Fight Aging!

A cell becomes senescent given sufficient stress, molecular damage, or on reaching the Hayflick limit on replication. A senescent cell ceases replication, grows in size, and secretes a potent mix of pro-growth, pro-inflammatory signals. In a young individual, senescent cells are rapidly removed by the immune system, but this clearance slows with age. Senescent cells accumulate as a result in tissues throughout the aging body. The greater the number of senescent cells, the more disruptive their signaling becomes, changing the behavior of surrounding cells for the worse, degrading tissue structure, and rousing the immune system into a harmful state of constant inflammatory behavior. Studies have shown that selective clearance of senescent cells in older mice improves health, extends life, and turns back many aspects of age-related disease.

Today's open access paper reviews what is know of the bidirectional relationship between the burden of cellular senescence and state of the aging immune system. Senescent cells degrade the performance of the immune system, while the aging of the immune system allows greater numbers of senescent cells to accumulate. Like many of the interacting aspects of aging, each side exacerbates the other in a feedback loop that accelerates over time. Under the hood, the details are far more complex than this simple summary of the situation, of course, and there much is yet to be mapped and understood. Still, what is known more than justifies a far greater level of attention and funding to be given to clinical trials of senolytic therapies to clear senescent cells.

Immunological consequences of senescence in physiology and pathology

Cellular senescence is a sublethal stress response characterized by a durable cell-cycle arrest and the acquisition of a complex secretory program known as the senescence-associated secretory phenotype (SASP), which can profoundly influence local and systemic immunity. In physiological contexts - including embryonic development, tissue repair, and acute tumour suppression - senescent cells coordinate the recruitment and activation of immune cells, enabling their timely immune-mediated clearance and facilitating tissue remodelling and restoration of homeostasis. However, during aging and chronic disease, immune surveillance mechanisms frequently become compromised, allowing senescent cells to accumulate and persist within tissues.

The persistence of senescent cells results in sustained SASP signalling that promotes chronic inflammation, immune dysfunction, and tissue remodelling processes linked to fibrosis, metabolic impairment, tumour progression, and defective tissue repair. In parallel, increasing evidence indicates that immune cells themselves can acquire senescent or senescence-like states, thereby weakening immunosurveillance and generating self-reinforcing feedback loops that further amplify senescent cell accumulation and tissue dysfunction.

The relationship between senescent cells and the immune system is reciprocal. Immune surveillance governs whether the senescence response is resolved or persists, yet immune cells themselves can adopt senescence-associated features that remodel tissue environments and propagate senescence systemically. Age-related decline or dysfunction within immune compartments can amplify inflammatory signalling, shift immune tolerance and generate niches that favour senescent-cell persistence, establishing feedback loops between immune aging and cellular senescence. Together, these observations position senescence not as an isolated cell-intrinsic programme but as a process shaped by continuous dialogue with the immune system. The strength of this senescence-immune crosstalk is shifting the therapeutic paradigm from classical senolytics toward immuno-senolytic strategies aimed at reactivating endogenous immune surveillance or deploying engineered immune cells to selectively eliminate senescent populations.

Machine learning approaches can be used to create aging clocks from near any set of biological data collected from people of various ages. The techniques are well established and many new clocks are published every year. A clock is really an age predictor (or a mortality predictor, or a predictor of some other outcome) trained on a single dataset. When the clock algorithm is applied to any given individual not in that data set, it is thought that the predicted age or mortality risk or other outcome is some reflection of biological age. It is hard to validate this proposition, as there is very little concrete connection between any easily measured biomarker and mechanisms of aging, and indeed all too little consensus on how to measure biological age in the first place. To my eyes more effort should go towards understanding the clocks we have and less to producing new clocks.

Biological aging is a key determinant of liver disease and mortality, but there is little evidence on noninvasive index for assessment of liver biological aging. We developed the Liver Aging Index (LAI) in the China Kadoorie Biobank (CKB, N = 21,629) using Cox-Gompertz proportional hazards model. The LAI incorporated three clinical factors (body mass index, systolic and diastolic blood pressure), eight plasma biomarkers (glucose, total cholesterol, triglycerides, high-density and low-density lipoprotein cholesterol, alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase), and two imaging biomarkers (fat attenuation parameter and liver stiffness measurement).

External validation was conducted in the National Health and Nutrition Examination Survey (NHANES; N = 3412) and the VCTE-Prognosis cohort (N = 12,170, 16 global centers). Across all cohorts, the LAI demonstrated strong discrimination for all-cause mortality (area under the receiver operating characteristic curve: 0.764 in NHANES; 0.759 in VCTE-Prognosis), outperforming chronological age. Liver aging acceleration (LAA), defined as the difference between LAI and chronological age, was associated with substantially elevated risks: each 1 standard deviation increase in LAA conferred a 22%-85% higher risk of all-cause mortality and a 34%-170% higher risk of liver-related event or mortality.

Using genetic instruments identified in CKB, we found genetic predisposition to accelerated liver aging was associated with higher risks of cirrhosis and liver cancer (hazard ratios = 3.94 and 7.82), further validated in Biobank Japan. Integrating genetics and proteomics revealed novel pathophysiological involvement of amyloid-beta clearance pathway and amyloid precursor protein in liver aging. These findings demonstrate the feasibility of a noninvasive, liver-specific biological aging index and provide new insights into mechanisms underlying liver aging.

Link: https://doi.org/10.1111/acel.70565

The public health side of the cardiovascular community has undertaken a range of messaging programs for physicians and the public at large over the years, attempting to convince more people to make the lifestyle choices that will reduce cardiovascular mortality in later life. Life's Essential 8 is a more recent example of this sort of messaging, a fairly simplistic packaging of what are known to be the largest lifestyle risk factors for cardiovascular disease, starting with diet and exercise and moving on to avoidance of self-sabotage via smoking and excess weight. The study noted here pays particular attention to the effects of lifestyle on mortality in centenarians, finding that effect sizes are relatively large in this age group. Maintenance of fitness and lifestyle doesn't stop producing benefits, in other words.

While Life's Essential 8 (LE8) provides a comprehensive measure of cardiovascular health (CVH), its association with mortality among the oldest-old, including centenarians, remains unclear. This study evaluated the relationship between LE8-defined CVH and all-cause mortality across adulthood using data from the China Kadoorie Biobank (Hainan cohort) and the China Hainan Centenarian Cohort Study, including 31,473 individuals aged 30-116. Participants were categorized by life stage and CVH score (low, moderate, high).

Higher CVH scores were associated with significantly reduced mortality risk at all life stages, including among centenarians, who experienced a 54.8% lower risk with high CVH. A near-linear dose-response relationship was observed. Population-attributable fractions for mortality reached 36.8% in centenarians. Physical activity and body mass were particularly important in reducing mortality among centenarians. These findings challenge therapeutic nihilism in the oldest-old while underscoring the need for age-specific strategies tailored to distinct physiological profiles is crucial for extending healthy lifespan across the adult life course.

Link: https://doi.org/10.1038/s41514-026-00395-5

Today's open access paper combines a few interesting topics. Firstly, the researchers involved describe a way to deliver a short-lived messenger RNA gene therapy selectively to the innate immune cells known as macrophages. Macrophages are normally responsible for engulfing all sorts of unwanted structures in the cell, and many of the specific features that induce that behavior have been identified. Encapsulating messenger RNA into lipid nanoparticles that mimic some of the surface features of cells undergoing programmed cell death results in aggressive uptake by macrophages. Macrophages arguably make a good target for gene therapies in which the goal is to manufacture a secreted molecule of some sort, such as an antibody, and have it fairly widely and evenly distributed throughout the body. For many secreted molecules, this is quite unnecessary; injecting a single subcutaneous fat depot with a small amount of a non-targeted vector can and does work. Distribution in the body is enough of a challenge in gene therapy for any and all alternatives to be welcomed, however.

The application of this novel approach to messenger RNA therapy is in this case a reduction of circulating MMP9. The secreted molecule generated by the targeted macrophages is an anti-MMP9 antibody, directly binding to and allowing clearance of MMP9. Increased circulating MMP9 is characteristic of aging, and here researchers demonstrate that it is the cause of further issues by clearing it and observing benefits. Targeted depletion of MMP9 from circulation achieved via this antibody manufacturing approach improved the function and structure of bone and cartilage tissue in treated mice. It is of course a long road from preclinical proof of concept to therapy in the clinic, and many such demonstrations are never further developed. One might hope that this will at least attract more attention to the production of novel drugs that can much more effectively and selectively reduce circulating MMP9 than is the case for present small molecule drugs known to affect MMP9 levels.

In vivo circRNA-engineered macrophages mediate localized MMP9 neutralization to rejuvenate aged bone

Age-related bone disorders (e.g., osteoporosis, impaired fracture healing, and osteoarthritis) rank among the most common and debilitating complications in elderly populations. However, current treatment strategies are predominantly palliative, focusing on symptom management rather than addressing the underlying causes or halting disease progression. Growing evidence suggests that these disorders share a common pathophysiological foundation, driven by chronic low-grade inflammation, cellular senescence, and dysregulated tissue remodeling.

Through transcriptomic analysis of serum and bone samples from elderly human individuals, we identified matrix metalloproteinase-9 (MMP9) as a potential central and consistently upregulated effector in age-related bone dysfunction. MMP9 is well-known for its role in extracellular matrix degradation, but its persistent elevation in aged individuals and osteoporotic bone suggests a broader pathological role in skeletal aging. Despite this, its mechanistic contribution to age-related bone loss and its potential as a therapeutic target remain unexplored.

Effective clearance of MMP9 in the blood and bone microenvironment as a therapeutic target could be a highly efficient strategy for treating degenerative bone diseases. Clearly, the introduction of neutralizing antibodies is the most direct approach. However, neutralizing antibodies have limitations in terms of safety and cost-effectiveness and lack effective bone-targeting capabilities. In recent years, mRNA-based protein replacement strategies have brought revolutionary breakthroughs to the field. While mRNA-based therapeutics have revolutionized vaccinology and oncology, their clinical application in age-related degenerative diseases, particularly within orthopedic settings remains elusive.

Here, we developed an in vivo messenger RNA based antibody-engineering strategy that specifically targets macrophages, converting them into biofactories for anti-MMP9 antibodies. Central to this therapy is an apoptosis-mimicking lipid nanoparticle incorporating phosphatidylserine with an optimized formulation (aMMP9-LNP), which enhances macrophage-specific recognition and endocytosis. Leveraging inflammation-guided chemotaxis, this approach enables systemic, targeted MMP9 neutralization. In aged mice, aMMP9-LNP injected intravenously reduced stem cell senescence, boosted osteogenesis, accelerated fracture repair, and mitigated cartilage degeneration. Mechanistically, MMP9 blockade dampened the senescence-associated secretory phenotype, restored osteoblast-osteoclast balance, and lowered p21/MMP3. Biodistribution confirmed bone-targeted delivery with preserved tissue homeostasis, supporting translational potential.

Weight loss drugs are a major focus of the pharmaceutical industry at present. It remains to be seen as to what will emerge as the next big class of weight loss drugs following GLP-1 receptor agonists. Since the primary effect of GLP-1 receptor agonist drugs is a reduction in calorie intake, all of the gathered data in humans is really just a sizable confirmation of the harms done by the presence of excess visceral fat tissue, and the benefits gained from losing that fat via dieting. It wouldn't much matter how these patients achieved that outcome, the resulting benefits would look much the same - and have in the past as a result of other strategies for weight loss.

Researchers analyzed data from a previously published clinical trial of 108 adults with HIV-associated lipohypertrophy, a condition in which excess fat builds up around the abdomen. About half of the participants received weekly injections of semaglutide, with the rest receiving placebo injections. The team used a set of biological "epigenetic clocks" to track cellular aging over the 32-week treatment period. These clocks detect DNA methylation, chemical marks on DNA that help regulate how genes are turned on or off without changing the genetic sequence itself. By measuring changes in these marks, the team could assess whether the treatment was associated with a slower or faster biological aging pattern.

Participants treated with semaglutide exhibited a broad pattern of slower biological aging across epigenetic clocks linked to inflammation and blood, brain, heart, kidney, liver and metabolic health. The drug slowed the pace of biological aging by 9%, as measured by the DunedinPACE epigenetic clock. The drug significantly slowed biological processes associated with the risk of all-cause mortality and age-related disease, as measured by the PCGrimAge epigenetic clock. Research suggests there are several mechanisms by which semaglutide may influence biological aging. By reducing inflammation and metabolic stress, GLP-1 drugs decreased chronic immune activation, a primary driver of accelerated aging in people with HIV. They also reduce visceral and ectopic fat that accumulates around the abdomen and organs, which may help curb the inflammatory and metabolic signals that promote aging.

Link: https://today.ucsd.edu/story/study-popular-glp-1-drug-may-slow-down-biological-aging

Here researchers report on a novel form of pathological protein aggregation in the aging brain and evidence for it to contribute to mitochondrial dysfunction in Alzheimer's disease. This phosphorylated GRK2 aggregation is argued to be a downstream effect of the other well-known forms of protein aggregation in the condition, those involving amyloid-β and tau, though that remains to be definitively proven. Certainly, given the inability of clearance of amyloid-β to produce sizable effects on the progression Alzheimer's disease, one might imagine other mechanisms are more involved in triggering GRK2 aggregation. Regardless, reducing GRK2 aggregation improves function in mouse models of Alzheimer's disease, suggesting some value in targeting this process.

The G-protein-coupled receptor kinase 2 (GRK2) exerts essential functions in cell growth and survival. Searching for a connection between GRK2 and the neurodegenerative Alzheimer disease (AD), we find increased aggregated serine-670-phosphorylated GRK2 (phospho-S670-GRK2) in brains of AD mice and patients with dementia likely due to AD. Harmful phospho-S670-GRK2 aggregation is induced by two hallmark proteins of AD: beta-amyloid and the neurofibrillary-tangle-inducing, TAU-P301L.

Aggregated phospho-S670-GRK2 triggers aggregation of TOMM6 (translocase of outer mitochondrial membrane 6), promotes mitochondrial dysfunction, and enhances beta-amyloid. Transgenic expression of inactive GRK2-K220R or a GRK-inhibitory peptide proves that neuropathological features are caused by GRK2 inactivation. Restoration of TOMM6 by neuron-specific TOMM6 expression reduces beta-amyloid plaques but enhances soluble beta-amyloid and increases mortality. In contrast, reconstitution of monomeric GRK2 and proteasomal phospho-S670-GRK2 degradation by small molecules counteracts neuropathological AD features, prevents neuronal loss, and improves survival. Thus, targeting of pathological GRK2 aggregation slows aging-induced neurodegeneration.

Link: https://doi.org/10.1016/j.xcrm.2026.102707

The medical biotechnology and pharmaceutical investment market was always very risk averse, giving rise to the valley of death between preclinical seed funding and early clinical stage funding; there are all too few investors willing to fund companies to move from late preclinical stage to early clinical stage. They would rather let promising companies die out and pick from the few that somehow find funds to run a first clinical trial in human patients than take the risk on a preclinical program. Further, investment is a herd industry, it polarizes to a few hot areas, fads, and sure things. In the recent years of various flavors of poor market environment for biotechnology and pharmaceutical drug development it seems that these tendencies have grown more exaggerated. A sizable fraction of all biotech investment pours into a small number of cellular reprogramming initiatives, a hot area of research and development, while investors have largely retreated from preclinical funding more generally. It will be interesting to see how long this lasts, as it is clearly unsustainable for every initiative in the field other than reprogramming.

This year alone has seen sizable funding devoted to Retro Bio and NewLimit for reprogramming efforts, though in fairness Retro Bio does have a number of other programs on the go. Life Biosciences raised a relatively smaller but still sizable amount in the grand scheme of things for their clinical trials in reprogramming. Couple all of this to the even greater funding still possessed by Altos Labs, and it seems fair to say that partial epigenetic reprogramming is the one area of aging-related biotechnology that needs no further assistance from patient advocates and other folk. Over the next decade or so we should expect the development community to establish answers to all of the fundamental questions regarding the construction of viable therapies based on reprogramming.

It remains strange to me that partial reprogramming captured the market and the interest in this way rather than senolytic therapies to clear senescent cells, given that senolytics were first on the scene by some years, and senolytic research continues to boast a far larger and more impressive portfolio of animal data for reversal of age-related disease and dysfunction. There is no accounting for how things turn out sometimes. Once enough funding flocks to a cause, there is a tipping point, and its popularity becomes a self-fulfilling prophecy. The funding carves a channel for more funding.

No limits: NewLimit lands $435m ahead of human trials

NewLimit believes it has found a way to help older liver cells behave more like younger ones. That idea sits within a growing area of longevity science known as epigenetic reprogramming. The company has raised $435 million in a Series C financing round led by Founders Fund, with participation from Thrive Capital, Greenoaks, Quiet Capital and existing investors including Kleiner Perkins, Eli Lilly Ventures and Human Capital. More notably, the company says it plans to bring its first age-reprogramming medicine into human clinical trials next year - a milestone it once thought was more than a decade away. Just a year ago, NewLimit closed a $130 million funding round and was still talking about the long road toward a clinic-ready therapy. Then something changed. According to NewLimit, a promising candidate emerged from the company's research platform far sooner than expected, prompting the company to accelerate its plans.

Retro Biosciences: Next Phase

Today, we're announcing the initial close of our next financing round at a pre-money valuation of $1.8 billion, led by 4P Capital alongside a group of investors who believe Retro is uniquely positioned to translate the biology of aging into a new generation of medicines. In three years, Retro moved from its first lab to a clinical candidate. In 15 months, that candidate RTR242 went from indication selection to first-in-human dosing. Alongside that progress, we've built cell therapy, tissue reprogramming, and AI-enabled protein engineering programs, all designed to support a growing pipeline of therapeutics targeting the underlying drivers of aging and age-related disease.

Everyone develops atherosclerotic plaque that narrows and weakens blood vessel walls in later life. A sizable fraction of all human mortality derives from the consequences of that plaque, such as rupture of unstable plaque to cause a stroke or heart attack. The maladaptive formation of blood clots within or attached to the plaque structure greatly reduces the stability of these structures, and is an important contribution to mortality. Here, researchers show that cells driven into a senescent state by the toxic plaque environment generate the circumstances that provoke inappropriate clot formation in and around an atherosclerotic plaque. Of note, other work has suggested that those same senescent cells may be structurally important to a plaque, and removing them may also cause loss of plaque stability. After a certain point, it becomes hard to resolve the issues a plaque presents. Here, as elsewhere in medicine, prevention is far more desirable than resolution.

Researchers have discovered a molecular pathway that drives certain stressed or aging cells to become abnormally active, causing inflammation inside blood vessel plaques. This results in disturbed blood flow and high-risk lesions that can lead to blood clots that cause heart attacks or strokes. The researchers studied senescent cells, which are stressed or aging cells that have stopped dividing but don't die. They discovered that losing key regulatory proteins, LATS1 and LATS2, in these cells activates the CD38 enzyme, which reprograms how these cells use energy and makes them more unstable. This leads to inflammation and an increased risk of blood clot formation inside plaques, a process known as atherothrombosis.

The researchers used advanced molecular profiling on preclinical models to show how endothelial cells - the cells lining blood vessels - change with the loss of LATS1/2 proteins, which usually help with healthy cell stabilization. Removing LATS1/2 in endothelial cells caused them to become senescent but also abnormally active. This led to instability, leaky vessels, inflammation, abnormal vessel growth and plaques that could form clots, all of which are pro-thrombotic features.

Further analyses showed that these senescent cells had a dramatic increase in CD38 levels, highlighting their potential role as key drivers of this hybrid state. Preclinical models demonstrated that overexpressing CD38 rewired the metabolic pathways and energy sources for endothelial cells, leading them to consume enough additional energy to drive inflammation. This destabilized plaques and led to the formation of blood clots. Inhibiting CD38 reversed these effects both in vitro and in vivo.

Link: https://www.mdanderson.org/newsroom/research-newsroom/researchers-uncover-how-aging-cells-may-trigger-heart-attacks-and-strokes.h00-159856134.html

Microglia are innate immune cells resident in the brain, responsible for defense against pathogens, destruction of senescent and potentially cancerous cells, and assistance with regeneration and tissue maintenance. In recent years, increasing attention has been given to changes in the behavior of microglia, particularly increased inflammatory signaling, as a contributing cause of age-related neurodegenerative conditions. Here, researchers make use of modern omics technologies to assess distinct states in subpopulations of microglia that associate with the presence or absence of Alzheimer's disease in older individuals. This sort of research sets the stage for later efforts to alter the behavior of microglia in order to improve brain function, such as via clearance of damaged or inflammatory microglia, or forcing overly inflammatory microglia into a more regenerative pattern of behaviors.

Alzheimer's disease (AD) is not an inevitable outcome of pathology but a dynamic process shaped by how brain cells respond to amyloid-β (Aβ) and tau. To disentangle these responses, we combined spatial transcriptomics and single-nucleus RNA sequencing of the superior frontal cortex from octogenarians living with or without dementia and from cognitively intact centenarians with comparable Aβ accumulation. We identified six distinct tissue domains representing a spatial pathological continuum of AD, with a key inflection point marked by a shift from Aβ-associated inflammatory changes to tau-associated cellular programs.

This transition was accompanied by a change in microglial states, from early inflammatory to late antigen-presenting phenotypes, termed early and late plaque-induced gene (PIG) programs. Resilient individuals showed distinct pathological patterns: octogenarians without dementia lacked late PIGs, whereas centenarians showed late PIG activation that was uncoupled from tau accumulation. Together, these findings highlight divergent resilience-associated mechanisms in human aging and position microglial state transitions at the Aβ-tau interface as candidate points of resilience with potential therapeutic relevance.

Link: https://doi.org/10.1038/s41591-026-04393-8

In recent years, greater attention has been given to efforts that push back against the present broad acceptance of established data on human life expectancy, particularly for the oldest surviving cohorts. It has been suggested, and the evidence for this assertion is broadly supportive, that the published data for exceptional longevity is largely of poor quality, and much of what has been hyped over the years (such as Blue Zones or Jeanne Calment's alleged life span of 122 years) is simply not real.

What is observed in the data is a selection effect for error, fraud, and outright falsehood that grows stronger at advancing ages. We should be quite confident that a small number of humans can survive into their 110s, as individual cases have been well vetted, but we should be much less confident about the accuracy of demographics of survival much past age 90.

Does any of this really matter? From the perspective of building therapies to treat aging, I think probably not. It doesn't affect the need for better ways to measure biological age than exist at present, and it doesn't change the list of programs and targets that should be undertaken to produce potential rejuvenation therapies. People do get somewhat up in arms about the demographics of aging, but it seems a tempest in a teacup to me, somewhat irrelevant to the real issue of making progress in the treatment of aging as a medical condition. Other people may see it differently, of course.

How long can humans live? We simply don't know

Many errors are undetectable and, therefore, we do not know their underlying frequency. This has prompted a rather absurd response from demographers, who say that, sure, some errors occasionally escape detection, but these errors must be rare. I usually ask them: if you cannot detect particular errors, how do you know that they are rare? The core problem is that age relies on one measurement system: paperwork. If a person's paperwork is consistent but wrong, there is no reproducible way of knowing. You often see a famous case discussed, the details exhaustively validated and all of the paperwork examined. But after decades, the case turns out to be false. It has passed every test that demography has, and it is still wrong.

I did not just observe this in individual cases. I found it in entire populations. In Greece, for example, at least 72% of centenarian records were cases of pension fraud. The person was left alive on paper while their younger relatives collected the pension cheques. That was the secret to longevity in Greece, and nobody in demography saw it for decades.

There are several overlapping error processes. Pension fraud is one. Clerical error is another, and that can be undetectable. People who have paperwork with incorrect details often do not know, because literacy rates a century ago were low. Some people purposefully increase their age to escape military service, others to marry or work earlier when they are young, and some just inherited paperwork from older relatives because it was easier than travelling or paying to register a new birth. Then there are identity substitutions. Imagine a room with 100 people over 100, all holding valid paperwork. Replace one of them with a younger sibling. How do you detect the swap? The paperwork is real. The person knows enough about their sibling to answer questions.

Even if you understand the social and administrative context, there is still no reproducible method to test whether the age on a person's paperwork is correct. That is the central issue. There are also broader patterns. Extreme longevity often appears in places with weak record systems, low incomes and low historical levels of birth certification. That pattern runs against expectations if the signal were biological.

The mathematical process for small errors to dominate at very old ages is counter-intuitive but simple. Normally, rare errors can be ignored. But in this case, they grow non-linearly. Take a large population at age 50. Introduce a small number of people whose true age is younger than this recorded age. These individuals are biologically younger than the rest, so they die at lower rates as the cohort ages. Each year, the proportion of people with an error in their records increases because people with an inflated age are more likely to survive than are people with accurate data. Even with tiny starting error rates, you can end up with a population that has a 100% rate of errors at very old ages.

This is a universal problem. Five to ten per cent of people in the United States misstate their age in the census. Often, they simply do not know. Nearly one-quarter of the world's children still do not receive a birth certificate. Add that to the slow historical roll-out of birth registration and you get widespread uncertainty. There has been a 40-year debate about whether there is a limit to human lifespan. Both sides seem to be wrong, and the data seem to be junk. Demographers have been drawing shaky inferences from bad data for decades.

Mitochondrial function is clearly important in the development of Parkinson's disease. The mutations associated with increased risk of Parkinson's are related to mitochondrial quality control and function. Greater mitochondrial dysfunction makes the dopaminergic neurons most vulnerable to Parkinson's pathology that much more vulnerable, though it is an open question as to whether this is more a matter of disrupted energy metabolism or increased inflammatory signaling, both of which result from the presence of failing mitochondria in cells. Here, researchers report that expression of IFNAR1 is reduced in Parkinson's disease. That reduced IFNAR1 expression causes mitochondrial dysfunction via impairment of the quality control mechanisms of mitophagy, the same sort of issue as accelerates Parkinson's in genetic cases. Establishing whether or not this discovery may lead to a viable therapy to delay onset and progression of Parkinson's disease via increased IFNAR1 expression will require further research and development.

Dysregulated interferon-alpha/beta-receptor 1 (IFNAR1) signaling was recently identified to contribute to the development of sporadic Parkinson's disease (PD) into PD with Dementia (PDD). The molecular, cellular, and phenotypic impacts of brain IFNAR1 loss in aging have not been explored in vivo, which may reveal novel disease mechanisms and therapeutic targets. Baseline IFNAR1 expression varies among major brain cell types, including neurons and astrocytes, and is differentially affected in PD and Lewy Body Dementia patients compared to unaffected controls.

Neuron- and astrocyte-specific transcriptomic and proteomic alterations in IFNAR1 knockout mice implicate mitochondrial defects, defective mitophagy, and synergistic dysfunctional neurotransmission upon IFNAR1 loss, leading to glucose hypermetabolism measured by functional metabolic analysis. Consequently, IFNAR1 knockout mice exhibited PDD-like pathogenesis, including dopaminergic cell loss in the substantia nigra, cortical neurodegeneration, Lewy-body-like inclusions, neuroinflammation, and progressive PDD-like behavior deficits. Brain cell-specific IFNAR1 loss examined in vivo revealed delayed but distinct development of PDD-like phenotypes, where neuropathology, motor, and cognitive behavior deficits were recapitulated only in mice lacking neuronal IFNAR1, and behavior resembling neuropsychiatric abnormalities recapitulated only in mice lacking astrocytic IFNAR1.

Link: https://doi.org/10.1186/s12929-026-01257-8

It seems perhaps overly reductionist to summarize the panoply of current efforts to treat aging into two camps of (a) things that affect the burden of cellular senescence and (b) things that affect metabolism. One has to cut out or diminish the importance of a fair number of line items that may be useful irrespective of their effects on cellular senescence. An increased burden of cellular senescence is only one of the major issues that drive aging. Nonetheless, that is the approach to categorization taken in this review paper.

Aging is a complex biological process characterized by progressive functional decline, driving the incidence of age-related diseases such as neurodegeneration, metabolic disorders, and cardiovascular diseases. Therapeutic strategies targeting aging hallmarks can delay aging and mitigate disease risk. Emerging interventions focus on modulating core aging mechanisms, including cellular senescence, metabolic dysfunction, epigenetic alterations, and mitochondrial impairment, etc.

Recent advances have focused on three strategies: senolytics (eliminating senescent cells, e.g., dasatinib + quercetin), senomorphics (inhibiting the senescence-associated secretory phenotype, e.g., rapamycin), and senoreversion (rejuvenating senescent cells via epigenetic reprogramming). Additionally, metabolic interventions such as caloric restriction mimetics (e.g., spermidine, α-ketoglutarate, ergothioneine) enhance mitochondrial function, activate autophagy, and reprogram energy metabolism, demonstrating lifespan extension and healthspan improvement in preclinical models. Collectively, these approaches hold promise for delaying aging and alleviating age-related pathologies, facilitating the transition to precision longevity medicine.

Link: https://doi.org/10.1038/s41392-026-02662-z

That part of the life science research community focused on better understanding and treating the panoply of age-related neurodegenerative conditions is increasingly focused on chronic inflammation in the brain. Aging, and neurodegenerative disease, is characterized by excessive, unresolved inflammatory signaling in brain tissue. A sizable focus is given to increased inflammatory behavior in microglia, for example, and how these innate immune cells of the central nervous system might be adjusted to reduce this problem. But much of the ongoing portfolio of fundamental research seeks to understand how the underlying biochemistry of aging gives rise to a state of chronic inflammatory signaling in various cell populations in the brain, including microglia, but not only microglia.

The authors of today's open access paper review review a topic of increasing interest in this context, the maladative overactivation of cGAS-STING signaling in aged brain cells. This is actually a global phenomenon throughout the body, so much of what is said here applies to other tissues as well. STING is a central hub in the regulation of inflammatory signaling, and is activated by a range of sensor proteins that react to various different circumstances in the cell. cGAS detects double-stranded DNA in the cytosol of the cell, where no double-stranded DNA should exist. This is an evolved defense against invasive pathogens such as bacteria and viruses, but it is is also triggered in a cell that has become dysfunctional enough to allow leakage of DNA fragments from the nucleus or mitochondria.

Aged cells are characterized by excessive cGAS-STING activation in particular due to mitochondrial dysfunction allowing mitochondrial DNA fragments to escape the mitochondria. This is one of the reasons why addressing mitochondrial dysfunction in the aging brain may help with neurodegeneration. It isn't just a matter of a dysfunctional energy metabolism allowing cells to run down, but also a matter of tidying up mitochondrial DNA to reduce cGAS activity.

Expanding roles of cGAS-STING signaling in neuroinflammation

The sensing of nucleic acids is a central component of innate immunity, enabling host defense against infection while shaping inflammatory responses within the central nervous system (CNS). Pattern recognition receptors (PRRs) function as molecular sentries that detect both pathogen-derived nucleic acids and endogenous danger signals. Among these, DNA is an important signal of infection and inflammation. Several PRRs act as DNA sensors, and cyclic GMP-AMP synthase (cGAS) has the unique ability to directly and sequence-independently detect double-stranded DNA (dsDNA) in both the cytosol and nucleus. The dsDNA inside cells sensed by cGAS originates from diverse sources, ranging from foreign viral or bacterial DNA to endogenous self-DNA caused by mitochondrial damage or chromatin instability. Upon binding to dsDNA, cGAS activates the adaptor protein STING and elicits a strong interferon (IFN) response. cGAS is highly evolutionarily conserved from bacteria to mammals, underscoring its fundamental role in innate immunity.

Neuroinflammation is typically characterized by persistent, low-grade inflammatory signaling, underscoring the importance of identifying the precise triggers and sustaining mechanisms of cGAS-STING activation in the CNS. Studies in Alzheimer's disease models have implicated mitochondrial DNA (mtDNA) leakage as a key activator of this pathway. However, whether additional sources of cytosolic DNA, or even non-DNA ligands, contribute to chronic cGAS-STING engagement remains unclear. This issue is particularly relevant in nonimmune cells such as neurons and endothelial cells, where the mechanisms governing cGAS activation, signal amplification, and persistence are still largely undefined.

The growing recognition of cGAS-STING signaling as a driver of chronic neuroinflammation positions this pathway as an attractive, yet complex, therapeutic target for brain disorders. Sustained or inappropriate activation of cGAS-STING in the CNS is increasingly linked to neurodegeneration, cognitive decline, and aging. This highlights the need for therapeutic strategies that selectively attenuate pathological signaling while preserving essential antiviral functions. Pharmacological inhibition of cGAS or STING has shown encouraging results in preclinical models of neurodegenerative disease and brain injury, where suppression of IFN-I and downstream inflammatory cascades reduce neuronal loss and improve functional outcomes. Small-molecule cGAS inhibitors, STING antagonists, and modulators of cyclic dinucleotide metabolism represent the most direct approaches.

While targeting the cGAS-STING pathway is of therapeutic interest, chronic inhibition may carry risks. Given its role in antiviral defense and tumor surveillance, sustained suppression could increase susceptibility to infection or impair immune function. A potential therapeutic strategy is partial and context-dependent modulation, as neurodegenerative conditions are often associated with elevated cGAS-STING activity and IFN-I signaling. To mitigate systemic effects, CNS-selective or temporally restricted approaches may be beneficial. Over time, more refined strategies, including microglia-biased small molecules or glia-targeted degraders, may further improve specificity and safety.

Mitochondria are power plants, hundreds of these organelles working in every cell to manufacture the adenosine triphosphate (ATP) chemical energy store molecule used to power cell operations. The decline of mitochondrial function with age impacts this supply, with negative consequences, but other equally important issues arise from mitochondrial dysfunction. For example, an important realization in aging research was that dysfunctional mitochondria contribute meaningfully to the chronic inflammation of aging, a topic that is a primary focus of this paper.

Mitochondria are increasingly recognized as master regulators of aging, integrating bioenergetics, redox control, stem cell fate, and innate immune signaling. This review synthesizes evidence that mitochondrial dysfunction is not only a hallmark but also an upstream driver of stem cell exhaustion and inflammaging. We discuss how age-associated mitochondrial DNA (mtDNA) mutations and clonal mosaicism impair respiration and reshape metabolite availability, thereby reprogramming long-lived epigenetic states that govern quiescence, lineage commitment, and regenerative output. In parallel, erosion of mitochondrial quality control (MQC), including fission-fusion balance, mitophagy, and the mitochondrial unfolded protein response (UPRmt), permits the persistence of reactive oxygen species (ROS)-producing organelles and lowers containment of mitochondrial danger signals.

A central advance is that mitochondrial damage can be decoded as inflammation: cytosolic mtDNA and other mitochondrial damage-associated molecular patterns (mtDAMPs) activate cGAS-STING and NF-κB pathways, reinforcing senescence-linked cytokine circuits and chronic inflammatory tone. We further highlight nicotinamide adenine dinucleotide (NAD) depletion as a metabolic bottleneck that compromises sirtuin-dependent resilience and can enforce mitochondrial dysfunction-associated senescence (MiDAS), linking redox collapse to altered senescence phenotypes and regenerative decline.

Finally, we evaluate emerging mitochondria-targeted rejuvenation strategies, NAD repletion, mitophagy enhancers, mitochondrial transplantation/engineering, and precision elimination of mutant mtDNA using mitochondria-targeted transcription activator-like effector nucleases (mitoTALENs) or zinc-finger nucleases (mitoZFNs), emphasizing tissue-specific thresholds and context dependence for effective healthspan extension.

Link: https://doi.org/10.1038/s41514-026-00422-5

Biochemistry is enormously complex. The closer that researchers look, the more that they will find. Details remain incompletely mapped and understood at every level; there are only so many researchers and only so much funding. Much of the ongoing fundamental research into interventions to treat aging remains focused on the ability of mild stress to provoke beneficial changes in cell behavior, such as the way in which calorie restriction or heat produce increased cell maintenance activities. Here, researchers delve into the extremely complex landscape of RNA molecules in the cell to search for specific RNAs that are essential to beneficial stress responses that slow aging.

Transfer RNA (tRNA) halves (tRHs) are generated via the cleavage of tRNAs, but their roles in aging and longevity remain poorly understood. Here, we demonstrate a direct role of tRHs in aging in metazoans. Through a genetic screen using Caenorhabditis elegans, we identify DIS-3/DIS3 as a ribonuclease that catalyzes tRH generation, including 5′-tRH-Gln and 5′-tRH-Asp, from tRNAs. Among them, 5′-tRH-Gln is essential for longevity conferred by various interventions, including dietary restriction.

Generation of 5′-tRH-Gln reduces translation via ribosomal protein binding and upregulates the SKN-1 transcription factor responsible for lifespan extension. We further show that mammalian DIS3 contributes to tRH generation and delays cellular senescence through translation downregulation by another tRH, 5′-tRH-Cys. Overall, our data demonstrate that DIS-3/DIS3 is an evolutionarily conserved tRH-generating ribonuclease that counteracts organismal and cellular aging.

Link: https://doi.org/10.1038/s41467-026-73295-7