Fight Aging!

A few species such as salamanders and zebrafish can regenerate lost limbs and even large sections of internal organs, provided they survive the injury. In comparison, mammals exhibit far less of a capacity for such proficient regeneration as adults, but the actual limits of regeneration vary widely across mammalian species. Spiny mice can regenerate full thickness skin, cartilage, and muscle as well as lost kidney tissue. The MRL mouse lineage can fully regenerate ear tissue, a capacity that was discovered because many researchers use ear notches to label their mice. Ordinary laboratory mice can regenerate the tips of their digits, and so can developing humans. Most such regenerative capacity for most mammals is lost somewhere between birth and adulthood, however.

The research community is attempting to develop a sufficient understanding of the biochemistry of proficient regeneration in salamanders and zebrafish to be able to provoke such regeneration in mammals. A few genes have so far surfaced as points of investigation, alongside significant differences in the behavior of macrophages and senescent cells in the context of injury and regrowth. In today's open access paper, researchers report on their investigations of the SP transcription factor family, leading to a focus on FGF8, one of the genes for which expression is modulated by SP transcription factors. Suitably guided upregulation of FGF8 expression, which required an enhancer from zebrafish, enhanced the ability of mice to regenerate lost digit tips. This is a modest starting point, and clearly not the whole picture, but years of research are now finally leading to the ability to at least modestly enhance regeneration in mammals.

For regrowing human limbs, this salamander gene could hold the key

Investigating a common gene in three very different species - salamanders, mice, and zebrafish - scientists have discovered the potential for a novel gene therapy aimed at eventually regrowing limbs in humans. In salamanders, SP8 does the work in regenerating limbs. Using CRISPR gene-editing technology, researchers removed SP8 from the axolotl genome. Without SP8, the axolotl could not properly regenerate the limb bones; a similar result occurred with the mouse digits missing SP6 and SP8.

With that information in hand, researchers used a tissue regeneration enhancer found in zebrafish to develop a viral gene therapy. That therapy delivered a secreted molecule called FGF8, a gene that is usually turned on by SP8, to encourage digit bone regrowth and partially restore the regenerative effects of the missing SP genes in mice. Human limbs don't have that kind of regenerative power - but might someday, with a therapy that emulates the abilities of SP genes.

Enhancer-directed gene delivery for digit regeneration based on conserved epidermal factors

Instructing regeneration of complex structures in mammals remains an unsolved problem. Gene therapy offers a compelling approach to foster endogenous regeneration by delivering therapeutic gene products to specific cells postinjury. We identified a conserved regeneration-linked epidermal transcriptional program in mouse digit regeneration centered on the SP6 and SP8 transcription factors, involving inflammatory responses from osteoclasts. Spatiotemporally focused expression of FGF8, a known target of SP factors, using a zebrafish-derived tissue regeneration enhancer element via adeno-associated viral vectors, could partially rescue digit tip regeneration in SP knockout mice and accelerate digit regeneration in wild-type mice. Our results demonstrate a contextual gene therapy approach to address limb loss based on genes like SP transcription factors conserved across multiple contexts of appendage regeneration.

Exercise influences the composition of the gut microbiome, which in turn influences capacity for exercise. Thus we see correlations in older people between the composition of the gut microbiome and observed level of physical activity and fitness, but breaking that down into specific contributing mechanisms and their relative importance is a challenge. The fastest path to answers is to alter the gut microbiome composition in defined ways and see how it affects capacity for physical activity. Approaches to alteration are in their infancy; the only approaches robustly demonstrated to produce lasting change are flagellin immunization and fecal microbiota transplantation, but while beneficial in the sense of reversing age-related changes in the composition of the gut microbiome, these approaches do not produce a well defined outcome. The future of this field will likely involve cultivation of defined mixes of hundreds or thousands of species in a synthetic microbiome, a major step up in complexity from the present manufacturing processes for probiotics.

Gut microbiota (GM) plays a crucial role in maintaining health through metabolic, endocrine, and immune functions. With ageing, shifts in GM composition, characterised by increased pathogenic and decreased health-promoting bacteria, contribute to dysbiosis, which is linked to several age-related diseases. Given the global trend of increasing sedentary behaviour (SB) and declining physical activity (PA) among older adults, this study aims to explore the relationships between GM and two critical indicators of healthy ageing, movement behaviours, and physical function.

This cross-sectional study assesses the GM composition, PA levels and physical function of 101 healthy, community-dwelling older adults aged 65-85 years. Participants undertook anthropometric measures and functional tests, wore an accelerometer for 7 days and provided a faecal sample which was analysed using 16s rRNA sequencing. All the results were adjusted for key covariates such as diet, age and activity levels.

Key findings include positive associations of Prevotella copri with moderate-to-vigorous PA, physical function, and negative associations with SB, while Roseburia species were linked to better mobility and strength measures. Conversely, potentially pathogenic taxa like Bilophila wadsworthia and Eggerthella were negatively associated with PA and handgrip strength, underscoring their possible detrimental roles in muscle function and healthy ageing. This cross-sectional study highlights the associations between GM, PA, physical function and healthy ageing in older adults. These findings emphasise the potential for leveraging GM and PA interactions to develop nonpharmacological strategies for promoting healthy ageing, warranting further research through interventional and longitudinal studies.

Link: https://doi.org/10.1155/jare/8981398

Senescent cells accumulate with age, generating disruptive inflammatory signaling that is disruptive to tissue structure and function. Numerous research groups and companies are developing therapies capable of either selectively destroying senescent cells or dampening their signaling. Animal studies and initial human trials suggest that the earliest senolytic treatments used to clear senescent cells, derived from cancer therapies, are safe and effective enough for widespread use. The drugs and compounds used cost relatively little, which is a meaningful argument for greater exploration of their utility. Unfortunately they are not a point of focus outside academia and a small number of anti-aging physicians. Few studies have directly compared first generation senolytic treatments, so the data noted here is interesting for supporting the dasatinib and quercetin combination over navitoclax.

Genetic background is a major determinant of disc degeneration, a leading cause of chronic back pain and disability. Herein, we demonstrate that premature disc cell senescence contributes to early-onset degeneration in SM/J mice and test two systemic senotherapeutic strategies to mitigate it: Navitoclax (Nav.) and a cocktail of Dasatinib and Quercetin (DQ).

While Nav. treatment did not improve severe degeneration in SM/J mice or senescence status, DQ-treated mice showed lower grades of degeneration and a decreased abundance of senescence markers, including p19ARF, p21, and the senescence-associated secretory phenotype (SASP). DQ improved disc cell viability and phenotype retention and retarded fibrosis of the nucleus pulposus tissue. Transcriptomic analysis revealed tissue-specific effects of the treatment, with cell cycle regulation and JNK signaling being commonly affected across different tissue types. A comparison of SM/J data with DQ-mediated aging-dependent amelioration of disc degeneration in C57BL/6 N mice identified Junb and Zfp36l1 signaling as shared DQ targets in the mouse disc.

Notably, the in vitro inhibition studies of the JUN pathway in human degenerated NP cells mimicked the benefits of DQ, namely, a reduction in senescence and SASP. This study reinforces the efficacy of senolytic treatment in ameliorating local senescence and intervertebral disc fibrosis.

Link: https://doi.org/10.1038/s41413-026-00526-4

Chronic kidney disease is largely age-related, though can occur in younger people under some circumstances. It is one of a number of conditions in which research strongly implicates cellular senescence in its onset, progression, and pathology. Senescent cells accumulate in tissues with age. Cells become senescent throughout life, both on reaching the Hayflick limit to replication and in response to stress or damage. A senescent cell ceases replication, grows in size, and generates pro-inflammatory, pro-growth signaling that attracts the immune system and alters the behavior of surrounding cells. In the short term, this signaling is helpful. In youth, senescent cells are cleared efficiently by the immune system, but in later life this clearance falters allowing senescent cells to accumulate in number. Sustained senescent cell signaling contributes to chronic inflammation and disruption of tissue structure and function.

Today's open access paper reviews what is known of cellular senescence in kidney aging versus chronic kidney disease, and notes the arguments for and against considering chronic kidney disease to be a form of accelerated kidney aging. Either way, kidney disease and dysfunction is fairly high on the list of conditions that may be treated earlier rather than later in the development of senotherapeutic drugs that either selectively destroy senescent cells or modulate their behavior to be less harmful. The diabetic form of kidney disease is one of the few conditions for which an initial clinical trial using first generation senolytic drugs has taken place. The similarities between kidney aging and kidney disease might provide hope that low-cost senotherapeutics can meaningfully reduce the burden of dysfunction in older individuals.

Chronic Kidney Disease and Cellular Senescence

As individuals age, kidney function naturally declines, with the decrease in estimated glomular filtration rate (eGFR) starting at around age 30 at a rate of 0.7-0.9 mL/min/1.73 m2 per year in healthy individuals. With age, the kidney undergoes a series of changes that resemble those observed in chronic kidney disease (CKD), including a reduction in the number and size of nephrons, glomerulosclerosis, tubular atrophy, inflammation, dyslipidemia, interstitial fibrosis, and an increase in the prevalence of vascular rarefaction and arteriosclerosis. Furthermore, aging kidneys, similarly to kidneys in CKD, are susceptible to injury, oxidative stress, inflammation, and fibrosis and often struggle to regenerate and recover. However, these changes are typically milder during normal aging than in CKD. Therefore, in many ways, CKD may be likened to a state of premature or accelerated renal aging.

This resemblance partly reflects the unique physiological context of the kidney, where high metabolic activity, chronic exposure to circulating toxins, susceptibility to hypoxia, and limited regenerative capacity of key cell populations amplify stress responses and promote the accumulation of senescent cells. At the cellular level, typical features of premature aging include the accumulation of senescent cells and stem cell exhaustion. Disruption or dysregulation of critical signaling pathways, such as DNA damage, oxidative stress, telomere shortening, loss of Klotho, and oncogene activation, can lead to premature aging. Recent proteomic and transcriptomic studies provide evidence that cellular senescence contributes to CKD progression rather than solely reflecting aging.

CKD patients can be stratified into senescence-based endotypes (sendotypes), where a high-senescence signature dominated by TNF, NF-κB, and MAPK signaling is associated with worse renal function and faster eGFR decline. These senescence-associated pathways were further validated in human CKD biopsies and kidney organoid injury models, confirming their involvement at the tissue level. These findings suggest that CKD is biologically heterogeneous with respect to senescence signaling. The sendotype framework may therefore provide a basis for precision senotherapeutic strategies, where therapies targeting specific inflammatory or senescence pathways (e.g., NF-κB or MAPK signaling) could be applied to patient subgroups most likely to benefit.

The literature highlights cellular senescence as a central mechanism driving both kidney aging and CKD. Nevertheless, determining whether renal senescence serves as a catalyst or an outcome of CKD remains challenging, as current evidence suggests a bidirectional relationship in which kidney injury promotes senescence, while senescent cells further promote inflammation and fibrosis, thereby contributing to disease progression.

A sizable portion of the field of dermatology, arguably the less reputable portion, has long been strongly financially motivated to address the visible signs of aging. In practice, this involved deploying approaches that did not work to any great degree, but were nonetheless popular with patients, one of the many triumphs of marketing over substance that characterize this modern world of ours. The times are changing, however. The advent of a new focus on the mechanisms of aging, coupled with early, narrowly focused rejuvenation therapies that do in fact work to a greater degree than was historically possible, such as the ability to meaningfully reduce the burden of senescent cells in skin, has started a process of transformation in the field. This is a prototype for the transformation that will eventually embrace all medicine for all age-related conditions, a move from coping and marginal therapies to approaches that actually work.

Aesthetic dermatology is undergoing a transformative shift, one that mirrors the broader societal focus on longevity and proactive health optimization. Traditionally, the goals of aesthetic medicine were tied to visible rejuvenation, smoothing wrinkles, restoring volume, and refining contours. Today, patients increasingly seek interventions that not only enhance appearance, but also preserve the vitality, structure, and biological performance of their skin over time.

This shift reflects the evolving science of longevity, which distinguishes between lifespan, the number of years a person lives, and healthspan, the number of years lived in good health, free from disease and functional decline. In dermatology, an analogous concept is emerging, skin healthspan, or skinspan, the duration over which the skin maintains optimal barrier function, immune defense, regenerative capacity, and aesthetic quality.

Cutaneous aging, like systemic aging, is now understood as a modifiable process, shaped by intrinsic genetic programs and extrinsic stressors such as UV exposure, pollution, and inflammation. Advances in epigenetics, cellular senescence research, and regenerative technologies offer an opportunity to shift the focus from late-stage correction to early, proactive biological support. This commentary explores mechanistic pathways underlying skin longevity, including telomeric preservation, epigenetic clocks, senescence reversal via partial reprogramming, and the modulation of mitochondrial function through biomimetic peptides and non-ablative energy-based technologies.

Link: https://doi.org/10.1111/jocd.70788

Cancer is a numbers game; mutations occur at some rate, and some of those mutations result in a cancerous cell. The more cells an individual has, the greater the risk of cancer, all other factors being equal. Of course those factors are not equal. For a physically large species to evolve to become physically large, it must also have evolved superior means of cancer suppression. As researchers explore the biochemistry of large and small mammals, from mice to whales, they are uncovering the mechanisms employed by large species to resist cancer, and which never evolved in smaller species. It is possible that some of these discoveries may lead to ways to prevent or treat cancer in humans, but practical applications resulting from the study of comparative biology remain a future prospect at the present time. Even where specific genes and interactions are identified, it remains unclear as to how best to make use of them in human medicine in a sufficiently safe way to pass muster with the very conservative regulatory bodies.

Across the animal kingdom, cancer risk should, in principle, scale with increasing body size and lifespan. Larger animals contain vastly more cells, and longer lives permit many rounds of cell division, both of which increase the probability of accumulating mutations and undergoing malignant transformation. However, this expectation does not always hold in nature. Some of the largest and longest-lived animals, such as whales and elephants, exhibit a remarkably low cancer incidence.

This incongruency, known as Peto's paradox, suggests that evolutionary pressures have endowed these animals with unusually potent anticancer mechanisms to counteract the mutational burden associated with large bodies and extended lifespans. Indeed, studies in elephants revealed that these large animals have evolved multiple copies of the tumor suppressor TP53 gene, which is associated with an increased apoptotic response that allows the prompt elimination of damaged cells before they become precancerous. Interestingly, sequencing and analysis of several whale genomes, including the bowhead whale - known to live for over 200 years - did not reveal the TP53 duplications seen in elephants, suggesting that whales rely on alternative, previously uncharacterized, anticancer strategies.

In this commentary, we discuss a recent study showing that a key contributor to bowhead whales' exceptional lifespan and cancer resistance is their superior genome maintenance capacity. We further discuss DNA repair as a determinant of longevity in other long-lived species and explore how these naturally occurring mechanisms could be harnessed to improve genome integrity, reduce cancer risk, and promote healthy aging in humans.

Link: https://doi.org/10.1002/1878-0261.70250

Aging is a collection of many varied forms of cell and tissue damage and forms of dysfunction in biological systems that all interact with one another as they progress. A cause can contribute to a consequence that in turn accelerates the cause. Except that in any narrow view there are likely another fifteen contributing causes and various consequences muddying the waters, making it challenging to assign relative importance to any one change or mechanism or interaction. Aging is a big ball of yarn, and there are only so many researchers and so much time. For any given mechanism or interaction, our understanding remains incomplete. Research into aging tends to focus on where the lamp presently shines, on the more well understood and well researched areas of cellular biochemistry and systemic dysfunction, but there is still a great deal that goes on elsewhere.

Today's open access paper is focused on a topic that doesn't come up all that often in the context of research into causes of aging. The authors are interested in the links between age-related changes in metabolism and the onset of frailty, a condition characterized by chronic inflammation, loss of muscle mass and strength, and loss of immune resilience. In the eyes of these researchers, evidence from clinical practice suggests that more attention should be given to metabolic acidosis in older people. This is a failure of metabolism to buffer against acidification of tissue environments. The chain of cause and consequence leading this outcome in aging is far from fully explored, as is the case for near all aspects of aging, but one can trace lines that lead from excessive acidosis to the various contributions to frailty.

Acid-Base Dysregulation Links Aging Metabolism to Frailty

For homeothermic humans, energetic efficiency is built on an optimal internal temperature and optimal pH, both of which are critical for maximizing enzymatic activity. Enzyme function underlies most biochemical reactions, including mitochondrial ATP production, the maintenance of membrane stability, membrane potential, and physiological performance. Overall, pH homeostasis at the intracellular and extracellular levels is preserved through complementary buffer systems and by regulation of cellular metabolism and activity, which are subject to both endocrine and behavioral control. Buffer systems such as the bicarbonate system provide the first line of defense against rapid pH fluctuations. Lungs respond within minutes by changes in ventilation, while the kidneys provide long-term regulation through excreting protons (H+) and generating new bicarbonate.

Accumulating epidemiologic evidence indicates that even "mild" deviations in serum bicarbonates have clinically meaningful implications for aging people. Observational studies have linked serum bicarbonate below 25 mEq/L - a threshold often considered clinically normal - to impaired physical performance, including slower gait speed, reduced muscle strength, and altered gait mechanics. Longitudinal data for initially well-functioning older adults (ages 70-79) further established low serum bicarbonate as an independent predictor of incident, persistent lower-extremity functional limitation. Notably, low bicarbonate level remains a significant risk factor for mortality even in individuals with preserved glomerular filtration rate (GFR > 60 mL/min/1.73 m2). The associations persist even with bicarbonate levels in the low-normal clinical range.

While lower bicarbonate levels are correlated with declining GFR, they also occur frequently in older adults with preserved renal function. In these cases, low bicarbonate plausibly reflects a mild or subclinical metabolic acidosis. The mechanistic association between acidosis and physical decline is thought to involve derangements in skeletal muscle metabolism that promote sarcopenia - the progressive loss of skeletal muscle mass, quality, and strength. These acidosis-induced derangements include catabolic signaling, insulin resistance, increased inflammatory cytokines, mitochondrial dysfunction, and oxidative stress, features that are also reported in the aging-related frailty phenotype. In comparison to aging, this catabolic process occurs more rapidly in chronic kidney disease (CKD) because of not only the greater severity of acidosis but also the accumulation of uremic toxins. Based on in vitro evidence, these toxins inhibit myogenic differentiation and damage mitochondria, further accelerating sarcopenia in CKD.

On this basis, it was proposed that acidosis-induced metabolic derangement in skeletal muscle also represents a key driver in aging-related frailty. However, it is critical to distinguish established mechanism from clinical hypothesis: while the cellular pathways are well-characterized in animal and CKD models, we lack longitudinal human data. Without tracking pH against frailty onset, it remains unclear if acidosis is a driver of frailty, a marker of its presence, or a consequence of muscle wasting (via loss of intracellular buffers).

Some decades ago, the pineal gland was overly mythologized by those interested in intervening in the aging processes, a lot of pseudoscience verging into mysticism. Nonetheless, the pineal gland is important component of the endocrine system, and its functions decline with age. Like the thymus and lymph nodes, the pineal gland becomes structurally disrupted with advancing age, and that is the primary focus of the paper noted here. The researchers seek to categorize this disruption and its relationship with the astrocyte population resident in the pineal gland.

The pineal gland (PG) is an endocrine organ in the brain, primarily composed of pinealocytes (about 95% of the cells); the rest are mainly astrocytes and microglia embedded in a network of blood vessels and nerve fibers. Pinealocytes produce melatonin, which plays an important role in the human body. Numerous studies state changes in the human PG as a result of aging and some neurodegenerative and mental pathologies. A relatively understudied issue is the alteration of the lobular structural organization of the human PG and its potential impact on glandular function.

By analyzing the lobular structure and astrocytic network of the human PG, we have identified two apparently distinct pathways of normal aging. In the first one, an increase in the number of astrocytes within the pineal parenchyma is observed, suggesting a partial compensatory role for astrocytes in maintaining pinealocyte function. In the second pathway, disruption of the lobular architecture appears to result in astrocytic atrophy and a decline in the functional integrity of all pineal components. These observations may explain our findings that the combination of a disrupted lobular structure and a light astrocytic network is the most common pattern, whereas the dense astrocytic network variant is found exclusively in structurally intact lobules of older individuals. Notably, the lobular organization of the pineal gland itself is highly variable and, apart from a slight tendency towards structural disruption with age, does not show a strong age-related pattern.

Another indicator of pineal degeneration is the presence of glial cysts, which are commonly observed in the pineal gland across the examined age range. Although typically asymptomatic, these cysts can significantly reduce the volume of the functional parenchyma. Notably, they are most commonly associated with the above-mentioned combination of a disrupted lobular structure and a light astrocytic network. Based on our findings, we propose that pathological conditions may contribute to structural degeneration of the pineal gland and a subsequent decline in melatonin production; however, normal aging appears to be the primary driver of this process.

Link: https://doi.org/10.3390/ijms27073093

The Gompertz law is a relatively simple equation that describes the exponentially increasing mortality rates observed in an aging population. One fits the equation to existing epidemiological data by adjusting the value of two parameters, α and β. Researchers here use the results of age-slowing interventions in large populations of nematode worms to assign physical, biological meanings to the changes in α and β produced by the treatment of aging. As the researchers describe here, β is related to length of time spent in poor health in later life, while α is related to length of time spent in good health in earlier life.

In populations of many animal species, including humans, mortality rates increase exponentially with advancing age. The scale and rate of increase can be set by two parameters, α and β, respectively, of the Gompertz equation. Interventions that extend lifespan can reduce either or both parameters. A long-standing supposition resulting from use of the equation in human epidemiology is that β corresponds to biological ageing rate, and α to ageing-independent causes of mortality.

Here, we investigate the biological basis of α and β using the nematode Caenorhabditis elegans, through the combined study in populations and individuals of effects of life-extending interventions on mortality and age-changes in health. We demonstrate that reductions in β arise not from slowed biological ageing, but rather from expansion of decrepitude (gerospan) in longer-lived population members. In contrast, reductions in α better reflect healthspan expansion, an indicator of slowed biological ageing. Thus, our investigation presents a new, empirical understanding of the Gompertz parameters that inverts their traditional interpretations.

Link: https://doi.org/10.1038/s41467-026-71780-7

Human life expectancy has increased steadily over time since the 1800s, but much of the analysis is focused on life expectancy at birth, where the dominant effects involve improvements in early life survival. More interesting are the measures of remaining life expectancy at some adult age. These measures also increase over time, but more slowly. In recent decades, the increase in life expectancy at age 65 has increased at a pace that is on the order of one year in every ten. Since this happened over a span of time in which little to no meaningful progress was made in deliberately treating aging as a medical condition, it is reasonable to ask how it happened. As is usual in matters of human epidemiology, firm answers are hard to come by. Correlations are easy to generate, but it is challenging to prove causation, or determine the relative importance of different contributions to an observed outcome.

Nonetheless, researchers have generated insight from the statistics of human mortality. For example work from fifteen years ago shows an equal split between (a) reduced premature mortality, compressing mortality to a smaller range of later ages, and (b) a reduction in mortality in those later ages. It is an open question as to whether these are both manifestations of the same underlying mechanisms, resulting from improvements in public health, reduced exposure to severe infection, general advances in medicine, and so forth. If we accumulate less damage along the way, do we also tend to live longer? Reliability theory suggests this is the case, building on what is known of the statistics of the failure of complex arrays of redundant parts.

In one sense a reduced mortality due to intrinsic causes and age-related disease is equivalent to a slower pace of aging, as aging is defined by its effects on mortality. In another sense, whether aging has been slowed depends on how one defines aging - at the level of mechanisms, capacity, and cellular biology rather than at the level of epidemiology and mortality, that is. Today's open access paper is a consideration of whether we can or should say that increased life expectancy means that aging is slowed versus postponed, and that is a distinction that really does force one to engage with how exactly aging is defined. What, mechanistically, is aging, exactly, if the pace of aging does not change, but the age of onset of aging can vary? This is a very different view to that provided by reliability theory.

The rhythm of aging: Stability and drift in the individual rate of senescence

Human aging is marked by a steady rise in the risk of dying with age - a process demographers call senescence. Over the past century, life expectancy has risen dramatically, but is this because we are aging slower, or simply starting it later? This has been framed as a testable hypothesis: the rate at which the risk of dying increases with age for humans may be a basic biological constant that is very similar and perhaps invariant across individuals and over time. From this perspective, gains in life expectancy would reflect delayed aging, not a change in the underlying process of senescence. But if the rate of aging is truly changing, it would suggest that the biological processes underlying senescence are more responsive to environmental, behavioral, or historical conditions than previously assumed.

We focus on actuarial senescence - the age-related rise in mortality risk - which, in most adult populations, shows an exponential increase in mortality with age, well described by the Gompertz law. The Gompertz slope measures how quickly risk accelerates as deterioration accumulates. Though not a direct biological measure, is widely used as a proxy for the rate of aging. Empirical tests of this hypothesis have yielded mixed findings. This may suggest that the variations in could be historically driven. Period events - such as wars, pandemics, and economic crises - strike multiple cohorts at once, just at different ages, and their lasting consequences can subtly distort the mortality patterns within each exposed cohort through cumulative shifts. As a consequence, when we estimate cohort by cohort, we may be tracing not a pure signal of the aging process, but the lasting effects of these shared historical events. As these shocks accumulate over time, they can produce variations that mimic a change in the slope of mortality, even if the underlying biological rate is constant.

We ask whether cohort-to-cohort variation in the Gompertz slope reflects a shift in the pace of aging or the effects of period shocks. We test this idea using a framework that decomposes the pace of senescence into three components: a biological baseline, a long-term trend, and the cumulative impact of period shocks. Applying this to cohort mortality data above age 80 from 12 countries, we find that once period shocks are accounted for, there is no statistical evidence of a long-term trend, consistent with the hypothesis. Analyses using lower starting ages yield the same qualitative conclusion. Rather than indicating a change in the process that drives senescence, these variations are consistent with echoes of shared historical events. Together, these findings indicate no evidence of a persistent directional change in the individual rate of aging.

This stability does not imply that aging is fixed in all aspects. Over the past century, survival has shifted toward older ages and life expectancy has increased substantially. These improvements may primarily reflect declines in baseline and background mortality rather than persistent changes in the rate at which mortality rises with age. In demographic terms, the onset of senescence may be postponed even if its tempo remains stable.

The aging and longevity of flies is very dependent on intestinal function. The noted longevity-associated gene INDY acts on intestinal function, for example. Here, researchers report on their investigation of the role of the gut microbiome in INDY-related longevity in flies. As might be expected given the present state of knowledge of the role of the gut microbe in long-term health and aging, there are signs of a contribution. These results are only a first step, however; the gut microbiome is a complex array of different microbial species, and there is a great deal more that might be catalogued in terms of its relationship to genetic associations with longevity in this species.

Reduction in the Indy (I'm not dead yet) gene, a plasma membrane citrate transporter, in Drosophila and its homolog in worms extends lifespan by promoting metabolic homeostasis. Indy reduction delays the onset of aging-associated pathology in the fly midgut, including preservation of intestinal barrier integrity and intestinal stem cell homeostasis. Gut microbiota has broad impacts on host metabolism, health, and aging. Age-related dysbiosis impairs intestinal barrier function and drives mortality. However, the underlying mechanisms that link increased microbial load to frailty and negative effects on health remain mostly unclear.

Here we show that Indy heterozygote flies have significantly lower bacterial load and increased diversity during aging compared to controls. However, the presence of the microbiome was not required for Indy lifespan extension, though removal of microbes did enhance the effects of Indy reduction on longevity, suggesting potential interactions between the microbiome and Indy. Indy down-regulation was linked to reduced expression of the JAK/STAT signaling ligands Upd3 and Upd2 in the midgut of young flies, which likely contributes to preserved intestinal stem cell homeostasis. Altogether, our results suggest that Indy reduction impacts microbiome load and composition, which preserves gut homeostasis and extends lifespan through impacts on JAK/STAT signaling pathway.

Link: https://doi.org/10.64898/2026.03.25.714291

PEPITEM is a circulating peptide involved in resolution of inflammation and reduction of chronic inflammation. Levels of PEPITEM decline with age, which is one of the reasons why inflammatory athritis becomes worse with age, in that this inhibitory mechanism declines in effectiveness. Studies in animal models have shown that injection of synthetic PEPITEM can improve symptoms; an example of this sort of work is noted here.

Inflammatory arthritis is a group of diseases, including rheumatoid arthritis (RA) and psoriatic arthritis (PsA), where the immune system attacks the joints, causing severe joint damage, pain, and disability. Under normal conditions, adiponectin in the bloodstream stimulates white blood cells to produce PEPITEM, which in turn reduces white blood cell migration in the tissues, preventing an unregulated inflammatory response. However, in inflammatory arthritis, white blood cells fail to respond to adiponectin, and secrete less PEPITEM in the joint. The natural 'break' that prevents white cell migration into the joint cavity is lost, and the inflammatory response becomes unregulated.

The initial study of peripheral blood mononuclear cells (PBMCs, white blood cells) harvested from treatment-naïve human donors with suspected inflammatory arthritis showed a reduced capacity to respond to adiponectin, which could be restored by the addition of PEPITEM. Further examination of whole blood indicated a lower bioavailability of PEPITEM in patients with early RA, leading the researchers to hypothesise that supplementation with PEPITEM could restore immune regulation and reduce the inflammatory changes seen in early-stage disease.

Their work in mouse models of inflammatory arthritis and gouty arthritis showed that injection of synthetic PEPITEM could prevent the onset of inflammatory arthritis, with significant reductions in disease incidence. In addition, joint swelling was reduced by PEPITEM when compared with infliximab - the current standard of care. Tissue studies confirmed that these changes were mirrored in synovial tissue (tissue inside the joints), with significantly less joint inflammation, cartilage damage, and bone erosion observed in PEPITEM treated mice, and significantly fewer white blood cells infiltrating the joints. Molecular studies showed significant down regulation of inflammatory mediators (NF-kB and COX2 protein) within the synovial tissue in PEPITEM-treated mice compared to controls, and a significant increase in the foxp3 transcript, which is crucial for the development of a type of white blood cell that suppresses the immune response, to prevent excessive inflammation and autoimmune disease.

Link: https://www.birmingham.ac.uk/news/2026/pepitem-replacement-therapy-shows-potential-for-early-stage-inflammatory-arthritis

The World Health Organization (WHO) launched intrinsic capacity into the space of ideas relating to the study of aging a decade ago; it is defined as "the composite of all the physical and mental capacities that an individual can draw on." At a more detailed level, intrinsic capacity is envisaged as the sum of motor capacity, sensory capacity, general vitality, psychological wellness, and cognition capacity. What the WHO authors did not specify is how to measure any of this, specifically and in detail.

Putting a fuzzy definition in front of the scientific community is like dangling catnip in front of a bunch of cats, and so now there exist a fair number of proposed approaches for measuring intrinsic capacity that are accompanied by published epidemiological data, but there is little to no consensus as to which of these approaches is the one to move ahead with, and no great ability to compare the data produced via one scientist's intrinsic capacity to data produced via another scientist's intrinsic capacity.

This hasn't stopped a continued flow of new publications in which researchers compare someone's definition of intrinsic capacity to other health data, such as epigenetic age. This may all settle into a consensus at some point, but postponing anything to await that outcome seems unwise. Free-form debates of this nature can last decades. Today's open access paper is another that seeks to build upon the concept of intrinsic capacity and efforts to define it precisely, this time in the direction of animal models of aging. Given that no-one can agree on how intrinsic capacity should be measured in human patients, why not expand that discussion to the animal models that inform the development of new therapies with the potential to slow or reverse aspects of aging?

Could animal models be used to longitudinally track intrinsic capacity during aging?

The World Health Organization (WHO) recently highlighted the importance of promoting healthy aging worldwide, a process characterized by the maximization of functional ability, enabling well-being in older adulthood. This concept inspired the development of the Integrated Care for Older People (ICOPE) program and the Intrinsic Capacity (IC) construct, with the latter serving as core element of ICOPE for clinical use. IC represents the composite of all mental and physical internal attributes of an individual. It is often operationalized through five key domains: cognition, locomotion, vitality, sensory function, and psychological capacity.

Research on IC during aging in humans is growing, being marked by high IC variability. Longitudinal monitoring must be prioritized to capture aging trajectories and identify modifiable risk factors. However, the need for a long-time window spanning decades of human life poses a significant challenge to investigating IC decline over time. In contrast, animal models offer a strategic alternative due to their shorter lifespans compared to humans. For example, the typical lifespan of a mouse is 2-3 years, whereas specific fish models (e.g., killifish) may live only 4-6 months. Thus, leveraging these models for longitudinal IC tracking offers a viable pathway that may expedite the elucidation of IC dynamics and mechanisms during aging.

Preserved functional ability can be objectively assessed through behavioral paradigms in animal studies. By using these measurements in observational or experimental settings, animal models can recapitulate the longitudinal trajectories of IC during aging. To facilitate crosstalk with humans and accurately capture age-related changes in IC, assessment tools should meet specific criteria: they should target the corresponding IC domains in humans, show a decline over time with aging, and exhibit sufficient amplitude to distinguish meaningful functional loss. Here, we discuss how longitudinal IC investigations in mice and fish may advance human research and care during aging. Particular attention will be given to assessing, in experimental models, all IC domains longitudinally, interactions across IC domains, and the definition of a set of potentially informative IC assessments in both mice and fish.

In the search for ways to slow the age-related loss of muscle mass that afflicts every older person, researchers here find that ATF5 is a point of control that regulates a trade-off between muscle mass and muscle quality. Mice lacking functional ATF5 retain muscle mass with age, but muscle quality declines to a greater degree instead. This rules it out as a target for therapy. It is always possible that further investigation of the interactions surrounding ATF5 will lead to insight into how to decouple mass versus quality, but that sort of investigation of biochemical pathways tends to take a very long time.

In skeletal muscle, the mitochondrial network is highly regulated by quality control (MQC) processes including the Integrated Stress Response (ISR) and the mitochondrial Unfolded Protein Response (UPRmt), controlled in part by the transcription factor, Activating Transcription Factor 5 (ATF5). With age, mitochondrial health and function become altered in muscle, but the role of ATF5 in regulating these processes has not yet been evaluated. This study therefore aimed to evaluate the role of ATF5 in mediating mitochondrial quality control and function during aging.

To investigate this, we utilized young (4-6 months) and middle-aged (14-16 months; denoted as aged) ATF5 whole-body knockout (KO) and wild-type (WT) male mice. The normal age-related decline in muscle mass was prevented in the absence of ATF5. This was accompanied by an attenuated rise in important protein degradation regulators, indicating that ATF5 regulates muscle protein turnover with age. Aged ATF5 KO muscle exhibited greater muscle fatiguability than WT counterparts, accompanied by accelerated mitochondrial reactive oxygen species production. The expression of the co-regulatory ISR/UPRmt transcription factors, CHOP and ATF4, was attenuated in response to acute contractile activity in the absence of ATF5. The lack of ATF5 led to a reduction in the levels of mitochondrial protease LonP and was accompanied by an increase in mitochondrial:nuclear derived protein imbalance.

Collectively, these results suggest that ATF5 functions to maintain mitochondrial quality control and muscle endurance at the expense of muscle mass, and its absence attenuates the normal compensatory stress response to contractile activity with age.

Link: https://doi.org/10.18632/aging.206365

Enormous costs are imposed by regulators in the US and Europe on the process of manufacturing a candidate drug to Good Manufacturing Practice (GMP) standards and then running a first clinical trial. Combine this with three years of a bad market for biotech, in which investors have pulled back from investing in preclinical companies, and one sees a much greater pressure than usual to expand alternative paths to obtaining initial human data in a responsible way. Right to Try initiatives within the US are underway, and ever more groups within the medical tourism industry are attempting to position themselves as service providers for an alternative to a first clinical trial in the US or Europe. Próspera in Honduras is the most visible of a fair number of entities. At the end of the day, much of the cost and requirements imposed by the FDA and other bodies are not necessary for responsible safety. When regulators make the task of conducting manufacture and a safety trial in humans cost $20M, but it can actually be accomplished responsibly for $5M, as is the case for many classes of therapy, something must change - and change is coming.

Mitrix Bio has reported preliminary Phase 1 safety results for what it describes as large infusions of transplanted mitochondria in humans, while simultaneously launching a small network of clinics offering the experimental intervention under Right to Try frameworks. Taken together, the announcements mark a transition from laboratory concept to early clinical deployment - albeit on a limited scale.

The initial safety work was conducted at a clinic in Dallas, Texas, involving two older participants who received escalating doses of transplanted mitochondria, with monitoring of blood chemistry and physical condition throughout. According to the company, no obvious adverse effects were observed during the study period. Alongside this, new Mitochondrial Transplant Institute clinics have opened in Newport Beach, Dallas and Palm Beach, where treatments will be offered on an individualized basis by physicians, targeting a wide range of chronic and degenerative conditions.

Mitrix's approach involves the use of bioreactors to grow mitochondria derived from an individual's own cells, with the aim of enabling larger-scale infusions. In the recent safety study, doses were increased incrementally, allowing investigators to assess tolerability before proceeding further. The absence of immediate adverse effects supports continued investigation, and though efficacy data has not yet been released, the company is aiming for full efficacy data by the end of this year.

Link: https://longevity.technology/news/mitrix-moves-mitochondria-into-the-clinic/

The National Institute on Aging's Interventions Testing Program (ITP) is the full stop at the end of many a debate over the merits of development of one substance or another as a hoped for treatment to modestly slow aging. The ITP uses a very large number of mice and considerable rigor to assess effects on life span. The program typically focuses on small molecules and supplements that have prior evidence for anti-aging effects, and usually those with a long history in the literature. Given the number of compounds that show no effect on life span in the hands of the ITP, this initiative serves as a reminder that any one study in a hundred mice that demonstrates modest slowing of aging does not in fact carry a great deal of weight. There are many such studies in the history of compounds that the ITP has shown to have no effect on life span.

There is always room to argue about dosing and methodology; there was some of that after the ITP reported that fisetin has no effect on longevity. But one can't argue with the large number of mice used and the efforts to impose rigor on the experimental process. Today's open access paper is the latest ITP publication in which possibly promising ways to modestly slow aging were demonstrated to have no effect once studied more rigorously. Of note, α-ketoglutarate is in the list; this had promising data in mice, considerable interest from a number of research and development groups, and made it all the way to a human clinical trial - which failed. In earlier mouse studies, α-ketoglutarate dosing was lifelong. The ITP tried starting at 18 months of age, which didn't work, and here tried starting at 7 months of aging, which also didn't work. If you'd like to look over the data, it can be found at the Mouse Phenome Database.

At a high level, the ITP results obtained over the years can be taken as support for the idea that attempting to discover bioactive molecules that favorably manipulate metabolism is not a viable path forward. It is very challenging, results vary meaningfully between groups, between species, by dose, by age of onset of treatment, and after all of that the best expected outcome is only a modest slowing of aging. This is not a good approach to the problem of aging. Instead, rational design of therapies that can repair known forms of cell and tissue damage seems far more likely to succeed in producing large enough and robust enough effects to care about.

Astaxanthin, meclizine, mitoglitazone, pioglitazone, alpha-ketoglutarate, mifepristone, methotrexate, and atorvastatin-telmisartan do not increase lifespan in UM-HET3 mice

The Interventions Testing Program (ITP) evaluated eleven compounds in genetically heterogeneous UM-HET3 mice to assess their potential to extend lifespan. These interventions included both novel agents and previously tested compounds administered at novel doses or starting ages. Despite prior evidence suggesting lifespan benefits of these proposed interventions in other models or under different conditions, none of the tested compounds significantly increased lifespan in male or female mice. Notably, astaxanthin, mitoglitazone, and meclizine - previously associated with lifespan extension in the ITP - showed no benefit when administered at different doses or starting at later ages.

In females, astaxanthin, late-start mitoglitazone, and pioglitazone were associated with significantly reduced lifespan when pooling the data from all three sites. However, site-specific analysis revealed unusually long lifespans in control females at The Jackson Laboratory, prompting reanalysis using data from the other two sites and only showed a negative effect for mitoglitazone and pioglitazone. This study underscores the importance of rigorous, multi-site testing and highlights the challenges of translating promising initial findings into consistent lifespan benefits at other doses or with alternate starting ages. These results suggest that timing and dosage are critical variables in aging intervention studies and reinforce the need for cautious interpretation of single-site or single-cohort findings.

One of the major projects within the study of comparative biology is the attempt to understand why adult individuals of some species can fully regenerate lost tissues following injury, while mammals such as our own species cannot. A variety of modest inroads into identifying potentially important differences in cellular biochemistry and activity have been made, such as work focused on senescent cells and macrophages, but it remains an unsolved challenge. Researchers here present more data to add to that already under consideration, focused on the role of oxygen sensing in the initial response to injury. It is unclear as to whether it can lead to dramatic improvements in mammalian regeneration, but the work suggests that regeneration could be improved via manipulation of oxygen sensing in injured tissues.

Some animals can regrow lost body parts. Salamanders and frog tadpoles can rebuild entire limbs after amputation. Mammals cannot. For decades, biologists have tried to understand why. Limb regeneration begins with wound healing. After amputation, cells at the injury site must rapidly seal the wound and switch into regenerative cell types. In amphibians, this process runs smoothly. In mammals, it stalls early. Wound closure is slow and scar formation takes over, blocking regeneration. One key difference lies in the environment. Amphibian larvae develop in water, where oxygen levels are lower than in air. Moreover, many regeneration-competent species live in aquatic environments. Meanwhile, mammalian tissues are typically exposed to higher oxygen levels after injury.

Researchers amputated developing limbs from frog tadpoles and mouse embryos and cultured them outside the body under controlled oxygen conditions. Oxygen levels were lowered to match aquatic environments or raised to levels close to air. They tracked how cells responded by measuring wound closure, cell movement, gene activity, metabolism, and epigenetic states, including changes to DNA packaging. The work focused on HIF1A, a protein that acts as a cellular oxygen sensor. When oxygen is low, HIF1A becomes stable and activates programs that set the stage for wound healing and regeneration.

Lowering oxygen levels had a clear effect on the limbs of mouse embryos. Under reduced oxygen, mouse cells closed wounds faster and showed signs of entering a regenerative program. Stabilizing HIF1A produced similar effects, even when oxygen levels remained high. Frog tadpoles behaved differently. Their limbs regenerated efficiently across a wide range of oxygen levels, including levels well above those normally found in air. Molecular analysis showed that their cells maintain stable HIF1A activity even when oxygen increases, due to low expression of genes that normally shut this pathway down.

By comparing frogs, axolotls, mice, and human datasets, the team found a consistent pattern. Regeneration-competent amphibians show reduced oxygen-sensing capacity, allowing regenerative programs to be initiated and sustained. Mammals show the opposite pattern. Their cells respond strongly to oxygen and switch regenerative programs off soon after injury. The results suggest that mammalian limbs retain latent regenerative potential at early stages, depending on how cells respond to environmental signals such as oxygen. This means that adjusting oxygen-sensing pathways might one day improve wound healing or regenerative responses in humans.

Link: https://www.tuebingen.mpg.de/280592/news_publication_26212730_transferred

Humans, and most other mammals, exhibit a common set of differences between males and females in the trajectory of aging and age-related disease. Females live longer, but with greater disability, for example. Dive deeper to look at the fine details of specific tissues and biological systems, and the list of differences expands. Researchers here report on their assessment of differences between men and women in the aging of the immune system, for example. While interesting, it isn't clear that differences in the progression of aging will be all that important in a future of effective rejuvenation therapies. It is certainly possible that any given narrow approach to rejuvenation that targets just one mechanism of aging will prove to be more or less effective to some degree in men versus women, but a package of approaches that produces comprehensive rejuvenation, addressing all of the causes of aging, should make the whole question of sex differences in aging moot.

Statistics show clear differences in the population's immune system according to sex: men are more susceptible to infections and cancers, while women have stronger immune responses, which translate, for example, into better responses to vaccines. Even so, with a more reactive immune system, the probability of the body attacking itself also increases, causing 80% of autoimmune disease development to occur in women. A new study has demonstrate that immunological aging follows different dynamics between men and women, identifying the cells and genes responsible for the process, and providing a molecular explanation for the differences that previously were only observed globally in the population.

The results reveal that women present more pronounced changes in the immune system with age, with an increase in inflammatory immune cells. This finding could help explain why autoimmune diseases are mainly developed by women, especially at advanced ages, as well as the worsening of certain inflammatory pathologies after menopause. On the other hand, the changes associated with immune system aging observed in men are globally less extensive, but an increase in certain blood cells presenting pre-leukemia alterations was observed, a fact that could explain why some blood cancers are more frequent in older men.

Finding these patterns was possible thanks to the analysis of blood samples from nearly 1,000 people of different ages covering the entire adult life, combined with a technology capable of analyzing each cell individually, called single-cell RNA sequencing. In total, the researchers analyzed the activity of 20,000 genes in more than one million blood cells, which allowed them to identify how the immune system changes over the years and detect clear differences between sexes.

Link: https://www.bsc.es/news/bsc-news/new-bsc-study-reveals-the-first-time-the-female-immune-system-changes-much-more-men-age

Cells have evolved responses to stress that enhance the chance of survival. Many of these responses converge of increased activity of maintenance processes, more recycling of materials, less protein synthesis, and a number of other common mechanisms. Researchers have found that mild stress of near any sort imposed upon a living organism will provoke a net gain in cell function and resilience, which in turn acts to modestly slow progression of the complicated cascade of accumulating damage and dysfunction that we call aging. The bounds of the possible are illustrated by the response to the nutrient stress, induced by fasting or calorie restriction. Short-lived mammalian species such as mice can live as much as 40% longer in response to a restricted but still sufficient nutrient intake. Longer-lived mammals certainly do not exhibit such a large plasticity of life span, even though calorie restriction and fasting appear to be quite beneficial in the short term.

There is no dramatically powerful rejuvenation therapy hiding in the mechanisms of calorie restriction, heat stress, cold stress, and so forth. Nonetheless, a sizable fraction (and perhaps even the majority) of research programs aimed at treating aging as a medical condition are focused on manipulation of stress responses. Today's open access paper is an example of the type. In this case, the stress takes the form of mild mitochondrial dysfunction, encouraging the cell to take steps to defend itself. The hundreds of mitochondria present in every cell manufacture adenosine triphosphate (ATP), a vital chemical energy store molecule. They also generate stress-inducing reactive oxygen species as a byproduct of this activity. When mitochondrial become dysfunctional, oxidative molecule production increases and ATP production diminishes. Our cells have evolved to treat this as a call to action: they increase efforts to clear out underperforming mitochondria, produce more antioxidants, and increase other maintenance activities. When mitochondrial dysfunction is mild, the result is an overall benefit.

Targeting Mitochondrial Stress Responses: Terbinafine and Miglustat as Novel Lifespan and Healthspan Modulators

Age-related diseases share numerous biological impairments. Among these, mitochondrial dysfunction has emerged as a key driver of aging and disease progression. Mitochondria are essential organelles participating in numerous cellular functions, including energy harvesting, biogenesis, regulation of homeostasis and apoptosis. Changes in mitochondrial integrity not only impact cellular metabolism but also critically influence whole-body metabolism, health, and lifespan. Consequently, mitochondrial-targeted therapies have gained significant attention for treating metabolic and age-related conditions.

One promising approach is the pharmacological induction of the mitochondrial stress response (MSR), an adaptive pathway that restores proteostasis and promotes resilience to stress. While severe mitochondrial dysfunction is detrimental, mild mitochondrial stress can extend lifespan and delay age-related decline, a phenomenon known as mitohormesis. MSR-inducing compounds have shown potential in mitigating age-related decline and improving outcomes in various conditions.

A key component of the MSR is the mitochondrial unfolded protein response (UPRmt), which coordinates cellular responses to mitochondrial stress and maintains mitochondrial proteostasis. In C. elegans, the UPRmt is initiated by misfolded proteins, leading to the activation of the transcription factor associated with stress 1 (ATFS-1), which induces chaperones, proteases, and metabolic regulators to re-establish mitochondrial homeostasis. Similar mechanisms are observed in mammals, where ATF4 and ATF5 mediate mitochondrial stress responses. Notably, mild mitochondrial perturbations, including mitochondrial ribosomal protein knockdown or antibiotic treatment, like doxycycline, can activate the UPRmt and extend lifespan in C. elegans and other species.

Despite progress in aging research, few pharmacological agents robustly activate the MSR without adverse effects. While antibiotics like doxycycline robustly induce the UPRmt, their antibacterial activity disrupts the microbiome and contributes to antibiotic resistance, limiting their therapeutic potential. Thus, identifying mitochondrial stress inducers without antibacterial properties is crucial.

Here, we screened 770 FDA-approved drugs to identify novel MSR activators. Using C. elegans, we identified terbinafine and miglustat as mitochondrial stress modulators that extend lifespan and healthspan without antibacterial activity. Mechanistically, both compounds activate the UPRmt and engage DAF-16-dependent insulin/IGF-1 signaling, distinct from its canonical activation, revealing a coordinated stress adaptation program. Importantly, terbinafine and miglustat also induce mitochondrial stress responses in human cells, supporting their translational relevance and highlighting new opportunities to target mitochondrial dysfunction in aging.

IGF-1 signaling is perhaps the most well studied mechanism of aging, with extensive work predating the modern enthusiasm for treating aging as a medical condition. Investigation of IGF-1 signaling in the context of aging was a fellow traveler to investigations of calorie restriction in the context of aging, and while these are roads that lead to a greater understanding of the evolution of aging and how pace of aging adapts to environmental circumstances, and have given rise to classes of drugs that may modestly slow aging, they are not likely to lead to any meaningful class of rejuvenation therapy. From a purely scientific point of view, the incomplete state of understanding of cellular biochemistry means that there is a lot left to learn on the topic of how aging progresses and shifts in response to circumstances, and how different systems and mechanisms interact with one another. Surprises remain to be discovered, though once again it seems unlikely that any of the surprises relating to IGF-1 signaling will be capable of giving rise to meaningful rejuvenation therapies.

One strategy to elucidate the relationships between the hallmarks of aging is to investigate how the disruption of one hallmark affects the trajectory of another. In doing so, it may be possible to assess whether these processes act independently, synergistically, or in opposition of each other as they shape human life span. In addition, this strategy may reveal if a hierarchy exists between aging pathways, which could lead to a more integrated and causally ordered model of the aging process. In this study, we apply this strategy to investigate the relationship between two critical drivers of the aging process, mitochondrial mutagenesis and insulin-like growth factor-1 (IGF-1) signaling.

A large body of evidence supports the idea that instability of the mitochondrial genome (i.e., changes in nucleotide sequence, copy number, and organization due to replication errors and DNA damage) leads to a progressive decline in mitochondrial function, which accelerates the natural aging process and contributes to a wide variety of age-related diseases, including sarcopenia, neurodegeneration, and heart failure. A similar body of work describes the role of IGF-1 signaling in the aging process. IGF-1 regulates the growth and metabolism of human tissues, and reduced IGF-1 signaling can not only extend mammalian life span but also confer resistance against various age-related diseases, including neurodegeneration, metabolic decline, and cardiovascular disease. However, how mitochondrial mutagenesis and IGF-1 signaling interact with each other to shape mammalian life span remains unclear.

Unexpectedly, we found that reduced IGF-1 signaling fails to extend the life span of mitochondrial mutator mice. Most of the longevity pathways that are normally initiated by IGF-1 suppression were either blocked or blunted in the mutator mice. These observations suggest that the prolongevity effects of IGF-1 suppression critically depend on the integrity of the mitochondrial genome, revealing an unexpected hierarchy in the pathways that control mammalian aging. Together, these findings deepen our understanding of the interactions between the hallmarks of aging and underscore the need for interventions that preserve the integrity of the mitochondrial genome.

Link: https://doi.org/10.1126/sciadv.aea4279

It is a struggle to derive evidence for causation from human data. It is well established that physical fitness correlates with a lower risk of age-related disease and mortality in humans, and well established that greater physical fitness causes a lower risk of age-related disease and mortality in animal studies. But as a practical matter one can't run the sort of study that would be needed to obtain direct proof of causation in humans. So researchers turn to approaches such as Mendelian randomization, in which one adds an additional set of genetic correlations in order to try to infer at least some support for causation. There are indeed genetic correlations with a tendency to greater physical fitness, and those do correlate in turn with risk of age-related disease and mortality.

We investigated potentially causal associations between genetically predicted aerobic fitness and multiple health phenotypes using a two-stage phenome-wide Mendelian randomization (MR) study. We screened 712 health-related phenotypes as outcomes using publicly available European-ancestry genome-wide association study (GWAS) summary statistics from OpenGWAS (Discovery GWAS n > 5,000), prioritizing non-UK Biobank/non-FinnGen datasets for Discovery when available and selecting an independent GWAS for Validation.

We identified 108 Discovery associations, of which 34 remained valid and statistically significant after Validation. Higher genetically determined aerobic fitness was associated with lower lacunar stroke risk, lower arterial stiffness, higher heart rate variability, lower diastolic blood pressure, more favorable anthropometric measures, lower use of antidiabetic drugs, lower asthma risk, lower C-reactive protein, higher bone mineral density, favorable liver function biomarkers, favorable platelet-related traits, multiple blood-count-derived hematological cell indices and counts, as well as higher years of schooling. Adverse associations were confined to atrial fibrillation, valvular heart disease, and systolic blood pressure.

Genetically determined aerobic fitness is linked to a broad pattern of favorable cardiometabolic, inflammatory, musculoskeletal, respiratory, hepatic, and hematological phenotypes, alongside a narrow set of potential cardiovascular hazards.

Link: https://doi.org/10.1249/MSS.0000000000003975

The tau protein is involved in maintaining stability of microtubule structures in the axons that connect neurons. It isn't the only protein that undertakes this task, and loss of functional tau doesn't produce immediate issues. Tau is important in some functions of memory, however, and mice lacking tau exhibit a range of cognitive defects that grow with age. Tau is well studied not for these aspects of its function, but because it is one of the few proteins that can be altered in a way that allows it to form solid aggregates that are disruptive to cell function. Tau aggregation to form the structures known as neurofibrillary tangles is a feature of late stage Alzheimer's disease. The consensus view of this stage of the condition is that tau aggregation and chronic inflammation form a feedback loop that accelerates dysfunction into widespread cell death in the brain.

The progression of Alzheimer's disease provides the appearance of a spread of tau aggregation from region to region in the brain. Study of the brain is challenging, however, and while there is a consensus on this point - that altered forms of tau can seed more dysfunction in a prion-like way and spread from cell to cell via synapses - there are other potential explanations for the observed outcomes. For example tau aggregation could be universal in the brain, but some regions are more vulnerable to the aggregation processes than others, and therefore exhibit a greater burden of neurofibrillary tangles earlier in the progression of the condition. Today's open access paper is an example of the way in which researchers must strive to circumvent the inability to directly access a large number of living human brains at various stages of Alzheimer's disease. Instead, the researchers synthesize a number of indirect approaches - models, genetics, postmortem tissues, and imaging data - to produce supporting evidence for the consensus view of a synaptic spread of tau aggregation.

Tau seeds induce neurofibrillary tangle formation across brain regions via individual-specific connectivity

Tau protein promotes assembly and stabilization of microtubules. In normal aging and Alzheimer's disease (AD), tau can become hyperphosphorylated, which reduces its affinity for microtubules and drives its mislocalization from axons to the body of the neuron and dendrites. Aberrant tau accumulation in the form of neurofibrillary tangles (NFTs) is a strong pathological correlate of cognitive decline. Based on postmortem human brain studies, the spatiotemporal progression of NFTs begins in layers II and III of the entorhinal cortex (EC), extends to the hippocampus and temporal cortex, entering the limbic system before reaching broader neocortical regions, which subsequent tau positron emission tomography (PET) studies confirmed in vivo. When tau is confined to the medial temporal lobe, patients typically experience memory problems, but once tau enters the neocortex, broader cognitive impairment often emerges.

The mechanisms underlying tau spread are unclear, but may rely on a process, referred to as tau seeding, in which abnormal forms of tau protein induce misfolding and aggregation of normal tau proteins in a template-dependent manner. Prior studies using cell cultures, mouse models, and human neuroimaging have each explored certain facets of tau pathology progression. However, whether endogenous tau seeds are the entities that induce NFTs across the aging human brain via naturally occurring connectivity remains to be confirmed. An alternative hypothesis that accounts for the observed NFT distribution is a gradient in region vulnerability, which does not involve tau seeds spreading from early-affected regions.

To investigate this question, we measured tau seed bioactivity data in synaptosomes from postmortem inferior temporal gyrus (ITG) and superior frontal gyrus (SFG) tissues of 128 individuals and combined this data with genotype and antemortem fMRI measurements from the same individuals. Via multimodal integration of these data, we provided supporting evidence that tau seeds from an early-affected brain region induce local NFTs as well as drive tau seeds and NFTs in a late-affected, far-removed region. Also, extending past tau-PET studies that demonstrated spatial correspondence between tau deposition and connectivity patterns, we further showed that individual-specific intrinsic connectivity modulates tau seed-NFT relationships. Our results thus support the hypothesis that tau seeds use synaptic connections to spread tau across connected regions in the human brain.

Dysfunction in the cells making up the inner lining of blood vessels, the vascular endothelium, is thought to be an important first step in the aging of the vasculature more generally, setting the stage for the development of atherosclerotic lesions, a declining capacity of smooth muscle to contract and dilate vessels in order to control blood pressure, and leakage of the blood-brain barrier, among other issues. Researchers here review the contribution of two important aspects of cellular aging to the aging of the vascular endothelium; firstly the growing number of senescent cells, and secondly the decline in mitochondrial function. These are connected, as mitochondrial dysfunction is considered to contribute to an increased pace at which cells become senescent.

The vascular endothelium performs numerous regulatory functions that impact inflammatory responses, thrombosis, vascular tone, and angiogenesis. Endothelial dysfunction is a key contributor to the pathogenesis of various human diseases, either as a primary trigger or as a consequence of organ damage. This review examines how ageing reshapes endothelial cell metabolism and mitochondrial function, progressively undermining endothelial homeostasis and resilience.

Age-related endothelial alterations, including reduced nitric oxide bioavailability, heightened oxidative stress, impaired vasodilatory capacity and pro-inflammatory activation, arise from coordinated shifts in energy production, substrate utilization and redox signaling. In this context, cellular senescence, a stable arrest of the cell cycle accompanied by distinct metabolic, secretory, and inflammatory changes, appears to be an important response to cumulative metabolic and mitochondrial stress. Senescent endothelial cells not only reflect this stress burden but also actively propagate dysfunction through sustained pro-inflammatory and pro-oxidant signalling, thereby accelerating vascular ageing. We highlight the central role of mitochondria in these events. Age-associated mitochondrial dysfunction disrupts bioenergetics, enhances reactive oxygen species generation, and fuels chronic low-grade inflammation, amplifying endothelial decline.

By bringing together current evidence-based knowledge on endothelial cell bioenergetics, mitochondrial impairment, and metabolic reprogramming, this review identifies mitochondria-driven metabolic deterioration as a key mechanism underlying endothelial ageing and underscores mitochondrial metabolism as a promising, yet underexploited, therapeutic target in age-related vascular dysfunction.

Link: https://doi.org/10.1016/j.arr.2026.103119

The extremely high cost of obtaining clinical approval for a new drug incentivizes the research and development communities to focus on finding new uses for existing drugs in place of the rational design of new drugs. This likely contributes to a reduced quality of therapies; we live in a world in which the creation of marginally effective drugs is favored over the search for better drugs because it is cheaper to find marginally effective drugs. One of the few drug repurposing exercises that is producing interesting results is the search for senotherapeutic therapies among drugs approved for the treatment of various cancers, as many of these drugs have positive effects on cancer precisely because they selectively destroy or otherwise suppress the inflammatory signaling of senescent cells, but were developed prior to an understanding of the importance of this mechanism.

The accumulation of senescent cells in white adipose tissue (WAT) is closely associated with the functional decline of WAT and plays a causal role in the pathogenesis of metabolic diseases. Therefore, the elimination of senescent cells in WAT holds promise for the treatment and prevention of age-related metabolic diseases. Using a drug-repositioning strategy for 2,150 clinically applied compounds, we discover that homoharringtonine (HHT), an FDA-approved anti-leukemic drug, manifests senotherapeutic activity in vitro in multiple cell types including human preadipocytes, while inflicting minimal cytotoxicity to non-senescent cells.

HHT treatment prevents diet- or age-induced metabolic abnormalities in male mice targeting senescent adipocytes and preadipocytes to improve WAT function and reduce WAT inflammation. Moreover, HHT treatment attenuates age-associated phenotypes of human adipose tissue. Mechanistically, the senotherapeutic effects of HHT are mediated through the direct interaction of HHT with heat shock protein family A member 5 (HSPA5). Importantly, we found that HHT treatment delays aging and extends the lifespan in progeroid and aged mice. Our study demonstrates the novel senotherapeutic potential of HHT to mitigate age- and obesity-related metabolic dysfunction and extend longevity in mice.

Link: https://doi.org/10.1038/s41467-026-70475-3

Control over the structure of nuclear DNA is critical to both gene expression and interactions between DNA damage and DNA repair systems. Most of us are by now at least passingly familiar with the concept of the chromosomes of nuclear DNA existing as a mix of (a) spooled and tightly packaged regions known as heterochromatin, where gene sequences are hidden from transcriptional machinery and genes are thus not expressed, versus (b) unspooled regions where transcription can take place, the gene sequences read to allow assembly of corresponding RNA molecules. Epigenetic decorations to DNA and supporting molecules drive a constant shift between spooled and unspooled structures. This necessary regulation of structure and function all changes for the worse with advancing age for reasons that are incompletely understood.

There is a lot more to DNA structure than just this, however. For example, the intricate regulation of nuclear DNA structure incorporates the presence of double-strand breaks known as DNA gaps, distinct from the harmful DNA double strand breaks that occur as a form of damage. These DNA gaps are thought to reduce potentially damage-inducing stress forces, but this may or may not be their primary function. Researchers have observed that the number of these DNA gaps declines with age, and have speculated that this change may produce harm. In today's open access paper, researchers provide fairly direct evidence for this proposition via use of a gene therapy that directly induces DNA gap formation in aged non-human primates. The researchers observe a range of improvements in biomarkers of health following treatment, suggesting that more DNA gaps leads to improved cell and tissue function; all in all, quite an interesting outcome.

Box A of HMGB1 plasmid reverses the age-related changes in the plasma proteomic profile of perimenopausal monkeys

A characteristic feature of aging is the accumulation of DNA damage, which plays a significant role in the deterioration of cellular function. The sustained destruction of DNA and the subsequent activation or failure of the DNA-damage response (DDR) are pivotal in the aging process, often leading to detrimental cellular outcomes such as senescence, apoptosis, and telomere shortening. Maintaining DNA integrity is crucial for cell viability. One mechanism employed by cells to ensure this integrity involves the dynamic regulation of DNA structures, often observed as DNA gaps, known as youth-DNA-gaps. These gaps are believed to minimize mechanical stress and torsion forces within the DNA structure, thereby protecting it from damage. Interestingly, the number of these physiological DNA gaps typically is reduced in yeast, rats, and human cells as they age, as well as in chemically-induced senescent cells.

The High Mobility Group Box 1 (HMGB1) protein has emerged as a key molecule involved in various biological processes highly relevant to aging, including inflammation, DNA repair, and cell senescence. The Box A domain of HMGB1 is a highly conserved DNA-binding domain crucial for modulating HMGB1's biological functions. Box A is known to bind DNA and interact with other proteins, acting as a molecular regulator that influences the formation of DNA gaps to enhance DNA integrity and protection. Growing evidence suggests that Box A-induced DNA gaps may reverse aging characteristics in vivo and in vitro, having been shown to inhibit liver fibrosis and improve aging brain functions in aged rat models. Furthermore, Box A can enhance stemness, suggesting a role in improving stem cell activity compromised by illness and aging.

This study investigates the potential role of the Box A domain HMGB1 in modulating age-related changes. We utilized a label-free quantitative proteomic technique to analyze the plasma proteome of three female adult and eight female perimenopausal cynomolgus macaques (Macaca fascicularis), with the perimenopausal group receiving an intravenous administration of the Box A plasmid. Proteomic analysis revealed differential expressions in proteins primarily associated with stress response, immune regulation, lipid transport, and cellular homeostasis following Box A plasmid intervention. Notably, the expression levels of key proteins, such as apolipoprotein E (APOE) and sex hormone-binding globulin (SHBG), showed a reversal effect, restoring levels closer to those observed in the younger, adult monkeys. These findings highlight the potential of the Box A of HMGB1 plasmid as a therapeutic candidate to mitigate age-related proteomic alterations, offering a novel avenue for targeted interventions in aging and associated diseases.

The burden of lingering senescent cells grows with age in tissues throughout the body. Cells enter the senescent state constantly, but the pace of clearance of senescent cells by the immune system falters with advancing age. Senescent cells secrete a mix of pro-inflammatory, pro-growth signals that are disruptive to tissue structure and function when sustained for the long term. Analysis of circulating molecules in a blood sample can in principle be used to measure the body-wide burden of senescent cells, though no strong consensus approach has emerged yet from the various methods demonstrated in recent years. Here, find another contender for that consensus approach, where researchers use proteomic assessment of blood samples to build a score based on the strength of senescent cell signaling, and find that this score correlates with mortality risk.

The accumulation of senescent cells is a recognized hallmark of biological aging and is associated with the onset of multiple chronic medical conditions. Senescent cells exhibit a distinct secretory profile, known as the senescence-associated secretory phenotype (SASP), which can propagate cellular senescence to neighboring and distant tissues. Measuring SASP factors in blood serves as a practical proxy for cellular senescence burden and may help track disease states and intervention outcomes.

We developed and validated a composite SASP Score by integrating large-scale population proteomics data with a semi-supervised deep learning framework. The analytical workflow included: (1) selection of biologically curated SASP proteins; (2) development of a Guided autoencoder with Transformer (GAET) model using data from the UK Biobank Pharma Proteomics Project (UKB-PPP); (3) internal evaluation and association analyses within the UK Biobank; and (4) external validation and longitudinal assessment in an independent randomized clinical trial cohort.

The deep learning-based SASP Score was a strong, independent predictor of mortality risk and incident serious, chronic medical conditions (e.g., dementia, COPD, myocardial infarction, stroke). In an independent cohort, multimodal exercise significantly changed the SASP Score trajectory over 18 months.

Link: https://doi.org/10.64898/2026.03.20.26348913

Excessive, constant inflammation in response to aspects of one's own cellular biochemistry is a feature of both autoimmune disease and aging. While transient inflammation is necessary for effective regeneration and defense against pathogens, constant unresolved inflammatory signaling is destructive to tissue structure and function. It is a major component of the pathology of common age-related conditions. The challenge in addressing this is that unwanted inflammation and desirable inflammation both involve the same molecular signals and points of control. To date, therapies that reduce chronic inflammation do so via crude blockade of signals or mechanisms, with the side effect of reduced immune capability, a reduction in the normal immune response when it is needed. The research community is slowly making progress towards finding points of distinction, however, approaches to intervention that have greater effects on unwanted inflammation than they do on the normal immune response. One such line of work is noted here, focused on autoimmunity.

Current autoimmune disease treatments like hydroxychloroquine work by broadly blocking endosomes, the compartments inside cells where incoming materials are sorted and processed, including molecules that trigger immune responses. While effective, this approach can lead to significant side effects - including gastrointestinal problems and, less commonly, vision damage-causing a significant number of patients to stop treatment.

Researchers focused on two proteins, Munc13-4 and syntaxin 7, that must bind together for immune sensors called Toll-like receptors (TLRs) to activate inside endosomes. This "molecular handshake" plays a key role in detecting the foreign DNA and RNA from invaders like viruses and bacteria. However, in autoimmune diseases, TLRs become overactive, detecting self-nucleic acids, for example, from neutrophil-extracellular traps, and trigger chronic, damaging inflammation even without a real threat.

The team screened roughly 32,000 compounds and identified molecules that specifically block the Munc13-4-syntaxin 7 interaction without disrupting other cellular functions. Because Munc13-4 is found mainly in immune cells, the compounds offer a targeted way to calm inflammation. "Most treatments for autoimmune diseases manage symptoms; they don't change the underlying course of the disease. What's exciting about this approach is its potential to be disease-modifying: targeting the specific molecular machinery that drives inflammation, rather than broadly suppressing the immune system."

The most potent compound, ENDO12, reduced inflammation in animal models that were also given a TLR-activating molecule. Blood levels of inflammatory markers - including immune system activators IL-6 and IFN-γ, and the enzyme myeloperoxidase - dropped significantly in those that were treated. Crucially, ENDO12 did not impair the animal models' ability to fight a real viral infection: they showed a normal antiviral immune response when exposed to a virus. This selectivity addresses a major concern with immunosuppressive drugs: that dampening inflammation might leave patients vulnerable to infections.

Link: https://www.scripps.edu/news-and-events/press-room/2026/20260406-catz-endotollins.html

A sizable body of evidence indicates that transposons contribute to degenerative aging. Transposons of various categories are DNA sequences that code for molecular machinery capable of writing copies of the original DNA into other locations in the genome. They are largely the remnants of ancient retroviral infections, altered and degraded over evolutionary time, while likely remaining an important mechanism of mutational change for future evolution. Transposons are suppressed in youth, the nuclear DNA sequences spooled and hidden from transcriptional machinery, but one of the noteworthy aspects of aging is a loss of epigenetic control over nuclear DNA structure and thus over gene expression. Stretches of DNA containing transposons unspool and become accessible to transcriptional machinery. Transposon expression produces molecules that are sufficiently virus-like for evolved defenses to react with inflammatory signaling, while the haphazard insertion of transposon sequences is a form of DNA damage, breaking genes.

Just like retroviruses, retrotransposons require reverse transcription to function. That part of the research and development community focused on HIV, human immunodeficiency virus, has spent decades developing ever better means of sabotaging reverse transcription. In today's open access paper, researchers report on their investigation of the effects of such antiretroviral drugs on measures of biological age. The researchers made use of data and samples originating from pharmacokinetic clinical studies of combinations of antiretroviral drugs in healthy volunteers. One combination of drugs did reduce measures of biological age, while the other did not. This suggests that there is indeed something interesting here, but that the fine details matter when it comes to the implementation of transposon suppression.

An FDA-Approved Tenofovir Alafenamide-Based Antiretroviral Therapy Reduces Biological Age in Healthy Adults: First Human Proof-of-Concept for Retrotransposon-Targeted Gerotherapeutics

Nearly half of the human genome (∼45%) is composed of transposable elements (TEs). Aging is accompanied by a progressive erosion of epigenetic silencing that permits the transcriptional reactivation of these TEs, particularly retrotransposons such as LINE-1 and endogenous retroviruses. In young somatic cells, these elements are maintained in a transcriptionally inert state by DNA methylation, heterochromatin, and KRAB-ZFP/KAP1 surveillance. However, with age the fidelity of these mechanisms declines, and retrotransposon-derived transcripts and cytoplasmic DNA accumulate. This age-dependent retroelement reactivation is now recognized as a proximal driver of biological aging hallmarks including a senescence-associated secretory phenotype (SASP) and age-related tissue dysfunction.

The dependence of retroelements on reverse transcription has made nucleoside reverse transcriptase inhibitors (NRTIs), which were developed and licensed for HIV treatment and prevention, attractive candidate gerotherapeutics. For instance, a retrospective analysis of longitudinal aging intervention studies identified antiretroviral therapy as one of the most consistent interventions associated with reductions across 16 epigenetic clocks. Early mechanistic work showed that multiple NRTIs including 3TC (lamivudine), tenofovir disoproxil fumarate (TDF), stavudine, and zidovudine can directly suppress human LINE-1 retrotransposition in cell-based reporter systems. Consistent with this, 3TC (lamivudine) blunted LINE-1 cDNA-triggered type I interferon signaling and components of the SASP in senescent human cells and reduced age-associated inflammatory signatures across multiple tissues in aged mice.

Here we evaluated DNA methylation-based measures of biological aging in healthy people without HIV (aged 18-50) using samples from two separate randomized, directly observed dosing pharmacokinetic studies of FDA-approved NRTI regimens containing emtricitabine / tenofovir-alafenamide (FTC/TAF; 200 mg/25 mg) or FTC / tenofovir-disoproxil fumarate (FTC/TDF; 200 mg/300 mg) for 12 weeks.

In the FTC/TAF study (N=36), epigenetic aging measures based on DNA methylation (DNAm) profiling decreased over follow-up, including DunedinPACE (-0.061) and PhenoAge (-6.33), with concordant reductions across additional systems-specific epigenetic clocks including those estimating brain aging. DNAm-based proxies of inflammatory biomarkers also declined, with significant reductions in epigenetic IL-6 (-0.058) and a trend toward reduced C-reactive protein (-0.231). In contrast, the FTC/TDF study (N=43) showed no significant changes across epigenetic clocks and proxies. These findings are consistent with TAF's more favorable cellular pharmacology compared with TDF and support gerotherapeutic effects of FTC/TAF.

Prospective placebo-controlled studies are warranted that integrate clinical pharmacology, direct transposable element readouts, and prespecified geroscience and DNA methylation-based aging endpoints.

There are apparently a great many people who at least intermittently use psilocybin. Interestingly, regular dosing with psilocybin has been shown to modestly extend life in mice, but it is likely that only a subset of human users approach the frequency of dosing used in the mouse studies. Finding those humans is ever the challenge, particularly if one wants to study long-term effects on aging. Here, a researcher takes an initial stab at comparing the longevity of psilocybin users with non-users based on publicly available information, but the sample size is so small that it isn't surprising to see a lack of useful results. The study is more interesting as a way to provoke (a) awareness of the evidence for psilocybin to interact with mechanisms of aging, and (b) some thought on what sort of study design would be both practical and useful.

Researchers have reported that psilocybin promotes resilience and extends lifespan in aged mice. This work garnered considerable media attention, with claims that psychedelics might also extend human lifespan. Psychedelics influence longevity-related pathways in rodents such as glucocorticoid receptor signaling and mitochondrial stress tolerance. In light of these findings and in search of some evidence that psychedelics can indeed extend human lifespan, we examined historical mortality patterns of psychedelic personalities (researchers and advocates who had documented, mostly self-claimed, psychedelic use) and compared this group to biomedical researchers (cancer and aging).

Using publicly available records, we identified individuals who died between 2010 and 2025: (i) psychedelic personalities with documented personal use (n = 11), (ii) cancer researchers (n = 12), and (iii) aging researchers (n = 5). Deaths before age 60 were excluded. Conditional life expectancy at age 40 for their birth cohorts (≈73-76 years, US/UK data) was used as a baseline. All three groups lived well beyond population averages, consistent with the survival advantage of highly educated professionals. Crucially, the psychedelic personalities did not outlive their biomedical peers.

Thus, while researchers have provided compelling mechanistic data in mice, translation to humans requires dose-specific and longitudinal studies to identify whether psychedelics such as psilocybin do indeed have some role in extending lifespan.

Link: https://doi.org/10.1038/s41514-026-00380-y

It is well established that females and males in mammalian (and many other) species exhibit meaningfully different trajectories of health and mortality in later life. It is also well established, at least in mice, that many of the interventions demonstrated to modestly slow aging have meaningfully different outcomes in males versus females. The question of why these differences exist has no satisfactory answer at the present time, however. There are a great many theories and potential contributions, but no data that concretely establishes the important mechanisms and relative sizes of these contributions to the overall effect.

The burden of aging is not shared equally between the sexes, as lifespan and healthspan differ between males and females. Lifespan, the length of time in which an organism is alive, is related to but distinct from healthspan, which is the length of time an organism is free of disease and disability. Women live longer than men in most countries, but women also experience more disease and disability than men.

While scientists seek interventions to increase both healthspan and lifespan, considering sex as a biological variable is imperative to ensure treatments will work optimally in both men and women, or to develop sex-specific interventions. Here, we review dietary, genetic, environmental, behavioral, and pharmacological interventions that increase lifespan in a sexually dimorphic manner in laboratory rodents, including the mouse which is the is most widely used mammalian model system in the aging field.

While sex differences in life history traits have long been of interest to evolutionary biologists, a cellular and molecular understanding of how these traits influence lifespan remains understudied. Starting from fertilization, differences in chromosome complement and hormone levels drive further morphological and behavioral differences. Crucial aspects of female biology, including the role of X chromosome regulation, the role of gonadal hormones, and the role of ovarian health, remain understudied in the context of aging interventions. Whether differences in response to interventions is due sex-specific differences in baseline lifespan, or differences in sexually dimorphic characteristics such as body size, adiposity, metabolism, or even gonadal hormone or chromosome status remains unknown.

Link: https://doi.org/10.1016/j.arr.2026.103123

In the US alone, new strains of influenza reliably emerge to kill tens of thousands of older people every year, hundreds of thousands in a bad year. The research and development community has yet to fully develop and deploy any of the possible approaches that might effectively shut down viral infections, such as descendants of the DRACO technology, and the aged immune system becomes ever less able to resist and control infections of all sorts. In later life, the immune system also becomes more inflammatory, more vulnerable to runaway inflammation during infection that leads to sepsis. Further, other aspects of aging make organs and tissues less able to resist the stresses that result from severe infection and accompanying inflammation.

One of the ways in which influenza infection and accompanying inflammation kills older people is by provoking what is known as a major adverse cardiovascular event, meaning a heart attack or stroke, that would otherwise not have occurred. One of the ways that influenza vaccination can help to reduce mortality is by preventing evident infection and all of its consequences. Another, as shown in today's open access paper, is by reducing the severity of the infection, the stress placed upon organ systems, and thus the risk of fatal heart attack and stroke. There are many good reasons to maintain a vaccination schedule in late life, even given the reduced capacity of the aged immune system, and this is one of them.

Influenza vaccination attenuates acute myocardial infarction and stroke risk following influenza infection: a register-based, self-controlled case series study, Denmark, 2014 to 2025

Influenza infection can trigger acute cardiovascular events through short-lived systemic inflammation that favours a pro-thrombotic state and destabilises vulnerable atherosclerotic plaques. Self-controlled case series studies, which compare event rates within individuals during prespecified risk time windows against their own baseline time, have consistently shown transient increases in cardiovascular risk after laboratory-confirmed influenza. A Canadian study reported a sixfold increase in acute myocardial infarction risk during the first 7 days after positive test results (incidence rate ratio (IRR) = 6.05); estimates from Spain and the Netherlands are similar. Studies employing finer temporal resolution have further characterised the risk profile, indicating that peak incidence increases within 3 days, then tapers back within 2-4 weeks.

Among mounting evidence suggesting that influenza vaccination reduces cardiovascular risk, a recent meta-analysis of randomised controlled trials estimated 32% lower risk. Two successive self-controlled case-series studies in the United Kingdom demonstrated a 20-23% reduced incidence for both acute myocardial infarction and stroke. In particular, the second study reported no evidence of sex-specific differences, and effects were slightly stronger among people vaccinated early in the influenza season. A meta-analysis including these same two studies provided further evidence of the protective effect of vaccination (pooled IRR = 0.84 for acute myocardial infarction).

In this self-controlled case series study in Denmark spanning 2014 to 2025, PCR-confirmed influenza was followed by a sharp, transient rise in the first-ever hospitalisations for acute myocardial infarction and stroke. Risk concentrated in the first week, peaking within 3 days, and declined back to baseline by 2 weeks. Prior influenza vaccination was associated with a significantly lower excess risk. This temporal profile aligns with studied mechanisms. Influenza infection has been shown to precipitate atherogenesis and has been epidemiologically linked to acute myocardial infarction and stroke in adults 40 years and older.

Vaccination can plausibly mitigate these effects by priming adaptive immunity and reducing viral replication, thereby dampening systemic inflammatory peaks. By vaccination status, the adjusted IRRs for cardiovascular events in this study were 4.7 and 2.4 for unvaccinated and vaccinated episodes, respectively. To our knowledge, this is the first study to show statistically significant attenuation of post-influenza cardiovascular risk by vaccination. A Canadian study observed similar results but possibly lacked statistical power to confirm them.

Researchers here describe a novel approach to encourage greater regeneration in heart tissue following the injury and lost function incurred during a heart attack. Their work falls into the growing category of practical gene therapies in which a small amount of easily accessible tissue, such as fat or muscle, is transfected to form a factory that generates and releases a beneficial circulating protein. Only a low dose of gene therapy vector is needed, and all of the present challenges in broader delivery of gene therapy are bypassed. The scope of possible uses is restricted to situations in which benefits can be derived from increased amounts of a specific protein in circulation, but this is still a large enough set of possibilities to support a broad industry.

During the first days of life, many mammals have a short-lived ability to regenerate heart muscle cells. A hormone called atrial natriuretic peptide (ANP) plays a key role by encouraging the growth of new blood vessels, calming inflammation, and reducing the formation of scars. As an individual ages, the amount of ANP in their bodies decreases substantially, and the regenerative capacity observed in newborn hearts largely disappears by adulthood. Researchers have understood the potential of ANP for decades, but it's difficult to use as a conventional drug because it begins breaking down after just a few minutes in the body.

Delivering a drug to the heart in a sustained and minimally invasive way is a significant challenge. Drugs aimed at organs such as the liver, lungs, or spleen can often accumulate naturally because of the unique features of their vascular systems and cellular uptake mechanisms. By contrast, the heart lacks such natural accumulation mechanisms, making efficient cardiac drug delivery more difficult. For researchers the solution was to stop trying to deliver the drug to the heart at all. Instead, they developed a two-phase approach that starts by creating a "prodrug" in skeletal muscle before transforming it into ANP within the heart itself.

The researchers designed RNA-lipid nanoparticles that encode Nppa, causing muscle cells in the thigh or arm to produce a molecule called pro-ANP. This molecule, which is not reactive in the body, circulates through the entire bloodstream. A specific enzyme, called Corin, transforms it into ANP. Corin is roughly 60 times more common in the heart than in other organs. In other words, the drug circulates until it reaches the one organ equipped to activate it. In lab experiments, a single injection significantly reduced scarring and improved heart function in small and large animals.

Link: https://www.engineering.columbia.edu/about/news/new-rna-therapy-could-help-heart-repair-itself

Researchers here review the landscape of immune aging with a particular focus on vulnerability to respiratory infections, such as influenza. As we age the immune system becomes ever less capable, the outcome of impaired manufacture of new immune cells, as well as issues that affect the internal workings of cells throughout the body, such as mitochondrial dysfunction and cellular senescence. At the same time the immune system becomes ever more active and inflammatory, a maladaptive reaction to forms of damage in cells and tissues. This creates a landscape in which infectious pathogens find it easier to overwhelm immune defenses, and in which inflammatory reactions to infection can readily become life-threatening, amplified by a dysfunctional immune system.

Every country around the globe is facing continuous growth in both the size and the proportion of older people; by 2050, the global population aged 60 years and above is projected to double, reaching approximately 2.1 billion people. As the population shifts towards older ages, new challenges are emerging, including increased healthcare demands. Among these challenges is "the destruction and remodelling of immune organ structure as well as innate and adaptive immune dysfunction with ageing", so-called immunosenescence, alongside inflammageing, a characteristic inflammatory state in which high levels of pro-inflammatory molecules are expressed. Both states predispose older adults to dysregulated immune responses and, inadvertently, to increased proportions of adverse outcomes, especially in the context of infections such as respiratory viral infections.

In this review, we examine the molecular and cellular pathophysiological mechanisms of immunosenescence and inflammageing that predispose older adults to increased morbidity and mortality from respiratory viral infections. We also outline the clinical implications of the ageing immune system, along with the most up-to-date evidence on possible biomarkers, preventative measures and treatment options aimed at mitigating the effects of immunosenescence on the vulnerability of older adults in respiratory viral infections.

Link: https://doi.org/10.1183/16000617.0248-2025

Cartilage tissue exhibits a relatively poor capacity for regeneration even in youth, but this capacity for maintenance and repair diminishes with age. There are thus some gains to be made in understanding why this happens and developing means of rejuvenation, but ultimately some form of regenerative medicine above and beyond natural degrees of healing will be needed in order to completely address the very prevalent joint issues that occur in later life and culminate in disabling degrees of cartilage loss and osteoarthritis. While this is widely studied, cartilage has so far proven to be a difficult tissue for the tissue engineering community to reproduce and manipulate. The load-bearing capacity and resilience necessary for its function in the body requires an accurate recreation of the complex extracellular matrix structure and cell behavior; pseudo-tissues of the sort that work well in tissue engineering for many organs are not good enough for cartilage.

Returning to the question of why cartilage tissue becomes less regenerative with age, in today's open access paper the authors turn their attention to macrophages. Macrophages of the innate immune system are present in large numbers in tissues throughout the body, and are deeply involved in the intricate processes that accompany tissue regeneration and tissue maintenance. Researchers have discovered a regulatory gene for macrophage behavior in cartilage that biases these cells towards pro-regenerative, anti-inflammatory patterns of behavior. Expression declines with age, however, and thus macrophages become increasingly inflammatory, leading to a reduced capacity for cartilage tissue maintenance and regeneration. Given the expression of this gene as a target, therapies can now be designed and tested to improve cartilage maintenance in older individuals.

Single-cell omics reveals arg-1 as a key regulator of age-dependent macrophage-mediated cartilage repair

Aging is a significant factor influencing the recovery capacity following cartilage injury, with notable differences observed between older and younger animals. Studies indicate that younger animals exhibit enhanced regenerative potential, including better cartilage repair and reduced inflammatory responses, compared to their older counterparts. This disparity may be attributed to age-related declines in stem cell activity, extracellular matrix synthesis, and immune function.

Macrophages play a multifaceted and context-dependent role in the pathogenesis of cartilage injury, contributing to both inflammatory progression and tissue repair. In the synovial microenvironment, macrophages exhibit remarkable plasticity, dynamically shifting between pro-inflammatory (M1-like) and anti-inflammatory (M2-like) phenotypes in response to local signals. While M1-polarized macrophages drive joint inflammation through the production of cytokines such as tumor necrosis factor-α (TNF-α), Interleukin-1β (IL-1β), and Interleukin-6 (IL-6), M2-like macrophages promote resolution of inflammation and tissue remodeling. However, this dichotomy is oversimplified, as single-cell studies reveal a spectrum of macrophage activation states in cartilage injury, with distinct subsets associated with disease severity and treatment response. Furthermore, synovial macrophages interact with fibroblasts, T cells, and osteoclasts, forming a complex cellular network that perpetuates joint destruction.

Our study employed single-cell RNA sequencing (scRNA-seq) to investigate the differential recovery capacity between young and aged animals following cartilage injury, explicitly addressing the inherent heterogeneity of immune cells within the joint. Through comprehensive profiling of joint tissues before and after injury, we aimed to identify age-dependent molecular mechanisms that govern post-injury recovery. Our analysis revealed that young animals exhibit a significantly higher proportion of anti-inflammatory macrophage subsets compared to aged counterparts, suggesting a link between specific immune cell states and enhanced tissue repair potential.

Further network analysis pinpointed Arg-1 (Arginase-1) as a central regulator within anti-inflammatory macrophages. Functional validation through in vivo and in vitro experiments demonstrated that Arg-1 overexpression inhibited inflammation and reactive oxygen species release in aged animals, partially rescuing their impaired recovery phenotype. These results not only elucidate the mechanistic basis for age-related disparities in cartilage injury recovery but also highlight Arg-1 as a novel therapeutic target to improve joint repair in elderly individuals. By integrating single-cell omics with mechanistic validation, this study provides critical insights into anti-inflammation macrophage in cartilage injury and offers a potential strategy to mitigate age-associated decline in tissue regeneration.

As the understanding of more recently discovered modes of programmed cell death are fleshed out, they receive greater attention from various groups focused on specific aspects of aging. In this review the programmed cell death mechanism is PANoptosis and the area of focus is the aging of the heart. Some means of preventing overly aggressive, maladaptive programmed cell death in the context of aging have performed fairly well in animal studies, but the details matter and progress towards useful therapies is ever slow and uncertain.

As the vital power organ of the human body, the health of the heart directly determines an individual's quality of life and longevity. With the accelerating global aging population, cardiac aging-related diseases have become a major public health threat. Although existing interventions (e.g., senolytics) can delay cardiac aging to some extent, their efficacy remains limited, necessitating the exploration of novel mechanisms to develop more effective therapeutic strategies.

In recent years, PANoptosis - an integrated cell death pathway - has emerged as a new research focus in cardiac aging. PANoptosis, a recently defined lytic cell death modality, integrates core molecular mechanisms of pyroptosis, apoptosis, and necroptosis into a dynamically regulated "death signaling network". As a unique programmed cell death paradigm, it transcends classical boundaries of these pathways by forming the PANoptosome complex, which orchestrates caspase family members. It may contribute to cardiac functional decline by accelerating cardiomyocyte loss, fibrosis, and chronic inflammation.

Targeting PANoptosis-based intervention strategies (e.g., gene editing, RNAi, combination therapy, and novel delivery systems) has demonstrated significant therapeutic potential, offering new preclinical avenues to delay or alleviate cardiac aging. This review summarizes the molecular mechanisms and roles of PANoptosis in cardiac aging, including its regulatory networks, key evidence driving cardiac aging, and targeted intervention strategies, thereby providing a theoretical foundation for developing PANoptosis-targeted therapies against cardiac aging.

Link: https://doi.org/10.3389/fcvm.2026.1759908

Does the correlation between late life vaccination and reduced risk of neurodegenerative conditions such as Alzheimer's disease exist because vaccination produces benefits such as reduced chronic inflammation via trained immunity, or because people who undergo vaccination tend to be more diligence in all matters relating to health? Mechanistic or behavioral, or both? And if both, how much of the overall observed effect size arises from each side? Researchers here find a way to obtain more insight into this correlation, as they show that different vaccine doses correlate with different degrees of reduced dementia risk. We should not expect this to be the case unless the outcome is driven by biological mechanisms resulting from vaccination.

Previous studies, including large cohort analyses comparing vaccinated and unvaccinated adults, suggest that routine immunizations such as inactivated influenza vaccines (IIVs) may reduce Alzheimer dementia (AD) risk. Whether AD risk differs after high-dose IIV (H-IIV) vs standard-dose IIV (S-IIV) remains unexamined. We hypothesized that AD risk would be lower among adults ≥65 years after H-IIV compared with S-IIV.

This retrospective cohort study analyzed data spanning 2014-2019 from IQVIA PharMetrics Plus for Academics, a US health care claims database. Eligible participants were ≥65 years with ≥2 years of continuous medical and pharmaceutical coverage and no previous diagnostic or pharmacotherapeutic indicators of cognitive impairment. Vaccinations were identified by name and Current Procedural Terminology codes. Participants were followed for up to 3 years postvaccination. Incident AD was defined using International Classification of Diseases codes and AD medication dispenses (cholinesterase inhibitors, memantine).

The H-IIV group included 120,775 unique participants (185,183 person-trials; mean age 74.4 ± 5.5 years; 57.3% female), and the S-IIV group included 44,022 participants (53,918 person-trials; mean age 73.0 ± 6.1; 56.4% female). H-IIV was associated with significantly lower AD risk during months 1-25 postvaccination. Further research is needed to clarify whether the observed difference reflects protection against influenza infection or non-infection-related mechanisms.

Link: https://doi.org/10.1212/WNL.0000000000214782

Transthyretin is one of a small number of proteins that can misfold and aggregate to cause pathology in tissues, primarily the cardiovascular system, but other organs as well once aggregation becomes very severe. Despite being a universal mechanism that operates in all older individuals, transthyretin amyloidosis is presently treated as a rare condition by the medical, development, and regulatory communities, because only the most severe cases exhibit evident symptoms that are easily diagnosed. Of those patients diagnosed, some have mutations that drive misfolding and aggregation of transthyretin, while some are simply the most severe examples of what is actually a prevalent issue in later later. Evidence from studies involving post-mortem examinations of tissues suggest that many very old people exhibit a degree of transthyretin amyloidosis that is in principle life-threatening, capable of contributing to cardiovascular mortality.

In recent years a number of drugs have been developed that act to reduce transthyretin misfolding and aggregation to a large enough degree to allow natural clearance mechanisms to catch up. As drugs go, they are fairly effective at achieving this outcome and have reasonable safety profiles. They are only used in the most severe, readily diagnosed patients, and thus regulated and priced as though transthyretin amyloidosis is a rare disease, however. Treatment is enormously expensive, as is usual for rare diseases, and will likely remain so until patent protection runs out and the drugs become generic. Before that point arrives there is all too little incentive for the drug owners to branch out and offer greater availability at a lower price point, regardless of the accumulating evidence for transthyretin amyloidosis to be a prevalent late life issue with meaningful effects on cardiovascular disease and mortality.

Nonetheless, it is worth keeping an eye on this part of the field as data accumulates from the long-term use of these transthyretin amyloidosis drugs. It provides an assessment of their value for a future of broadened generic use in the older population, once the market catches up with the science regarding implementation of that broader use. Today's open access paper is of interest in this regard, providing data on long-term use of acoramidis. Transthyretin exists in a dynamic equilibrium between monomer and tetramer forms, and only the monomer form contributes to amyloidosis. The better of the existing drugs, like acoramidis, act by stabilizing the tetramer form and thereby greatly reducing the size of the monomer pool. Clearly this works to reduce both amyloid and pathology.

Long-Term Durability of Acoramidis Efficacy in Transthyretin Amyloid Cardiomyopathy

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive disorder caused by destabilization of serum transthyretin (sTTR). Acoramidis, an approved therapy that achieves near-complete (≥90%) sTTR stabilization, demonstrated clinical benefit through month 30 in ATTRibute-CM, which was incremental through month 42 in the open-label extension (OLE); however, the longer-term durability of outcomes has not been reported.

This OLE of the ATTRibute-CM randomized clinical trial is an international, multicenter, ongoing OLE study. Data accumulated between October 2021 and April 2025 through month 24 of the OLE (month 54) are reported. Participants (aged 18-90 years) who completed ATTRibute-CM and met the OLE eligibility criteria were invited to enroll in the OLE. Data were analyzed from May 2025 through November 2025. All OLE participants received open-label oral acoramidis, 800 mg, twice daily. Acoramidis recipients from ATTRibute-CM continued therapy (continuous acoramidis) and placebo recipients switched to acoramidis (placebo to acoramidis).

The primary outcome was time to event for all-cause mortality (ACM), cardiovascular-related mortality (CVM), and first cardiovascular hospitalization (CVH), which was assessed for both groups. Biomarkers of disease progression (N-terminal pro-B-type natriuretic peptide [NT-proBNP]), sTTR, functional capacity (6-minute walk distance [6MWD]), and heart failure-related health status (Kansas City Cardiomyopathy Questionnaire-Overall Summary [KCCQ-OS] score) were analyzed.

In ATTRibute-CM, 632 participants were randomized to receive acoramidis (n = 421) or placebo (n = 211); mean (SD) age was 77.3 (6.6) years, and 62 participants (9.8%) were female. Overall, 389 participants enrolled in the OLE (263 in the continuous acoramidis group; 126 in the placebo-to-acoramidis group). Continuous acoramidis treatment reduced risks of ACM (hazard ratio [HR] 0.55) and CVM (HR 0.51) through month 54, with consistent efficacy across all prespecified subgroups. Continuous acoramidis reduced time to first CVH (HR 0.53) through month 54. Through month 54, continuous acoramidis stabilized increases in NT-proBNP, sustained higher sTTR levels, and stabilized KCCQ-OS score and 6MWD. Switching from placebo to acoramidis at month 30 was associated with stabilization of NT-proBNP and KCCQ-OS score and improvements in sTTR and 6MWD through month 54. No new long-term safety concerns were identified.

The capacity for neurons to regrow the axons that connect them is relatively limited. The tissue of large nerves, largely made up of axons, does not readily regenerate; the closer to the central nervous system one comes, the less the capacity for regrowth following injury. This is not the case for all species, and thus - in principle at least - there must be regulatory controls in cellular biochemistry that can be adjusted to encourage lesser degrees of obstructive scarring and greater regrowth of axons. Here, researchers report on one recently discovered way to enhance axon regrowth that works in both peripheral nerves and the spinal cord.

Axon regeneration is limited in the mammalian central nervous system. Neurons must balance stress responses with regenerative demands after axonal injury, but the mechanisms remain unclear. Here we identify aryl hydrocarbon receptor (AhR), a ligand-activated basic helix-loop-helix/PER-ARNT-SIM transcription factor, as a key regulator of this stress-growth switch. We show that ligand-mediated AhR signalling restrains axon growth, whereas neuronal deletion or pharmacological inhibition of AhR promotes axonal regeneration and functional recovery in both peripheral nerve and spinal cord injury models.

Mechanistic studies reveal that nerve injury induced AhR activation in dorsal root ganglion neurons enforces proteostasis and stress-response programs to preserve tissue integrity. By contrast, AhR ablation redirects the neuronal response towards elevated de novo translation and pro-growth signalling, enabling axon regeneration. This growth-promoting effect requires HIF1α, with shared transcriptional targets enriched for metabolic and regenerative pathways. Single-cell and epigenomic analyses further revealed that the AhR regulon engages the integrated stress response and DNA hydroxymethylation to rewire neuronal injury-response programs.

Together, our findings establish AhR as a neuronal brake on axon regeneration, integrating environmental sensing, protein homeostasis, and metabolic signalling to control the balance between stress adaptation and axonal repair.

Link: https://doi.org/10.1038/s41586-026-10295-z

New senolytic drugs to clear the accumulation of senescent cells in aged tissues are working their way into clinical trials at the usual slow pace for medical development, slowed even further by the poor biotech investment market of the past three years. Rubedo Life Science's first drug to target GPX4 mechanisms has now made it through a phase 1 trial; the company took the safer path of a topical application in skin conditions where cellular senescence is thought to be an important driver of pathology. That strategy looks promising based on the initial data. The largest challenge for biotech and pharmaceutical companies lies in convincing people to fund the first clinical trials in the first indication for their approach to drug development; given success, matters become easier after that point. So companies tend to initially pursue safer, more certain paths rather than those that may offer greater rewards in terms of addressing the burden of disease in the population.

Rubedo Life Sciences, focused on discovering and rapidly developing selective cellular rejuvenation medicines targeting aging cells, today announced preliminary results from a single-center, ascending-dose, randomized, double-blind, vehicle-controlled trial in patients with plaque psoriasis, atopic dermatitis, and skin aging (photo-aged skin). The recently completed Phase 1 clinical trial, conducted in the European Union, was designed to assess the safety, tolerability, clinical effects, plasma bioavailability, and pharmacodynamics of topical RLS-1496 - the first-ever GPX4 (selective glutathione peroxidase 4) modulator to be studied in human trials, and the first specifically targeting cellular rejuvenation, an area of great interest to the scientific community as a new therapeutic pathway. The study met its primary endpoint, with RLS-1496 also demonstrating early signs of efficacy.

In psoriasis patients an overall reduction in senescent cells seen with RLS-1496 in the mid- and high-dose cohorts. Some subjects treated with RLS-1496 had a reduction of senescent cells, which was associated with a reduction of inflammatory cytokines such as IL-19 and S100A7; this reduction was not seen in the vehicle cohort. An average 20% reduction in epidermal thickness was observed on histology in subjects treated with RLS-1496 for one month. A statistically significant relationship was seen between target engagement and improvement in clinical psoriasis severity.

In atopic dermatitis patients, even higher levels of target engagement and substantial clinical improvement were seen in atopic dermatitis subjects on RLS-1496. After one month of treatment, 25% of subjects on RLS-1496 had a ≥4-point change in pruritus (or itching) on the numeric rating scale (NRS); no vehicle subjects had a 4-point or more change on the NRS.

Early photo-aging data show a dose-dependent target engagement in non-lesional photo-aged skin. Histology, proteomics, and spatial transcriptomics indicate that collagen gene and protein expression increase with treatments over time, in particular, spatial transcriptomics shows an effect in dermal fibroblasts. Spatial transcriptomics show indication that senescence-associated secretory phenotype and inflammatory biomarkers decrease with treatments over time in keratinocytes.

Link: https://www.businesswire.com/news/home/20260326810310/en/Rubedo-Life-Sciences-Announces-Positive-Preliminary-Phase-1-Clinical-Trial-Results-for-Lead-Drug-Candidate-RLS-1496-in-Patients-with-Plaque-Psoriasis-Atopic-Dermatitis-and-Skin-Aging

Many capabilities in biotechnology are assuredly possible, just not possible today. The tools are too crude, the knowledge of cellular biochemistry still incomplete. The goal at the end of the day is as complete a control as possible over cell and tissue behavior. This naturally implies the ability to grow new organs, even new bodies, for use in medicine to support the aged and the diseased. There is no reason to think it is actually impossible just because it is presently impossible.

Research proceeds incrementally. We can look at the well-funded, very mainstream efforts to produce new organs for transplantation, a goal that remains impossible as a practical concern at the present time, and see the various stages of evolution of the process. At each stage, there must be some product that can sustain commercial efforts and attract further funding for research and development. So on the road to tissue engineering of new organs, we can see the first steps as the production of organoids: finding recipes that allow the self-assembly of pseudo-tissues that recapture some of the features of the real thing. Organoids exist for many tissue types, across a spectrum spanning cells in a dish to actual tissue with a fully developed extracellular matrix, are the basis for potential regenerative therapies via transplantation to support a failing organ, and are widely used in research.

We can look at the far less advanced efforts that could ultimately lead to the generation of new bodies, such as the work of R3 Bio and Kind Biotechnology, and see that this part of the field has similar early stage goals. In this case, it is the production of pseudo-embryos lacking brains and other features, collections of organs working together much as they do in a real embryo, and which can be used in research and development, or to grow small amounts of tissues for transplantation. They represent a step beyond organoids in terms of recreating something more relevant to a real tissue, can potentially replace some animal studies, and presumably will find a market that can support further evolution of the technology. As is the case for organoids, this first step isn't a simple matter; a great deal of work and discovery is required to obtain a useful result.

The production of pseudo-embryos lacking brains and other features is unlike other human organoid work in that it will likely rouse some degree of reflexive opposition. Thus working with human materials will probably remain off the table until the world at large has had a chance to digest the existence and use of mouse and non-human primate pseudo-embryos. A sizable reduction in the number and scope of animal studies is a noble goal, but the collective laity is not rational about the progression of medicine and biotechnology. The spirit that drove historical popular opposition to autopsies remains alive and well, as demonstrated by the relatively recent opposition to embryonic stem cell research; it will no doubt rouse itself again for the use of human pseudo-embryos in research, once awareness spreads, spurred on by a journalistic profession that has become a cog in an outrage machine, no matter how many animals are spared.

Cellular senescence has been increasingly implicated in the development of pulmonary fibrosis, a largely irreversible condition with a poor prognosis under the current standard of care. An early clinical trial of first generation senolytic drugs to clear senescent cells showed promising results, but the condition remains a low priority among companies developing various forms of novel senolytics. Here, researchers discuss one of the primary mechanisms targeted by early senolytics, the BCL-2 protein known to be involved in preventing apoptosis in senescent cells, in the context of pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease that develops in response to chronic epithelial injury. Unlike injury-induced homeostatic lung repair during which fibroblasts undergo apoptosis and clearance, the lungs of IPF patients continue to accumulate apoptosis-resistant, pro-fibrotic, extracellular matrix-producing fibroblasts.

Here, we show that prevention of PDGFRα+ fibroblast apoptosis by conditional BCL-2 expression leads to the emergence and persistence of senescent, pro-fibrotic fibroblasts along with enduring, pathologic fibrotic lung remodeling. Additionally, spatial transcriptomic studies of human IPF lungs confirmed the presence of senescent, BCL-2 expressing α-smooth muscle actin+ myofibroblasts in fibrotic regions.

Of translational significance, selective BCL-2 inhibition with ABT-199 in fibrotic mice re-engaged the apoptotic pathway in fibroblasts, reduced senescence, and promoted fibrosis resolution and lung regeneration. Our findings suggest that sustained BCL-2 expression in fibroblasts prevents homeostatic lung repair, drives persistent fibrosis and is a therapeutically relevant target to reverse persistent pulmonary fibrosis.

Link: https://doi.org/10.1038/s41467-026-69865-4

uPAR is expressed as a surface marker on senescent cells, and researchers have published the results of targeting chimeric antigen receptor (CAR) T cell therapies to uPAR in the context of clearing senescent cells from aged tissues. Absent an enormous reduction in cost, it is unlikely that CAR T therapies will see much use in this context, but they continue to be used in cancer therapy. Here, researchers show that targeting uPAR-expressing cells in and around solid tumors enables CAR T therapy to work in this context. CAR T therapy was developed for leukemia and has so far struggled to make the jump to the more complex environment of solid tumors; different approaches are needed, and this one seems to be producing positive results so far.

The urokinase plasminogen activator receptor - or uPAR - is a protein found on the outside of cells. In healthy tissue, very few cells have uPAR on their surface; it's primarily found on myeloid immune cells, and helps with processes associated with wound healing. But in cancer, which co-opts the body's normal wound healing programs, both tumor cells and cells in the fibrous "niche" that support the tumor produce a lot more uPAR. By focusing on uPAR, the new approach allows researchers to target cells in a particular state rather than a specific type of cell.

The CAR T cells that target CD19 in leukemia and lymphoma, for example, primarily target B cells - including cancer cells that develop from B cells. uPAR, on the other hand, tends to show up on the most dangerous, identity-shifting cancer cells - as well as on nearby support cells that are stuck in a constant wound-healing mode, building scar tissue and suppressing the immune response. In the study, researchers found uPAR was elevated in 12 of the 14 human cancer types they analyzed, with especially high levels in some types of ovarian, pancreatic, colon, lung, and brain cancers.

In preclinical experiments, uPAR-targeted CAR T cells were effective at killing cancer cells across multiple cancer models. And their effect could be further enhanced by combining them with senescence-inducing treatments such as the chemotherapy agent cisplatin, which raised uPAR levels and made tumor cells easier for the engineered T cells to attack. In a mouse model of ovarian cancer, for example, uPAR-targeting CAR T cells were able to wipe out metastases, leading to durable remissions. And mice whose tumors had been eliminated also resisted developing new tumors when researchers tried to introduce cancer again later, indicating the CAR T cells remained active.

Link: https://www.mskcc.org/news/cell-surface-protein-upar-may-hold-key-to-targeting-solid-tumors-with-car-cell-therapy

Rapamycin is increasingly prescribed off-label by anti-aging physicians based on animal studies and very limited human data (even including the relatively recent crowdfunded PEARL trial) for it to improve late-life metabolism. Rapamycin and other mTOR inhibitors are calorie restriction mimetics, provoking a greater level of autophagy to improve cell maintenance. In mice, rapamycin results in a ~20-25% increase in life span, a sizable fraction of the ~40% that is possible via calorie restriction. We know that human calorie restriction is beneficial to health in many ways, but doesn't add more than a few years to life span - while no actual assessment has been carried out, it would be hard for an effect of more than five years or so to remain hidden from interested epidemiologists and scientists across the course of history.

Rapamcyin can be prescribed off-label because it has long been used as an immunosuppressant drug at much higher doses than the anti-aging use, and the safety profile for that use is well mapped. The drug has existed for long enough that it is now generic, outlasted its patent protection. Generic drugs tend to see little further formal clinical trial activity because they cannot produce enough income to sustain the high costs imposed by regulatory authorities. That doesn't stop academics from sometimes managing to obtain enough funding to explore unanswered questions, however.

While enough people are presently using rapamycin off-label at anti-aging doses for a recent study to find more than 300 individuals who were willing to provide information on their rapamycin use, in general this sort of use generates next to no actually useful, robust data. To obtain that data clinical trials of some sort, at the very least run by a reputable organization, remain needed. At present, there is no great consensus that any of the present range of anti-aging doses used in the community are in fact the optimal dose for humans. There are also remaining questions as to the dose at which undesirable immunosuppressive or hyperglycemic effects begin to emerge, and how prevalent they are. So it is good to see that an academic group has found the funds needed to run an initial set of trials aimed at answering these questions.

Large rapamycin clinical trial launches

Researchers are launching a multi-phase clinical study to better understand the biological effects of rapamycin in older adults. The study reflects a shift toward evidence-based dosing, safety, and long-term outcomes rather than off-label and speculative use of rapamycin. "Rapamycin is widely discussed in popular culture as a longevity drug. But there's a difference between something that is biologically plausible and something that has been rigorously tested in people."

The current study is structured as a series of interconnected sub-studies, each designed to answer a specific question. The translational pipeline will move from biological benchmarks to long-term clinical observation. The first sub-study establishes a reference point by examining immune and metabolic markers in younger adults. These measurements help define what "optimal" function looks like before aging-related changes begin.

The second sub-study will determine the optimal rapamycin dosage for older adults that will safely bring them back to the optimal functioning seen in the younger population. The dosage used for transplant patients may be too high for safe use in generally healthy older adults, so the scientists are testing different dosing schedules to determine how much rapamycin is needed to reach biological targets without negative side effects. "This phase is about precision. We're asking how much drug it actually takes to achieve a desired biological effect, not more than that."

The third sub-study is the largest cohort and will run the longest. It is a randomized, placebo-controlled clinical trial involving approximately 84 older adults who will receive either daily rapamycin, intermittent dosing, or a placebo. Participants will be treated for six months and followed for an additional six months to assess both short-term effects and sustained effects after treatment ends.

Muscle tissue is metabolically active to a degree perhaps not fully appreciated in past years. An only partially explored class of signals known as exerkines are generated by muscle tissue in response to physical activity and produce beneficial outcomes to cell behavior and tissue function throughout the body. Much of the signaling that passes between cells is carried by extracellular vesicles, membrane-wrapped packages of molecules of various sorts. As we enter an era in which extracellular vesicles are harvested from donors and cell cultures to be used as a basis for therapies, in much the same way as stem cells have been used, there is an increasing interest in muscle cells as a source of potentially therapeutic extracellular vesicles.

In recent years, a paradigm shift has occurred in the understanding of intercellular communication, moving beyond soluble factors (e.g., myokines) to embrace the critical role of extracellular vesicles (EVs). Among these, exosomes, small lipid-bilayer vesicles (30-150 nm) derived from the endosomal pathway, have emerged as powerful mediators of both localized and long-distance cellular crosstalk. These nanovesicles, which contain a diverse and specific cargo of proteins, lipids, and nucleic acids, are increasingly recognized as "fingerprints" of their originating cells, reflecting their metabolic and physiological state. The confluence of these fields - exercise physiology, exosome biology, and muscle pathology - has given rise to the "exerkine" hypothesis, which posits that the systemic benefits of exercise are, in part, mediated by the modulation of exosomal cargo.

This review will integrates the current evidence supporting this hypothesis, exploring the mechanisms by which exercise-induced exosomes influence muscle health, detailing their role in inter-tissue communication, and critically evaluating their potential as therapeutic tools and biomarkers. Importantly, the circulating EV pool induced by exercise is heterogeneous and originates from multiple tissues and cell types (e.g., skeletal muscle, adipose tissue, endothelium, immune cells, platelets), each contributing distinct cargo signatures and biological effects. Moreover, the physiological impact of a given exosome is not determined solely by its source cargo, but also by the recipient tissue's state (e.g., aging, inflammation, insulin resistance), which shapes uptake, signaling competence, and downstream transcriptional responses.

In this review we detail how exosomal cargo, including non-coding RNAs and proteins, regulates muscle stem cell activation and differentiation, counteracts age-related decline (sarcopenia) by modulating protein homeostasis and inflammation, and facilitates systemic metabolic crosstalk with distant tissues such as adipose tissue. We also critically discuss the burgeoning therapeutic potential of engineered exosomes for musculoskeletal health, while highlighting significant and interconnected challenges in the field, including the lack of standardized methodologies and regulatory frameworks.

Link: https://doi.org/10.3389/fcell.2026.1706977

Epidemiological studies consistently show a sizable difference in mortality rates between those who exercise regularly and those who do not. Clearly at some point aging forces a reduction in activity, and those more impacted by aging will tend to have a greater mortality risk. But animal studies show that exercise does in fact slow aging; it doesn't have much of an effect on maximum life span in mice, but it does reduce mortality and postpone frailty and mortality to lengthen median life span. How much of the observed correlation in humans is due to causation in one direction versus the other is up for debate, but the consensus is that physical activity is beneficial.

Long-term causal evidence comparing different physical activity patterns and mortality outcomes is needed. Using observational data to emulate a randomized controlled trial, this study compared different physical activity patterns over 15 years in relation to mortality from all causes, cardiovascular disease (CVD) and cancer in 11,169 mid-aged women in the Australian Longitudinal Study on Women's Health.

Two emulated interventions were compared against consistent non-adherence (control) to World Health Organization moderate-to-vigorous physical activity (MVPA) recommendations during the 15-year 'exposure period': (1) consistent adherence to recommendations (at least 150 min/week) over 15 years (2001-2016; women were 50-55-65-70 years); and (2) starting to meet the recommendations at age 55, 60, or 65 years.

Mortality outcomes that occurred between surveys (women were 53-58 at the first survey and 68-73 years at the last survey), were ascertained from Australian death registries. Comparing consistent adherence to MVPA recommendations with consistent non-adherence, there was evidence (Bayes factor [BF] = 5.71) for a protective effect for all-cause mortality (risk ratio [RR]: 0.50; risk difference [RD]: -5.2%). Findings for cardiovascular disease (BF = 2.05; RR: 0.50; RD: -2.1%) and cancer mortality (BF = 2.26; RR: 0.35; RD: -3.3%) were more uncertain and less conclusive, as were those for an effect of starting to meet MVPA recommendations in the mid-fifties on mortality outcomes.

Link: https://doi.org/10.1371/journal.pmed.1004976

Cells in aged tissues suffer a range of biochemical dysfunctions; broken proteins, altered structures, leakage of materials from one compartment to another. Many of these issues provoke the cell into inflammatory reactions. A range of sensors operate in every cell, triggered by different forms of damage and stress characteristic of aging, and converging on the activation of regulators of inflammatory signaling. One example is the interaction between cGAS and STING. cGAS acts to detect the presence of DNA in the cell cytosol, an evolved defense against infectious pathogens. Unfortunately it is maladaptively triggered by leakage of fragments of DNA from the cell nucleus or mitochondria, a feature of cells in aged tissues. cGAS then interacts with STING to produce inflammatory signaling.

Today's open access paper is interesting for the discussion of what exactly might be done about unwanted cGAS-STING interactions in aging tissues. The focus is the aging of the ovary, but this is a problem that occurs throughout the body. The primary challenge in attempting to suppress unwanted inflammation is that control of unwanted inflammation runs through the same pathways as control over desirable inflammation. Known approaches to interfere in the regulation of inflammation and inflammatory signaling shut down both excessive and necessary inflammation, resulting in undesirable side effects. But perhaps there can be better ways forward, the ability to better distinguish between these modes of activation. As yet there are only hints in early stage research that this can be possible, however.

The inflammatory clock: how cGAS-STING ticks in the aging ovary

Premature ovarian insufficiency (POI) is more than a fertility issue; it's a silent epidemic of accelerated systemic aging in young women, with current treatments failing to address its root cause. For too long, the relentless decline of ovarian function has been viewed as an inevitable mystery. But what if the ovary holds an internal "inflammatory clock," ticking away with each cellular insult and dictating the pace of its own decline? Here, we spotlight a surprising culprit: the cGAS-STING signaling pathway. Far beyond its day job in antiviral defense, this pathway emerges as a master integrator of ovarian aging.

We reveal how stresses like DNA damage and mitochondrial dysfunction leak genetic material into the cell's interior, where cGAS-STING sounds a relentless alarm. This alarm does not just trigger inflammation; it initiates a vicious, self-amplifying cycle of cellular senescence, tissue fibrosis, and follicle destruction - a cycle that may explain why ovarian aging often feels like a one-way street.

Therapeutically, we move beyond mere symptom management to explore strategies for resetting this inflammatory clock. We dissect both direct "brakes" - novel small molecules that silence cGAS or STING - and upstream "shields" that protect mitochondria and genome integrity. Most provocatively, we introduce the concept of "signal reprogramming": not just shutting down the pathway, but cleverly rewiring its output to favor repair over destruction. By repositioning cGAS-STING from a simple sensor to the central processor of ovarian aging, this review charts a course for a new class of therapeutics aimed at preserving ovarian function, not just managing its loss.

In oncology models, persistent STING activation has been shown in certain settings to promote an immunosuppressive microenvironment; notably, co-administration of a TLR2 agonist was reported to "reprogram" STING downstream signaling by enhancing NF-κB activity while attenuating IRF3-dependent interferon responses, thereby overcoming therapeutic resistance. This oncology-informed framework provides a conceptual basis for cautiously exploring whether selective downstream signaling modulation, rather than global pathway inhibition, could theoretically attenuate chronic inflammation while permitting adaptive tissue responses in ovarian aging models.

Researchers here present an interesting view of heart failure and atrial fibrillation, providing evidence for both to be manifestations of reduced TBX5 expression. TBX5 is a transcription factor, and thus influences expression of a very large number of genes; transcription factors are thus often central points of regulation for cell and tissue behavior. The evidence suggests that the present quite distinct treatments for atrial fibrillation and heart failure could potentially be replaced in the future by forms of therapy that increase TBX5 expression, a point of intervention that is upstream of present targets.

Heart failure occurs when the heart muscle is damaged and unable to pump enough nutrient-rich blood to meet the body's needs for oxygen. Heart failure is usually evaluated in the heart's lower chambers, called ventricles, which provide most of the pumping power. Atrial fibrillation is an arrhythmia - an irregular heart rhythm - that originates in the heart's upper chambers, known as the atria. During atrial fibrillation, the heart beats too fast, resulting in a lower blood flow to the body and a higher risk for clots or stroke. Epidemiologists have observed that these two conditions aren't independent of one another: People with heart failure are much more likely to have atrial fibrillation, and vice versa. Patients' outcomes also tend to be worse when they have both conditions.

New research was guided by a past study in which scientists created a mouse model by "turning up" a gene linked to human heart failure in the mouse heart. "We expected to get a heart failure mouse model, but instead we got an atrial fibrillation model. That observation put us on the right path." This focused attention on a gene called TBX5. TBX5 is a transcriptional regulator - a protein in the cell nucleus that controls which genes are turned on or off at a given time. When TBX5 levels are decreased in the atrium, it disrupts the normal gene expression needed to maintain a stable heart rhythm.

Zeroing in on transcriptional responses, the researchers compared different mouse models of heart failure and atrial fibrillation, finding that an atrial fibrillation model created by removing TBX5 from the atria actually creates gene expression changes almost identical to those seen in heart failure. "That made us think that diminished TBX5 may be important in heart failure. So, we looked at human gene expression data, and lo and behold, TBX5 was very downregulated in the atria of patients with heart failure, but not the ventricles."

Further analysis revealed that over 100 other transcription factors - proteins that regulate gene expression - were altered in both the heart failure and TBX5-deficient atrial fibrillation models. Almost all the key transcription factors changed in the same direction in both conditions. Researchers argue that the results should prompt a fundamental shift in how atrial fibrillation is understood. The rhythm disorder seen in atrial fibrillation may be a symptom of underlying atrial muscle dysfunction similar to the ventricular dysfunction in heart failure.

Link: https://www.uchicagomedicine.org/forefront/heart-and-vascular-articles/heart-failure-atrial-fibrillation-same-disease

As for the gut microbiome, the composition of the oral microbiome appears to change with age. The oral microbiome receives less attention than the gut microbiome, but the same scientific tools can be used to correlate specific changes with specific age-related conditions. Here, researchers correlate abundance of specific microbial species with the existing known relationship between periodontal disease and manifestations of neurodegeneration, such as loss of cognitive function. One mechanism that likely contributes to these associations is the contribution of the oral microbiome to chronic inflammation, when microbes and microbial metabolites leak into circulation via damaged gums, but the size of the effect remains debated, and there are other possible mechanisms to consider as well.

Emerging evidence implicates the oral-brain axis in neurodegeneration, yet large community-based studies remain limited. This study aimed to examine associations between periodontal health, oral microbiome, and cognitive performance, and to explore potential biological pathways underlying these relationships. We conducted a cross-sectional analysis of 1,157 participants from the community-based Taizhou Imaging Study, all of whom underwent comprehensive periodontal examinations, salivary microbiome profiling, and cognitive assessments. Periodontal health and microbiome features were treated as exposures, and cognitive performance as the outcome.

Five clinical periodontal indices were found to be inversely associated with cognitive performance. Ten microbial genera (e.g., Haemophilus), 21 functional pathways (e.g., FoxO signalling), and two co-abundance modules, including a Treponema module, were significantly related to cognitive function. Mediation analysis suggested that 11 features, including nitrate-reducing taxa and a Treponema-driven inflammatory module, may partially mediate the relationship between periodontal health and cognition. These community-based findings reveal microbiome-mediated links along the oral-brain axis and highlight periodontal health and oral microbial homoeostasis as potential targets for early prevention of cognitive decline.

Link: https://doi.org/10.1016/j.ebiom.2026.106231

Low density lipoprotein (LDL) particles are a class of cholesterol transporter, carrying cholesterol out from the liver where it is manufactured to the rest of the body via the bloodstream. LDL and its cargo can become oxidized as a result of interactions with the variety of oxidizing molecules produced in the normal operation of metabolism. This oxidized LDL is toxic and places stress upon cells in the blood vessel walls that encounter it. The level of oxidation increases globally with age, one of the known issues in an aged metabolism, and as a consequence there are more oxidized LDL particles and oxidized cholesterol molecules to cause problems in the vasculature. The research community is largely focused the role of oxidized LDL and oxidized cholesterol in the onset and progression of atherosclerosis, meaning the damage done to vascular endothelium that leads to excess accumulations of cholesterol, dysfunction in the macrophage cells drawn to attempt a repair, and the growth of an atherosclerotic plaque. There are other downstream consequences, however.

In today's open access review, researchers largely skate over the topic of atherosclerosis to discuss how oxidized LDL particles can contribute to vascular dementia. This is a matter of inflammation, endothelial dysfunction, and blood-brain barrier compromise in the microvasculature of the brain, issues distinct from the atherosclerotic plaque that forms in large arteries. At the high level, we might envisage the vasculature in the brain as a transformer that converts the biochemical issue of too many oxidizing molecules into chronic inflammation and related dysfunctions in brain tissues. Oxidative stress, mitochondrial dysfunction, and unresolved inflammatory signaling all circle round one another in aging, feeding into one another and downstream issues. It remains to be seen as to what the best points of intervention are, but clearing senescent cells and fixing mitochondrial dysfunction seem the best starting points at the present time.

LDL oxidation and cerebrovascular aging: mechanisms of endothelial dysfunction, inflammation, and vascular cognitive impairment and dementia

Converging evidence indicates that the interplay of aging, LDL, and especially oxidized LDL (oxLDL) is a critical driver of cerebrovascular injury underlying vascular cognitive impairment and dementia (VCID). Epidemiological studies have demonstrated that midlife hypercholesterolemia is associated with an increased risk of dementia, with each ∼1 mmol/L rise in LDL levels linked to an estimated 8% higher incidence of all-cause dementia. Mechanistically, atherosclerosis-prone conditions like high LDL promote intracranial arterial disease that compromises cerebral perfusion and precipitates ischemic injury. Beyond large vessels, cholesterol and its oxidized derivatives can accumulate in the cerebral microvasculature, inciting local inflammation and neurodegeneration.

In the aging brain, these processes are compounded by an intrinsically fragile vasculature, establishing a strong case that aging, LDL, and oxLDL must be studied synergistically in the context of brain microvascular health and VCID pathogenesis. OxLDL emerges as a particularly deleterious player within the neurovascular unit (NVU). Once native LDL particles undergo oxidation, they trigger endothelial dysfunction more potently than native LDL. OxLDL engages endothelial cells to upregulate adhesion molecules and pro-inflammatory pathways, while directly degrading the integrity of the endothelial barrier. This damage to the blood-brain barrier (BBB) permits leakage of neurotoxic blood-derived factors into the brain parenchyma, exacerbating oxidative stress and inflammation within brain tissue.

Indeed, oxLDL creates a vicious cycle: it is readily taken up by macrophages and brain glia, generating foam cells and further reactive oxygen species (ROS) and cytokine release. The result is chronic neurovascular inflammation, reduced nitric oxide bioavailability (impairing vasodilation), and breakdown of microvascular structure, changes that manifest as small vessel disease, microhemorrhages, and ultimately cognitive impairment. Thus, aging-related oxidative stress and oxLDL together destabilize the BBB and cerebral perfusion, linking peripheral dyslipidemia to the hallmark microvascular lesions of VCID.

Cartilage is one of the least regenerative tissues in the body, and thus damage and aging leads to osteoarthritis, disability, and joint pain. There is considerable interest in finding ways to effectively repair or replace cartilage, provoke existing tissue into greater regenerative capacity, or adjust cellular biochemistry to make cartilage more resilient to damage and cell death. Here, researchers report on the manipulation of a regulatory protein in cartilage cells, NR0B2, also known as SHP, that is reduced in expression as osteoarthritis progresses, and appears to be protective. It might prove to be a useful target to slow the progression of cartilage loss and osteoarthritis.

Osteoarthritis (OA), characterised by cartilage destruction, is the most common degenerative joint disease. However, no effective disease-modifying OA therapy is currently available. Herein, we report orphan nuclear receptor small heterodimer partner (SHP, NR0B2) as a novel catabolic regulator of OA pathogenesis. NR0B2 expression was markedly downregulated in cartilage from patients with OA.

Global or chondrocyte-specific Nr0b2 deletion in male mice exacerbated OA-related pain and structural changes following surgical destabilization of the medial meniscus, accompanied by increased matrix metalloproteinase (MMP)-3 and MMP-13 expression in chondrocytes. Conversely, adeno-associated virus-mediated Nr0b2 overexpression in knee joints of male mice protected against accelerated knee OA caused by Nr0b2 deficiency. Mechanistically, NR0B2 inhibited IKKβ kinase activity via IKK complex interaction, downregulating NF-κB signalling.

Our results demonstrate that NR0B2 has a chondroprotective role in OA progression by regulating matrix-degrading enzymes in an IKKβ/NF-κB-dependent manner, and gene therapy targeting Nr0b2 may be a promising therapeutic strategy for OA.

Link: https://doi.org/10.1038/s41467-026-69864-5

A range of evidence suggests that severe infection causes lasting damage that accelerates degenerative aging. That damage includes an increased burden of senescent cells and their inflammatory signaling, and changes to the immune system that reduce capacity and increase chronic inflammation. Here, researchers process epidemiological data to show that weathering a severe infection is associated with an increased risk of later dementia. Neurodegeneration is accelerated by the chronic inflammation of aging, as are most of the common, ultimately fatal age-related diseases. Unresolved, constant inflammatory signaling is disruptive to tissue structure and function.

Severe infections have been linked to an increased risk of dementia, but both conditions often coexist with other illnesses that may confound this association. Using nationwide Finnish health registry data, we examined the role of noninfectious mental and physical illnesses in the association between severe infections and dementia. This register-based study included 62,555 individuals aged 65 or older in Finland in 2016 who were diagnosed with late-onset dementia between 2017 and 2020 and 312,772 dementia-free controls matched for year of birth, sex, and the follow-up period. Analyses were adjusted for education, marital status, employment, and area of residence, with age and sex accounted for through the matched conditional design and analysis.

Applying a 1-year lag period, we identified 29 hospital-treated diseases that occurred 1-21 years before dementia diagnosis in cases (or index date in controls), had a prevalence of ≥ 1% prior to dementia, and were robustly associated with increased dementia risk (confounder-adjusted rate ratio ≥ 1.20). In addition to 2 infectious diseases (cystitis and bacterial infection of an unspecified site), these included 27 mental, behavioural, digestive, endocrine, cardiometabolic, neurological, and eye diseases, as well as injuries. 29,376 (47%) of the dementia cases had at least one of these diseases diagnosed before dementia.

The associations between the two infectious diseases and dementia risk were not attributable to the 27 comorbid dementia-related diseases diagnosed before infections. The adjusted rate ratio for cystitis was 1.22 before and 1.19 after adjustment for comorbidities, while for bacterial infections of an unspecified site, the rate ratios were 1.21 and 1.19, respectively. The findings were comparable across subgroups defined by sex and education, and stronger for cases of early onset dementia.

Link: https://doi.org/10.1371/journal.pmed.1004688

Animal studies show that ascending doses of nanoplastic particle infiltration into tissues eventually rise to the level of inducing dysfunction. Evidently harmful nanoplastic exposure doses are considerably higher than what are thought to be environmental exposure doses in the wild at the present time, but equally it is challenging, costly, and takes a long time to build a body of literature focused on subtle effects that may only emerge over the long term to affect the pace of aging. This is a work in progress.

The difference between nanoplastics and particulate air pollution is that there is a very large body of evidence to quantify the harms done by exposure to air pollution in human populations, alongside convincing mechanistic studies to show how long-term health and pace of aging can be negatively impacted. That body of evidence has yet to be constructed for nanoplastic exposure in human populations, so while there is a great deal of concern around this topic, it is unclear as to how much of that concern is justified. The level of interest in the topic means that the necessary epidemiological and supporting mechanistic data, analogous to the existing body of work covering air pollution, will almost certainly be produced in the years ahead, however.

Micro- and Nanoplastics Exposure Across the Lifespan: One Health Implications for Aging and Longevity

Microplastics and nanoplastics (MNPs) are pervasive environmental contaminants with growing relevance for human health across the lifespan. Older adults may be especially vulnerable to their effects due to cumulative lifetime exposure, age-related physiological changes, and a higher burden of chronic disease. Adopting a One Health perspective, this review synthesizes current evidence on the sources, exposure pathways, and biological effects of MNPs, integrating findings from environmental, animal, and human studies with a specific focus on aging populations.

Experimental studies consistently show that MNP exposure triggers oxidative stress, inflammation, mitochondrial dysfunction, and cellular senescence, mechanisms central to biological aging. These processes are linked to dysfunction of the cardiovascular, nervous, gastrointestinal, and immune systems, suggesting that MNPs may contribute to the development or progression of age-related diseases. Within the One Health framework, MNPs also act as carriers of chemical additives and environmental pollutants, potentially amplifying health risks through combined and cumulative exposures along food chains and ecosystems.

Despite increasing mechanistic evidence, direct epidemiological data in older adults remain limited. This review highlights key knowledge gaps and emphasizes the need for integrative, longitudinal research to clarify the role of MNPs in aging and to inform public health and environmental policy.

Partial reprogramming involves exposure of cells to one or more of the Yamanaka factors, (OCT4, SOX2, KLF4, and MYC, collectively OSKM) in order to induce a shift in epigenetic management of nuclear DNA structure to a more youthful state, while avoiding any dedifferentiation of target cell populations into induced pluripotent stem cells. This strategy has been demonstrated to produce some degree of rejuvenation in mice, but comes with the risk of cancer and tissue dysfunction if not carefully managed, particularly in the liver and intestines. Most of the funding presently devoted to development of rejuvenation therapies is focused on partial reprogramming, concentrated in a small number of well funded organizations, primarily Altos Labs. The first clinical trial of partial reprogramming has commenced, conducted by Life Biosciences. It is narrowly focused on the eye, where exposure can be limited and controlled. Significant challenges remain to be overcome before reprogramming can be reasonably safely applied to more of the body, however.

Despite its therapeutic promise, in vivo partial reprogramming remains far from clinical readiness. The primary obstacle is the risk that cells may inadvertently revert to pluripotency. Even brief or low-level induction of pluripotency factors can, in some cells, cross the threshold into dedifferentiation, producing teratomas and tissue dysfunction in animal models. The tissue microenvironment further complicates this dedicate balance, as certain proinflammatory signals can sensitize cells to reprogramming, which makes it difficult to limit OSKM activity to the desired level or location.

Heterogeneous expression and delivery of reprogramming factors is another concern. Systemic delivery of doxycycline-inducible OSKM often yields unequal induction: some tissues receive too much, while others receive too little. Organs with naturally high plasticity, such as the liver and the intestine, are especially vulnerable, given their rapid uptake of doxycycline, plus their intrinsic epigenetic flexibility, which means they reprogram first and most strongly, leading to malabsorption and toxicity long before other tissues benefit. Achieving precise spatial and temporal control remains technically demanding.

Chemical partial reprogramming avoids genomic integration but introduces new challenges. A deeper molecular understanding of each small-molecule cocktail is needed to minimize off-target effects, as many compounds affect multiple pathways. On top of all this, reprogramming itself is stochastic and inefficient; only a fraction of cells respond as expected, making outcomes unpredictable and raising dosing concerns.

In vivo reprogramming, therefore, reflects an intrinsic trade-off between regenerative plasticity and pathological risk. Transient relaxation of cell identity and proliferative constraints can enhance tissue repair in permissive contexts, yet the same plasticity may drive teratoma formation, tumorigenesis, or organ dysfunction when genetic safeguards are compromised or tissue context is unfavorable. Accordingly, the outcome of OSKM induction is dictated by dosage, duration, tissue context, and genetic background, underscoring the need for precise spatiotemporal control.

Progress will depend on tools that can quantitatively define and monitor the 'safe window' of rejuvenation temporally and spatially, including real-time biomarkers of epigenetic reset, tissue-specific or stress-responsive promoters, and nonintegrating delivery systems. Integrating these advances with single-cell profiling and longitudinal functional assays will be essential to establish whether partial reprogramming can be applied safely and predictably in humans.

Link: https://doi.org/10.1016/j.molmed.2026.01.007

The composition of the gut microbiome changes with age to favor inflammatory microbial species at the expense of those producing useful metabolites. Fecal microbiota transplantation is a way to permanently alter the composition of the gut microbiome, moving that of the recipient much closer to that of the donor. A number of studies in mice and other species have demonstrated that transplantation from young to old produces improved health and greater longevity, while transplantation from old to young has the opposite effect, as in the study noted here. While fecal microbiota transplantation is used in human medicine, only a few small studies have assessed outcomes in older people receiving material from young donors. The size of the effect in animal studies is promising, and thus we might hope that future studies demonstrate meaningful benefits in human patients.

The gut microbiota communicates with the homeostatic systems (nervous, immune, and endocrine). As we age, there is an increase in oxidative stress, which can deteriorate these systems, the microbiota, and the communication between them. It has been suggested that the microbiota influence the aging process, though its specific effects remain unclear. This study aimed to assess the impact of transferring microbiota from old to adult mice on behavioral, immune, and redox parameters, as well as their rate of aging and longevity.

Adult female mice were divided into three groups (N = 10/group): old microbiota (received 200 μL of old mice feces resuspended in PBS/3 days week/2 weeks, after a previous intestinal lavage with polyethylene glycol), adult microbiota (received adult mouse feces following the same procedure), and control (no manipulation). Feces were collected after treatment for microbiota and short-chain fatty acid analyses. After microbiota transfer, behavioral tests were performed, and peritoneal leukocytes were extracted to analyze immune and redox parameters, and to quantify biological age. These parameters were re-evaluated in old age, and the animals' longevity was recorded.

The results showed that old microbiota group was characterized by the increase of Akkermansia, Anaerostipes, Dubosiella, and Ruminococcus, among others. In addition, the group displayed elevated levels of anxiety, impaired immune function, and increased oxidative-inflammatory stress, effects that continued into old age. These changes translated into higher biological age and lower longevity. In conclusion, microbiota transfer from old to adult mice disrupts neuroimmune homeostasis, increases oxidative-inflammatory stress and accelerates aging process, reducing longevity.

Link: https://doi.org/10.1016/j.mad.2026.112177