Fight Aging!

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

Fecal microbiota transplantation from young donor to old recipient can reset the composition of the aged gut microbiome to produce benefits to health. Animal studies are very positive. Unfortunately fecal microbiota transplantation doesn't mix all that well with the present approach to regulation of medicine in the US and EU. One product, meaning one approach to donor screening and some attempt at standardization, has been approved by the FDA for use in the treatment of C. difficile infection. Following that the FDA has made it hard for other donor screening and connection services such as Human Microbes to operate at all for any purpose in the US, so for most people the situation is now worse than it was.

Regulators want standardization, which is always going to be challenging and expensive to achieve for donor material given the high human to human variability in gut microbiome composition. So the incentive exists to develop the means to create artificial gut microbiomes with a standarized composition. Unfortunately the state of probiotic manufacture is a long way removed from being able to assemble hundreds or thousands of species in defined proportions in a cost-effective manner. Still, inroads are being made; if researchers can produce a 15 species mix today, then working with defined mixes of hundreds and then thousands of species will become viable in time.

Engineered gut bacteria therapy emerges as scalable potential alternative to fecal microbiota transplants following clinical trial

Recurrent C. difficile infection is a serious and often debilitating condition that can occur after antibiotic treatment disrupts the natural balance of bacteria in the gut. Although fecal microbiota transplants (FMT) - a treatment that transfers stool from healthy donors to restore gut bacteria in patients with severe or recurrent infections - have proven effective for many patients, more standardized and scalable therapeutic options are needed.

To address this challenge, the investigators developed a cost-effective production platform capable of manufacturing live biotherapeutic product (LBP), composed of known bacterial strains rather than whole-stool material. The first product generated using the platform was evaluated in patients with recurrent C. difficile infection and compared directly with FMT prepared from the same donor source used to isolate the bacterial strains. The team compared treatments using microbes from the new platform with those using FMT. The study enrolled 18 participants across four groups: low- and high-dose FMT and low- and high-dose LBP, with four to five patients in each arm. "We demonstrated comparable safety and efficacy between undefined stool-based FMT and a defined, in vitro-manufactured LBP. We also found that bacterial strains delivered through both FMT and LBP durably engrafted in recipients."

The new approach uses a defined consortium of bacterial strains isolated from donor stool and grown under controlled manufacturing conditions. Unlike traditional fecal microbiota transplants, which can vary from donor to donor, the platform is designed to produce standardized microbial therapies at scale. The researchers say the findings support the feasibility of manufacturing defined microbiome therapeutics that may one day offer a more standardized alternative to traditional fecal microbiota transplants.

15-strain live biotherapeutic product or same donor fecal microbiota transplant for recurrent Clostridioides difficile infection: a randomized phase 1b trial

Fecal microbiota transplant (FMT) is an effective therapy for recurrent Clostridioides difficile infection (rCDI) but has undefined composition and poor scalability. In vitro manufactured live biotherapeutic products (LBPs) enable both scalability and defined strain composition but with higher manufacturing complexity, resulting in few LBP clinical trials. Here we show how an accessible platform to produce human-grade LBPs could accelerate LBP development. We provide regulatory documentation and manufacturing protocols to facilitate translating microbiome advances to human trials.

With this platform, we conducted the first direct comparison of the same bacterial strains from donor-sourced FMT compared to an in vitro manufactured 15-strain LBP drug product, MTC01, for the treatment of rCDI. In a phase 1b randomized controlled trial, 18 of 20 screened patients met eligibility and were randomized equally to one of four arms: low-dose FMT (n = 4), high-dose FMT (n = 5), low-dose MTC01 (n = 4) or high-dose MTC01 (n = 5), with a 5:1 female:male ratio. The primary outcome of safety was met with 10 adverse events across eight patients, evenly spread across MTC01 (five events) and FMT (five events) recipients and no treatment-related adverse events across all four groups. For secondary outcomes of efficacy and engraftment, rCDI was prevented 8 weeks after dosing in seven out of nine LBP patients, similar to eight out of nine FMT patients. Strain engraftment was high and durable for both FMT and MTC01 with a dose effect for the LBP.

The concept of antagonistic pleiotropy looms large over present thought on the evolution of aging: that the proteins produced from a given gene can have multiple functions that are beneficial in youth but harmful in later life. Evolution selects for such a gene because the advantage of early life reproductive success near always wins out over the disadvantage of a shorter overall reproductive life span. Thus near all species undergo degenerative aging. More subtly the concept can also apply to systems, protein interactions, or other higher level constructs in cells and tissues. Finding specific, simple, defensible examples of antagonist pleiotropy in cellular biochemistry has proven to be surprisingly hard, suggesting that this is largely a systems-level issue, but here researchers put forward the gene VGLL3 as a candidate.

The antagonistic pleiotropy theory of aging predicts genetic trade-offs between early-life and late-life fitness. However, empirical evidence for such trade-offs in vertebrates remains scarce, particularly from causal genetic experiments. Here, combining genetic perturbation with longitudinal phenotyping in the turquoise killifish (Nothobranchius furzeri), we identify vestigial-like 3 (vgll3), previously linked by genome-wide association studies (GWAS) to age at maturity in humans and male Atlantic salmon, as a gene with antagonistically pleiotropic effects.

Selective disruption of vgll3 isoforms accelerates male growth and maturation in a dose-dependent manner. Transcriptomic and cellular analyses indicated increased cell division, corroborated in vivo by elevated germline and intestinal stem-cell proliferation. However, early-life maturation incurs a late-life cost, linked to altered DNA damage response. Older mutant males develop melanoma-like tumors, validated via transplantation into immunodeficient rag2 models, and exhibit a shortened lifespan. Thus, we identify vgll3 as a key regulator of life-history variation with antagonistic effects across ages, balancing early-life fitness against late-life mortality.

Link: https://doi.org/10.1038/s41467-026-72381-0

Rapamycin is an immunosuppressant long used in transplant medicine at relatively high doses. At lower doses, it slows aging and extends life in animal studies by mimicking some of the beneficial metabolic reactions to calorie restriction, such as increased autophagy. A fair number of people use rapamycin with the hopes of achieving the same outcome, though the human data for this use case and dosage remains sparse. Normally rapamyin is taken once a week, but here researchers mix it in with the diet in a study of immune aging in mice.

Aging is the gradual accumulation of structural and functional changes in an organism over time, including immune remodeling and a progressive increase in basal inflammation, or inflammaging. The mTOR pathway is a central driver of aging-related diseases, such as cancer, chronic inflammation, and neurodegeneration; pharmacological inhibition with rapamycin is associated with reduced aged-related morbidity and increased lifespan across species. Nonetheless, concerns remain about the use of rapamycin, a well-established immunosuppressant in transplant medicine, as an anti-aging intervention.

Here, we evaluated the impact of prolonged low-dose dietary rapamycin on the aging immune system. Treatment did not significantly alter innate or adaptive immune cell populations, including brain resident microglia; however, it attenuated the age-associated accumulation of IL-17-producing γδ T cells, particularly in the peritoneal cavity. After a peripheral inflammatory endotoxin challenge, circulating IL-17 levels were significantly reduced and correlated with an attenuation of microglia inflammatory phenotype. These findings suggest that prolonged low-dose rapamycin exposure exerts minor systemic immune changes, while selectively limiting age-related γδ T cell expansion and neuroinflammation associated with systemic inflammation.

Link: https://doi.org/10.1371/journal.pone.0343183

Nucleic acids such as DNA and RNA should in the normal course of events largely remain localized within the cell nucleus and mitochondria, the locations of the nuclear genome and mitochondrial genomes respectively. Changes that take place with age disrupt everything, however, and this disruption includes the mislocalization of DNA and RNA fragments into the body of the cell. One of the many lines of defense against infectious pathogens such as viruses and bacteria deployed by cells takes the form of sensor proteins that detect inappropriate DNA and RNA in the cytosol of the cell, and then trigger inflammatory signaling and potentially even cell death. Thus a sizable portion of the chronic inflammation characteristic of later life is a maladaptive reaction to some aspects of the poor state of structural organization within aged cells.

Today's open access paper reviews these mechanisms, with a particular emphasis on the connection between age-related chronic inflammation and increased tendency towards an inappropriate coagulation response in the aging vasculature, the cause of thrombosis. An important facet of present research into immune aging is the effort to find ways to interfere in chronic inflammatory signaling without disabling necessary inflammatory responses. This has so far proven to be challenging, as all inflammation runs through much the same triggers and regulatory systems. The only alternative is to remove the underlying damage of aging that causes maladaptive inflammatory responses, but at present that is not the primary focus of the research community.

Misplaced nucleic acids as a trigger of Coagul-Aging

Aging is characterized by a gradual decline in tissue homeostasis and regenerative capacity, accompanied by the emergence of a chronic, low-grade inflammatory state termed inflammaging. This sterile inflammation stems from the accumulation of cellular and molecular damage, defective clearance of self-derived debris, and persistent activation of innate immune pathways. Inflammaging plays a central role in the development of age-related pathologies, including cardiovascular and thrombotic diseases.

One of the major vascular consequences of inflammaging is the establishment of a prothrombotic phenotype, referred here to as coagul-aging. This state results from endothelial dysfunction, platelet hyperreactivity, and altered hemostatic balance. Importantly, inflammation and coagulation are not isolated processes but are functionally intertwined through the concept of thrombo-inflammation, a coordinated response originally evolved to contain infection and repair tissue damage. When chronically activated, however, this crosstalk becomes maladaptive, sustaining vascular injury and thrombotic risk.

Emerging evidence suggests that misplaced nucleic acids, including extracellular or cytosolic DNA, RNA, and RNA:DNA hybrids, act as molecular triggers of both innate immune activation and coagulation. These nucleic acids, often derived from endogenous retroelements or senescence-associated damage, are sensed by pattern recognition receptors such as cGAS-STING, TLR9, and RIG-I-like receptors, promoting type I interferon responses, cytokine release, and tissue factor expression. In parallel, they may directly activate the contact pathway of coagulation via factor XII, providing a non-inflammatory route to thrombin generation.

In this review, we examine the role of nucleic acid accumulation and dysregulation in linking inflammaging to coagul-aging. We propose that extracellular nucleic acids act as central effectors of age-associated thrombo-inflammatory circuits, not only by sustaining chronic immune activation, but also by directly triggering coagulation, potentially bypassing classical inflammatory pathways. These properties position nucleic acids as both mechanistic drivers and potential therapeutic targets in vascular aging.

Individuals are transient vehicles for the immortal lineage of germline cells. Incompletely understood processes firstly ensure that the germline remains relatively untouched by aging, and secondly ensure that new individuals generated from the cells of two aged individuals are born functionally young. In recent years, researchers have discovered some of the regulatory systems that drive rejuvenation in early embryonic development, the conversion of an old oocyte into a mass of young embryonic stem cells. This has given rise to the techniques of cell reprogramming to generate induced pluripotent stem cells, and of much greater interest at the present time, the techniques of partial reprogramming to restore more youthful function to adult tissues. Yet this is just a first step, and the methods used reflect only a very partial understanding of what exactly happens in the oocyte during reproduction. There is work yet to be done.

Aging‌‌ biology has largely focused on the gradual deterioration of somatic tissues. DNA damage accumulates, epigenetic regulation becomes unstable, mitochondria lose efficiency, senescent cells accumulate, and regenerative capacity wanes, together with many other categorized hallmarks of aging. This framework is remarkably successful in explaining many features of tissues and organismal aging, yet it fails to account for one of the most fundamental processes in biology: the generation of offspring that begin life biologically young, even when derived from aged parents. Somewhere during reproduction, aging is not merely slowed but actively and effectively reversed.

The mammalian ovary embodies this paradox. It is among the first organs to exhibit functional decline, with fertility and endocrine function decreasing well before the end of life. Nonetheless, even decades after its formation, the ovary still produces a subset of oocytes capable of generating an "age zero" offspring. No other cell type in adult mammals, besides the oocyte, routinely performs such a comprehensive reset. The oocytes are therefore intrinsically endowed with the capacity for what we define here as rejuvenation. While it is undoubtably true that oocytes' developmental competence declines with age, it is remarkable to consider that whenever natural conception occurs successfully, the chronological and/or biological age of the oocytes (i.e., of the mother) is not vertically transmitted to the following generation.

Historically, reproductive biology and geroscience have developed as largely separate and divergent disciplines. The ovary has been studied primarily in the context of fertility and endocrine regulation, whereas aging research has focused on loss of function in somatic tissues such as the brain, muscle, immune system, and heart, including the ovary. This separation has obscured an essential insight: the ovary is not only a site of age-related decline but also the only mammalian tissue that naturally preserves an intrinsic rejuvenation capacity within its oocytes.

We argue that the ovary, and the oocyte in particular, represent nature's most compelling example of controlled rejuvenation. We examine how epigenetic reprogramming, mitochondrial quality control, and proteostasis operate in oocytes to preserve cellular youth. We also explore how tissue homeostasis mechanisms differ fundamentally within the ovarian niche from aging processes in somatic tissues and discuss how insights from ovarian biology can inform emerging rejuvenation strategies, including partial reprogramming, senescence modulation, and niche engineering. Finally, we discuss how the ovary itself could be a gateway to systemic rejuvenation and extended healthspan.

Link: https://doi.org/10.1371/journal.pbio.3003804

A small number of humans with an inherited PAI-1 loss of function mutation live up to seven years longer than peers. PAI-1 appears involved in cellular senescence, and thus effects on health and life span may reflect a lower burden of harm resulting from the presence of increasing numbers of senescent cells with advancing age. Researchers have been developing small molecule drugs to inhibit PAI-1 activity, and here find a review paper covering these efforts. Recall that inhibition via a small molecule drug tends to have a much smaller effect than a loss of function mutation, as firstly the drug is only used for part of a life span, and secondly the drug does not produce complete inhibition of activity. This is nonetheless how research and development tends to progress.

Plasminogen activator inhibitor-1 (PAI-1), encoded by SERPINE1, is the principal physiological inhibitor of tissue-type and urokinase-type plasminogen activators and a central regulator of fibrinolysis. Beyond its canonical hemostatic role, PAI-1 has emerged as a pleiotropic mediator of tissue remodeling, fibrosis, metabolic dysfunction, cancer progression, cellular senescence, and age-associated immune dysregulation. A central argument of this review is that PAI-1 should be understood not only as a downstream biomarker of aging-associated pathology, but also as an active effector linking senescence-associated secretory phenotype (SASP) signaling, chronic low-grade inflammation, impaired immune surveillance, fibrotic extracellular matrix remodeling, and a prothrombotic state.

In this framework, PAI-1 may function as an immune-aging checkpoint: a molecular node through which senescent, stromal, malignant, and inflammatory cells reinforce immune evasion and tissue dysfunction. Structure-guided drug discovery has enabled the development of small-molecule PAI-1 inhibitors, including TM5275, TM5441, TM5509, and TM5614. Among these, TM5614 is an orally available investigational compound that has progressed to clinical evaluation. Preclinical studies support anti-thrombotic, anti-fibrotic, anti-inflammatory, anti-senescent, and tumor-microenvironment-modulating effects of PAI-1 inhibition, while early clinical studies have evaluated TM5614 in chronic myeloid leukemia, immune-checkpoint-refractory malignant melanoma, non-small-cell lung cancer, and COVID-19-associated pneumonia.

This review summarizes the biology of PAI-1, expands the discussion of immunoaging, reviews representative preclinical and clinical data, compares available PAI-1 inhibitors, and discusses the translational opportunities and safety considerations for TM5614 and related compounds.

Link: https://doi.org/10.3390/cells15100941

Many bat species are extremely long-lived for their size, rivaling naked mole rats when it comes to a comparison with shorter-lived and similarly sized mammals. One hypothesis is that the very high metabolic demands of flight forced bats to evolve highly efficient defenses against metabolic stress, and particularly stresses generated by mitochondrial activity. Other factors have come to light, however, related to bat resilience to viral infection, triggers of chronic inflammation, and DNA damage. Bats exhibit far greater control over chronic inflammation than other mammals, for example, and researchers have experimented with moving some of the relevant biology into mice to reduce their age-related inflammation.

Today's open access paper grows from the seed of an interesting idea: can we categorize the biology of bat longevity in ways that can then be applied usefully to thinking about variation in human longevity? What does that categorization look like, and what insights emerge from it? Unfortunately the lead author is primarily involved in dietary research, and so this interesting idea, once established and explored, thereafter collapses into dietary recommendations rather than any more useful exploration of the possibilities of drug development and applied biotechnology. Departmental affiliation in academia comes with an intellectual tax that must be paid, in terms of fitting one's interesting ideas into what the department ostensibly does. Still, there something here worthy of greater consideration.

Bat-Inspired Longevity: Immune Damage Management and Nutritional Modulation for Healthy Aging

The exceptional longevity of bats challenges classical theories of inflammaging and suggests an alternative that improved resilience in responding to pathogens and cellular damage can increase longevity. Accordingly, we have developed the Core Longevity State Vector (CLSV-6) to characterize an expanded explanation for inflammaging that can be predictive of successful aging and used to develop potential strategies for successful aging. Despite high metabolic rates and persistent viral exposure, many bat species have much longer lifespans than would be predicted for mammals of their size. The increased longevity of many bat species is achieved through damage tolerance, regulated inflammasome activity, constitutive basal antiviral defenses, enhanced autophagy-mitophagy, and efficient resolution of inflammation, rather than through heightened inflammatory immunity.

The CLSV-6 is introduced as a multidimensional immunotype framework integrating six conserved mechanisms that link bat immunity to bat longevity and to human healthy aging: (1) damage tolerance, (2) autophagy-mitophagy, (3) proteostasis (management of degraded proteins), (4) basal immune readiness without activation, (5) inflammasome regulation, and (6) inflammatory resolution capacity. Together, these mechanisms enable a robust antiviral defense when needed without chronic inflammation. Notably, human centenarians converge toward this bat-like configuration. Studies suggest that centenarians often preserve more functional natural killer cells, better macrophage regulation, and improved anti-inflammatory control, with both bats and humans exhibiting reduced activation of the NLRP3 inflammasome, resulting in greater immune resilience.

Building on this framework, functional foods - including polyphenols, fermented foods, and herbal extracts - are proposed as practical strategies to shift human immunity toward bat-like, CLSV-6 immunotype by enhancing cellular quality control, regulating inflammasome activity, strengthening basal antiviral readiness, and supporting inflammatory resolution, thereby redirecting longevity strategies from immune stimulation toward damage containment and repair. This review reframes longevity as an emergent property of integrated immune damage management and provides a mechanistic roadmap for nutritional interventions to engineer healthier human aging inspired by bat immunity.