Fight Aging!

Setting aside a few early attempts, the longevity industry started in earnest in the mid-2010s. It had the feel of a hype cycle, a land rush, in the context of a broader bull market. A lot of those companies no longer exist; there are disadvantages in being first into a space. One of those disadvantages is that the first cohort in any venture has the privilege of mapping the novel pitfalls by falling into them. That is done now, and we're into the next stage, which is, quite honestly, a lot more complex, messy, diverse, and hard to explain. We know how this story ends: at some point there will be no distinct longevity industry, because the goal of slowing or reversing the aging process by addressing the underlying causes of aging directly will merge into the ordinary, day to day cut and thrust of pharmaceutical and biotech development. It will be become unremarkable to attempt to treat aging as a medical condition.

We are not there yet! From the extremely conservative point of view of those who steer large pharmaceutical industry companies, treating aging remains a distinct, unproven proposition. That will continue to be the case until novel anti-aging drugs are approved by the FDA and EMA, used by hundreds of thousands of patients, produce undeniable results, and, most importantly, generate a large amount of revenue. The number of such approved drugs is somewhat less important than the collective revenue generated. You might look at the opinion of the powers that be on weight loss drugs and how that has shifted across the advent of GLP-1 receptor agonists as an example of how this shift in will take place for the first very successful anti-aging drugs.

But back to what the longevity industry looks like now, and how that differs from the early days. Today's open access paper offers an opinion on the topic, backed by some analysis. It is an interesting read, albeit very focused on just a few parts of the mainstream of the field, the most popular topics. For my part, I'd have to say that I think matters would be fairly different if the bull market in biotech and pharma had sustained itself across the 2020s rather than vanishing into geopolitics and doldrums. A new industry struggles to forge itself in an environment where funding is tight all round. Much of the present character is the character of an industry in which it is exceptionally challenging to raise funds for clinical development, no matter the promise of the technology in question. But this too shall change.

From lifespan extension to hallmark-informed gerotherapeutic prioritization: A bibliometric-guided, strategy-oriented review of anti-aging drug research

Aging is increasingly understood as a shared upstream biological process that increases vulnerability across cardiovascular, neurodegenerative, metabolic, musculoskeletal, renal, and neoplastic disorders. This view was crystallised by the original hallmarks framework and reinforced by its expanded update, which organise aging into interconnected molecular and cellular processes rather than isolated organ-specific events. The translational implication is substantial because interventions directed at aging biology could, in principle, delay or modify several age-related conditions rather than treating each disease independently. The interdependence of aging hallmarks also provides a rationale for evaluating secondary cross-hallmark effects.

Over the past decade, geroscience has moved from a conceptual proposition to an intervention-oriented discipline aimed at extending healthspan and disability-free survival. This shift has been driven by growing recognition that aging is biologically malleable and clinically consequential at the population level. Mechanisms such as cellular senescence, deregulated nutrient sensing, mitochondrial dysfunction, chronic inflammation, loss of proteostasis, and impaired stress adaptation are now regarded as potentially tractable pharmacological entry points. Accordingly, gerotherapeutic development increasingly requires alignment between molecular or pharmacological design, an aging-related biological vulnerability, measurable target engagement, an appropriate population, and a clinically meaningful endpoint.

The landscape of anti-aging drug research has shifted markedly from exploratory lifespan-extension studies toward a more structured, mechanism-informed, and translationally aware framework. Bibliometric analysis reveals that the field coalesces around three partially overlapping intervention logics - senescence-directed therapeutics, nutrient-sensing and metabolic modulators, and homeostasis-restoring compounds - each anchored in reproducible biological hallmarks. These axes collectively provide a coherent rationale for prioritizing interventions based not solely on historical visibility but on mechanistic plausibility, preclinical evidence, and early human translational signals.

The composition of the gut microbiome changes with age in ways that negatively impact health. There is enough variance in this process of change that correlations can be observed between specific species and metrics of overall composition on the one hand and risk or status of disease on the other. Researchers are building a growing body of knowledge regarding such correlations, and in many cases have found mechanisms indicating that a poor composition of the gut microbiome is a contributing factor in the development and progression of age-related disease. This is a matter of which metabolites are produced by the gut microbiome and in what amounts; some metabolites are necessary for health, others are harmful or provoke chronic inflammation. This work is the first step towards the development of therapies that can alter the composition of the gut microbiome in specific, tailored ways in order to improve health and slow the progression of aging.

Although commonly used tools, such as the Fried Frailty Phenotype, the Rockwood Frailty Index and the Clinical Frailty Scale, capture specific aspects of frailty, existing indices often fail to encompass its full functional, psychological, and physiological dimensions. The Charlson Comorbidity Index (CCI), while widely adopted for mortality risk stratification, is disease-centric and lacks sensitivity to the broader construct of frailty. To better capture this multidimensional nature, we developed the Frailty Mortality Index (FMI), a composite measure integrating functional and psychosocial aspects in addition to comorbidities. Specifically, the FMI is defined by anthropometrics (age and weight), physical function (walking speed and chair stand), current smoking, mental quality of life (QoL) survey, hospital stay duration, and the CCI.

The gut microbiome is increasingly recognized as a regulator of host physiology and potential contributor to frailty pathophysiology. It influences systemic inflammation, metabolism, musculoskeletal function, and immune and neuroendocrine signaling. While aging alters gut microbiota composition and function, gut microbiome profiles observed in frailty differ from those associated with healthy aging, reflecting not just chronological age but also deterioration of physiological processes.

In this work, we use metagenomic sequencing to investigate species-level features associated with frailty-related phenotypes captured by the FMI in SUPERB, a large Swedish cohort including 2,081 women aged 75-80 years. We demonstrate that the FMI is more strongly associated with frailty-related clinical outcomes, including injurious falls, hip fractures, and mortality, than the CCI. We further show that higher FMI is associated with reduced microbiota diversity, including lower gene richness and Shannon index. At the species level, FMI is associated with different species in Enterocloster, Clostridium, Dysosmobacter and Faecalibacterium in models accounting for the overall decline in microbiome gene richness associated with ageing, thereby distinguishing FMI-associated microbial features from general microbiota decline.

Link: https://doi.org/10.1038/s41467-026-75176-5

Neurogenesis is the name given to the creation of new neurons in the central nervous system, arising from neural stem cell populations, maturing, and then merging with existing neural networks. Neurogenesis is essential to memory and to the maintenance of brain tissue, the only way to replace neurons lost to damage or dysfunction. The pace of neurogenesis declines with age and in neurodegenerative conditions. Here, researchers investigate the link between inflammatory signaling and lost neurogenesis. The aged brain, like the aged body, is characterized by continual unresolved inflammatory signaling, a maladaptive reaction to forms of cell and tissue damage that changes cell behavior for the worse. It is disruptive to tissue structure and function. Any comprehensive package of rejuvenation therapies will have to include some way to address unwanted chronic inflammatory signaling without sabotaging the normal function of the immune system; so far, this has proven to be a difficult challenge.

Adult hippocampal neurogenesis is essential for learning, memory, and mood regulation, and its disruption is implicated in ageing, neurodegeneration, and mood disorders. However, the mechanisms linking inflammation to adult hippocampal neurogenesis impairment remain unclear. Here, we identify chronic tumour necrosis factor-alpha (TNF-α) signalling as a key driver of neurogenic dysregulation via a previously unrecognised type I interferon autocrine/paracrine loop in human hippocampal progenitor cells.

Using a female-derived human in vitro neurogenesis model, single-cell RNA sequencing, and functional T cell migration assays, we show that tumour necrosis factor-alpha induces a robust type I interferon response in hippocampal progenitor cells, promoting chemokine-mediated and CXC motif chemokine receptor 3 (CXCR3)-dependent T cell recruitment and suppressing neurogenesis. This inflammatory signalling cascade drives a fate switch in hippocampal progenitor cells from a neurogenic trajectory towards an immune-defensive phenotype, with critical implications for infectious and inflammatory disease pathogenesis.

These findings uncover a key inflammatory checkpoint regulating human adult hippocampal neurogenesis and highlight potential therapeutic targets to restore neurogenesis in chronic inflammatory states.

Link: https://doi.org/10.1038/s41467-026-74104-x

Aging clocks can be built from any sufficiently complex set of biological data measured in a sufficiently large number of people across a sufficiently large range of different ages. Machine learning techniques are used to find algorithmic combinations of data points that predict age to some sufficient threshold of accuracy. The algorithm is then applied to people who were not in the original sample populations, and most such clock algorithms do an acceptably good job of hitting the mark when considered over groups of people. Unfortunately they are not all that useful for an individual; in part the variance is a problem, but the main challenge is that it is entirely unclear in most clocks as to what the results actually mean. It is also unclear as to how we should expect any given clock to react to any given intervention used to treat aging.

The best path forward to making aging clocks useful for individuals, and for the assessment of novel therapies to treat aging, is probably to collect as much data as possible and observe the emerging patterns. Classes of therapy will have to be assessed in parallel with clocks. Different populations and different strategies for clock use will have to be assessed against actual outcomes, such as mortality rate and disease incidence years later. This won't be a fast process.

Nonetheless, interesting new findings emerge on a fairly regular basis as the use of clocks spreads. In today's open access paper, for example, research demonstrate that change over time in clock assessments is a useful piece of information, perhaps much more useful than single measures. This is particularly relevant to the use of clocks by an individual rather than in a population study, as many of the unknowns become irrelevant when one person uses the same clock repeatedly over a period of years to measure something that may be closely related to the pace of biological aging.

Longitudinal changes in epigenetic clocks predict survival in the InCHIANTI cohort

Over the past years, several proxy biomarkers of biological aging have been developed and validated, with the most advanced using data from DNA methylation. Broadly termed 'epigenetic clocks,' these methylation-based markers of aging have been shown to predict several adverse health outcomes, including mortality, independently of chronological age.

However, whether longitudinal changes in these phenotypes provide additional information on health outcome prediction over and beyond one single measure has not been demonstrated. Based on cross-sectional studies, we cannot definitively exclude that deviations of DNA methylation age from chronological age are determined early in life and are not modulated by behavioral, environmental exposures or changes in health status. In addition, if biological aging clocks are to be used to track the effectiveness of intervention over time, it is important to demonstrate that deviations of epigenetic clock trajectories reflect meaningful changes in health status.

In this longitudinal study of 699 adults from the InCHIANTI cohort followed for up to 24 years, we evaluated whether temporal acceleration of several epigenetic clocks-including first-, second- and third-generation epigenetic clocks-was associated with mortality. We found that faster increases in several clocks were linked robustly to higher risk of death, independent of baseline epigenetic age and other confounders. These findings suggest that dynamic changes in epigenetic aging reflect evolving health status and may serve as sensitive indicators for interventions aimed at extending healthspan and longevity.

When a cell becomes senescent, it ceases replication, grows in size, and devotes its energies to secreting a potent mix of pro-growth, pro-inflammatory signals. Cellular senescence serves useful purposes in embryonic development, wound healing, and suppression of cancer. It also marks the Hayflick limit on replication of somatic cells; a somatic cell either undergoes programmed cell death or becomes senescent on reaching the Hayflick limit. In those scenarios, the senescent cells are destroyed by the immune system shortly after serving their purpose. Unfortunately, the aging immune system becomes ever less capable of efficiently clearing senescent cells, and senescent cells begin to accumulate. Their signaling becomes harmful when sustained over the long term, disruptive to tissue structure and function. This is an important component of degenerative aging.

Senescence is a highly heterogeneous phenotype, and this heterogeneity arises from several layers of biological diversity. Different cell types may vary in their susceptibility to enter senescence and in the molecular pathways they activate upon entering this state, in addition to the core cell-cycle arrest machinery. This context-dependent variability is pronounced, such that senescent cells do not share a universal molecular signature, necessitating the use of multiple markers for their accurate identification. Microenvironmental conditions, including inflammatory cues, extracellular matrix composition, oxygen levels, and immune context, further shape the senescence response and senescence-associated secretory phenotype (SASP). Moreover, distinct senescence-inducing stimuli may engage overlapping but not identical signaling networks, leading to variation in gene-expression profiles, metabolic changes, and secretory programs. Together, these factors can create a spectrum of senescent cell phenotypes that differ in their impact on tissue physiology.

In this review, we focus on the major inducers of cellular senescence. While well-established inducers such as DNA damage and oxidative stress are central drivers of senescence in aging and disease, we also discuss physiological and context-specific triggers to provide a more comprehensive and integrative perspective on senescence induction. Starting from the first-described form of senescence, replicative senescence associated with prolonged cell culture, we provide a comprehensive overview of the major inducers of cellular senescence, including DNA damage, oxidative and mitochondrial stress, telomere attrition, oncogene activation, cell-cell fusion, senescence-induced senescence and developmental stimuli, and summarize the molecular mechanisms through which they trigger the senescence program. Integrating insights into these distinct stimuli, the signaling pathways they engage, and their functional consequences might help to clarify how distinct populations of senescent cells contribute to aging, cancer, and age-related pathologies, and assist in the development of new therapeutic strategies aimed at modulating senescence and its deleterious consequences without deteriorating its beneficial functions.

Link: https://doi.org/10.18632/aging.206391

An interesting question with regard to the growth in the age-related burden of senescent cells is the degree to which it is altered by lifestyle choice. Or, to put it another way, we know the degree to which better lifestyle choices affect pace of aging and life expectancy: how much of that effect is due to a reduced burden of senescent cells? Can the existing burden be reduced by better lifestyle choices, and by how much? Here, researchers review the evidence for dietary lifestyle choices to influence cellular senescence and find it lacking, as the existing body of clinical trial data is not large enough and consistent enough to support definitive statements. As the researchers note, the data is supportive of the hypothesis that dietary choice has more of an impact on the behavior rather than number of senescent cells. The burden remains.

Cellular senescence is a fundamental mechanism of ageing, characterised by stable cell cycle arrest and the acquisition of a pro-inflammatory secretory phenotype (SASP). Nutritional interventions are widely proposed to modulate ageing biology, but their effects on cellular senescence in humans remain unclear. We systematically synthesised evidence from interventional human studies assessing the impact of nutritional strategies on biomarkers of cellular senescence.

Twenty-nine articles (27 trials; 3,811 participants) were included. Across studies, nutritional interventions modulated multiple senescence biomarkers to varying extents, with calorie restriction producing the most recurrent reductions in circulating inflammatory and secretory factors commonly included in SASP panels as well as senescence-associated transcriptomic signatures. Classical markers of cell cycle arrest (e.g., CDKN2A/p16, CDKN1A/p21) and telomere length were largely unchanged or highly variable. Calorie restriction mimetics, particularly metformin and rapamycin, showed context-dependent effects, most evident under conditions of metabolic or physiological stress. Among dietary supplements, n-3 polyunsaturated fatty acids may modulate selected inflammatory/SASP-related circulating markers, although the evidence for dietary supplements remains limited and heterogeneous.

In humans, available evidence suggests that nutritional interventions may preferentially affect senescence-associated inflammatory and secretory biomarker profiles, particularly SASP-related mediators, rather than markers more directly related to senescent cell abundance. However, because SASP factors and circulating cytokines are heterogeneous and not specific to senescent cells, these findings should be interpreted as evidence for possible modulation of senescence-associated markers rather than definitive effects on senescence burden. These observations support the use of multi-marker and functionally relevant endpoints in future clinical studies targeting biological ageing and cellular senescence.

Link: https://doi.org/10.1016/j.arr.2026.103224

It seems a little early in the development of partial epigenetic reprogramming as a class of therapy to be thinking about which of the other approaches to aging it can best be combined with. Nonetheless, a proposal for therapeutic plasma exchange and partial epigenetic programming to go well together is the topic of today's open access paper. The argument is that these two classes of approach are addressing different layers of the dysfunction of aging, and should this do little to interfere with each other's benefits.

Until such time as someone comes up with a safe, viable small molecule reprogramming therapy, it seems likely that reprogramming will remain quite limited in scope because of the delivery challenges inherent in gene therapy. Very few delivery systems have any potential to deliver a payload well to the whole body (or even most of the body), and none of the established options are capable of this outcome. Even when delivery is good for a given tissue, the many different cell types making up that tissue likely vary widely when it comes to optimal dose and duration of reprogramming agents. It is a challenge.

On the therapeutic plasma exchange front, even the most basic, initial questions around dosing and efficacy remain to be answered. Because there is little profit in this type of therapy, no-one with deep pockets has any incentive to run the extensive trials that would be needed to provide definitive answers. As things stand, it seems likely that forms of therapeutic plasma exchange and plasma dilution will spread throughout the medical tourism space, but no firm data will emerge in the near future. This the case for numerous therapies adopted by clinics outside the US and Europe, but which do not bring in enough revenue for someone to sponsor formal clinical trials.

Systemic recalibration and epigenetic resetting as complementary strategies in ageing biology

Systemic and cellular rejuvenation strategies differ fundamentally in their therapeutic targets and in the biological level at which they intervene. Systemic interventions such as therapeutic plasma exchange or young blood administration primarily modify the extracellular and circulating environment. Through removal of pro-ageing and pro-inflammatory factors, or provision of pro-youthful factors, these approaches may improve intercellular communication and reduce adverse systemic influences such as chronic inflammation. Their principal strength lies in the breadth of action across multiple tissues. Their principal limitation is that they do not directly reverse intracellular age-associated changes. Cells with aged epigenomes, altered transcriptional programmes, and accumulated damage may therefore remain only partially responsive.

Partial reprogramming intervenes at the level of intracellular ageing mechanisms. It directly addresses loss of epigenetic information, which the Information Theory of Ageing proposes as the fundamental cause of mammalian ageing. By resetting elements of the epigenetic landscape, partial reprogramming reverses age-associated states such as mesenchymal drift and metabolic dysfunction at their source. Its principal strength lies in mechanistic depth. Its limitation is contextual dependence, because a persistently aged tissue environment may still impose inflammatory, structural, and extracellular constraints that partial reprogramming alone cannot fully resolve. The most important translational question is not which strategy is generally superior, but which biological constraint dominates in a given disease setting and whether both levels require simultaneous intervention.

The dilution hypothesis is examined together with its limitations and the unresolved complexities of systemic interventions. The challenge of cell-autonomous ageing is also considered, particularly the persistence of cell populations that remain refractory to systemic rejuvenation. A conceptual framework integrating these two axes of ageing is then presented. This framework suggests that combined systemic recalibration and targeted partial reprogramming warrant further investigation as a multimodal approach to ageing intervention. Future research priorities include mechanistic clarification of this systemic-cellular interaction and development of robust biomarkers to evaluate multimodal interventions.

Every mechanism of aging influences all of the other mechanisms of aging. Our biology is a big tangled ball of interactions. As a follow up to a recent post on the connection between mitochondrial dysfunction and senescent cell accumulation in the context of intervertebal disc degeneration, here find a different viewpoint that focuses on the connection between epigenetic aging and senescent cell accumulation. In the nucleus of the cell, epigenetic decoration of nuclear DNA and supporting molecules control its structure; these decorations include DNA methylation and modifications to the histone proteins that DNA is spooled onto. Structure in turn determines which genes are expressed, which proteins manufactured. Patterns of epigenetic control over nuclear DNA structure change with age in characteristic ways, some mix of adaptive and maladaptive reactions to other mechanisms of aging, possibly mixed in with a fundamental disruption to this system of control deriving from the repeated operation of DNA repair.

Intervertebral disc degeneration (IDD) is the leading pathological cause of low back pain, while current clinical treatments are only palliative and cannot reverse the programmed cellular senescence driven by epigenetic dysregulation. This process is characterized by progressive loss of nucleus pulposus (NP) cell identity and establishment of a self-amplifying senescence-associated microenvironment. In this review, we synthesize recent advances elucidating how heterogeneous senescent cell populations and their secretory phenotype (SASP) orchestrate a destructive vicious cycle in IDD.

We further dissect the synergistic interplay among DNA methylation, histone modifications, and non-coding RNAs that constitutes the "epigenetic aging clock" and drives premature cellular aging within the disc. Notably, we evaluate emerging therapeutic strategies aimed at clock reversal, including senolytic clearance of senescent cells, epigenetic remodeling using small-molecule inhibitors or CRISPR-Cas9 editing, and cellular reprogramming approaches ranging from induced pluripotent stem cell (iPSC) differentiation to direct lineage conversion. We propose a synergistic "clear, prime, then seed" roadmap that sequentially combines these interventions for optimal regeneration. This work provides a systematic theoretical framework for the clinical translation of epigenetic-targeted therapy for IDD, and breaks through the cognitive limitation of traditional mechanical wear theory.

Link: https://doi.org/10.3389/fragi.2026.1842955

STING is a master regulator of inflammatory signaling, triggered by a range of different sensor proteins for foreign material or forms of damage within a cell. With age, these sensors become overly active even in the absence of the usual stimuli, such as the presence of infectious agents, and the resulting inflammatory response is maladaptive, spreading harms further rather than helping the situation. Continual, unresolved inflammatory signaling is characteristic of old age, and it is disruptive to tissue structure and function. Here researchers note that inflammatory signaling in the body harms the brain via long-range communication between cells that is mediated via production and uptake of extracellular vesicles. Vesicles are small membrane-wrapped packages of molecules, carrying information from one cell to another. Their contents can change dramatically depending on the state of the originating cell, and this is one of the ways in which harms can spread, particularly in the context of chronic inflammation.

All animals age. However, aging is a heterogeneous process, and individual organisms age differently. Moreover, within the same organism, cells or organs do not age at the same speed. For instance, neurodegeneration, a hallmark of aging, generally manifests later than other peripheral aging signs. The genetic determinants of aging are not completely understood.

Gain-of-function (GoF) mutations in leucine-rich repeat kinase 2 (LRRK2GoF) are major genetic risk factors for Parkinson's disease (PD). By analyzing PD patients and LRRK2GoF mice, we show that PD represents an accelerated aging disorder driven by STING-dependent inflammation. This inflammation begins peripherally, disrupts the blood-brain barrier, and causes dopaminergic neurodegeneration.

Mechanistically, aging or LRRK2GoF causes endolysosomal decline, resulting in cytosolic self-DNA accumulation and the release of DNA-containing extracellular vesicles (EVs) that activate the cGAS-STING pathway within and between cells. Our findings identify LRRK2GoF as a key driver of accelerated aging and systemic inflammaging through DNA-containing EVs, highlighting potential therapeutic targets to counteract inflammaging and neurodegeneration.

Link: https://doi.org/10.1016/j.celrep.2026.117640

Intervertebral disc degeneration is a complex dysfunction in the tissue maintenance and tissue properties of the discs between vertebrae. The discs allow flexibility of the spine, cushion impacts, and hold the spine together. Weakening of disc structures leads to tears and other failures that produce a sizable negative impact on the ability of an individual to function. A large subset of the population shows measurable degeneration of intervertebral discs even before reaching age 40, and after that point it becomes a majority. This is a universal aspect of aging, and the question is only how long it will take before something important breaks under stress.

Interestingly, intervertebral disc degeneration is strongly connected to cellular senescence. There are clear lines to be drawn between the burden of senescent cells and the mechanisms leading to loss of disc structural integrity. Senolytic therapies to selectively clear senescent cells have done well in animal models of degenerative disc disorders. Similarly, mitochondrial dysfunction is also strongly linked to intervertebral disc degeneration. Both loss of mitochondrial function and burden of senescence are correlated - the former tends to increase the pace at which the latter grows. It is interesting to note today's open access study, in which improved mitochondrial function also reduces cellular senescence in the course of restoring some lost function to an aged tissue.

Activation of Sirt3 reprograms mitochondrial function to regenerate intervertebral disc degeneration

Intervertebral disc degeneration is the principal pathological basis of low back pain. Currently, there are limited therapeutic strategies to regenerate intervertebral disc. In this study, we found the expression of SIRT3 is significantly negatively correlated with the degree of disc degeneration in humans. In mice, knockout of Sirt3 resulted in pronounced disc degeneration accompanied by increased expression of inflammatory mediators and senescence-associated factors.

Transcriptomic analyses in mice revealed that Sirt3 deficiency was closely associated with dysregulation of calcium signaling pathways and impaired adenosine triphosphate (ATP) synthesis. Bioinformatics analyses identified Ckm and Atp2a1 as hub genes linking Sirt3 deficiency to calcium homeostasis disruption and ATP metabolic dysfunction.

Importantly, the administration of Sirt3 activator 2-APQC in a D-galactose-induced aging mouse model significantly ameliorated intervertebral disc degeneration-associated pathological changes, evidenced by restored mitochondrial function, reduced inflammation and cellular senescence, and rescued expression of hub genes Ckm and Atp2a1.

Studies tend to show that even a late life adjustment of lifestyle can meaningfully improve health and reduce mortality risk. It is never too late to gain some benefit from a better diet, more physical activity, greater physical fitness, and loss of excess visceral fat tissue. As an illustration of this point, researchers here show that older people who improve their lifestyle choices exhibit a sizable reduction in the risk of cognitive impairment versus those who retain a poor set of lifestyle choices.

This study included 6,765 older adults from the Chinese Longitudinal Healthy Longevity Survey. Data on lifestyle, including dietary habits, sleep quality, physical, cognitive, and social activity were self-reported from 2008 to 2014. Cognitive function was measured using the Mini-Mental State Examination from 2014 to 2018. Over a mean follow-up period of 5.9 years, 1,659 participants (24.5%) developed cognitive impairment. Three distinct lifestyle behavior trajectory classes were identified: "Low-Declining" (n = 4,342, 64.2%), "Moderate-Improving" (n = 1,777, 26.3%), and "High-Declining" (n = 646, 9.5%).

Compared with the Low-Declining group, the Moderate-Improving group was associated with a lower risk of cognitive impairment (hazard ratio, HR = 0.368), a longer time to cognitive impairment onset (mean = 6.433 years) and a slower rate of annual cognitive decline (0.806 points per year). Similarly, the High-Declining group showed a reduced risk (HR = 0.629, delayed onset (mean = 4.969 years) and a slower decline rate (0.543 points per year) compared with the Low-Declining group. Thus an upward trajectory of moderate lifestyle engagement, as well as a high but declining class, was associated with better cognitive outcomes compared with persistently low or declining engagement.

Link: https://doi.org/10.1186/s13690-026-02007-w

How far can one go, practically speaking, and in the relatively near future, to develop therapies to treat aging based on replacement of worn parts? Some forms of replacement therapy have existed for decades, and have arrived at a fairly sophisticated level of development. These approaches include organ transplantation and replacement of damaged bone with non-biological materials. These therapeutic options have their limitations and drawbacks, the largest of which is the need for major surgery. One view of the present era in biotechnology is that it represents an effort to move from approaches requiring major surgery to approaches that regrow and replace tissues in situ without major surgery, based on either cell therapies or manipulation of native cell populations. This transition is a slow one, clearly.

Recent discoveries and therapeutic developments in longevity science have made it increasingly clear that a vast amount of age-related damage and systemic changes at the level of molecules, organelles, cells, tissues, organs, and organisms must be reversed to yield durable and multi-tissue rejuvenation as well as further extensions in healthy lifespan. Advanced biological and synthetic replacement, maintenance, and multi-targeted damage-removal strategies for cells, tissues, and organ systems represent some of the most promising longevity interventions, with the potential to reverse an unprecedented fraction of age-related changes, and to prevent, slow, or even reverse age-related diseases and dysfunction.

We define replacement-based ageing interventions as strategies that replace cells, tissues, organs, physiological systems, or cellular components (e.g., mitochondria or genes) with biological or synthetic alternatives. Biological replacements include transplantation of stem cells, organs, and bioprinted tissues (e.g., progressive brain replacement using cells and biomaterials), bioengineered cell therapies (e.g., CAR-T and synthetic cells), and therapeutic plasma exchange. Synthetic replacements include prostheses, external medical devices (e.g., dialysis machines), and brain-machine interface systems (e.g., cortical implants).

Replacement-based approaches are predicted to act synergistically with emerging regeneration and synthetic damage-removal technologies capable of targeting and exporting hundreds of molecular and organellar damage types from cells without relying solely on inherently limited and declining endogenous repair, clearance, and export processes.

Link: https://doi.org/10.1111/acel.70516

Age-related impairment of drainage of cerebrospinal fluid from the brain is a topic of increasing interest. This was pioneered by the work of Leucadia Therapeutics, specifically focused on the drainage path for the olfactory bulb leading through the cribriform plate, but most present work is focused instead on the glymphatic system drainage that parallels the vasculature supplying the brain. The two pathways decline in capacity with age, but for very different reasons, and will need different forms of therapy. Thin channels for fluid flow through the cribriform plate ossify shut with age. The glymphatic system suffers from a failure of regulation of peristaltic flow through vessels, however.

Cerebrospinal fluid drainage is a way to remove metabolic waste from the brain. Declining flow means that this waste will build up. This includes the protein aggregates associated with neurodegenerative conditions, and probably a great many other forms of metabolic waste that individually have more subtle effects, but collectively act to provoke cell dysfunction when present at high levels. One of the more important consequences is thought to be a maladaptive inflammatory reaction in glial cells in the brain, which in turn drives the onset and progression of neurodegenerative conditions.

In today's open access paper, researchers assess measures indicative of loss of cerebrospinal fluid drainage in patients with isolated rapid eye movement (REM) sleep behaviour disorder (iRBD), which is a failure of the normal suppression of muscle activity during REM sleep. iRBD is now recognized as a very early symptom of synucleinopathies such as Parkinson's disease. Synucleinopathies are characterized by the aggregation and spread of misfolded α-synuclein through the central nervous system, and associated neuroinflammation. A failure of cerebrospinal fluid drainage can only make this worse, closing off one way to remove aggregated proteins, and increasing inflammation as a consequence.

CSF turnover dysfunction: a hidden early biomarker in iRBD?

Evidence in Alzheimer's disease and other dementias shows that changes in cerebrospinal fluid (CSF) turnover and perivascular spaces (PVS) volume are associated with disease progression through impairment of waste-clearance glymphatic pathways. Volume of CSF, PVS, and drainage structures such as venous sinus are mostly excluded in current MRI studies of premanifest synucleinopathy.

Here, we used MRI to investigate whether modifications in CSF, PVS, and venous sinus volumes occur in 18 prodromal synucleinopathy patients (namely isolated rapid-eye-movement sleep behavior disorder, iRBD) compared to 20 healthy young and 18 elderly controls. Our results demonstrated increased CSF and PVS volumes in iRBD without a matching increase in drainage venous structures, as observed in elderly controls. This suggests increased CSF and PVS fluid stasis, possibly due to impaired CSF filtration, a mechanism that could reduce glymphatic function and exacerbate the neurodegenerative process in iRBD.

Vaccinations can produce a lasting effect known as trained immunity, altering the behavior of the innate immune system and resulting in both a reduction in the chronic inflammation of aging and a more effective immune response to unrelated infectious agents. Arguably the largest body of research into trained immunity involves the BCG vaccine for tuberculosis, widely used outside the United States. A lesser body of work examines the trained immunity effects of a small number of other vaccines that are more commonly provided to adults rather than children. For most vaccines, there is no human data, and trained immunity itself is well documented, but not well understood in detail. Here, researchers report on a small trial to assess the effects of BCG vaccination on older people with and without Alzheimer's disease, to see whether the changes produced by trained immunity are sizable enough to justify further trials and widespread use.

Immune aging may contribute to Alzheimer's disease. Bacillus Calmette-Guérin (BCG), a vaccine known to induce trained immunity, has been linked to reduced Alzheimer's risk in prior studies. However, whether trained immunity can be observed in the human central nervous system remains unclear. We conducted two related one-year, open-label clinical trials in adults aged 55 years or older (n = 12 without Alzheimer's-related pathology; n = 11 with Alzheimer's-related pathology) recruited at a single center. Participants received two intradermal BCG vaccinations one month apart.

We show that BCG induces persistent, trained immunity-like changes in immune cells in cerebrospinal fluid, including enhanced innate responsiveness and associated transcriptional programs. These responses differ from blood, suggesting compartment-specific immune imprinting. In participants without Alzheimer's-related changes, these immune shifts are accompanied by decreased amyloid-β levels in cerebrospinal fluid and increased levels in blood. BCG was well tolerated, with no unexpected safety signals observed. This approach may represent an early neurodegenerative intervention strategy, although larger controlled studies are needed to confirm these observations.

Link: https://doi.org/10.1038/s43856-026-01691-7

Senescent cells are involved in tissue regeneration. Cells enter a senescent state following injury, and in the usual course of events assist in the intricate coordination between immune cells, stem cells, and other cell types that is required to regrow tissue. These senescent cells are then cleared by the immune system. With age, in poorly regenerative tissues, or in severe or persistent injuries, the presence of senescent cells following injury can become excessive and maladaptive. The signaling produced by senescent cells lasts too long, the cells are not cleared, and it causes further harm. As researchers here note, this is what happens following a heart attack, suggesting that there is likely some timing for the delivery of senolytic therapies to selectively destroy the cells become senescent immediately following the ischemic injury of a heart attack that could improve patient outcomes.

Currently, the primary causes of death following myocardial infarction include sudden cardiac death, malignant arrhythmias, and acute heart failure, all resulting from myocardial necrosis caused by coronary artery occlusion. Cellular senescence refers to the permanent arrest of cell proliferation in response to stress stimuli; it serves as a crucial tumor defense mechanism and is closely associated with tissue aging and chronic inflammation. The senescence-associated secretory phenotype (SASP) is one of the most characteristic features of senescent cells. Cardiac cells develop a SASP and secrete SASP factors in response to stimuli such as oxidative stress, DNA damage, and hypoxia, playing a key role in immune regulation and tissue repair following myocardial infarction.

The SASP exhibits marked spatiotemporal heterogeneity following myocardial infarction: during the acute phase, it contributes to inflammatory amplification and immune cell recruitment; during the subacute phase, it is involved in inflammation resolution, matrix remodeling, and scar formation; and during the chronic phase, it promotes chronic inflammation, paracrine senescence, pathological fibrosis, and cardiac dysfunction. Spatially, the SASP influences scar stabilization in the infarct zone, inflammation-electrophysiological coupling in the border zone, and compensatory remodeling in the distal region. The sustained expression of the SASP is a major driver of adverse ventricular remodeling and excessive fibrosis following myocardial infarction.

Therefore, targeting senescent cells and persistent, pathological SASP represents a highly promising therapeutic strategy in the field of cardiovascular regenerative medicine. This review will discuss senescence in different cell types following myocardial infarction, the spatiotemporal heterogeneity of the immune response mediated by the SASP after myocardial infarction, and the immune cells regulated by the SASP.

Link: https://doi.org/10.3389/fimmu.2026.1850084