13059-026-04119-6

Researchers here discuss a bidirectional relationship between age-related alterations in bile acid metabolism, centered in the liver, and changes in the composition of the gut microbiome. These changes take place in the context of increasing dsyfunction of the intestinal barrier with age, allowing unwanted bacteria and bacterial metabolites into the body to provoke chronic inflammation and other dysfunction. Researchers have demonstrated in animal studies that restoration of a youthful gut microbiome composition can improve health and extend life; an interesting question is the degree to which restoration of a youthful bile acid metabolism can achieve similar outcomes.

Bile acids (BAs), byproducts of cholesterol metabolism in the liver, are not only vital for lipid digestion and absorption of lipid-soluble vitamins but also act as signaling molecules influencing aging, inflammation control, immune homeostasis, and tumor development. They regulate gut microbiota growth and composition, while gut microbiota significantly influence BA hydrolysis and the synthesis of secondary and tertiary BAs. This interplay affects immune function and metabolic phenotypes, and may contribute to obesity, diabetes, non-alcoholic fatty liver disease, inflammatory bowel disease, and certain cancers.

100 elderly and 100 young participants were enrolled in this study. Fecal and serum BAs were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS), while gut microbiota composition was assessed through 16S rRNA gene sequencing. Elderly participants exhibited significantly lower levels of primary fecal BAs, particularly cholic acid (CA) and chenodeoxycholic acid (CDCA), alongside an increase in secondary BAs such as lithocholic acid (LCA), leading to a marked reduction in the primary/secondary BAs ratio.

Serum showed a decline in both conjugated and unconjugated BAs, primary/secondary BAs ratio, while a notable rise in 12α-OH/non-12α-OH BAs. Furthermore, increased levels of P21, LPS, IL-6, and TNF-α in the elderly were associated with specific BA changes, including reduced fecal unconjugated primary BAs and increased LCA. Significant differences in gut microbiota composition were observed, with the elderly displaying a higher abundance of microbiota capable of 7α-dehydroxylation. Correlations were observed among BAs, gut microbiota alterations, and markers of chronic inflammation and intestinal barrier dysfunction.

In conclusion, aging is associated with significant changes in the BA pool, which are associated with gut microbiota dysbiosis. These alterations may be related to intestinal barrier dysfunction and chronic low-grade inflammation. Modulating BA metabolism presents a potential strategy for mitigating the aging process.

Link: https://doi.org/10.3389/fragi.2026.1741360