Fight 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

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.

In this opinion article, the authors suggest the principles and discuss the implementation of precision gerontometry using recent advances in 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