Fight Aging!

The consensus on the immune system and aging is that dysfunction in immune function is an important contribution age-related degeneration and disease. Firstly increased, constant inflammatory signaling drives harmful changes in cell and tissue function; all of the major age-related diseases are characterized by inflammation. Secondly, loss of immune capacity allows senescent cells, cancerous cells, and infectious pathogens to slip through the net and prosper. Senescent cell burden increases with age, cancer risk scales up with age, and infectious disease is far more a threat to older people than to younger people.

The two aspects of immune aging, chronic inflammation and a growing ineffectiveness, are aggregated under the single heading of loss of immune resilience. Immune resilience is defined as maintaining both an effective immune response to challenges while also controlling inflammation, though different researchers may use different ways of coming to a specific set of measures and numbers that represent immune resilience.

In this context, the authors of today's open access paper mount an interesting argument. They agree that loss of immune resilience to be an important aspect of aging, but, for the span of human age from the 40s to the 70s, suggest that it is only loosely coupled to what we might think of as the rest of aging, whether we think of that more as the accumulation of damage and dysfunction in non-immune cells and tissues after the SENS model, or in terms of the non-immune hallmarks of aging. Thus interventions specifically focused on immune aging may go a long way to reducing mortality in this age range, even if other aspects of aging are not addressed. In practice, whether this is in fact the case will only be established in certainty by developing and widely deploying therapies to restore lost immune function - which should be an important goal regardless!

The 15-Year Survival Advantage: Immune Resilience as a Salutogenic Force in Healthy Aging

Environmental factors, particularly infections, have fundamentally shaped human evolution by selecting for protective inflammatory response mechanisms that enhance survival. This evolutionary pressure has created a core biological paradox: inflammation is indispensable for host defense, yet its dysregulation significantly heightens disease and mortality risk. This fundamental tension raises three fundamental questions about human aging and immunity: (1) How have selective pressures driven the evolution of mechanisms to balance inflammation's protective benefits against its harmful consequences? (2) Why does substantial variability in healthspan persist despite historically stable rates of aging? (3) Does evolutionary prioritization of reproductive fitness inherently limit longevity?

To address these questions, we developed an integrated evolutionary framework comprising four interconnected dimensions. At its foundation lies immune robustness - the ability to neutralize pathogenic threats while minimizing collateral tissue damage. This capability represents a critical evolutionary adaptation balancing protection against immediate threats with long-term tissue integrity. The remaining dimensions include (1) inflammatory stressors (environmental challenges that activate immune responses), (2) salutogenesis (health-promoting processes derived from Latin roots meaning "the origin of health" - "salus" meaning "health"), and (3) immune resilience (the dynamic capacity to respond to and recover from immunological challenges).

When immune robustness fails, it triggers what we term the "pathogenic triad" - three interconnected processes that accelerate biological aging: (1) inflammaging (sterile, chronic low-grade inflammation), (2) immune senescence (progressive impairment of innate and adaptive immunity), and (2) accumulation of senescent cells through Senescence-Associated Secretory Phenotype-driven damage. Importantly, these processes do not simply correlate with aging-they actively accelerate age-related morbidity independent of chronological age and mirror the established molecular hallmarks of organismal aging. Environmental triggers can initiate this triad, thereby elevating the risk of infection, multimorbidity, and mortality.

Our framework posits that immune robustness - shaped by evolutionarily optimized strategies - provides the foundation for salutogenesis, supporting systemic resilience by counteracting the aging hallmarks encompassed in the pathogenic triad. These salutogenic mechanisms mitigate age-related pathologies and extend lifespan through what is conceptualized as a "biological warranty period" encompassing both reproductive and post-reproductive phases. This warranty period closely aligns with the 2024 global average life expectancy of 73.4 years. We propose that premature mortality (before approximately 70 years) likely reflects a failure to sustain salutogenic adaptations rather than representing inherent biological constraints of aging.

To empirically investigate these concepts, we conducted longitudinal multi-omics profiling in approximately 17,500 participants exposed to diverse inflammatory challenges across the lifespan, from birth to over 90 years of age. We specifically mapped immune resilience (IR) trajectories and the emergence of the pathogenic triad across health-to-disease transitions. Our findings demonstrate that maintaining optimal IR with elevated transcription factor 7 (TCF7) levels establishes a clinically actionable salutogenic trait. This TCF7-associated trait significantly reduces the emergence of the pathogenic triad. Mechanistically, TCF7 encodes TCF1, an evolutionarily conserved master regulator of T-cell immunity and stemness. Through genome-wide screening of 1380 transcription factors, we identified a TCF7-centered regulatory network governing IR mechanisms, alongside six co-regulated factors. This finding helps explain the substantial variability in healthspan despite stable aging rates by identifying specific biological mechanisms that can vary between individuals.

A great many ways to slow the progression of atherosclerosis have been demonstrated in mice, and some these have been shown to work in large mammals such as pigs and non-human primates. Slowing atherosclerosis isn't the hard problem; regressing existing atherosclerotic plaque so as to clear arteries and restore cardiovascular function is the outcome that the research and development community continues to struggle with. None of the existing approaches used in the clinic produce reliable, large regression of plaque, and only a few ways of achieving some degree of reliable plaque regression have been demonstrated in mouse studies. Here, researchers demonstrate yet another approach to slow plaque growth in large mammals, an orally delivered peptide that likely produces this outcome by reducing inflammatory signaling in the plaque environment.

Advanced atherosclerotic lesions and vascular calcification substantially increase the risk of cardiovascular events. However, effective strategies for preventing or treating advanced atherosclerosis and calcification are currently lacking. This study investigated the efficacy of DT-109 (Gly-Gly-Leu) in attenuating atherosclerosis and calcification in nonhuman primates, exploring its broader therapeutic potential. In this study, twenty male cynomolgus monkeys were administered a cholesterol-rich diet ad libitum for 10 months. Then, the animals were treated either orally with DT-109 (150 mg/kg/day) or a vehicle (water) for 5 months while continuing on the same diet. Plasma lipid levels were measured monthly and at the end of the experiment, pathological examinations of the aortas and coronary arteries and RNA sequencing of the coronary arteries were performed. To explore possible molecular mechanisms, the effects of DT-109 on smooth muscle cells (SMCs) were examined in vitro.

We found that DT-109 administration significantly suppressed atherosclerotic lesion formation in both the aorta and coronary arteries. Pathological examinations revealed that DT-109 treatment reduced lesional macrophage content and calcification. RNA sequencing analysis showed that DT-109 treatment significantly downregulated the pro-inflammatory factors NLRP3, AIM2, and CASP1, the oxidative stress factors NCF2 and NCF4, and the osteogenic factors RUNX2, COL1A1, MMP2, and MMP9, while simultaneously upregulating the expression of the SMCs contraction markers ACTA2, CNN1, and TAGLN. Furthermore, DT-109 inhibited SMC calcification and NLRP3 inflammasome activation in vitro.

These results demonstrate that DT-109 effectively suppresses both atherosclerosis and calcification. These findings, in conjunction with insights from our previous studies, position DT-109 as a novel multifaceted therapeutic agent for cardiovascular diseases.

Link: https://doi.org/10.1038/s41392-025-02201-2

Why does the ability to generate new blood vessels decline with age? One manifestation is a loss of capillaries, which become less dense in tissues with age. Another issue is that efforts to produce therapies that provoke the growth of new vessels, as a way to treat conditions such as peripheral artery disease results from reduced blood flow through vessels obstructed by atherosclerotic plaque, have struggled due to this age-related impairment of blood vessel growth processes. Here, researchers provide evidence for senescent macrophage cells to be an important contributing cause of dysfunction in blood vessel growth and maintenance in older people. This is yet another reason to push for more clinical trials and greater use of existing low-cost senolytic treatments such as the dasatinib and quercetin combination.

Peripheral arterial disease is a common vascular disease in the elderly. Therapeutic revascularization, including angiogenic and arteriogenic therapy, is a promising treatment approach for peripheral arterial disease. However, the progress of clinical trials is not ideal, possibly due to insufficiency of preclinical models, such as not taking into account the effect of aging on vascular regeneration. Macrophages are crucial in angiogenesis and arteriogenesis.

The aging microenvironment typically makes recruited monocytes and macrophages more susceptible to senescence. However, the feature of macrophages in ischemic muscle of old individuals and their underlying role remains unclear. In this study, we reveal that macrophages of ischemic skeletal muscle in old mice are more senescent and proinflammatory. By transplanting macrophages into mice following hindlimb ischemia, we find senescent macrophages inhibit revascularization.

Mechanistically, these senescent macrophages induce endothelial dysfunction via increasing vascular endothelial growth factor A-165B (VEGF-A165B) expression and secretion, and eventually impair revascularization. Due to the presence of two splicing isoforms, the role of VEGF-A in revascularization is complex: VEGF-A165A is the the proangiogenic isoform, while VEGF-A165B is the antiangiogenic isoform. Notably, plasma VEGF-A165B levels are elevated in old patients with peripheral arterial disease and positively associated with a lower ankle brachial index, an assessment of disease severity. Our study suggests that targeting the senescent macrophages presents an avenue to improve age-related revascularization damage.

Link: https://doi.org/10.1111/acel.70059

Microglia are innate immune cells resident in the brain, somewhat analogous to macrophages elsewhere in the body. Like macrophages, microglia exhibit a diverse set of states, and can shift from one state to another in response to circumstances. At the high level, much of the literature focuses on the inflammatory M1 state, capable of hunting and destroying pathogens and errant cells, versus the anti-inflammatory M2 state, focused on regeneration and tissue maintenance. But, as the authors of today's open access paper point out, this is an oversimplification of a much more complex continuum of states, some of which don't fit well into the M1 or M2 buckets.

So while it is possible to argue that microglia are important in neurodegenerative conditions in large part because too many of them become inflammatory and dysfunctional in response to the aged tissue environment in the brain, the fine details do matter. Some microglia are more harmful than others, some are more helpful than others, and attempts to broadly adjust the state of microglia may be less helpful than hoped. The suspicion is that more of the panoply of states must be understood in greater detail, and targeted distinctly.

The dual role of microglia in Alzheimer's disease: from immune regulation to pathological progression

Despite extensive research, the role of microglia in Alzheimer's disease (AD) remains complex and dual. The aim of this review is to summarize the most recent advances in research regarding the dual role of microglia in AD concerning both immunomodulation and pathological progression by considering mechanisms of activation of microglia, effects on amyloid-β (Aβ) clearance, tau pathology, and impacts due to genetic variations on microglial functions.

The functional state of microglia, the principal immune cells of the central nervous system (CNS), is far more complex than the traditional M1 and M2 phenotype polarization. Current studies have shown that the state of microglia in AD can comprise a wide variety of different phenotypes that play different roles in different stages of the disease and microenvironments. Aside from the classic M1 and M2 phenotypes, studies have characterized conditions such as disease-associated microglia (DAM) and reactive microglia (RAM) that have specific functional and molecular profiles in AD pathology.

M1 microglia are activated when stimulated by proinflammatory factors such as interferon-γ and lipopolysaccharide, and release proinflammatory factors such as TNF-α, IL-6, IL-1β, and inducible nitric oxide synthase. Excessive secretion of these factors aggravates neuroinflammatory reaction and toxic injury of neurons, and promotes the accumulation of Aβ and the hyperphosphorylation of tau protein. In contrast, M2 microglia are activated by anti-inflammatory factors such as interleukin-4 (IL-4) and interleukin-13 (IL-13), and secrete anti-inflammatory and neurotrophic factors such as interleukin-10 (IL-10), transforming growth factor β (TGF-β), BDNF, and glial-derived neurotrophic factor (GDNF).

Additionally, disease-associated microglia (DAM) have distinct initial AD gene expression patterns and are found surrounding Aβ plaques and clear Aβ as well as modulate tau pathology. TREM2 variants were significantly associated with AD risk increase and that its physiological function is to allow for DAM formation and thus increased Aβ clearance. Pathology of tau also significantly increases with deficient TREM2 function or microglial deficiency, pointing toward an essential role of DAM in the prevention of tau spreading. The phenotypes of AD in microglia are beyond the simple M1 and M2 phenotypes but more evolved phenotypes such as DAM. Each state has its own corresponding functions to perform in the different stages of the disease and microenvironment, and in the future, further molecular mechanisms and functional difference among the states would have to be investigated by studies to un-scramble the multi-functional role of microglia in AD.

One of the potential complications following surgery or injury (or indeed many other forms of acute stress) in older individuals is inflammation in the brain, triggered by inflammation in the body. This can lead to issues such as postoperative delerium, or more lasting cognitive decline. Researchers here provide evidence to suggest that the inflammatory signaling produced by senescent cells is an important mediator of this unwanted side-effect. This signaling can trigger senescence in bystander cells, and given sufficient levels of inflammation, this can occur throughout the body. Timely administration of senolytic treatments that selectively destroy senescent cells can in principle prevent this from happening, however.

Aging has been identified as a leading risk factor for many diseases, including neurodegenerative disorders. While cellular senescence has been linked to age-related neurodegenerative conditions, its involvement in peripheral stress-associated brain disorders is just beginning to be explored. In this study, we investigated the impact of senescent cells on peripheral stress-induced neuroinflammation using orthopedic surgery as a model.

Our results demonstrate an increased accumulation of senescent cells and neuroinflammation in the aged mouse hippocampus following surgery. Intermittent treatment of the mice with the senolytic drugs dasatinib and quercetin (D/Q) showed a significant reduction in surgery-induced senescent cell burden. This reduction in senescent cell accumulation was correlated with reduced surgery-induced neuroinflammation, as evidenced by decreased glial cell activity. Consistent with these observations, we also observed reduced levels of proinflammatory senescence-associated secretory phenotype factors in circulation, following fracture surgery, in mice treated with D/Q.

Overall, our findings underscore the pivotal role of cellular senescence in surgery-induced neuroinflammation and highlight the therapeutic potential of eliminating senescent cells as a potential strategy to manage peripheral stress-induced neuroinflammatory conditions.

LinK: https://doi.org/10.1093/pnasnexus/pgaf103

A growing body of work implicates the accumulation of senescent cells in degeneration of function and structure in the discs that separate vertebrae in the spine. This is a prevalent issue, causing pain and loss of function. The ability to restore lost function is limited at best, but clearance of senescent cells via senolytic drugs has shown promise in animal studies of degenerative disc disorders. Here, researchers employ a novel senolytic approach to produce beneficial outcomes in mice.

Low back pain (LBP) is often related to IVD degeneration and is the number one global cause of years lived with disability. The personal costs of reduced quality of life and the economic cost to healthcare systems are enormous. Senescent cells (SnCs) accumulate in degenerating intervertebral discs (IVDs) and are proposed to directly contribute to disease progression and back pain. Senescence-associated secretory phenotype (SASP) factors secreted by SnCs generate a pro-inflammatory environment that accelerates the breakdown of the extracellular matrix (ECM) and worsens IVD degeneration.

The senolytic drugs o-vanillin and RG-7112 remove human senescent IVD cells and reduce SASP factor release from cells and intact IVDs. The senolytic drug RG-7112 is a p53/MDM2 complex inhibitor. o-Vanillin is a natural senolytic and senomorphic substance that has been shown to reduce senescence burden and SASP factor release and to improve tissue homeostasis in human IVDs, indicating that they could potentially reduce pain. Here we treated sparc-/- mice, an animal model of LBP, with oral administration of o-vanillin and RG-7112 as single or combination treatments. Treatment reduced LBP and SASP factor release and removed SnCs from the IVD and spinal cord. Treatment also lowered degeneration scores in the IVDs, improved vertebral bone quality, and reduced the expression of pain markers in the spinal cord.

Together, our data suggest RG-7112 and o-vanillin as potential disease-modifying drugs for LBP and other painful disorders linked to cell senescence.

Link: https://doi.org/10.1126/sciadv.adr1719

Broadly, there are two viewpoints on the approach the treatment of aging as a medical condition. The first approach is most clearly represented by the Strategies for Engineered Negligible Senescence (SENS). The goal is to repair or otherwise address the underlying cell and tissue damage that causes aging. This damage is already catalogued and new additions have been few and far between in recent decades. There is little expectation that therapies will have to be personalized to any great degree. Any one therapy that addresses any one cause of aging will produce benefits in every older person. In this, the damage repair approach is analogous to the initial development and early use of antibiotics. Antibiotics applied in much the same way to every patient produced such a large improvement in outcomes that personalization of use, even were it possible at the time, was a low priority. Personalization of treatments came only later. Thus the first step in the SENS program of damage repair is to produce therapies and test them to see how effectively they produce rejuvenation.

The second approach to the treatment of aging is called geroscience, and is largely focused on manipulating the operation of metabolism so as to slow aging. Today's open access paper provides a good summary of the geroscience program and goals. As a field it is very connected to personalized medicine, systems biology, and other views that prioritize differences between individuals. Geroscience starts from the point of considering that some people age more slowly than others, and then asks how we can do that for everyone, and whether there are ways to go a little further than presently exists in nature. The first step for the geroscience program is a great deal of further research aimed at obtaining a greater understanding of how specific differences in genetics, metabolism, and environment act to produce the observed differences in pace of aging and vulnerability to specific forms of cell and tissue damage and dysfunction.

At the end of the day, the most important difference between SENS-style damage repair and geroscience is that the latter is very limited in its ambitions (and most likely in outcomes) in the matter of human healthy life span. It seeks only to modestly slow aging, and will likely only achieve that goal. In contrast, damage repair approaches aim at outright rejuvenation. These two approaches to aging are not in conflict in principle, are complimentary strategies - but they are in conflict when it comes to the space of ideas, funding, and the will to make progress.

From geroscience to precision geromedicine: Understanding and managing aging

The last decade has witnessed a dramatic change in aging research. Geroscience is an emerging field that seeks to understand the biological mechanisms of aging and how they contribute to age-related diseases. It operates on the principle that aging is the primary risk factor for many age-related diseases, such as diabetes, cardiovascular disease, cancer, and neurodegenerative disorders. By studying the biological processes that drive aging, mostly in rodents and occasionally in non-human primates, geroscientists aim to develop interventions that can extend the quality of life and healthspan, i.e., the period of life spent in good health. In addition, geroscientists analyze specimens from healthy and diseased individuals of various ages to identify diagnostically relevant biomarkers of biological aging and to deconvolute age-associated pathways that can be targeted by gerotherapeutics for prevention or treatment of specific diseases. The acceleration of geroscientific discoveries has been fueled by the growing societal interest in aging, the creation of specific research centers, the expansion of public and private funding programs, and the increasing number of venture funds and biotech companies developing potential anti-aging remedies. The field holds promise for transforming the way we approach age-related diseases, shifting the focus from treating manifest conditions to targeting aging itself as a root cause.

Aging can be viewed as a process that is promoted by overactivation of gerogenes, i.e., genes and molecular pathways that favor biological aging, and alternatively slowed down by gerosuppressors, much as cancers are caused by the activation of oncogenes and prevented by tumor suppressors. Such gerogenes and gerosuppressors are often associated with age-related diseases in human population studies but also offer targets for modeling age-related diseases in animal models and treating or preventing such diseases in humans. Gerogenes and gerosuppressors interact with environmental, behavioral, and psychological risk factors to determine the heterogeneous trajectory of biological aging and disease manifestation. New molecular profiling technologies enable the characterization of gerogenic and gerosuppressive pathways, which serve as biomarkers of aging, hence inaugurating the era of precision geromedicine.

In our vision, geromedicine should pursue three general objectives that distinguish this discipline from other medical specialties that usually target manifest diseases. First and foremost, in (apparently) healthy individuals, geromedicine should apply a systems biology approach analyzing interactions of biological, clinical, psychological, social, and environmental measures to model and predict health trajectories, incidence of disease, and utilization of gerotherapeutics, hence proposing "proactive measures" to decelerate, halt, or reverse such effects. Second, geromedicine should spot "precocious derangements" - the potential precursors of disease - in still-healthy individuals to prevent the development of specific pathologies. Third, geromedicine should seek the biomarker-informed detection of "subclinical lesions" (such as asymptomatic cancers or arterial stenoses) to intercept them by early therapeutic intervention and hence to avoid their transition to clinically manifest diseases and the consequent health deterioration that would affect the entire organisms.

Researchers here report on a novel approach to encourage nerve regeneration, and demonstrate positive results in mice with spinal cord injury. Delivering platelet-derived growth factor BB (PDGF-BB) as a protein therapy to the injured nerve tissue changes the behavior of pericyte cells that normally interfere in any possible regrowth of the axons making up the nerve. In the presence of PDFG-BB, pericytes act to indirectly encourage axon regrowth. As the researchers note, this discovery likely has other applications beyond treating spinal cord injuries.

Spinal cord injuries are severe not only because they prevent transmission of information across the site of the injury, but because all of the vasculature structure and function is also compromised. Previous research suggesting pericytes interfere with spinal cord injury recovery had led some scientists to recommend clearing them from the lesion site to aid repair. But cancer research has indicated pericytes' properties change when they're exposed to a protein called platelet-derived growth factor BB (PDGF-BB), and the cells act to encourage blood vessel formation. This is one way tumors generate their own blood supply.

Earlier neuroscience research also indicated that pericytes are highly "plastic," meaning they are very responsive to changes in the microenvironment - including the presence of PDGF-BB. Researchers saw potential to harness that cell-protein relationship to stabilize the vasculature surrounding a spinal cord injury. In the process, they found the newly sprouted blood vessels established a pathway for regenerated axons to follow.

Turning to experiments in animals with spinal cord injury, researchers waited for seven days after the injury - the equivalent of about nine months in a human adult - before injecting a single dose of PDGF-BB at the injury site. Analysis of tissue four weeks after the injury showed that the PDGF-BB injection produced robust axon regenerative growth compared to the axon response in injured control mice. Electrophysiological and movement assessments of injured animals treated with PDGF-BB detected sensory activity beyond the lesion site and showed the mice regained better control of their hind limbs compared to control mice. The animals also were less sensitive to a non-painful stimulus, suggesting they did not experience the neuropathic pain that is often triggered by a spinal cord injury.

Link: https://news.osu.edu/building-cellular-bridges-for-spinal-cord-repair-after-injury/

This very interesting paper finds evidence of early adult impairment of cognitive function to correlate with Alzheimer's-associated biomarkers such as tau and neurofilament light chain. It is well known that Alzheimer's disease has a decades-long onset. Measurable biomarkers are associated with future pathology well in advance. Nonetheless, to extend that back to as early an age as mid-20s is a novel way of looking at the progression of cognitive decline over a lifetime. One has to wonder to what degree this is a measurement of the effects of poor lifestyle maintenance or exposure to persistent pathogens on the brain in early adult life. Similarly, whether a continuum of the same pathological processes leads unbroken from low levels in early life to high levels in late life, or whether early life and late life exhibit significantly different mechanisms that happen to converge on impaired cognitive function.

Data from the National Longitudinal Study of Adolescent to Adult Health were analyzed. Analytic sample sizes ranged from 4,507 to 11,449 participants in Wave IV and from 529 to 1121 participants in Wave V. The survey-weighted median (IQR) age was 28 (26-29) years in Wave IV and 38 (36-29) years in Wave V. We measured the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) score comprised of age, education, sex, systolic blood pressure, body mass index, cholesterol, and physical activity, and also apolipoprotein E ε4 allele (APOE ε4) status. We further measured total Tau and Neurofilament light (NfL), high sensitivity C-reactive protein (hsCRP), Interleukin (IL)-1β, IL-6, IL-8, IL-10, and Tumor necrosis factor alpha (TNF-α). Outcomes included immediate word recall, delayed word recall, and backward digit span.

Several key risk factors for Alzheimer's Disease were associated with standard measures of cognition in 24- to 44-year-olds in the U.S., suggesting that these factors may be related to cognitive function decades before the onset of Alzheimer's Disease. The CAIDE score was consistently linked to all three cognitive function measures (immediate recall, delayed recall, and backward digit span). Notably, a key genetic risk factor, APOE ε4, was not associated with recall nor backward digit span, suggesting that the effects of APOE ε4 may not become apparent until middle to older age. Total Tau was associated with lower immediate word recall but not backward digit span scores. Although higher levels of NfL showed a trend toward lower backward digit span scores, the association was not statistically significant. A limited number of immune markers were significantly associated with cognitive function at ages 24-34 years; however, some of these associations appeared to become more robust in the following decade of life. For instance, IL-6 was not associated with backward digit span in Wave IV but showed a significant association with lower backward digit span in Wave V. Similarly, IL-8 was not associated with cognitive scores in Wave IV but was associated with all three measures of cognition in Wave V.

These findings suggest that cardiovascular, neurodegenerative, and immune markers may be associated with critical measures of cognitive function at much younger ages than previously recognized, with some associations becoming more prominent between the early midlife ages of 33 and 44.

Link: https://doi.org/10.1016/j.lana.2025.101087

Microglia are innate immune cells resident in the brain. They are quite similar to the macrophages found elsewhere in the body, but specialized to the central nervous system. In addition to the tasks of chasing down pathogens and participating in regenerative from injury, they are also involved in the processes of maintaining and altering synaptic connections between neurons. Like macrophages, microglia can adopt different packages of behavior in response to environment and circumstances. This is commonly described in terms of the broad M1 and M2 states, where M1 is pro-inflammatory and aggressive where M2 is anti-inflammatory and regenerative. With advancing age, ever more microglia become inflammatory, and this is thought to be an important contribution to neurodegenerative conditions.

Why do microglia become inflammatory in aged tissues? There are any number of contributing mechanisms. There is the inflammatory signaling generated by the rest of the aged immune system, biasing microglia to joining in. Senescent cells also generate inflammatory signaling. Aging diminishes drainage of cerebrospinal fluid from the brain, allowing metabolic waste products to build up and aggravate cells. These waste products include the misfolded and altered proteins such as amyloid-β that are characteristic of neurodegenerative conditions. And so forth; many of the forms of molecular damage and cell dysfunction that occur with age tend produce a maladaptive inflammatory reaction from microglia. Some of this is quite direct, but today's open access paper describes a more indirect consequence of the underlying causes of aging that acts to increase microglial inflammation.

Modulating the brain's immune system may curb damage in Alzheimer's

Norepinephrine is a major signaling factor in the brain and affects almost every cell type. In the context of neurodegenerative diseases such as Alzheimer's disease, it has been shown to be anti-inflammatory. In our brains, immune cells called microglia usually help keep things in balance. Microglia have a receptor called β2AR, which acts like a "switch" and directs the cells to respond to norepinephrine and calm down inflammation. In Alzheimer's disease and as we age, this calming switch becomes less active, especially in areas of the brain where harmful protein clumps called amyloid plaques build up. As these plaques form, the nearby microglia lose more of their β2AR receptors, making it harder for them to fight inflammation.

When scientists removed or blocked the β2AR receptor, the brain's damage worsened: more plaques, increased inflammation, and more harm to brain cells. On the other hand, when they stimulated or "turned up" the receptor, the harmful effects were reduced. Interestingly, the results appeared to depend on factors like the animal's sex and how early the treatment started. Traditionally, Alzheimer's has been seen as a problem of damaged brain cells due to plaque buildup. This study shows that a loss of norepinephrine's calming effect on microglia might be a key factor that makes the disease worse, even before large amounts of nerve cell damage occur. The findings also suggest that problems with the β2AR receptor could start very early in the disease process, meaning that future treatments might be more effective if started sooner rather than later.

Noradrenergic signaling controls Alzheimer's disease pathology via activation of microglial β2 adrenergic receptors

Norepinephrine (NE) is a potent anti-inflammatory agent in the brain. In Alzheimer's disease (AD), the loss of NE signaling heightens neuroinflammation and exacerbates amyloid pathology. NE inhibits surveillance activity of microglia, the brain's resident immune cells, via their β2 adrenergic receptors (β2ARs). Here, we investigate the role of microglial β2AR signaling in AD pathology in the 5xFAD mouse model of AD. We found that loss of cortical NE projections preceded the degeneration of NE-producing neurons and that microglia in 5xFAD mice, especially those microglia that were associated with plaques, significantly downregulated β2AR expression early in amyloid pathology. Importantly, dampening microglial β2AR signaling worsened plaque load and the associated neuritic damage, while stimulating microglial β2AR signaling attenuated amyloid pathology. Our results suggest that microglial β2AR could be explored as a potential therapeutic target to modify AD pathology.

This open access paper could serve as an introduction to aging clocks for someone who has previously given little attention to the ongoing attempts to build ways to quickly and cost-effectively measure biological age. Near every complex set of biological data obtained from an individual can be used to build clocks that estimate age. The present major challenge is the inability to trust the results of any specific clock for any specific scenario involving the use of therapies to treat aging. There is next to no understanding of how in detail the clock data is driven by mechanisms and dysfunctions of aging, and thus no ability to predict ahead of time whether a clock will give useful answers for any given therapy targeting a mechanism of aging. Clocks must be calibrated to their uses, and this is a slow and expensive process.

Aging research has delineated the aging process by classifying two separate but interconnected mechanisms: intrinsic and extrinsic aging. Intrinsic aging describes changes in biological hallmarks including cellular and molecular changes, genetics, and hormonal changes that have been described to occur naturally over time. Extrinsic aging, however, is regulated by exposure to environmental stressors, dietary habits, oxidative stress, and other factors that accelerate physiologic aging. Traditionally, aging has been quantified by chronological age, which is the exact number of years an individual has lived. However, chronological age does not fully capture the heterogeneity of the aging process, excluding many extrinsic factors that contribute to aging.

Subsequently, the calculation of biological age, which aims to account for interindividual variations in aging rate, has become a topic of interest in aging research. Aging clock models are tools that utilize various modeling approaches to estimate chronological or biological age. Moreover, aging clock models can estimate the rate of aging (ΔAge), otherwise known as the difference between model-predicted biological age and chronological age. Positive differences between model-predicted biological age and chronological age indicate accelerated aging whereas a negative difference indicates decelerated aging. If the calculated ΔAge exceeds the mean absolute error (MAE) of the aging rate estimation, these individuals can be determined to be fast or slow agers.

Aging clocks models may utilize any hallmark changes that occur because of aging, and these may include epigenetic changes, telomere length, genomic stability, altered intercellular communication, chronic inflammation, and gut microbiome dysbiosis, among others. Notably, some of the first aging clock models include the Horvath clock (2013) and Hannum clock (2013), which are both epigenetic clocks modeled after changes in DNA methylation patterns and varying cytosine phosphate guanine (CpG) sites across the genome. Several aging clock models have emerged since then, varying from microbiome-based clocks to proteomic clocks.

Link: https://doi.org/10.3389/fragi.2024.1487260

To what degree is it possible to slow or regress atherosclerosis by clearing senescent cells from plaque and artery walls? A few lines of evidence from animal studies suggest that slowing plaque growth is possible. These include efforts to clear senescent macrophages that have become foam cells in plaque using small molecule senolytics, or Bitterroot Bio's targeting of CD47 to achieve a similar outcome. This does not appear to produce plaque regression, however, most likely because it doesn't address the toxic cholesterol that makes up a plaque. That cholesterol will continue to attract new cells and drive those cells into dysfunction and senescence for so long as it is present.

CDKN2A/p16INK4a, a key marker of cellular senescence, is substantially upregulated during cell senescence. The elevated expression of CDKN2A inhibits the activation of CDK4 and CDK6, decreases Rb phosphorylation and blocks the G1/S transition of the mitotic cell cycle. The expression of CDKN2A increases significantly with age driven by oxidative stress and reactive oxygen species (ROS) accumulation in endothelial progenitor cells and modulates age-dependent senescence of these cells. Elimination of CDKN2A/p16INK4a-positive senescent cells has proved to be effective to attenuate age-dependent changes in several organs including kidney and heart. Therefore, CDKN2A appears to play a critical role on the onset and progression of cellular senescence. Control of CDKN2A expression is therefore a crucial mechanism for suppressing cellular senescence. To date, no studies investigated whether preventing the activation of CDKN2A and CDK4 and CDK6 pathway ameliorates vascular cellular senescence and atherogenesis in vivo and in vitro.

In our studies, β-galactosidase activity and ROS production were significantly elevated in human and mice atherosclerotic lesions. β-galactosidase, co-localized with CD31, was obviously upregulated in atherosclerotic lesions, indicating endothelial cellular senescence in vivo. CDKN2A, co-localized with CD31, was markedly increased in atherosclerotic lesions. Colocalization of CDKN2A with CDK4 and CDK6 revealed the potential connection in vivo.

Knockdown of CDKN2A counteracts endothelial cell senescence induced by oxidized LDL. CDK4 and CDK6 inhibitor palbociclib, a potent anti-proliferative agent for the treatment of breast cancer, is demonstrated to accelerate endothelial cell senescence in vitro and deteriorate atherogenesis in vivo. Our findings suggest that by ameliorating endothelial cell senescence, modulating CDKN2A and CDK4 and CDK6 pathway may represent a new highly promising strategy for the treatment of atherosclerosis.

Link: https://doi.org/10.1016/j.bcp.2025.116916

Proteins make up most of the cogs, wheels, and switches of the intricate machinery of the cell. Their assemblies and interactions depend on the proteins involved having the correct structure. A protein is a complicated molecule and assembly alone, by joining amino acids together in a ribosome according to the blueprint provided by a messenger RNA molecule, doesn't guarantee that the resulting protein ends up folded into the right shape. Chaperone molecules exist to guide protein folding, but one of the forms of stress that a cell can suffer is the accumulation of unfolded or incorrectly folded proteins. Too much of this and the cell behavior changes to become problematic, or the cell dies.

Cells respond to this form of stress with what is known as an unfolded protein response, which can focus on the endoplasmic reticulum where most proteins are folded, those encoded in the nuclear genome, or it can focus on mitochondria. As the descendants of ancient symbiotic bacteria, mitochondria have their own small genome and can manufacture their own proteins independently of the rest of the cell. Thus they can also suffer unfolded protein stress, and can mount a response against it.

As researchers point out in today's open access review, the generally beneficial consequences of the mitochondrial unfolded protein response are not limited to the mitochondria, but have important effects on other parts of the cell, other cells, and even other tissues in the body. In part this is because most formerly mitochondrial genes have migrated to the cell nucleus over evolutionary time, but producing distant benefits is generally a characteristic of cell stress responses, as illustrated by the response to calorie restriction, heat shock, and so forth.

The mitochondrial unfolded protein response: acting near and far

The paramount importance of maintaining a healthy protein pool is highlighted by the significant fraction of the proteome that is devoted to protein surveillance across species. An extensive plexus of chaperones and the proteolytic degradation machinery, coordinated by stress response pathways, collectively referred to as the proteostasis network (PN), safeguards proteostasis. Notably, the efficacy of the PN declines with age, leading to the accumulation of misfolded proteins, toxic oligomers, and protein aggregates, culminating in proteotoxicity. Post-mitotic cells, such as neurons, are particularly susceptible to protein aggregation and PN dysfunction. Intensive scientific efforts have been focused on slowing PN decline to mitigate late-onset neurological disorders.

Mitochondria are the result of endosymbiotic events between ancestral eukaryotic cells and free-living proteobacteria. They are central to cellular metabolism, producing ATP via oxidative phosphorylation (OXPHOS) and being involved in processes such as the TCA cycle and the beta-oxidation of fatty acids, but are also critical for the production of essential cofactors and regulatory metabolites. Mitochondrial dysfunction is a key hallmark of aging and is associated with the manifestation of a wide spectrum of human pathologies affecting the muscular, neuronal and immune systems. Sophisticated quality control and protein turnover mechanisms (i.e. chaperones, proteases, mitochondrial-associated degradation) maintain protein integrity in various mitochondrial compartments, while others ensure that irreversibly damaged or superfluous mitochondria are removed by autophagic degradation (i.e. mitophagy). The vast majority (more than 99%) of mitochondrial proteins are encoded by the nuclear genome, translated by cytosolic ribosomes and then imported into the mitochondria. Therefore, any change in the mitochondrial status should be communicated to the nucleus so that the mitochondrial network can successfully adapts to ever-changing physiological demands and functionally recover from stress.

To ensure proper mitochondrial function under misfolding stress, a retrograde mitochondrial signaling pathway known as the mitochondrial unfolded protein response (UPRmt) is activated. The UPRmt ensures that mitochondrial stress is communicated to the nucleus, where gene expression for several mitochondrial proteases and chaperones is induced, forming a protective mechanism to restore mitochondrial proteostasis and function. Importantly, the UPRmt not only acts within cells, but also exhibits a conserved cell-nonautonomous activation across species, where mitochondrial stress in a defined tissue triggers a systemic response that affects distant organs. Here, we summarize the molecular basis of the UPRmt in the invertebrate model organism Caenorhabditis elegans and in mammals. We also describe recent findings on cell-nonautonomous activation of the UPRmt in worms, flies and mice, and how UPRmt activation in specific tissues affects organismal metabolism and longevity.

Epidemiological evidence for improved health and reduced late life mortality in vegans and vegetarians is both extensive and much debated at the detail level. The study noted here is an interesting addition to this body of work, the researchers having found a sizable population with a long-standing practice of cycling between periods of vegan and omnivorous diets. This produces a more compelling picture of beneficial metabolic changes that take place when animal products are eliminated from the diet. It remains a question as to how much of this is due to a reduced calorie intake in a vegan diet versus other mechanisms.

Dietary interventions constitute powerful approaches for disease prevention and treatment. However, the molecular mechanisms through which diet affects health remain underexplored in humans. Here, we compare plasma metabolomic and proteomic profiles between dietary states for a unique group of individuals who alternate between omnivory and restriction of animal products for religious reasons. We find that short-term restriction drives reductions in levels of lipid classes and of branched-chain amino acids, not detected in a control group of individuals, and results in metabolic profiles associated with decreased risk for all-cause mortality.

We show that 23% of proteins whose levels are affected by dietary restriction are druggable targets and reveal that pro-longevity hormone FGF21 and seven additional proteins (FOLR2, SUMF2, HAVCR1, PLA2G1B, OXT, SPP1, HPGDS) display the greatest magnitude of change. Through Mendelian randomization we demonstrate potentially causal effects of FGF21 and HAVCR1 on risk for type 2 diabetes, of HPGDS on BMI, and of OXT on risk for lacunar stroke. Collectively, we find that restriction-associated reprogramming improves metabolic health and emphasise high-value targets for pharmacological intervention.

Link: https://doi.org/10.1038/s44324-025-00057-2

One of the primary ways in which the beneficial, age-slowing response to calorie restriction is regulated is via sensing of methionine levels. Methionine is an essential amino acid, used in all protein synthesis, but not manufactured in the body. It must come from the diet. There is plenty of evidence for methionine restriction, meaning to construct a diet that is low in methionine without reducing calorie intake, to slow aging in rodents. Researchers here demonstrate that it remains beneficial when started in old age in mice. Interestingly, they also find that it doesn't affect epigenetic age, which is an intriguing outcome akin to the insensitivity of early epigenetic clocks to physical fitness.

We and others previously demonstrated that both steady-state levels of methionine and methionine flux are altered during aging using Drosophila as a model system. Moreover, targeting methionine metabolism via dietary manipulations of fly food, enzymatic degradation, or manipulation of enzymes either directly involved in methionine metabolism or those that affect the levels of methionine metabolism metabolites extend health- and lifespan. In addition to results seen in Drosophila, methionine restriction (MetR) extends lifespan in yeast, rodents, and human diploid fibroblasts.

Here, we determine whether targeting either methionine metabolism with dietary MetR started late in life in 18-month-old male and female C57BL/6J mice for 6 months affects various aspects of aging-related phenotypes. Dietary MetR does not affect mouse epigenetic clocks despite multiple improvements in different parameters of metabolic health, neuromuscular function, lung function, and frailty index. Similarly, we did not observe any effects of dietary MetR on human epigenetic clocks.

Using single-nucleus RNA sequencing (snRNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) on the muscle tissues, we identified several subtype-specific processes and transcription factors (TFs) activated by dietary MetR that indicates a cell type-specific response to MetR. In addition, we confirm the beneficial effects of dietary MetR on neuromuscular function in a separate disease cohort using the Alzheimer's disease 5XFAD mouse model. Based on these mouse studies, targeting methionine metabolism holds great promise as an antiaging intervention in humans.

Link: https://doi.org/10.1126/sciadv.ads1532

Navigating a pharma or biotech startup company from preclinical proof of concept of some new and potentially useful technology to the stage of running clinical trials is hard at the best of times. To a first approximation, institutional investors, those with deep enough pockets to fund the enormous regulatory costs imposed upon drug manufacture and clinical trials, do not fund new directions, new mechanisms, truly novel therapies. We can debate whether those at fault are more the venture capitalists who run the funds or the limited partners who hold the purse strings, but the end result is a strong aversion to any risk that is not well understood - such as the prospects for any new class of therapy. Investors like small tweaks on proven existing drugs, which is how we end up with overinvestment in strategies for lowering LDL cholesterol, despite the fact that none of these drugs is capable even in principle of reliably reversing cardiovascular disease.

On top of that, most of the last decade has been a decided gloomy market environment for drug development. Good technologies have fallen to the wayside. The latest to succumb is Covalent Biosciences, developer of catalytic antibodies. They are shutting down, preparing some scientific publications to explain the aspects of their platform and research not already published, and in a few years their patents will expire. Catalytic antibodies are in principle vastly more effective than normal antibodies, as the catalytic antibody can interact with countless target molecules rather than just one. The Covalent Biosciences team sought to apply this technology to transthyretin amyloidosis and Alzheimer's disease, among other targets.

If we want to speculate as to the reasons why Covalent Biosciences failed to attract the necessary funding to run clinical trials, one might think that it was because they couldn't have picked a worse period of years to work on transthyretin amyloidosis and Alzheimer's disease. In the former case, therapies based on stabilizing transthryretin to prevent misfolding emerged to prove effective enough to give investors pause on funding other approaches yet to reach the clinic. In the latter case, amyloid-targeting immunotherapies deployed by large pharmaceutical companies have had their moment of success in recent years, eclipsing any alternative path to amyloid clearance for now.

Secondly, investors care about remaining patent life span, how much is left of the 20 years since the filing date. The high valuation of a drug development company derives from the legal monopoly over its technology given by a patent. Without that high valuation, a company cannot raise the enormous funds required by regulators set up manufacturing and run clinical trials. If a company goes too long without having successfully made the leap to the clinic, then its present and potential future value falters in the eyes of investors. Covalent Biosciences was working with core patents that were already well advanced in years.

One can hope that, once in the public domain, someone will advance the catalytic antibody platform and find uses for it. By the way that the biotech industry works, that will necessarily mean establishing some novel antibody or approach to catalytic antibodies in order to generate novel patents and start the clock ticking once more. Looking at what has happened elsewhere, this might take a decade or more to come to pass - look at how long it took for a company to emerge to pick up work on the DRACO antiviral approach. What we most likely won't see is a company making use of the existing advances and drug candidates, for the reasons of valuation and funding noted above; off-patent technologies do not attract funding, but still have the same regulatory costs. This is the same reason that generic drugs and supplements are largely ignored by the clinical industry, even if they might be very useful, such as the dasatinib and quercetin combination to clear senescent cells. If you think that there really should be a better way to run medical research and development, well, you are not the only one!

The balance of microbial species making up the gut microbiome has been shown to change with age. Inflammatory microbes grow in number at the expense of species that generate beneficial metabolites such as butyrate. Patients with neurodegenerative conditions, diseases that are characterized by chronic inflammation and immune dysfunction, have been shown to exhibit a distinctly dysfunctional gut microbiome. In human populations, there remain the questions on direction of causation, but in animal models researchers can quite readily demonstrate that transplanting a young gut microbiome into an old animal improves health, while the reverse happens when an old gut microbiome is transplated into a young animal.

Gut microbiota alteration during the aging process serves as a causative factor for aging-related cognitive decline, which is characterized by the early hallmark of hippocampal synaptic loss. However, the impact and mechanistic role of gut microbiota in hippocampal synapse loss during aging remains unclear. Here, we observed that the fecal microbiota of naturally aged mice successfully transferred cognitive impairment and hippocampal synapse loss to young mouse recipients. Multi-omics analysis revealed that aged gut microbiota was characterized with obvious change in Bifidobacterium pseudolongum (B.p) and indoleacetic acid (IAA), a metabolite of tryptophan, in the periphery and brain. These features were also reproduced in young mouse recipients that were transplanted with aged gut microbiota.

In human patients, fecal B.p abundance was reduced in patients with cognitive impairment compared to healthy subjects and showed a positive correlation with cognitive scores. Microbiota transplantation from human patients who had fewer B.p abundances into mice yielded worse cognitive behavior in the mice than transplants from human patients with higher B.p abundances.

Supplementation of B.p was capable of producing IAA and enhancing peripheral and brain IAA bioavailability, as well as improving cognitive behaviors and microglia-mediated synapse loss in 5xFAD transgenic mice. IAA produced from B.p was shown to prevent microglia engulfment of synapses in an aryl hydrocarbon receptor-dependent manner. This study reveals that aged gut microbiota induced cognitive decline and microglia-mediated synapse loss that is, at least partially, due to the deficiency in B.p and its metabolite, IAA. It provides a proof-of-concept strategy for preventing neurodegenerative diseases by modulating gut microbiome and their tryptophan metabolites.

Link: https://doi.org/10.1111/acel.70064

Epigenetic clocks of various sorts have become quite diverse in recent years, and it is worth noting that more recent clocks do not exhibit the insensitivity to physical fitness that was a characteristic of the earliest clocks. We should assume that any clock will have quirks, even those that do well with exercise. Since the relationships between specific causes and dysfunctions in aging and the specific epigenetic marks used in epigenetic clocks remain almost entirely unknown, a clock cannot be trusted to correctly assess the impact of any specific intervention on aging. The clock has to be calibrated against that intervention. This defeats the whole point of the exercise, which is to find ways to quickly assess the merits of potential novel rejuvenation therapies, without having to run lengthy studies to assess life span and mortality.

Epigenetic clocks include several specific measures such as HorvathAge, HannumAge, SkinBloodAge, LinAge, WeidnerAge, VidalBraloAge, ZhangAge, and PhenoAge. Ageing research increasingly focuses on understanding the biological mechanisms that contribute to ageing and how lifestyle factors, such as physical activity (PA), can influence these processes. The above epigenetic ageing indicators represent different approaches to estimating biological age and have been associated with various health outcomes. Recent studies have highlighted the stronger and more consistent associations between PA and epigenetic aging, especially with GrimAge.

This study investigates the relationship between physical activity (PA) levels and DNA methylation (DNAm)-predicted epigenetic clocks in a U.S. population sample (n = 948, mean age 62, 49% female). The eight above mentioned epigenetic clocks were analyzed, revealing that higher PA levels were significantly associated with younger biological ages across all indicators, with the strongest effects observed for SkinBloodAge and LinAge. Subgroup analyses indicated that these associations were more pronounced among non-Hispanic whites, individuals with a BMI of 25-30, and former smokers, suggesting that the impact of PA varies across different groups. These findings emphasize the role of PA in slowing biological ageing and reducing age-related health risks.

Link: https://doi.org/10.1038/s41514-025-00217-0

A great many studies have used large human population data sets to show statistical relationships between specific gene variants or specific protein levels on the one hand and age-related disease and mortality on the other. Near all of these relationships represent a small effect size, and further fail to replicate in different study populations. Still, researchers keep trying. Some successful replications have been achieved, and a few genes and proteins are generally accepted as being longevity-associated in humans. It remains unclear as to whether they are of any great practical relevance to extending the healthy human life span, however. Some, such as klotho and APOE, are the subject of programs to develop treatments to improve late-life health or treat specific age-related diseases.

Today's open access paper is an interesting example of establishing a protein association with increased mortality and accelerated aging, and then tracing it back to a relationship with lifestyle factors, cancer incidence, and mechanisms relating to cellular senescence. Senescent cells accumulate with age and are an important contributing factor in age-related disease and loss of function. The research focuses on PDAP1, a protein that appears to be upregulated in stressed and senescent cells, and also acts to induce senescence in bystander cells. One would imagine that the next step here is to run studies of PDAP1 inhibition in aged mice, to see whether long term health and mortality are improved.

Identifying PDAP1 as a Biological Target on Human Longevity: Integration of Mendelian Randomization, Cohort, and Cell Experiments Validation Study

Identifying factors affecting lifespan, including genes or proteins, enables effective interventions. We prioritized potential drug targets and provided insights into biological pathways for healthy longevity by integrating Mendelian randomization, cohort, and experimental studies. We identified causal effects of tissue-specific genetic transcripts and serum protein levels on three longevity outcomes: the parental lifespan, the top 1% and 10% extreme longevity, utilizing Mendelian randomization and multi-traits colocalization, combining the latest genetics data of gene expression (eQTLGen and GTEx) and proteomics (4746 proteins from five studies). We then evaluated associations of these potential genetic targets with mortality risk and life expectancy in the UK Biobank cohort. We performed in vitro cellular senescence experiments to confirm their effects.

Fourteen plasma proteins and nine transcripts in whole blood had independent causal effects on longevity, where a cascading effect of both the tissue-specific transcripts and plasma proteins of LPA, PDAP1, DNAJA4, and TMEM106B showed negative effects on longevity. PDAP1, also known as platelet-derived growth factor subunit A-associated protein 1, is a multi-tissue-expressed protein in the pathway that suppresses T-cell function. It has become a potential target for c-myc and contributes to carcinogenesis. Mediation analysis suggested that PDAP1 decreased longevity via decreased SHBG, increased waist circumference, blood pressure, smoking, and alcohol consumption in addition to cancer.

Studies also suggested that lower SHBG levels may increase testosterone levels, leading to cardiovascular risk factors. The harmful effects of altered diseases or traits were also consistent with the epigenetic acceleration of aging caused by PDAP1. These results were consistent with our findings from the UK Biobank, where the plasma level of PDAP1 was significantly associated with all-cause mortality and life expectancy. In addition, the in vitro experiments indicated targeting PDAP1 offers a dual advantage by potentially promoting senescence in cancerous cells to inhibit growth, while delaying senescence in healthy cells to enhance tissue regeneration and extend cellular lifespan.

Reactive astrocytes in brain tissue are those that have become inflammatory in response to the local environment. With aging this becomes a prevalent phenomenon, driven by forms of molecular damage characteristic of aging, which range from greater inflammatory signaling from other cells, including senescent cells, to the build up of metabolic waste in the brain as drainage of cerebrospinal fluid falters. Widespread astrocyte reactivity is maladaptive, and contributes to the onset and progression of neurodegenerative conditions. The research community tends not to focus on how to prevent reactivity, such as by repairing the damage of aging, but rather on the worse course of trying to force reactive astrocytes into better behavior, one aspect at a time. The research here is one example of this strategy in practice. Even if successful, the reactive astrocytes remain present, causing other problems in other ways.

Astrocytes, once thought to only support neurons, are now known to actively influence brain function. In Alzheimer's disease, astrocytes become reactive, meaning they change their behavior in response to the presence of amyloid-beta (Aβ) plaques, a hallmark of the disease. While astrocytes attempt to clear these plaques, this process triggers a harmful chain reaction. First, they uptake them via autophagy and degrade them by the urea cycle, as discovered in previous research. However, this breakdown results in the overproduction of GABA, which dampens brain activity and leads to memory impairment. Additionally, this pathway generates hydrogen peroxide (H2O2), a toxic byproduct that causes further neuronal death and neurodegeneration.

Researchers set out to uncover which enzymes were responsible for excessive GABA production, hoping to find a way to selectively block its harmful effects without interfering with other brain functions. Using molecular analysis, microscopic imaging, and electrophysiology, the researchers identified SIRT2 and ALDH1A1 as critical enzymes involved in GABA overproduction in Alzheimer's-affected astrocytes. SIRT2 protein was found to be increased in the astrocytes of the commonly used AD mouse model as well as in post-mortem human AD patient brains.

"When we inhibited the astrocytic expression of SIRT2 in AD mice, we observed partial recovery of memory and reduced GABA production. While we expected reduced GABA release, we found that only short-term working memory of the mice was recovered, and spatial memory was not. This was exciting but also left us with more questions. We found that inhibition of SIRT2 continued H2O2 production, indicating that neuronal degeneration might continue even though GABA production is reduced."

Link: https://ibs.re.kr/cop/bbs/BBSMSTR_000000000738/selectBoardArticle.do?nttId=25775

As researchers here note, age-related diseases of the retina are age-related because underlying mechanisms of damage and dysfunction place stress on cells, changing their function and even killing them. Measuring changes in gene expression that take place in stressed cells is one way to look at these unfortunate effects, though it gives little insight into the fine details of why cell behavior changes. The various forms of damage and dysfunction that cause aging are fairly well catalogued, but it is presently unknown as to how they interact with one another in detail, and which of them is the most important in any given context. The easiest way to find out at present is to build a therapy that can address a form of damage, and test it in animal models.

Aging of the retinal pigment epithelium (RPE) leads to a gradual decline in RPE homeostasis over time, significantly impacting retinal health. During the physiological aging process, retinal tissues undergo functional decline and degeneration with the RPE serving as the primary site of damage in many age-related retinal diseases. While aging itself may not invariably lead to the onset of conditions such as age-related macular degeneration (AMD), retinitis pigmentosa (RP), and diabetic retinopathy (DR), age-related changes can predispose the eye to these diseases

Understanding the mechanisms underlying RPE aging is crucial for elucidating the background in which many age-related retinal pathologies develop. In this study, we compared the transcriptomes of young and aged mouse RPE and observed a marked upregulation of immunogenic, proinflammatory, and oxidative stress genes in aging RPE. Additionally, aging RPE exhibited dysregulation of pathways associated with visual perception and extracellular matrix production.

Link: https://doi.org/10.18632/aging.206219

About a decade ago, researchers developed a way to use magnetic resonance imaging (MRI) to measure the passage of fluid through channels leading from the brain into the body. One can use MRI to assess the diffusion of water molecules in many small volumes of scanned tissue. If there is a flow, then it appears as though the "diffusion" is biased in a specific direction. There is one small section of the glymphatic system that drains cerebrospinal fluid from the brain in which the vessels run in parallel, and this allows researchers to measure the flow of cerebrospinal fluid from the brain.

This ability to measure glymphatic fluid flow is important because the drainage of cerebrospinal fluid from the brain into the body carries away metabolic waste with it. This process of drainage occurs through a few different important channels, but the flow rate declines with age in all of them. Researchers hypothesize, and with a growing body of experimental and epidemiological data to support these hypotheses, that impaired drainage allows a buildup of waste in the brain that contributes to inflammation and neurodegeneration. You might recall a recent study linking reduced glymphatic flow with progression of Alzheimer's disease. In today's open access paper, researchers perform much the same study for the earlier progression of mild cognitive impairment leading into the initial onset of Alzheimer's disease. Again, an impaired drainage of cerebrospinal fluid correlates with worse loss of cognitive function and progression towards disease.

One can be done about this? Well, there are some promising initial signs. Loss of glymphatic flow may be largely a problem of dysfunctional lymphatic vessels, unable to contract efficiently enough to sustain a pulsatile flow of fluid. Classes of drug that affect the smooth muscle that surrounds these vessels were recently shown restore the ability of aged glymphatic vessels to drive fluid flow. Further, since a great deal of work has gone into ways to manipulate blood vessel behavior, and blood and lymphatic vessels share many similarities, there may be more existing options beyond this that will also work to restore cerebrospinal fluid drainage.

Poor glymphatic function is associated with mild cognitive impairment and its progression to Alzheimer's disease: A DTI-ALPS study

The glymphatic and meningeal lymphatic systems are crucial for clearing metabolic waste from cerebrospinal fluid (CSF) in the brain, and their dysfunction, particularly regarding the accumulation of amyloid-β and extracellular tau, may contribute to Alzheimer's disease (AD). Recently, researchers developed a method to measure diffusivity along the perivascular space (ALPS) based on diffusion tensor images, which allows for noninvasive and efficient assessment of glymphatic function. This approach quantifies the diffusion of water within the perivascular space along deep medullary veins and has been correlated with glymphatic clearance by dynamic contrast-enhanced imaging. Recent studies have shown that the ALPS index is associated with cognitive decline, AD, and multiple neurological disorders, and might serve as a biomarker for neurodegenerative diseases. However, no studies have been conducted on the association of ALPS index with mild cognitive impairment (MCI) and its progression to AD.

This study included 519 adults including 253 cognitively normal (CN) and 266 MCI participants from Alzheimer's Disease Neuroimaging Initiative. Glymphatic function (assessed by along the perivascular space [ALPS] index) was measured by diffusion tensor image at baseline. During follow-up (median 3.6 years), 30 (11.86%) participants developed MCI in the CN cohort and 73 (27.4%) participants progressed to AD in the MCI cohort. The hazard ratios of the higher ALPS index, indicating greater glymphatic flow, was 0.605 for MCI and 0.501 for AD. In addition, participants with high ALPS index had 3.837 and 3.466 years prolonged onset of MCI and AD, separately.

In conclusion, high ALPS index decreases MCI risk and delays MCI progression to AD by approximately 3.5 years. Amyloid-β in choroid plexus, tau in cortex, and executive function may partially mediate the MCI-AD progression in relation to ALPS index.

Aged tissues are characterized by increased levels of oxidative stress, meaning the generation and presence of more oxidizing molecules than cells can comfortably handle. A major source of oxidizing molecules is the activity of mitochondria, and an increase in this production of oxidizing molecules is one of the reasons why mitochondrial dysfunction is important in aging. Oxidative reactions damage molecular machinery in the cell, impairing function. Lipid molecules are particularly vulnerable to oxidation that produces damaging consequences. To cope with this, cells can either more aggressively repair that damage or more aggressively produce antioxidants, but there are limits to the degree to which these approaches can compensate.

Lipid peroxidation involves a series of chemical reactions in which lipid molecules, particularly polyunsaturated fatty acids (PUFAs), are oxidatively attacked by free radicals or non-radical species in the cell membrane or intracellular structures. This process generates lipid radicals and peroxides, which damage the cell membrane structure and function, triggering a chain reaction that further impairs cellular function and induces apoptosis.

Cells have endogenous defense mechanisms to counteract this oxidative damage. The main defense mechanisms include antioxidant enzyme systems (such as superoxide dismutase, catalase, and glutathione peroxidase) and non-enzymatic antioxidants (such as glutathione, vitamin E, and vitamin C). These mechanisms protect cells from oxidative damage by scavenging reactive oxygen species (ROS) and neutralizing lipid peroxidation products. However, under aging or chronic disease conditions, these endogenous defense mechanisms may be impaired, leading to elevated lipid peroxidation levels and exacerbating cellular damage, potentially contributing to diseases such as muscle atrophy.

In sarcopenia, lipid peroxidation may impact muscle health through several pathways. Firstly, lipid peroxidation products directly damage muscle cell membranes, leading to apoptosis and muscle loss. Secondly, lipid peroxidation products can induce inflammation and oxidative stress, further exacerbating muscle damage. Additionally, lipid peroxidation influences sarcopenia through various mechanisms, including metabolic disorders, ferroptosis, mitochondrial dysfunction, autophagy and apoptosis, extracellular matrix remodeling, cell signaling pathways, as well as lifestyle and nutritional factors. This review summarizes the current research on lipid peroxidation and sarcopenia, including the molecular mechanisms by which lipid peroxidation influences muscle atrophy, protective mechanisms that reduce lipid peroxidation in slowing sarcopenia progression, and lipid peroxidation-based therapeutic strategies for sarcopenia.

Link: https://doi.org/10.3389/fmed.2025.1525205

Researchers here find that one of the protein components of nuclear pore structures has an independent function in regulating the response to nutrient sensing. As is now well known, low nutrient availability resulting from reduced calorie intake triggers a range of adaptive responses that collectively act to slow the progression of aging. Evidence suggests that increased autophagy is the most vital of these mechanisms, but it is far from the only mechanism involved. Thus interventions such as mTOR inhibitors that increase autophagy are beneficial, but not as beneficial as calorie restriction.

The nuclear pore complex (NPC) is a massive protein complex that is best known for its role in gating communication between the cell cytosol and nucleus. The NPC consists of about 30 different proteins, known as nucleoporins, as a heteromultimeric assembly of more than 1000 protein subunits that mediate nuclear pore permeability, active transport, and on-site transcription.

In this study, we demonstrate that the NPC subunit NPP-16/NUP50 bridges energy sensing and metabolic adaptation independently of its canonical role in nuclear permeability and transport. In response to energetic and nutrient stress, NPP-16/NUP50 is post-translationally activated by AMPK, and subsequently promotes the transcription of lipid catabolic genes. Overexpression of NPP-16/NUP50 is sufficient to induce lipid catabolism in both nematodes and mammalian cells. NPP-16/NUP50 overexpression robustly extends the lifespan in C. elegans by enhancing the transcriptional activity of the metabolic transcriptional regulators NHR-49/HNF4 and HLH-30/TFEB, driving lipid catabolism.

Unlike scaffold nucleoporins, altered levels or activity of NPP-16/NUP50 do not affect nuclear transport and permeability; instead, increased NPP-16/NUP50 levels are necessary and sufficient to promote metabolic adaptation and longevity via interaction of its intrinsically disordered region (IDR) with the promoters of lipid catabolic genes. Our findings identify a heretofore unappreciated, conserved role of a specific nucleoporin in energy sensing and deployment of metabolic stress defenses against aging and further uncover a noncanonical role for nucleoporin IDRs in direct transcriptional regulation.

Link: https://doi.org/10.1101/2025.02.17.638704

To what degree is the burden of senescent cells in the tissues of old or obese people dynamic, capable of being reduced by circumstances? Cells become senescent constantly throughout life, and are then cleared by the immune system or destroy themselves via programmed cell death mechanisms. That clearance falters with advancing age, however. We might also think that the pace at which cells become senescent is likely higher in tissues stressed by the molecular damage of aging or by the aberrant metabolism of obesity, but there is less direct evidence for this to be the case than there is for impaired immune clearance of senescent cells. It is certainly the case that obese individuals have a higher burden of senescent cells than their similarly aged peers, and this makes it worth paying some attention to what is learned of the way in which this burden changes in response to lifestyle.

Can one produce much the same effects of a senolytic therapy to clear senescent cells, but slowly over time via exercise? It seems to the case that either slowing the creation of senescent cells or incrementally improving clearance via the immune system can reduce the number of senescent cells in tissue over time. A study of senescent cells in skin treated with a topical mTOR inhibitor, which does not kill senescent cells, but does slow their creation, shows that even in older people the immune system is still destroying senescent cells. Given enough time of a lower pace of creation the immune system can catch up to reduce the burden of senescent cells to a lower level. Whether exercise is acting through a slowed pace of creation of senescent cells or an improvement to immune function is an interesting question - there are good arguments in either case.

That said, the size of the effect of exercise on the burden of cellular senescence leaves something to be desired; today's open access paper shows that exercise clearly isn't as good as a senolytic drug after only four weeks of physical training. The aforementioned topical mTOR inhibition study ran for half a year, so it is always possible that better effects would be be seen after a much longer period of training. Nonetheless, there really isn't that much data on how the burden of cellular senescence can be shifted by lifestyle choice alone. Given the amazing results in reversal of age-related conditions produced by senolytic therapies in mice, and the inability to achieve the same outcome by exercising mice, it does seem unlikely that six months of becoming more fit could achieve the same results as a robust senolytic treatment, however.

Physical training reduces cell senescence and associated insulin resistance in skeletal muscle

Cell senescence (CS) is a conserved aging mechanism characterized by the irreversible arrest of the cell cycle along with alterations in cell function and the secretion of pro-inflammatory factors collectively known as the senescence-associated secretory phenotype (SASP). This process contributes to chronic inflammation, tissue dysfunction and a reduced capacity for cell regeneration. As individuals age, senescent cells accumulate in various tissues, including skeletal muscle (SkM), impairing muscle function and leading to sarcopenia, the age-related loss of muscle mass and strength. Impairment of SkM function can lead to significant metabolic disturbances. Since SkM is a primary site for glucose uptake, dysfunction in this tissue results in reduced insulin responsiveness, contributing to metabolic disorders such as type 2 diabetes (T2D). This highlights the importance of maintaining muscle health to prevent adverse metabolic outcomes.

Obesity is a well-established risk factor for numerous chronic diseases which can accelerate the onset of aging in several metabolic tissues, including SkM, by promoting CS. Indeed, obesity triggers local tissue inflammation, oxidative stress and metabolic abnormalities, which are key drivers of CS also in SkM. Chronic low-grade inflammation originating from the adipose tissue in obesity, as well as insulin resistance and altered muscle metabolism, are factors that can contribute to the acceleration of muscle aging and dysfunction.

CS can impact multiple cell types within SkM, including muscle stem cells (satellite cells), fibrogenic/adipogenic progenitors and resident immune cells, each of which plays a crucial role in muscle regeneration and maintenance. Satellite cells, which are normally quiescent, become activated in response to muscle injury or stress leading to proliferation and differentiation into new muscle fibers, thereby playing a critical role in skeletal muscle generation and repair. Thus, senescence in satellite cells can have profound consequences on SkM health, leading to diminished muscle maintenance, impaired regeneration, reduced responsiveness to exercise, and increased metabolic dysfunction.

Regular physical exercise is a highly effective strategy for preserving SkM function and metabolic health, while also reducing several chronic diseases associated with age. Exercise interventions have also been shown to reduce circulating biomarkers of CS in man and the burden of senescent cells linked to aging and age-related conditions in colon mucosa. However, very little is known about the impact of exercise on CS in SkM itself. Understanding if exercise may influence senescence markers in SkM is crucial, as it could provide insights into mechanisms that promote healthy aging of SkM and improve metabolic health.

In this study, we investigated the effects of physical exercise on CS markers in human SkM by analyzing muscle biopsies from people with normal body weight and with obesity, before and after regular exercise. Notably, physical intervention led to significant improvements in metabolic parameters, a reduction in CS markers and activation of satellite cell responses. Moreover, in vitro experiments demonstrated that senescence negatively impacts satellite cells by reducing key regulatory genes and impairing insulin signaling. Together these findings underscore the critical role of CS in regulating insulin sensitivity and highlight the potential of physical exercise as a therapeutic strategy to mitigate these effects in human.

The ability of PF4 to reduce chronic inflammation and restore some degree of lost function in the aging brain has been a topic of interest for a few years now. We'll likely be hearing much more in the years ahead as researchers move from investigation to attempts to build therapies based on the direct upregulation of PF4 expression. That said, one might look at the decades it has taken investigations of klotho to move from interesting science to initial attempts at clinical applications. Biotechnology is not a field known for rapid progress from lab to clinic.

Platelet factor 4 (PF4), a platelet-derived chemokine found in the blood, has been identified as a critical factor in modulating the rejuvenation of the aged brain. Increasing evidence suggests that PF4 secretion is a prerequisite for the cognitive benefits associated with young blood transfusion, the longevity factor klotho, and exercise. Systemic administration of exogenous PF4 has been shown to reduce circulating pro-aging immune factors and restore peripheral immune function in the aged brain by mitigating age-related hippocampal neuroinflammation, promoting molecular changes in synaptic plasticity, and improving cognitive function in aged mice.

Clinically, reduced serum PF4 levels have been significantly associated with cognitive decline and core pathological biomarkers in Alzheimer's disease. Mechanistically, the chemokine receptor CXCR3 partially mediates the cellular, molecular, and cognitive benefits of systemic PF4 administration in the aged brain. However, several critical questions remain, including the potential role of PF4 in blood-brain communication, its interaction with neurotransmitters and neuropharmacological processes, and how these findings might be translated into clinical practice.

Link: https://doi.org/10.17305/bb.2025.11960

Given sufficient sensitivity and the right target, many age-related conditions could be detected in their earliest, pre-symptomatic stages. Early detection offers a greater opportunity to change course to slow progression, even with the techniques of today. Here, researchers note a specific transfer RNA fragment that appears in the context of Parkinson's disease. Transfer RNAs are necessary for the process of translation, where proteins are produced from the template of a messenger RNA by a ribosome. The transfer RNA shows the ribosome how to translate messenger RNA sequences to specific protein amino acid sequences. Thus widespread changes in cell status could in principle be reflected in some way in circulating remnants of transfer RNA, given sufficient sensitivity for a test.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease. PD diagnosis often follows considerable neuronal damage manifested as severe motor impairments, such as bradykinesia, rigidity, and tremors. However, earlier symptoms, including smell loss and rapid eye movement sleep disorders, may appear years beforehand. Molecular changes characteristic of this early disease phase may constitute a basis for a pre-symptomatic diagnostic test.

Recent PD diagnostic tests have focused on elevated cerebrospinal fluid (CSF) levels of the α-synuclein (α-Syn) protein or reduced blood mitochondrial DNA as biomarkers. However, CSF sampling is invasive; purification and detection of α-Syn are cumbersome and insufficiently sensitive; and measurements of specific proteins show high inter-individual variability. Ideally, an easy, safe and affordable diagnosis should be based on multiple highly sensitive and specific blood biomarkers.

From our study, transfer RNA fragments (tRFs) carrying a conserved sequence motif (RGTTCRA-tRFs) emerged as potentially suitable biomarkers that may constitute patient-specific 'fingerprints' and carry short conserved sequence motifs that enable single measurement of multiple tRFs. Intriguingly, we found that RGTTCRA-tRFs accumulate in the brain, CSF and blood of male and female patients with PD at diverse disease stages but not in matched controls or in patients with Alzheimer's disease. Moreover, motif-carrying RGTTCRA-tRFs consistently showed linkage to PD symptoms and disease stages, and their levels were elevated in correlation with Lewy body scores in patients' substantia nigra.

Additionally, part of the identified RGTTCRA-tRFs stem from tRNAs that carry phenylalanine or cysteine amino acids, known to be the rate-limiting factors in the dopamine synthesis and in glutathione reductase antioxidant mechanism, respectively. Thus, shortage of these intact tRNAs (as they are enzymatically cut into the observed tRFs) may correspond to impaired dopamine synthesis or to processes that limit cellular antioxidation. Compatible with the known mitochondrial damage in PD (which leads to general reduction in mitochondrial transcript levels), we further found reduced levels of mitochondrial tRFs in the CSF and substantia nigra of idiopathic PD patients and in the blood of early PD patients carrying disease-related mutations.

Link: https://doi.org/10.1038/s43587-025-00851-z

Senescent cells accumulate with age in all tissues, including skin. These errant cells secrete inflammatory signals that degrade tissue structure and function when sustained for the long term. OneSkin is one of the earlier longevity industry companies, built on the development of a senotherapeutic compound called OS-01. The founders chose to take the topical, cosmetics regulatory pathway to market. It is a lot faster than drug development, but has drawbacks, such as being taken less seriously by the scientific community.

OS-01 reduces the burden of senescence in tissue models of skin, suggesting that it encourages senescent cells to undergo programmed cell death. But it still could be the case that it primarily functions by slowing the pace at which cells become senescent, allowing processes of clearance to catch up. If one looks at mTOR inhibitors applied at low doses to skin, they have been shown to act to reduce the burden of senescence over a period of months, and we know that mTOR inhibitors do not kill senescent cells.

Today's open access paper is the latest published by the OneSkin team, in which they show use of OS-1 to correlate with reduced systemic markers of inflammation in addition to improved skin function. This is an interesting result. Skin is by far the largest organ in the body, and as a result of this, it is thought that senescent cells in aging skin contribute meaningfully to inflammation throughout the body. The OneSkin paper isn't clear on how much of the skin for any given individual was treated with OS-1, and the control treatment should have been the OneSkin formulation minus OS-1 rather than a different commercial formulation. That and the relatively small study population means that we should take this less at face value and more as a strong incentive for someone to fund a much larger study of the effects of topical senotherapeutic use on systemic markers, whether with OS-1 or low dose mTOR inhibitors.

OS-01 Peptide Topical Formulation Improves Skin Barrier Function and Reduces Systemic Inflammation Markers: A Pilot 12-Week Clinical Trial

As the body's largest organ, the skin plays a crucial role in defending against external stressors. Skin characteristics change with age, decreasing skin barrier integrity and compromising skin and body health. This study aimed to investigate the potential of a topical formulation containing OS-01 (a.k.a. Peptide 14), a senotherapeutic peptide, to counteract age-related skin changes and their systemic consequences.

A randomized, double-blinded clinical trial involving 60 female volunteers aged 60-90 was conducted over 12 weeks. Participants received either an OS-01 topical formulation or a commercially available moisturizer control formulation. Skin parameters, subjective perceptions, and circulating cytokine levels were assessed. Skin instrumental analysis included transepidermal water loss (TEWL), skin hydration, and pH measurements.

Participants treated with the OS-01 topical formulation displayed significantly improved skin barrier function and hydration compared to the control group. Participant perceptions aligned with objective findings: after 12 weeks, 70% of participants in the OS-01 group noticed an improvement in general skin appearance versus 42% for the control group. The systemic levels of proinflammatory cytokines tended to normalize, with a significant decrease in IL-8 in the blood analysis of participants from the OS-01 group. On the other hand, the control group demonstrated an increase in a few circulating cytokines, particularly TNF-ɑ and IFN-γ. Moreover, GlycanAge analysis measuring participants' biological age suggested the slowing of systemic aging in the group treated with the OS-01 topical formulation.

The study suggests that the OS-01 formulation can impact skin health by improving the skin barrier function, potentially influencing systemic inflammation and biological age. In conclusion, the study supports that targeting skin health may contribute to better longevity outcomes, underscoring the skin's pivotal role in systemic aging and supporting an integrated approach to health management.

A sizable body of evidence demonstrates that exposure to particulate air pollution correlates with an increased risk of neurodegenerative conditions and cognitive decline with age. The most plausible biological explanations revolve around the harmful downstream effects of increased inflammation resulting from the interaction of particles with cells in the respiratory system. Inflammation sustained over the long term, even at relatively low levels, is disruptive to cell and tissue function, contributing to the onset and progression of age-related disease. Ways to control unwanted inflammation that do not also suppress the necessary inflammatory response to infection and injury would likely prove to be very beneficial, reducing many of the contributions to aging and age-related disease.

There is growing evidence that exposure to particulate matter (PM) is associated with impaired cognitive function. However, limited studies have specifically examined the relationship between PM exposure and domain-specific cognitive function. This study involved 2,668 female participants from the Lifestyle and Healthy Aging of Chinese Square Dancer Study. Global cognitive function was assessed using a composite Z-score derived from four tests: the Auditory Verbal Learning Test (AVLT), Verbal Fluency Test (VFT), Digit Symbol Substitution Test (DSST), and Trail Making Test-B (TMT-B). These tests evaluated specific cognitive subdomains: memory (AVLT), language (VFT), attention (DSST), and executive function (TMT-B).

After adjusting for basic sociodemographic factors, a 10 mg/m3 increase in 3-year exposure to PM10 was significantly associated with a worse DSST score by -0.05 and a worse TMT-B score by 0.05. When further adjusting for gaseous pollutants (SO2, NO2, and O3), even stronger associations were observed between 3-year exposure to either PM2.5 or PM10 and performance in both global cognition and specific cognitive subdomains. Specifically, in the DSST subdomain, a 10 µg/m³ increase in 1-year PM10 exposure was associated with a worse score by -0.10. Age-stratified analyses further indicated that older participants were consistently more vulnerable to PM exposure. Notably, 3-year exposure to both PM2.5 and PM10 was linked to declines in DSST scores across both middle-aged and older age groups.

Link: https://doi.org/10.1186/s12889-025-22126-3

The evidence for long term exposure to forms of air pollution to increase the risk of age-related disease and mortality is quite compelling, including large studies in very similar populations with different levels of exposure. The important underlying mechanism is likely increased chronic inflammation deriving from the interactions of respiratory system tissues with particles and chemicals characteristic of industrial air pollution. Unresolved, constant inflammation drives dysfunction in the aging body and brain, contributing to the onset and progression of all of the common age-related conditions.

The longitudinal association between multiple air pollutants and frailty risk remains unexplored, and it is unclear which factors may modify this relationship. Using data from 10,584 Chinese adults aged 45 years and older in the 2011-2020 waves of the China Health and Retirement Longitudinal Study (CHARLS), we investigated whether exposure to PM1, PM2.5, PM10, O3, and NO2 affects frailty over a median follow-up of seven years. Air pollutant data were obtained from the China High Air Pollutants (CHAP) dataset, and frailty was assessed using a 44-item Frailty Index (FI ≥ 0.25).

Time-varying Cox proportional hazards models, adjusted for demographic, socioeconomic, and behavioral factors, indicated that each 10 μg/m³ increase in PM1, PM2.5, PM10, and NO2 corresponded to a 7.8%, 4.2%, 3.8%, and 12.9% higher risk of frailty, respectively, while O3 showed no significant association. Individuals who were sufficiently active appeared less affected by pollution, whereas those with no formal education were more vulnerable. Implementing future policies and interventions to reduce air pollution can potentially decrease the risk of frailty and promote healthy ageing.

Link: https://doi.org/10.1016/j.jhazmat.2025.138105

There may be a tendency for the unfit to look at the fit and feel somewhat hopeless, that a mountain lies between where they stand in unfitness and any benefits that might result from exercise. In fact, the data on exercise and measures of health suggests quite the opposite. The further removed from the pinnacle of fitness one stands, the more one benefits from just a little incremental extra exercise. When actually fit, adding additional exercise to the schedule brings only diminished benefits. So one sees studies of older people in which, when using accelerometers to accurately measure differences in lower levels of activity, those who walk and garden a little are far better off than those who are more sedentary.

This applies more or less regardless of how impacted by aging and disease one is. Thus in today's open access paper, covering the results of a study of physical activity in hypertensive patients, the most sedentary have a worse prognosis than those who exercise at least a little. Becoming more fit is actually one of the better ways to treat hypertension, though it has to be said that having high blood pressure is so very damaging that the well-established antihypertensive drugs can appear an attractive option over the time taken for physical activity to control high blood pressure to the same degree as the pharmaceuticals can.

Effects of physical activity on blood pressure and mortality among aged hypertensive patients: A cross-sectional study

More than 1 billion individuals across the globe are affected with hypertension (HTN). One of the leading causes of cardiovascular illness and death globally is HTN. It is a major risk factor for cardiovascular disease in the elderly, which accounts for around 13.5% of all deaths worldwide. The risk of cardiovascular disease is doubled for every 20/10 mm Hg increase in systolic/diastolic blood pressure (SBP/DBP). Cardiovascular events and all-cause mortality are still linked to high SBP levels, even in elderly HTN patients who are taking antihypertensive medication. To reduce the possibilities of cardiovascular events and mortality, it is crucial to focus on reducing blood presure (BP) in elderly individuals with HTN.

We conducted a cross-sectional study using 10 cycles of the National Health and Nutrition Examination Survey data from 1999 to 2018. Our sample consisted of respondents aged 65 years or older with HTN, who underwent thorough in-person home interviews. We used a questionnaire to assess their physical activity (PA) levels and divided them into 2 groups: physically active and inactive. We then used logistic analysis to determine the association between PA and death in HTN patients. The gender distribution was nearly equal among the 11,258 participants, with a mean age of 74.36 ± 5.88 years.

Patients in the physically active group were less likely to suffer from comorbidities than those in the inactive group. A negative correlation was found between physically active and systolic blood pressure and a positive correlation between physically active and diastolic blood pressure. There was a much higher risk of death from any cause and heart disease in the inactive group in the uncorrected proportional hazards model (all cause hazard ratio 2.96; cardiovascular hazard ratio 3.48). The risk of death from any cause and HTN mortality was still significantly higher in the physically inactive group, even after controlling for age, sex, and race or taking all covariates into account. These results emphasize the importance of PA in reducing the risk of HTN and mortality in aged patients.

The inflammatory signaling produced by senescent cells is harmful when sustained over the long term, and the number of these cells grows with age. Much of the signaling produced by cells is carried in extracellular vesicles, and here researches identify CAP1 as a important cargo in senescent cell extracellular vesicles that accelerates dysfunction and increases the burden of cellular senescence in the endothelium that lines blood vessels. Senescence of endothelial cells is a significant contributing factor in the formation and growth of atherosclerotic plaques.

Endothelial senescence (ES) contributes to aging-related disorders and triggers a senescence-associated secretory-pattern (SASP), releasing Extracellular Vesicles (EVs), potentially impacting atherosclerosis. We used EVs from young (8 weeks) and aged (24 months) ApoE-knockout mice to detect ES in human aortic endothelial cells (HAEC) and coronary endothelial cells (CAEC). Age-related atherosclerosis was confirmed by increased atheroma plaque formation in aged compared to young ApoE-knockout mice fed a high-fat diet, and the contribution of EVs from aged ApoE-knockout mice on ES was evidenced by a replicative senescence assay in cultured HAEC and CAEC, starting with the promotion of ES.

A proteomic analysis depicted the recently PCSK9-associated CAP1 protein as a cargo component in EVs from aged animals and highly expressed in mouse and human endarterectomy plaques. Gene silencing of CAP1 inhibited HAEC and CAEC ES while overexpressing CAP1 in these cells restored the senescent-phenotype. The in vivo contribution of CAP1 was assessed by injecting CAP1-containing EVs isolated from aged ApoE-knockout mice into wild-type (WT) mice fed either a regular or high-fat diet.

Compared to the EVs from young mice, the CAP1-containing EVs led to a pronounced ES along with the formation of intraluminal atheroma plaques. Similarly, young ApoE-knockout mice developed thickened and calcified atheroma plaques, along with increased ß-Gal-positive aortic staining when injected with EVs isolated from aged ApoE-knockout mice, like the atheroma plaques observed in aged ApoE-knockout animals. In conclusion, early molecular targets of ES may contribute to better management of atherosclerosis, in which here we unveiled CAP1 as a new molecular target.

Link: https://doi.org/10.1186/s13062-025-00646-7

The immune system of the central nervous system is distinct from that of the rest of the body, although there is a great deal of direct and indirect cross-talk between the two. The innate immune cells known as microglia are the central nervous system version of macrophages, and are involved in defense against pathogens, clearance of metabolic waste, and aspects of the normal function of brain tissue, such as maintenance of synaptic connections between neurons. With age, microglia become increasingly inflammatory, and many lines of evidence suggest that this behavior becomes maladaptive and is important in driving the onset and progression of neurodegenerative conditions. The research community is engaged in the search for ways to manipulate microglia into a better pattern of behavior, such as the example here.

Tim-3 is an immune checkpoint molecule involved in immunity and inflammation recently linked to late-onset Alzheimer's disease (AD), but its role in the brain was unknown until. Now researchers have used preclinical models to uncover Tim-3's role in microglia, the brain's resident immune cells, and have identified it as a promising therapeutic target for Alzheimer's disease. "Microglia are pivotal in neuroinflammation and neurodegeneration, and therapeutic targeting of Tim-3 in microglia may alter them to an optimal state to fight the disease pathology in AD."

Using a mouse model of AD, researchers determined that Tim-3 is only expressed in microglia in the central nervous system, where it helps the cells maintain a healthy state of homeostasis. Tim-3 can also, however, prevent the brain from effectively clearing out the toxic amyloid plaques that accumulate during AD. The researchers found that deleting Tim-3 helped kickstart plaque removal by prompting the microglia to eat up more of the plaques, while also producing anti-inflammatory proteins to reduce neuroinflammation, and limiting cognitive impairment.

Over a half-dozen clinical trials are currently testing therapeutics that target Tim-3 to treat patients with immunotherapy-resistant cancers. The new study highlights the therapeutic potential of adapting these treatments to enhance plaque clearance and mitigate neurodegeneration in Alzheimer's disease.

Link: https://www.massgeneralbrigham.org/en/about/newsroom/press-releases/potential-alzheimers-target-in-brain-immune-cells

Elastin is an important component of the extracellular matrix in flexible tissues. It is, as the name might suggest, necessary for tissue elasticity. Elastin fibers in the extracellular matrix become damaged with age, and this process is thought to be important in a number of ways, not just because it alters the structural properties of the tissue, but also because it changes cell behavior for the worse. The presence of elastin fragments can provoke inflammation or other maladaptive responses, for example. It isn't entirely clear how best to tackle this aspect of aging, as elastin fibers are near all created during development, and cells make relatively little elastin in adult life. Some form of controlled recreation of developmental activities would likely be needed, coupled with some way to selectively clear out damaged elastin.

In today's open access paper, researchers review an entirely different aspect of elastin, meaning what it might be doing inside cells rather than outside cells in the extracellular matrix. Interestingly, elastin may be protective, acting to help cells resist cellular senescence in response to stress by interacting with mitochondria in some way. It remains unclear as to what is going on in detail; at this stage, researchers are taking the traditional path of disabling elastin expression and examining the consequences. Building a coherent picture of the underlying interactions that take place in a normal cell between elastin and mitochondria is a longer term prospect.

ELN regulates cellular senescence: emerging hypothesis for a non-canonical role

Tropoelastin, also named elastin, is an essential protein. It is encoded by the ELN gene as a secreted monomer. In the extracellular matrix, it undergoes complex and organized post-translation modifications, mainly crosslinking, to form mature elastic fibers. To date, research on ELN has been mainly focused on elastic fibers. Whether ELN also exerts non-canonical elastic fiber-independent functions, which could contribute to ELN role in physiological and pathological conditions, is barely known.

Elastic fibers are mainly produced during development and at young age, and then ELN expression decreases and largely ceases in adulthood. With aging, or during exposures that cause accelerating aging, elastic fibers are damaged without possibility of proper repair. This deterioration is thought to contribute to physiological tissue and organism aging as well as to pathological aging, altering parameters such as breath capacity during chronic obstructive pulmonary disease or blood circulation in some cardiovascular diseases.

In addition to exerting mechanical effects on tissues, the degradation of elastic fibers during the aging process or the development of age-related diseases also results in the production of elastin-derived peptides (EDP), also known as elastokines. These peptides have the potential to exert biological activity and have been linked to a range of detrimental effects, including those observed in pathologies associated with senescent cells.

The links of ELN or cellular senescence with the processes of aging and age-related diseases have prompted the suggestion that the two may be functionally connected. A key role of ELN in the regulation of cellular senescence has recently been demonstrated. Interestingly, this new function has been found to probably be independent of elastic fibers. All the studies concluded that ELN protects from cellular senescence, nevertheless the use of different tools and cells make more advanced direct comparison of the results hazardous.

Transcriptome and Gene Set Enrichment Analysis (GSEA) of fibroblasts upon ELN knockdown revealed a significant enrichment of a gene set associated with response to oxidative stress. An increase in mitochondrial reactive oxygen species was indeed detected early after ELN downregulation, supporting that ELN loss impacts mitochondria. We propose that loss of ELN results in alterations of the mitochondrial electron transport chain activity, which is a strong candidate to mediate reactive oxygen species production and senescence induction. Still, we can speculate that elastic fibers, by impacting elasticity and mechano-transduction, and/or when degraded by releasing elastokines and by inducing specific signaling, could also regulate cellular senescence through other mechanisms.

We might think of medicine as largely a matter of exerting control over cells, beginning with changing their behavior in defined ways, and moving on to creating cells and complex structures made of cells as needed. For all that this is an age of biotechnology, the research community has yet not advanced all that far along this road. Present capabilities are far removed from what we know to be possible in principle. Greater control over cells and ability to build with cells will enable many forms of rejuvenation, regeneration, and replacement relevant to treating age-related diseases and extending healthy life.

In regenerative medicine, there are three major therapeutic categories known collectively as the "R3" paradigm: (1) Rejuvenation - restoring the functional capacity of existing cells or reversing cellular aging processes; (2) Regeneration - stimulating repair or regrowth of tissues using stem cells or host repair mechanisms; and (3) Replacement - directly substituting lost or damaged cells with functional ones. The objective of this review is twofold: (1) to critically analyze the processes of cellular senescence that contribute to neurodegenerative disorders, and (2) to discuss cell-based strategies in the R3 context.

In recent years, remarkable advancements have been made in the field of regenerative medicine. By integrating R3 concepts, we distinguish how certain approaches focus on rejuvenation, some on regeneration, and others on outright replacement. These strategies aim to counteract the effects of aging and mitigate neurodegeneration by specifically targeting the underlying mechanisms of aging, such as cellular senescence. This review comprehensively examines the mechanisms of cellular senescence and explores potential R3 strategies. Specifically, it summarizes the role of cellular senescence in neurodegenerative diseases, highlighting its contributions to disease onset, progression acceleration, and the hindrance of traditional treatment effectiveness.

Additionally, various cell-based strategies, such as stem cell therapy, direct lineage reprogramming, and partial reprogramming, are explored. Their potential benefits and challenges in treating neurodegenerative diseases are evaluated, with a focus on how these strategies may target senescent cells to restore functionality (rejuvenation), enhance endogenous repair (regeneration), or replace lost neurons (replacement). By delving into these underlying mechanisms and investigating innovative therapeutic approaches, we aim to pave the way for more effective treatments that can enhance patients' quality of life and potentially delay or even reverse the aging process.

Link: https://doi.org/10.1186/s13287-025-04285-7

Researchers here look at differences in life expectancy by income over the period of time in which obesity emerged to became a major issue. Recall that income, wealth, status, education, intelligence, and life expectancy all tend to correlate with one another, and identifying the arrow of causation is a challenge. Researchers found that the difference in life expectancy between high income and low income segments of the population has widened over the past 60 years. The glass half full viewpoint is that this is because people with higher incomes are undertaking more effective means of maintaining long term health. The glass half empty view is that obesity is very damaging to health and longevity, and people with lower incomes become obese to a greater degree than those with higher incomes.

This study examines the long-term association between income and life expectancy in Sweden between 1960 and 2021. The study is based on register data that include all Swedish permanent residents aged 40 years and older. The results show that the gap in life expectancy between the top and bottom income percentiles widened substantially: For men, it increased from 3.5 years in the 1960s to 10.9 years by the 2010s, and for women, from 3.8 years in the 1970s to 8.6 years by the 2010s. Despite a reduction in income inequality and an expansion of social spending from the 1960s to the 1990s, health inequality continuously increased over the period under study.

The changes of the relation between real income and life expectancy, the so-called Preston curve, reveal a much faster improvement in life expectancy in the upper half of the income distribution than suggested by the cross-sectional relation between income and life expectancy. Analysis of causes of death identified cardiovascular diseases as the main contributor to improved longevity, while cancer contributed more to the increased gap in life expectancy for women and equally for men. Finally, analysis of the change in the income gradient in avoidable causes of death showed the strongest contribution of preventable causes, both for men and women.

This study reveals that the income gradient in life expectancy in Sweden has steadily increased since the 1960s, despite a reduction in income inequality until 1990. This challenges the "absolute income hypothesis" - the notion that economic resources per se affect life expectancy and that increasing income inequality directly drives health disparities. Instead, a "third factor" appears to be associated with both income and life expectancy, leading to greater gains in life expectancy among higher income groups. These gains are evident in both preventable and treatable disease mortality and appear more strongly for preventable causes, suggesting that higher-income individuals are more rapidly adopting healthier lifestyles. This finding highlights the need to consider factors beyond economic resources in addressing health inequalities.

Link: https://doi.org/10.1073/pnas.2418145122

Neurogenesis is the process by which new neurons are created from neural stem cell populations, then mature, migrate, and integrate into neural circuits. This is necessary for memory, learning, normal tissue maintenance in the brain, and the small degree of regeneration from injury the brain is capable of. Neurogenesis declines with age, for a range of reasons including the usual reduced activity of stem cells that occurs in every tissue, and this is thought to contribute to some degree of the loss of cognitive function observed to occur in later life.

Researchers are interested in finding ways to increase the pace of neurogenesis, as this could partially compensate for the damage and losses of aging and neurodegenerative conditions. It could also enhance cognitive function in younger people. There are many approaches to achieve this end, but the size of the effect is important. Exercise increases neurogenesis (and cognitive performance) at all ages, for example, but one can't exercise one's way out of an Alzheimer's diagnosis, even though fitness maintained over the long term evidently reduces the risk of neurodegenerative conditions. The same is true of other commonly used options, such as antidepressant therapies. If more dramatic outcomes are desired, then much larger increases in neurogenesis are needed than are offered by presently available strategies.

Therapeutic modulation of neurogenesis to improve hippocampal plasticity and cognition in aging and Alzheimer's disease

Immature and new neurons in the adult dentate gyrus (DG) play important roles in different forms of learning and memory that depend on the hippocampus. Numerous studies manipulated levels of hippocampal neurogenesis in rodent models and showed an effect of learning and memory. Among others, these studies utilized irradiation, chemical, or genetic manipulation to target neurogenesis. Manipulations that led to reduced or diminished levels of neurogenesis resulted in impaired performance in various cognitive tasks, including contextual discrimination (pattern separation), spatial navigation, long-term spatial memory retention, spatial pattern discrimination, trace conditioning, contextual fear conditioning, clearance of hippocampal memory traces, and reorganization of memory to extra-hippocampal substrates. On the other hand, manipulations that led to the enhancement of neurogenesis, such as environmental enrichment, running, deep brain stimulation, or genetic manipulation, led to improved performance in these tasks. Mounting evidence has linked impaired neurogenesis to cognitive deterioration in Alzheimer's disease (AD).

The identification of signals that are altered in the aging or diseased DG may be possible therapeutic targets or open up new avenues in that regard. For example, imbalance between bone morphogenetic proteins (BMP2 and BMP4) and noggin, where BMP is upregulated is implicated in reduced neurogenesis in depression and aging. One of the homeostatic mechanisms affected in the aged brain that might contribute to the decline in neurogenesis is the Wnt signaling pathway. A downregulation of Wnt ligands and an upregulation of Wnt inhibitors (Dkk1 or sFRP3) has been observed in the aged brain that impairs neurogenesis and the Wnt β-catenin signaling has been proposed as a potential therapeutic target. Endogenous neurotrophic growth factors, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glia-derived neurotrophic factor (GDNF), and insulin-like growth factor 1 (IGF-1), play vital roles in promoting development, proliferation, and differentiation of neural stem cells (NSCs) in the central nervous system.

Many of these neurotrophic factors activate tropomyosin-related kinase (Trk) receptors, including type A and B, initiating intracellular signaling cascades that govern NSC self-renewal and fate determination. The indispensability of BDNF-TrkB signaling in the enhancement of hippocampal neurogenesis and the survival of newly generated neurons during adult neurogenesis has been unveiled. Considering the significant contributions of neurotrophic factors to neuronal plasticity and function, alterations in levels and expression of their respective receptors are associated with a multitude of psychiatric and neurodegenerative disorders.

Small molecules that can modulate specific neurogenic signals or processes may have a therapeutic potential. For example, protein kinases of the protein kinase C (PKC)-activating diterpene small molecule has been shown to facilitate NSC proliferation in neurogenic niches when injected into cerebral ventricles. PKC stimulates the release of growth factors that stimulate NSC proliferation. ACEA, harmine, D2AAK1, methyl 3,4-dihydroxybenzoate, and shikonin may induce neuronal proliferation/differentiation through the activation of pathways: MAPK ERK, PI3K/AKT, NFkB, Wnt, BDNF, and NPAS3. Combinations of these compounds can potentially transform somatic cells into neurons. This transformation process involves the activation of neuron specific transcription factors such as NEUROD1, NGN2, ASCL1, and SOX2, which subsequently leads to the transcription of downstream genes, culminating in the transformation of somatic cells into neurons.

All classes of antidepressant drugs tested thus far, including 5-HT reuptake inhibitors (SSRIs), tianeptine, and mood stabilizers such as lithium, were shown to increase the proliferation and survival of new neurons in the dentate gyrus. Similarly, under chronic treatment conditions, CRHR1 receptor antagonists and V1b receptor antagonists improved deficits in neurogenesis caused by chronic mild stress. Chronic administration of antidepressants such as fluoxetine, reboxetine, tranylcypromine, and electroconvulsive shock (ECS) enhances neurogenesis in adult rodents, with similar effects observed in non-human primates for fluoxetine and ECS. Antidepressants targeting different neurotransmitter systems, including serotonin and norepinephrine, as well as SSRIs, tricyclics, mood stabilizers, and atypical antidepressants, promote neurogenesis and cell proliferation.

The PEARL trial of rapamycin was crowdfunded by Lifespan.io, something that we should see happen more often, at a much larger scale, for all of the presently available low-cost treatments that might influence aging. While results were initially published late last year, the researchers have had some months since then to refine the paper and further follow up on some of the questions raised about dosing. The compounded form of rapamycin used in the trial turns out to be much less bioavailable than the commercially produced options for this drug, which is an important point for anyone thinking about trying this themselves.

Few clinical trials to date have evaluated the effects of rapamycin and its derivatives in generally healthy individuals, and those that have been conducted are often challenged by small cohort size, short-term follow-up, or both. While the most robust of these studies have suggested improvements in age-related immune decline in healthy elderly individuals administered low-dose everolimus for 6 to 16 weeks, many questions regarding low-dose rapamycin for supporting healthy aging in normative aging individuals remain, particularly regarding the safety of long-term low-dose use. The PEARL trial represents one of the largest efforts to date for evaluating the long-term safety of low-dose rapamycin (5 mg and 10 mg once weekly for 48 weeks) for longevity in a normative aging cohort, and provides preliminary support for the suggestion that low-dose rapamycin may be useful in combating age-related decline by improving healthspan measures.

Importantly, in the midst of this trial, we learned that compounded rapamycin, which was used for this work due to placebo generation considerations, could have reduced bioavailability relative to commercial formulations. This trial was temporarily paused while we explored this possibility in an independent cohort. It was subsequently discovered that compounded rapamycin did indeed have approximately 1/3 the concentration in blood after 24 hrs relative to commercial.

The primary goal of the current study was to evaluate the relative safety of low-dose rapamycin use over 48 weeks, and to evaluate whether any clear patterns of concerning side effects emerged in a preliminary cohort. Overall, reports of adverse events (AEs) were relatively consistent across all groups. While rapamycin users appeared to have more gastrointestinal symptoms than placebo users, no other clear patterns of AEs for rapamycin users emerged. Particular attention was given to immune challenge symptoms for rapamycin users; however, overall reports of cold/flu-like illness and slowed recovery were similar across all groups.

We saw strong improvements in the secondary outcome measure of lean tissue mass, and in self-reported pain symptoms for women taking 10 mg of compounded rapamycin (equivalent to ~3.33 mgs of generic Sirolimus). We further observed modest improvements in other measures of self-reported well-being for some groups in both genders (general health and emotional well-being). These effects are largely in keeping with the suggested benefits of low-dose rapamycin use in the longevity community, and provide some measure of clinically validated support for rapamycin's reputed effects on this front despite the small sample numbers.

Link: https://doi.org/10.18632/aging.206235

Some lower animal species are capable of exceptional feats of regeneration. Planarians are capable of regrowing an entire new body after being cut in half, for example. One way of thinking about this is that some of these species blur the line between developmental growth and regeneration. Adults make continued use of processes that occur during development, unlike most higher animals. One of the interesting aspects of early development is that adult germline cells undergo rejuvenation, shedding age-related changes in gene expression. Here, researchers show that adult planarians are in fact undergoing rejuvenation while they regrow lost body parts.

Long-lived species provide unique opportunities to uncover naturally evolved mechanisms for the extension of healthspan and lifespan. Freshwater planarians are commonly referred to as immortal due to their extremely long lifespan and unique tissue regeneration capabilities. It was reported that telomeres shorten, eyes change, and viable progeny decline in older planarians. Whether planarians experience aging and show a typical age-dependent decline in physiological, cellular and molecular functions has not been systematically examined, in part because of the challenges inherent in measuring lifespan in a long-lived animal, or even defining age in asexual planarians that undergo a vegetative mode of reproduction.

Inbred lines of the sexual lineage of S. mediterranea have been established to study genetic variations and chromosome biology. This resource provides a unique opportunity to examine aging in this long-lived model system and disentangle genetic control from environmental effects. To use this model for aging research, we define chronological age as time since fertilization, thus overcoming the challenges involved in lineages that rely on vegetative reproduction.

Here we report that the sexual lineage of S. mediterranea exhibits physiological decline within 18 months of birth, including altered tissue architecture, impaired fertility and motility, and increased oxidative stress. Single-cell profiling of young and older planarian heads uncovered loss of neurons and muscle, increase of glia, and revealed minimal changes in pluripotent stem cells, along with molecular signatures of aging across tissues. Remarkably, amputation followed by regeneration of lost tissues in older planarians led to reversal of these age-associated changes in tissues both proximal and distal to the injury at physiological, cellular, and molecular levels. Our work suggests mechanisms of rejuvenation in both new and old tissues concurring with planarian regeneration, which may provide valuable insights for antiaging interventions.

Link: https://doi.org/10.1038/s43587-025-00847-9

Which gene sequences are actively read by transcription machinery in the cell nucleus to produce RNA (some of which is then translated into proteins) is determined by the structure of nuclear DNA. The various assemblies of proteins making up that transcription machinery will read whatever sequence they can attach to. Regions of nuclear DNA can be packaged away and tightly furled, made inaccessible, or otherwise become accessible for a time through alterations to histone proteins, methylation of specific sites on the genome, and other strategies. All of this changes constantly in response to circumstances, many dynamic feedback loops of RNA and protein production and structural change to DNA all interacting with one another.

In today's open access paper, researchers offer a view of DNA structure that is less commonly discussed in the context of aging and longevity. This view emerges from the use of spectroscopy, which can be employed to gain insight into different structural variants of DNA. The double helix structure familiar to laypeople is known as B-DNA, but A-DNA and Z-DNA also exist. Spectroscopy can further can be used to visualize a range of small-scale features in the chemical structure of DNA, such as sugar puckers. Evidently, however one looks at DNA and gene expression, one is going to see differences between short-lived rodents and long-lived rodents.

What can be done with this information? At present very little. As is the case for epigenetic measures, there is no bridge of cause and consequence yet built to link specific structural DNA changes and specific forms of damage and dysfunction in aging. So one can measure structural differences across life spans within species and between species of different life spans, but it doesn't yet much help in the matter of how to build effective rejuvenation therapies.

Structural features of DNA and their potential contribution to blind mole rat (Nannospalax xanthodon) longevity

The structural architecture of DNA, extending beyond its sequence-dependent genetic code, has emerged as a critical determinant of genomic stability, cellular function, and organismal longevity. B-DNA, which has a right-handed double helix structure with Watson-Crick base pairing, can form non-B DNA structures such as hairpins, triplexes, cruciform, left-handed Z-forms, G-quadruplexes, and A-motifs under specific conditions. While canonical B-form DNA represents the classical double-helical structure, dynamic conformational shifts, such as transitions to A-DNS or Z-DNA alter biochemical properties like flexibility, stability, and protein interactions, with profound implications for aging and disease.

Structural changes, such as the transition from B-DNA to A-DNA, influence DNA stability and flexibility and are affected by factors like DNA methylation and sugar puckering. This study is the first to investigate the relationship between DNA conformational changes and lifespan in two rodent species. The analysis focused on long-lived Anatolian blind mole-rat (Nannospalax xanthodon) and shorter-lived rat (Rattus rattus), utilizing infrared spectroscopy and principal component analysis (PCA) to examine liver DNA.

Results indicated that transitions from B-form to A-form and Z-form were more prevalent in N. xanthodon than in R. rattus. However, the dominant DNA conformations in both species are in B-form. Additionally, N-type sugar puckers (C3-endo conformation), associated with these DNA forms, were more prominent in N. xanthodon. In contrast, S-type sugar puckers (C2-endo conformation), characteristic of B-DNA, were found at lower levels in N. xanthodon. Furthermore, variations in methylation-specific structural modifications of nucleobases were quantitatively assessed among these species.

The study proposes a significant connection between the long lifespan of N. xanthodon, which live underground, and their unique DNA structure, offering insights into how different DNA forms, as well as the conformations of their backbone and sugar-base components, may affect longevity, highlighting potential research avenues regarding the biomolecular aspects of aging.

It is always interesting to see data on life span in short lived species for an intervention with a fair amount of human data for health benefits. The broad pattern is that short-lived species exhibit a much greater extension of life in response to interventions, but on the other hand near all of the data is focused on only a few different ways to alter metabolism, such as the upregulation of stress responses and increased cell maintenance observed in calorie restriction. Supplementation with β-hydroxy-β-methylbutyrate is yet another way to manipulate the systems of regulation linking nutrient availability and cell maintenance, in an attempt to capture some fraction of the benefits of exercise and calorie restriction.

Two lifestyle interventions that may improve muscle function and attenuate the negative physical outcomes of the aging process include exercise and dietary protein and amino acid supplementation. At the molecular level, leucine serves as a direct substrate for muscle protein synthesis as well as an activator of protein synthesis through the multi-protein complex mechanistic Target of Rapamycin Complex 1 (mTORC1). Branched-chain amino acid aminotransferase transaminase (BCAT) converts leucine to keto-isocaproic acid (KIC), which is then reduced to 𝛽-hydroxy-𝛽-methylbutyrate (HMB). Dietary HMB supplementation has been shown to have a positive effect on muscle function in several rodent studies and human trials.

A growing body of evidence suggests that HMB supplementation improves lean body mass composition and muscle function in older subjects, and can mitigate loss of lean mass in elderly subjects during periods of bed rest. Several mechanisms of HMB action on muscle have been described, including both an anabolic mechanism through an up-regulation of protein synthesis via the mTOR pathway, and an anti-catabolic mechanism through a down-regulation of muscle protein breakdown via the ubiquitin-proteasome proteolytic pathway.

We investigated the feasibility of utilizing Drosophila as a model organism to study the biological effects of HMB on aging muscle when consumed throughout adult life. Using flight ability as an index of flight muscle function, we found that HMB attenuates the age-dependent decline in flight ability. Male and female flies fed a diet supplemented with 10 mg/mL HMB had significantly higher flight scores from median age until the onset of flight senescence than control flies fed a standard diet. HMB supplementation also resulted in improved flight scores in males before median age and delayed the onset of flight senescence in females. Notably, the consumption of HMB throughout adult life increased the rate of survival and extended lifespan. The effect on lifespan did not result from changes in food consumption or body weight. Old flies on the HMB-supplemented diet retained a higher proportion of flight muscle mitochondria whose morphology resembled that of young flies than the control diet group. Together, these results suggest that HMB attenuates the age-dependent decline in flight ability and prolongs lifespan by enhancing muscle health.

Link: https://doi.org/10.3390/ijms26062664

The practice of calorie restriction improves health and extends life, though the effect on life span is much larger in short-lived species such as mice than in long-lived species such as humans. Researchers here focus on changes in lipids in mice that result from calorie restriction and a number of different calorie restriction mimetic drugs. One of course expects fat tissue to change greatly as a result of a low calorie diet sustained over time, but changes in lipid levels and distributions of different lipids change throughout the body. Calorie restriction mimetic drugs only capture a fraction of the overall effects of calorie restriction, but still tend to push things in a similar direction. The interesting observation here is that, overall, these changes look like rejuvenation, tending to move measures lipid metabolism towards a more youthful outcome.

Caloric restriction is associated with slow aging in model organisms. Additionally, some drugs have also been shown to slow aging in rodents. To better understand metabolic mechanisms that are involved in increased lifespan, we analyzed metabolomic differences in six organs of 12-month-old mice using five interventions leading to extended longevity, specifically caloric restriction, 17-α estradiol, and caloric restriction mimetics rapamycin, canagliflozin, and acarbose.

These interventions generally have a stronger effect in males than in females. Using Jonckheere's trend test to associate increased average lifespans with metabolic changes for each sex, we found sexual dimorphism in metabolism of plasma, liver, gastrocnemius muscle, kidney, and inguinal fat. Plasma showed the strongest trend of differentially expressed compounds, highlighting potential benefits of plasma in tracking healthy aging. Using chemical set enrichment analysis, we found that the majority of these affected compounds were lipids, particularly in male tissues, in addition to significant differences in trends for amino acids, which were particularly apparent in the kidney.

We also found strong metabolomic effects in adipose tissues. Inguinal fat exhibited surprising increases in neutral lipids with polyunsaturated side chains in male mice. In female mice, gonadal fat showed trends proportional to lifespan extension effect across multiple lipid classes, particularly phospholipids. Interestingly, for most tissues, we found similar changes induced by lifespan-extending interventions to metabolomic differences between untreated 12-month-old mice and 4-month-old mice. This finding implies that lifespan-extending treatments tend to reverse metabolic phenotypes to a biologically younger stage.

Link: https://doi.org/10.1111/acel.14465

Aging is an accumulation of damage and dysfunction, but a quite specific collection of forms of damage and dysfunction. One can create conditions that look like premature aging, or very selective forms of premature aging of specific tissues and organs, with any number of damaging interventions, such as administration of toxins or altered expression of genes. These are not aging. Just because an intervention produces dysfunction and damage that looks like aging doesn't necessarily mean that it has any relevance to normal aging. The details matter. It is worth remembering this point.

In today's open access paper, the authors report on their discovery that artificially increased expression of IGF-1 in skin produces accelerated aging of hair follicles by encouraging cellular senescence. Clearing out the senescent cells or interfering in downstream targets of IGF-1 reverses this effect, restoring hair follicle function. None of this implies that IGF-1 signaling is in any way a useful target in the normal aging of hair follicles, even given that reducing IGF-1 signaling is a well studied topic when it comes to slowing aging in short-lived species, and even given evidence for increased IGF-1 signaling in skin with age. Any approach to induce greater cellular senescence in a specific cell population is going to harm its function, and there are many, many ways to go about this, few of which are relevant to cellular senescence in normal aging. To close the loop for this paper, the researchers would need to show that the treatments that work in their model of increased IGF-1 signaling also work in old mice, but they did not do that.

Targeting IGF1-Induced Cellular Senescence to Rejuvenate Hair Follicle Aging

The insulin-like growth factor-1 (IGF-1) signaling pathway is known as a potent aging modifier, disruption of which consistently associates with lifespan extension across diverse species. Despite this established association, the mechanisms by which IGF-1 signaling modulates organ aging remain poorly understood. In this study, we assessed age-related changes in IGF-1 expression across multiple organs in mice and identified a more prominent increase in skin IGF-1 levels with aging - a phenomenon also observed in human skin.

To explore the consequences of elevated IGF-1, we developed transgenic mice ectopically expressing human IGF-1 in the epidermis, driven by the bovine keratin 5 promoter (IGF-1 Tg). These mice exhibited premature aging of hair follicles, as evidenced by accelerated hair graying and loss. Single-cell RNA sequencing analyses of dorsal skin highlighted an upsurge in cellular senescence markers and the senescence-associated secretory phenotype (SASP) in hair follicle stem cells (HFSCs), alongside a decline in hair growth and HFSC exhaustion.

Our findings indicate that excessive IGF-1 triggers HFSC senescence, thereby disrupting hair follicle homeostasis. Remarkably, interventions in IGF-1 signaling via downstream mechanisms - specifically blocking acetylated p53 activation via SIRT1 overexpression or senolytic treatment for senescent cell clearance, or reducing IGF-1 through dietary restriction - significantly reduced senescence markers, mitigated premature hair follicle aging phenotypes, and restored the stem cell pool. Our findings provide fundamental insights into the biological processes of hair aging and highlight the therapeutic promise of targeted interventions to rejuvenate aged HFSCs and promote hair follicle health.

While short-term inflammation is useful and necessary, such as in the response to infection or injury, that same inflammatory signaling sustained over the long term becomes harmful. It becomes disruptive to tissue structure and function, altering the behavior of cells in damaging ways. Chronic inflammation is a feature of aging, and clearly contributes to the onset and progression of all of the common age-related conditions. It seems unlikely that age-related chronic inflammation can be effectively prevented, other than by removing the various forms of underlying cell and tissue damage that provoke continual maladaptive inflammatory responses. While one can suppress specific inflammatory signals in blunt ways, that only affects some inflammation, and also suppresses the normal, short-term inflammation necessary for defense against pathogens and regeneration from injury.

The relationship between aging and peripheral inflammation represents a complex and multifactorial process, with many molecular mechanisms contributing to a prolonged state of chronic low-grade inflammation, also called inflammaging. In contrast to acute inflammation, which is a transient response to infection or injury, inflammaging is a persistent, low-grade inflammatory state that develops as a result of the combined influence of internal and external factors accumulated throughout life. This process is characterized by sustained immune pathway activation, the increased production of pro-inflammatory cytokines, and the dysregulation of immune homeostasis, all of which contribute to the progressive functional decline associated with aging.

Aging affects multiple peripheral organs, including the liver, adipose tissue, skeletal muscles, and gastrointestinal tract, all of which play a crucial role in modulating systemic inflammation. The progressive dysfunction of these organs with age is primarily caused by molecular and cellular alterations, including oxidative stress, genomic instability, epigenetic changes, mitochondrial impairment, and cellular senescence. All of these create an inflammatory microenvironment that evokes tissue damage, ultimately contributing to the onset and progression of many age-related diseases, including cardiovascular disorders, neurodegenerative conditions, and cancer. At the molecular level, inflammaging involves a complex network of inflammatory mediators, including cytokines, acute-phase proteins, and damage-associated molecular patterns (DAMPs), which activate various intracellular signaling pathways.

A defining feature of inflammaging is the senescence-associated secretory phenotype (SASP). As aging occurs, senescent cells accumulate in several tissues, promoting a pro-inflammatory environment that supports immune system activation and drives tissue remodeling. An additional factor in inflammaging is gut microbiota dysbiosis, which has become increasingly recognized as a significant regulator of systemic inflammation in aging individuals. Age-related alterations in gut microbiota composition can result in increased intestinal permeability, facilitating the translocation of bacterial endotoxins, such as lipopolysaccharide (LPS), into the circulation. This process triggers sustained immune cell activation, further enhancing systemic inflammation.

Link: https://doi.org/10.3390/biom15030404

Why would people who underwent shingles vaccination in later life exhibit a lower risk of later developing dementia? Firstly, one has to elect to take this vaccine, and so this could be selecting for people who tend to take better care of their health, and thus are in better shape than their peers, on average. Secondly, vaccination produces an effect called trained immunity that makes people incrementally more resistant to the chronic inflammation of aging. Lastly, there is some evidence for persistent viruses such as the varicella-zoster virus that causes shingles to contribute to the onset and progression of dementia, for reasons yet to be fully understood. Epidemiological studies such as this one don't shed much light on biological mechanisms, but do add expected value to seeking vaccination rather than passing it up.

Shingles, a viral infection that produces a painful rash, is caused by the same virus that causes chicken pox - varicella-zoster. After people contract chicken pox, usually in childhood, the virus stays dormant in the nerve cells for life. In people who are older or have weakened immune systems, the dormant virus can reactivate and cause shingles. Previous studies based on health records have linked the shingles vaccine with lower dementia rates, but they could not account for a major source of bias: People who are vaccinated also tend to be more health conscious in myriad, difficult-to-measure ways. Behaviors such as diet and exercise, for instance, are known to influence dementia rates, but are not included in health records.

But two years ago, researchers recognized a fortuitous "natural experiment" in the rollout of the shingles vaccine in Wales that seemed to sidestep the bias. The vaccination program specified that anyone who was 79 was eligible for the vaccine for one year. People who were 80 were out of luck - they would never become eligible for the vaccine. The researchers looked at the health records of more than 280,000 older adults who did not have dementia at the start of the vaccination program. They focused their analysis on those closest to either side of the eligibility threshold - comparing people who turned 80 in the week before with those who turned 80 in the week after. The same proportion of both groups likely would have wanted to get the vaccine, but only half, those almost 80, were allowed to by the eligibility rules.

Over the next seven years, the researchers compared the health outcomes of people closest in age who were eligible and ineligible to receive the vaccine. By factoring in actual vaccination rates - about half of the population who were eligible received the vaccine, compared with almost none of the people who were ineligible - they could derive the effects of receiving the vaccine. As expected, the vaccine reduced the occurrence over that seven-year period of shingles by about 37% for people who received the vaccine, similar to what had been found in clinical trials of the vaccine. Seven years later, one in eight older adults, who were by then 86 and 87, had been diagnosed with dementia. But those who received the shingles vaccine were 20% less likely to develop dementia than the unvaccinated.

Link: https://med.stanford.edu/news/all-news/2025/03/shingles-vaccination-dementia.html

Research can be interesting even if the future development of therapies based on that research seems challenging. Today's open access paper is chiefly interesting for its outline of the developmental and ongoing relationship between skin and the brain, and the signaling that passes between the two. It is intriguing that this relationship means that one can harvest extracellular vesicles generated by cells in the brain and use them to change skin cell behavior in order to produce scar free regeneration from injury.

However, to make this into a therapy would require either (a) a much greater understanding of the specific signaling mechanisms involved, in order to replace the vesicles with some other way to manipulate those mechanisms, or (b) the ability to maintain human organoid brain tissues at scale for the purpose of harvesting vesicles. Since the researchers harvested the vesicles directly from brain tissue, it is unclear as to which cells produced them, and which of the various types of vesicle are important to the end result. Other options seem more impractical, such as access to a lot of waste cerebrospinal fluid from young individuals. So it seems best to look on this as a tool that might lead to a better understanding of targets to suppress scarring in skin tissue, and a line of research that will take some time to come to a practical basis for therapy.

Youthful Brain-Derived Extracellular Vesicle-Loaded GelMA Hydrogel Promotes Scarless Wound Healing in Aged Skin by Modulating Senescence and Mitochondrial Function

The intricate relationship of the "brain-skin axis" has been described in the literature, with both considered to originate from the same germ layer. The neuroendocrine networks have long been well recognized, especially with the discovery of corticotropin-releasing factor (CRF), which defines the upper regulatory arm of the hypothalamic-pituitary-adrenal (HPA) axis. The skin has been identified as a neuroendocrine organ, expressing a variety of brain and pituitary hormones, as well as multiple neuropeptides, to regulate local homeostasis in response to stress. In contrast, abnormal mental states such as stress can promote skin aging.

It remains unclear whether cultivating a healthy, youthful brain can promote the healing of skin wounds in older adults. While the tight regulatory crosstalk between brain and skin has been represented in cellular phenotypic alterations, the underlying mechanisms remain to be elucidated. Extracellular vesicles (EVs) are membrane-bound vesicles expelled from cells, body fluids, and tissue into the extracellular space and can carry materials (proteins, RNA, and DNA) from one cell to another. EVs from elderly subjects are mediators of the progressive deterioration of age-related tissue dysfunction over time. In recent decades, EV therapies have shown promise in the field of aging.

In this study, we hypothesized that brain-EVs, as a novel paradigm, regulate aging fibrocyte metabolism and functions by delivering mitochondrion-related proteins. We identified youthful brain-derived extracellular vesicles (YBEVs) and created a composite hydrogel material incorporating YBEVs that encourages scarless wound healing in aged skin. We found that YBEVs reduce the expression of senescence, senescence-associated secretory phenotypes, and inflammation-associated proteins, and even restore dysfunction in senescent cells. Furthermore, by encouraging collagen deposition, angiogenesis, epidermal and dermal regeneration, and folliculogenesis, we demonstrated that YBEV-containing composite hydrogels accelerated scarless wound healing in skin wounds of aged rats. The pro-repairing speed and effect of this composite hydrogel even matched that of young rats.

Subsequent proteomic analysis revealed the presence of numerous proteins within YBEVs, some of which may play a role in the regulation of skin energy intake, particularly through oxidative phosphorylation and mitochondrial function. In conclusion, the findings suggest that maintaining a youthful brain could potentially alleviate skin aging, and the proposed YBEV-containing hydrogel emerges as a promising strategy for addressing age-related impairments in skin healing.

Full reprogramming of cells occurs in the early embryo, driven by Yamanaka factor expression, the factors used often abbreviated to OSKM. It turns adult germ cells into embryonic stem cells, resetting epigenetic patterns and restoring mitochondrial function. Researchers have replicated this process to produce induced pluripotent stem cells from any adult cell sample. Partial reprogramming is intended to expose cells to Yamanaka factor expression for long enough to produce the reset of epigenetic patterns and improvement in mitochondrial function, but not for so long as to change cell state in other ways. This is thought to be a promising path to the production of rejuvenation therapies, but there are many challenges to overcome on the way to the clinic. Not least of these is that different cell types in any given tissue may have quite different requirements in terms of length of exposure or level of exposure to produce beneficial reprogramming with mimimal risk of generating potentially cancerous pluripotent cells.

Partial and full reprogramming can partially reverse age-related transcriptomic and epigenetic changes. Yet, it is unclear to what extent aging clocks are measuring biological age or cellular/organismal health. Regardless of what epigenetic aging clocks measure exactly, there are other biomarkers of rejuvenation that can be measured in partial reprogramming experiments. For example, if cycles of short-time reprogramming factor expression are followed by a recovery phase, phenotypic rejuvenation effects can be observed. By default, rejuvenation markers must be evaluated on a tissue-by-tissue basis.

An intriguing example is the brain, where cyclic OSKM without a recovery phase restores the proportion of neuroblasts and improves the production of neurons in vivo. Moreover, in vivo studies performed on mouse neurons and rat dentate gyrus cells suggest that OSKM can reverse age-associated neurological decline and enhance memory. Other mouse in vivo studies have shown that reprogramming enhances liver regeneration, promotes the repair of crushed optic nerves and ameliorates aging-associated loss of visual acuity, allows for muscle fiber regeneration, improves skin wound healing in aged mice, and promotes heart rejuvenation following myocardial infarction.

The mechanism of rejuvenation appears to partially depend on how cells are reprogrammed. Indeed, it was found that the mechanism of somatic cell reprogramming via small molecule regimens is distinct from transcription factor-mediated reprogramming. By constructing chromatin landscapes, researchers identified hierarchal histone modifications and sequential enhancer recommissioning which underlies regeneration programs following chemical reprogramming; this regeneration program appears to reverse the loss of regenerative potential in organismal aging but apparently it is not activated in OSKM reprogramming.

Reprogramming specific cells in vivo affects surrounding tissue. For example, it was found that in vivo activation of OSKM in myofibers led to proliferation of satellite cells in the stem cell niche of the myofibers, without inducing myofiber dedifferentiation; likely these changes are at least partially modulated via changes to the extracellular matrix (ECM). In fact, the ECM and its constituents are frequently affected by partial reprogramming. As mice age, collagen-associated transcript levels decrease in the pancreas but increase again, at least partially, following OSKM treatment with a two-week recovery period. Also, in fibroblast and adipocyte mesenchymal cell experiments with no recovery period, some ECM-associated processes are upregulated by partial reprogramming, including pathways linked to collagen.

Link: https://doi.org/10.1016/j.arr.2025.102737

RNA splicing is the process by which RNA is assembled from intron and exon sequences in genes. A given gene can be assembled into different RNAs depending on what is included or excluded. The balance of different RNAs produced from a gene tends to change with age, and this may be a cause of dysfunction. Starting from a position of screening for compounds that reduce age-related dysregulation in RNA splicing in nematode worms, researchers happen upon a compound that achieves this goal and extends life by manipulating the activities of gut microbes. Determining how and why life extension occurs in this case will take somewhat longer than the discovery of the approach - it need not have anything to do with RNA splicing. It seems unlikely that this specific compound will be relevant to mice or humans, given the large differences in the gut microbiome between lower animals and mammals, but someone will get around to checking in mice at some point.

Aging is associated with alternative splicing (AS) defects that have broad implications on aging-associated disorders. However, which drugs can rescue age-related AS defects and extend lifespan has not been systematically explored. We performed large-scale compound screening in C. elegans using a dual-fluorescent splicing reporter system. Among the top hits, doxifluridine, a fluoropyrimidine derivative used in chemotherapy, rescues age-associated AS defects and extends lifespan.

Combining bacterial DNA sequencing, proteomics, metabolomics, and the three-way screen system, we further revealed that bacterial ribonucleotide metabolism plays an essential role in doxifluridine conversion and efficacy. Furthermore, doxifluridine increases production of bacterial metabolites, such as linoleic acid and agmatine, to prolong host lifespan. Together, our results identify doxifluridine as a potent lead compound for rescuing aging-associated AS defects and extending lifespan, and elucidate the drug's functions through complex interplay among drug, bacteria, and host.

Link: https://doi.org/10.1371/journal.pgen.1011648

The most robust measurement of pathology in neurodegenerative conditions is conducted via imaging technologies, but these don't do well when it comes to the assessment of the more subtle earlier stages of these conditions. Further, imaging is relatively expensive. So for some years researchers have worked to develop a range of less costly, more convenient biomarkers to assess disease risk and disease progress. Progress has been made. Useful blood tests are emerging for Alzheimer's disease, for example.

Today's open access paper reviews recent advances and the present state of fluid biomarker assays for neurodegenerative conditions. Being able to use bodily fluids other than cerebrospinal fluid is arguably even more important than moving away from imaging when it comes to cost and convenience; no-one particularly wants to undergo the lumbar puncture procedure needed to access cerebrospinal fluid. Using blood, saliva, and so forth, becomes possible with the development of more sensitive assay technologies, able to detect the much lower levels of molecules related to neurodegeneration found outside the central nervous system.

Fluid-based biomarkers for neurodegenerative diseases

Neurodegenerative diseases are characterized by various pathological mechanisms, such as the accumulation of misfolded proteins, oxidative stress, neuroinflammation, and impaired neuronal signaling. For example, Alzheimer's disease (AD) is primarily associated with amyloid-beta (Aβ) plaque deposition and intracellular tau protein hyperphosphorylation leading to neurofibrillary tangles, while Parkinson's disease (PD) involves the accumulation of aggregated alpha-synuclein (α-syn) forming Lewy bodies. In contrast, amyotrophic lateral sclerosis (ALS) is marked by motor neuron loss, and multiple sclerosis (MS) is distinguished by demyelination and axonal damage. Despite varying pathologies, these diseases share common features, such as progressive neuronal loss, a lack of disease-modifying treatments, and the need for early diagnosis to mitigate disease progression. Currently, diagnostic tools such as cognitive assessments and neuroimaging (e.g., magnetic resonance imaging [MRI] and positron emission tomography [PET]) are widely used, but they are often only valid when the disease has reached advanced stages. This creates a need for novel diagnostic and prognostic tools that can detect and stage these diseases in their preclinical stages.

Fluid biomarkers, which can be obtained from bodily fluids like cerebrospinal fluid (CSF), blood, saliva, and urine, offer a non-invasive and potentially more sensitive means of detecting neurodegenerative diseases. Biomarkers are molecules that could reflect underlying pathological changes in the body, such as protein misfolding, neuronal damage, and neuroinflammation, at times even before clinical symptoms emerge. Detecting these changes early through fluid biomarkers may enable the timely trial of interventions which have the potential to slow or prevent disease progression. CSF has been a traditional source for detecting biomarkers of neurodegenerative diseases, as it is in direct contact with the central nervous system. In AD, for example, the CSF biomarkers Aβ42, total tau (t-tau), and phosphorylated tau (p-tau) are well-established indicators of disease pathology. However, the invasive nature of lumbar punctures limits the routine use of CSF biomarkers in clinical practice.

Recent advances in fluid biomarker research have expanded beyond CSF to include blood and saliva, which are more accessible and less invasive. Blood-based biomarkers have gained particular attention, as they allow for repeated measurements over time and are suitable for large-scale population screening. Plasma Aβ42/40 ratios, various p-tau species, and neurofilament light chain (NfL) have shown promise in detecting Alzheimer pathology with accuracies comparable to CSF biomarkers. In PD, the detection of α-synuclein in blood has also demonstrated early diagnostic potential. Additionally, elevated levels of NfL in both blood and CSF have been observed in ALS and MS, making it a valuable marker for neuroaxonal injury across multiple neurodegenerative diseases.

Salivary levels of α-synuclein have been investigated as a potential marker for PD, while Aβ42 and tau proteins in saliva show potential for diagnosing Alzheimer's. Although concentrations of these biomarkers are lower in saliva compared to blood or CSF, advances in detection technology are improving the sensitivity of salivary biomarkers, making them a potential tool for large-scale screening. Urine biomarkers are also under investigation, with early studies identifying changes in the levels of proteins like Aβ, tau, and oxidative stress markers in the urine of patients with neurodegenerative diseases. Although urinary biomarkers are still in the early stages of research, they offer another non-invasive method for detecting disease-related changes, particularly in resource-limited clinical settings.

Alzheimer's disease progresses from an early aggregation of amyloid-β in brain tissue and mild cognitive symptoms to a later and much more harmful combination of inflammation and tau aggregation in brain tissue. A few years ago, researchers reported that measuring a tau species known as MTBR-tau243 in blood could be used to assess the state of this progression of Alzheimer's disease, and did so as accurately as more expensive brain imaging approaches. Here find an update on this approach to testing and its continued validation in patients at various stages of the progression of Alzheimer's disease.

Several blood tests for Alzheimer's disease are already clinically available. Such tests help doctors diagnose the disease in people with cognitive symptoms, but do not indicate the clinical stage of the disease symptoms - that is, the degree of impairment in thinking or memory due to Alzheimer's dementia. Current Alzheimer's therapies are most effective in early stages of the disease, so having a relatively easy and reliable way to gauge how far the disease has progressed could help doctors determine which patients are likely to benefit from drug treatment and to what extent.

In a new study, the researchers found that levels of a protein called MTBR-tau243 in the blood accurately reflect the amount of toxic accumulation of tau aggregates in the brain and correlate with the severity of Alzheimer's disease. Analyzing blood levels of MTBR-tau243 from a group of people with cognitive decline, the researchers were able to distinguish between people with early- or later-stage Alzheimer's disease and separate both groups of Alzheimer's patients from people whose symptoms were caused by something other than Alzheimer's disease.

Link: https://medicine.washu.edu/news/highly-accurate-blood-test-diagnoses-alzheimers-disease-measures-extent-of-dementia/

Researchers here explore the age-related nature of the correlation between atrial fibrillation and dementia risk. The earlier that atrial fibrillation is diagnosed in life, the higher the increased risk of later dementia. The interesting question is which of the possible mechanisms are most important in driving this relationship. The nature of atrial fibrillation suggests that both it and dementia arise from the same underlying causes, and that the atrial fibrillation is an earlier sign of those causes. It is associated with excess weight and hypertension, for example, both of which are harmful to the brain over the long term.

In a new study, the researchers assessed the independent association between atrial fibrillation (AF) and incident dementia in Catalonia, Spain. The population-based observational study included individuals who, in 2007, were at least 45 years old and had no prior diagnosis of dementia. The study included 2,520,839 individuals with an average follow-up of 13 years. At baseline, 79,820 patients (3.25%) had a recorded diagnosis of AF. In multivariable analyses adjusting for potential confounders, AF was, overall, a statistically significant but weak predictor of dementia, linked with a 4% increased risk of dementia.

However, age was found to significantly affect the association between AF and dementia. In prespecified analyses stratified by age, the strength of the association progressively weakened with increasing age: in patients aged 45-50, those with AF were 3.3 times more likely to develop dementia than those without AF. But in patients aged over 70 years, no association was found. Further analysis shows the association lost statistical significance from 70 years. By contrast, in patients diagnosed with AF before the age of 70, the condition independently increased the risk of dementia by 21%, and an even stronger effect was observed for early-onset dementia diagnosed prior to age 65, with AF increasing the risk by 36%.

Sensitivity analyses that removed cases of previous stroke during follow-up yielded similar results: AF was associated with a modest increase (6%) in the risk of dementia in the overall population, a stronger association (23% increased risk) in those diagnosed with AF in midlife (younger than 70 years old) and had the greatest effect towards early-onset dementia (52% increased risk). Therefore, patients with AF without a prior stroke still have a higher risk of dementia, with the greatest risk observed in early-onset dementia.

"The observation that the association between AF and dementia remains unchanged after excluding patients with prior stroke indicates that other mechanisms must be involved in the increased risk of dementia among AF patients. These mechanisms may include silent strokes - meaning those that showed no clinical symptoms and can only diagnosed with CT scan or MRI - and also microinfarcts, and microbleeds. Haemodynamic changes, which involve alterations in the flow and pressure of blood in the body caused by AF, and autonomic dysregulation, which refers to an imbalance in how the body controls automatic functions like heart rate, breathing, or blood pressure, could also play a role in the disease of small blood vessels in the brain associated with dementia. Additionally, systemic inflammation associated with atrial fibrillation may amplify these effects, creating a synergistic pathway that further increases dementia risk."

Link: https://www.eurekalert.org/news-releases/1078453

The ovary, along with the thymus, is one of the earliest organs to age into dysfunction. Studying the basis of ovarian aging may tell us something about aging more generally, an attractive prospect for researchers. For those who develop therapies, ovarian dysfunction may provide a somewhat easier point of intervention when assessing potential rejuvenation therapies that target underlying causes of aging, as the patients will be in better overall health, with fewer complicating comorbidities.

While those causes of aging are well catalogued at the present time, it remains challenging to understand their relative importance to any given age-related outcome. The web of cause, consequence, and interaction that lies between fundamental causes of aging and age-related conditions is very complex and little understood. The best way to find out whether a given cause of aging is important to give condition is to develop and test potential rejuvenation therapies that selectively target only that cause of aging. Here, for example, that would mean therapies targeting senescent cells, and assessing their effects on ovarian function.

Exploration of the mechanism and therapy of ovarian aging by targeting cellular senescence

Ovarian aging refers to the progressive decline in ovarian function with age, characterized by reduced follicle numbers, decreased quality of oocytes, changes of menstrual cycle, decreased fertility, and ultimately menopause. The decrease in estrogen levels due to ovarian aging can cause a series of clinical symptoms, such as vasomotor symptoms, osteoporosis, urogenital symptoms, neuropsychiatric dysfunction, cardiovascular diseases, endocrine diseases, and others. This aligns with the previous perspective that ovarian aging acts as a sensor for the overall aging of the female body. In humans, ovarian function typically begins to decline around 35 years of age, progressively deteriorates after 37, and ultimately ceases reproductive function around age 50. Notably, a growing number of women have been opting to delay childbearing to later stages of life, often influenced by social factors. Consequently, the diminishing fertility attributed to ovarian aging poses a significant challenge in the field of reproductive medicine, as no treatment modality has been proven to delay ovarian aging.

Cellular senescence refers to an irreversible cell cycle arrest caused by multiple stress responses, including accumulation of advanced glycation end products, oxidative stress, mitochondrial dysfunction, DNA damage, telomere shortening, and chronic inflammation. Cellular senescence exists throughout the life of multicellular organisms from development to death, and it also ubiquitously exists in both normal and senescent organs. Under physiological conditions, cellular senescence promotes organ differentiation and development by removing unwanted cells. With the accumulation of time or the degree of aging, cellular senescence further promotes organ aging through a variety of pathways, such as reducing the number of cells, decreasing cell quality, reducing metabolic level, accumulating metabolic waste, producing reactive oxygen species (ROS), thus damaging the organ and weakening the physiological function of the organ. Recently, cellular senescence was hypothesized to contribute to the age-related decline in ovarian function. Nevertheless, there remains a lack of a comprehensive theoretical framework concerning the role of cellular senescence in ovarian aging. Therefore, elucidating the role that cellular senescence may play in ovarian aging could lead to the development of novel therapies for reversing ovarian aging.

This review explores how cellular senescence may contribute to ovarian aging and reproductive failure. Additionally, we discuss the factors that cause ovarian cellular senescence, including the accumulation of advanced glycation end products, oxidative stress, mitochondrial dysfunction, DNA damage, telomere shortening, and exposure to chemotherapy. Furthermore, we discuss senescence in six distinct cell types, including oocytes, granulosa cells, ovarian theca cells, immune cells, ovarian surface epithelium, and ovarian endothelial cells, inside the ovary and explore their contribution to the accelerated ovarian aging. Lastly, we describe potential senotherapeutics for the treatment of ovarian aging and offer novel strategies for ovarian longevity.

A number of studies in recent years have shown that patients with Alzheimer's disease have a distinct gut microbiome composition in comparison to age-match peers. The gut microbiome changes with age, losing beneficial microbes and their production of metabolites necessary for tissue function, while gaining inflammatory microbes that contribute to the characteristic increase in chronic inflammatory signaling observed in older people. When it comes to the pro-inflammatory gut microbiome of Alzheimer's patients, it is still an open question as to whether this relationship exists because of the inflammation, in that inflammation drives the onset and progression of Alzheimer's disease, or whether other factors are at play. For example, a more pronounced age-related immune dysfunction could be a major contributing cause of both neurodegenerative conditions and shifts in the composition of the gut microbiome.

Alzheimer's disease (AD) is the most common form of dementia, characterized by an irreversible decline in cognitive function. The pathogenesis of several neurodegenerative disorders has been linked to changes in the gut microbiota, transmitted through the gut-brain axis. We set out to establish by case-control study methodology whether there were any differences in the composition and/or function of the gut microbiota between older resident adults in care homes with or without an AD diagnosis via analysis of the microbial composition from fecal samples. We performed primary analysis comparing controls (n = 19) against AD patients (n = 24).

These results indicate clear differences in the relative abundance of certain bacterial species and bacterial metabolites between care home residents with and without Alzheimer's disease that could be indicative of variable gut-brain axis activity. The AD cohort had significantly higher proportions of pro-inflammatory bacterial species and fewer 'beneficial bacteria'. We also found clear correlations between concentrations of beneficial bacterial metabolites and abundance of 'healthy bacteria'.

AD patients had increased levels of Escherichia/Shigella and Clostridium_sensu_stricto_1, which are linked to higher levels of gut inflammation. Escherichia/Shigella species can lead to higher levels of circulating lipopolysaccharide (LPS) and have been found in greater concentrations in the gut microbiota of individuals with mild cognitive impairment and in several prior AD studies. Certain strains of Escherichia/Shigella are known to form amyloid protein structures, known as curli, similar to those seen aggregating in the brains of AD patients. Although this is not definitively linked, it does raise one possibility as to how high levels of Escherichia/Shigella could potentially contribute to increased Alzheimer's pathology.

Similar to other studies, the AD cohort had decreased relative abundance of Bacteroides, Faecalibacterium, Blautia, and Roseburia species which are typically linked with good health. Both Roseburia and Faecalibacterium sp. are key butyrate producers and a significant decrease in the number of butyrate-producing bacteria, and subsequently butyrate, has previously been associated with AD. What cannot be determined from our data is whether the difference in microbiota is contributing to AD pathology or whether AD itself causes the microbial dysbiosis.

Link: https://doi.org/10.3390/geriatrics10020037

SIRT6 overexpression slows aging in mice for reasons that are yet to be fully understood. It influences a range of different mechanisms associated with aging, including efficiency of DNA repair. Efforts to determine which of these effects are the important ones, and the relationships of cause and effect between the outcomes it produces, will likely continue for years following the first clinical use of therapies based on SIRT6 upregulation. Research is slow and biology is complicated. Here is an update on one approach to therapeutic SIRT6 upregulation, using gene therapy to introduce a variant SIRT6 gene found in long-lived individuals. Using the standard sequence would probably also work, as that is what was done in the animal studies conducted to date - but would be harder to patent and otherwise defend in the ways needed to obtain funding from biotech investors.

Longevity biotech Genflow Biosciences has commenced a gene therapy trial aimed at addressing age-related decline in dogs. The trial is designed to evaluate the safety and efficacy of the company's SIRT6 gene therapy in extending healthspan in older canines. By targeting the SIRT6 gene, which has been linked to extended lifespan in centenarians, Genflow hopes to generate insights that could inform future treatments for both veterinary and human applications.

The study involves 28 dogs aged ten years and older. Over the course of a year, dogs receiving the therapy via intravenous injections will be compared to an untreated control group. Researchers will assess biological age using the GrimAge methylation clock, monitor changes in muscle mass and strength, evaluate mitochondrial function, track coat condition, and measure overall well-being. The six-month treatment period will be followed by a six-month observation phase to assess lasting effects. The results of the trial are expected by the end of 2025.

Genflow's broader focus is on developing gene therapies targeting aging-related diseases in humans, with its lead compound, GF-1002, in the pre-IND phase for metabolic dysfunction-associated steatohepatitis (MASH), a prevalent chronic liver condition. GF-1002, which delivers a variant of the SIRT6 gene found to be enriched in centenarians, has demonstrated adipogenic, anti-fibrotic, and anti-tumoral properties in preclinical studies.

Link: https://longevity.technology/news/genflow-begins-sirt6-gene-therapy-trial-in-dogs/

Senescent cells cease to replicate and start to secrete a potent mix of growth factors and inflammatory signals. In youth, senescent cells are removed fairly rapidly by the immune system or mechanisms of programmed cell death. They are created constantly as cells reach the Hayflick limit on replication, but also as a result of potentially cancerous DNA damage or in response to injury. The normal, useful purpose of a senescent cell present for only a limited period of time is to help attract the attention of the immune system, coordinating regeneration and clearance of damaged cells.

Unfortunately the immune system falters in its task of clearing senescent cells as people become older, and a population of lingering senescent cells accumulates. The inflammatory signaling that is helpful in the short term becomes disruptive and harmful when sustained. Senescent cells provide a meaningful contribution to degenerative aging, and their signaling actively maintains tissue dysfunction. Studies in mice in recent years have demonstrated meaningful degrees of rejuvenation to result from the targeted removal of senescent cells in old animals.

A senotherapeutic drug is one that in some way targets senescent cells. Most of the focus is on senolytics, treatments that exploit one or more of the distinctive biochemical features of senescent cells in order to destroy them while minimizing harms to other cells. But there are other strategies, such as inhibiting entry to the senescent state, suppressing senescent cell signaling, improving the ability of the immune system to clear senescent cells, reversing the senescent state, and so forth.

In today's open access paper, the authors sketch a big tent when it comes to deciding whether or not a given therapy is senotherapeutic. Just about anything that upregulates autophagy could be called senotherapeutic for its ability to reduce the pace at which cells becoming senescent. We when look to the future we would like to see a more profound, rapid rejuvenation result from targeting senescent cells. We would like to see the research community improve greatly on early senolytics and their impressive results in aged mice, rather than focus on the modest effects produced by exercise or mTOR inhibitors like rapamycin, both of which upregulate autophagy and reduce the creation of new senescent cells.

Senescent cells as a target for anti-aging interventions: From senolytics to immune therapies

The selective elimination of senescent cells with molecule chemicals represents an innovative approach to target the hallmarks of aging. Since the discovery of the dasatinib and quercetin combination as the first senolytic agent, numerous clinical drugs, synthetic products and natural compounds have been identified as candidate senolytics and senomorphics. The therapeutic benefit of senolytics is supported by evidence from preclinical studies in diseased and physiological aging models, which has fueled their progression into multiple clinical trials. Mechanistically, most senolytics inhibit survival pathways to induce apoptosis in senescent cells with relatively little harm to normal, proliferating cells. On the other hand, senomorphics inhibit the senescence-associated secretory phenotype (SASP) expression and reduce inflammation in the surrounding tissue without inducing cell death, offering an often equally effective but safer alternative to senolytic drugs.

Despite the efforts of ongoing clinical trials, the safety profile of chronically administering these small molecule senotherapeutics remains to be validated. A primary consideration is the tradeoff broad-spectrum senolytic effect and the negative effects on normal proliferating cells, due to the lack of clearly defined boundaries between senescent and cells undergoing milder, but non-senescence-inducing stresses, or even non-senescent cells that express markers of senescence. For example, some well-known side effects of continuous navitoclax treatment include thrombocytopenia, internal bleeding, and neutropenia, which might arise from the inhibition of anti-apoptotic Bcl-2 family proteins in platelets and neutrophils. The same is true for other chemotherapeutic-derived senolytics, whose inherent genotoxicity may pose unwanted risks for normal cells. In contrast to small molecules, senescent cell associated antigen directed immune therapies offer a more targeted approach to senescent cells with uniquely upregulated surface markers. Preliminary studies have demonstrated efficacy in reducing senescent cell burden and improving physical parameters. However, there remains the question whether established such antigens are sufficiently representative of the heterogeneous senescent cell population, and to what extent they are able to ameliorate senescent cell burden in vivo. To date the number of candidate antigens remains relatively few, yet emerging technologies such as single cell proteomic and multi-omic analyses may dramatically enhancing the efficiency of antigen discovery.

During the development of senescent cell targeted therapies, it is important to note that the elimination of senescent cells may not always be beneficial. Cellular senescence is known to play beneficial roles during embryogenesis, wound healing, tumor suppression and maintenance of tissue integrity. Transient initiation of senescence as a response to liver damage or cutaneous injury is known to promote tissue regeneration and prevent excessive fibrosis. Studies have shown that genetic depletion of p16 high cells may lead to disrupted physical barrier and fibrogenesis in the liver, as p16-enriched sinusoids are eliminated without eliciting replacement by new cells. Where the elimination of senescent cells is unfeasible or may lead to adverse effects, reversing the senescent cell age through epigenetic reprogramming could be an alternative solution. Proof-of-concept studies with partial reprogramming have been successfully carried out through transient activation of Yamanaka factors or administration of chemicals. Although the full mechanism behind this epigenetic-mediated rejuvenation effect remains to be elucidated, it is nevertheless an intriguing research avenue awaiting future exploration.

To date, a number of senotherapeutics have progressed into clinical phase and tested in those with age-related disorders. Studies with longer durations in larger patient cohorts utilizing composite markers for a comprehensive evaluation of senescence are needed to thoroughly assess the long-term systemic effect of senotherapeutics in combating diseases and aging, hence their overall translational potential.

Since the characterization of the first senolytics, the field of senotherapeutics has expanded rapidly to encompass nearly all aspects of translational medicine. By integrating principles of pharmacological treatment and immunotherapy to eliminate or rejuvenate senescent cells, it is possible to achieve therapeutic effects superior to symptomatically intervening on aging-related diseases. Although unresolved challenges exist, we maintain a positive outlook that the safety and applicability of senotherapeutics will be improved. Continued efforts in this area of study, particularly in rigorous studies in discovery science and collaboration to validate the effectiveness and safety of senotherapeutics in clinical trials, hold great importance in combating aging and improving human longevity.

Studies show that the established pharmaceutical strategies for controlling high blood pressure produce a meaningful reduction in mortality risk, even though they do nothing to repair or reverse the underlying cell and tissue damage that causes hypertension. This outcome is possible because the raised blood pressure of hypertension is very damaging in and of itself, harming vital tissues throughout the body. The kidney is particular vulnerable to pressure damage, as researchers note here.

Researchers analysed kidney tissue from a total of 99 patients who either suffered from high blood pressure (arterial hypertension) and type 2 diabetes or did not have either of the two conditions. The investigation was conducted on unaffected renal tissue samples from tumour nephrectomies, a surgical procedure in which a kidney is removed in whole or in part to treat a kidney tumour.

Using modern imaging and computer-assisted methods, the size and density of the podocytes and the volume of the renal corpuscles (glomeruli) were determined in the tissue samples. Podocytes are specialised cells of the renal corpuscles (glomeruli) that play a crucial role in the filtering function of the kidney. Their size and density are important indicators of the health of the kidney tissue. Artificial intelligence in the form of deep-learning-based image analysis was used for the analysis. With the help of a specially trained algorithm, digital tissue sections were automatically analysed to precisely capture the structure of podocytes and glomeruli.

The results show that patients with hypertension have a reduced density of podocytes compared to healthy controls and that their cell nuclei are enlarged compared to those of healthy controls. These changes occurred independently of the additional diagnosis of type 2 diabetes and likely represent the first microscopically visible step towards impaired renal function. The study authors see this as an indication that high blood pressure can cause structural damage to the kidneys at an early stage and before clinical symptoms appear.

Link: https://www.meduniwien.ac.at/web/en/ueber-uns/news/2025/news-in-march-2025/hypertension-causes-kidney-changes-at-an-early-stage/

Researchers here review what is known of the structural and functional aging of the adrenal gland, and conclude that this is an understudied area. While it is fairly clear that changes in signaling generated by the adrenal gland can be hypothesized to be harmful over the long term, based on what is known of the roles of DHEA, cortisol, and so forth, it remains to be demonstrated conclusively that adrenal gland aging directly contributes to the onset and progression of the age-related conditions it correlates with.

Our hypothesis is that structural and functional changes of the adrenal cortex develop and progress with increasing age, resulting in reduced secretion of DHEA/DHEAS and increased secretion of cortisol. It is important to obtain further evidence to better characterise the degenerative changes of the adrenal cortex, and to elucidate the clinical consequences of this. Adrenal cortex senescence is an emerging entity which appears to fulfil the criteria for an ageing-related pathology.

Functional changes are observed with increasing chronological age, in particular there is reduced secretion of DHEA and DHEAS, and there is increased output of cortisol. Such changes are associated with a range of adverse clinical outcomes, including an increased risk of premature mortality, systemic lupus erythematosus (SLE), dementia, breast cancer, rheumatoid arthritis, schizophrenia, bipolar affective disorder, depression, Alzheimer's disease, diabetes, and low bone mineral density. These findings have been reported in studies carried out in humans.

However, further evidence is required before adrenal cortex senescence can be definitively regarded as an age-related pathology. Whilst numerous diseases are associated with low serum DHEA/DHEAS, this may just be an association, or a consequence of the disease process. It remains to be determined whether reduced secretion of DHEA/DHEAS has any pathological outcomes. Similarly, it is important to advance the understanding of whether the increased cortisol output observed with increasing age mediates any adverse clinical effects, its underlying pathophysiology, and to better characterise the ageing-related changes in aldosterone secretion. Furthermore, much of the research considering the structural and morphological changes of the ageing adrenal gland has been carried out in animal models, and evidence from human studies is relatively scarce.

Link: https://doi.org/10.1007/s40618-025-02566-9

Chronic inflammation contributes to the onset and progression of all of the common age-related conditions. Researchers can examine a population of patients with a specific age-related disease and note specific differences in the immune system that contribute to inflammation. Because one is selecting for patients with greater inflammation by selecting those with the condition means that this sort of study may or may not represent a useful advance in knowledge. The need for better, more sophisticated approaches to reduce the chronic inflammation of old age is well understood. Some of these studies could reveal targets for the development of novel anti-inflammatory treatments, many will not.

The real challenge inherent to efforts to reduce late-life chronic inflammation is that, so far, it appears that the systems of regulation involved in maladaptive chronic inflammation are exactly the same as those needed for normal, transient inflammation. Changing the operation of the immune system to suppress unwanted inflammation also suppresses necessary inflammation, weakening the immune response to pathogens and potentially cancerous cells. The best path forward is to remove the age-related damage and dysfunction that provokes the immune system into inflammatory behavior, but comprehensively identifying and addressing all of those mechanisms that is a somewhat more distant prospect than the development of further ways to alter immune function.

Phenotypic alterations in peripheral blood B Lymphocytes of patients with Alzheimer's Disease

The immune system plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Microglia, the primary phagocytic cells in the brain, are responsible for the clearance of the amyloid-β (Aβ) and tau proteins. A significant number of AD-associated risk genes identified through genome-wide association studies (GWAS) are linked to the immune system. However, the phenotype and functional aspects of humoral immunity in AD remain incompletely understood. Our previous studies reported a panel of autoantibodies that are involved in the pathogenesis of AD. Other studies have also identified various autoantibodies in the circulation and cerebrospinal fluid of AD patients. In the AD brain, many brain-reactive autoantibodies are associated with Aβ deposition, supporting an autoimmune hypothesis in AD. Nevertheless, the mechanisms underlying the dysregulated autoantibody profile in AD have yet to be fully addressed.

B lymphocytes, a key component of the adaptive immune system, not only function as antigen-presenting cells to activate T cells and regulate inflammatory responses but also play a pivotal role in humoral immunity by secreting autoantibodies. We evaluated the immunophenotype of peripheral B lymphocytes in 27 AD patients confirmed by PET-Amyloid scan and 32 cognitively normal controls. We show that the phenotype of B lymphocytes is altered in AD patients. AD patients exhibit a decrease in both the numbers and proportions of switched memory (SwM) B cells and double-negative (DN) B cells. Additionally, B cells that produce proinflammatory cytokines including GM-CSF, IFN-γ, and TNF-α are increased, while those that produce the anti-inflammatory cytokine IL-10 are decreased in AD patients after in vitro stimulation. These alterations in B cell populations were linked to cognitive functions and biomarkers, including Aβ42/40 and pTau181, in AD patients.

UNITY Biotechnology was one of the first senolytics companies, and now conducts clinical trials of small molecule senolytic therapies based on well-established mechanisms by which senescent cells can be selectively forced into programmed cell death. The company has consistently pursued a strategy of delivering senolytic drugs locally to affect only specific diseased tissue, and has been criticized for doing so. Firstly such drugs will have limited off-label uses, and secondly for at least some conditions it seems plausible that local senescent cells are only part of the problem. There are many more senescent cells elsewhere in the body, and their signaling still contributes to inflammation in the affected organ. Still, it seems that UNITY's macular edema program has achieved better results in clinical trials than the program for knee osteoarthritis.

UNITY Biotechnology Announces Topline Results from the ASPIRE Phase 2b Study in Diabetic Macular Edema

UNITY Biotechnology, Inc., a biotechnology company developing therapeutics to slow, halt or reverse diseases of aging, today announced topline results from the Phase 2b ASPIRE clinical trial of intravitreal UBX1325 in patients with diabetic macular edema (DME) who had poor vision despite prior anti-VEGF treatment. UBX1325 is a novel BCL-xL inhibitor that is designed to eliminate senescent cells in diabetic retinal blood vessels, while leaving healthy ones intact. UBX1325 is administered via intravitreal injections that are standard procedure in clinical practice, minimizing treatment complexity and reducing the challenges of adapting to other technologies or surgical procedures.

Of the 1.7 million people in the U.S. with DME, approximately 750,000 patients have been diagnosed and are being treated. For the last 20 years, the standard of care for DME treatment has been anti-VEGF-related agents such as aflibercept. Despite vision improvements and stabilization with anti-VEGF therapy, one half of patients have a sub-optimal response and discontinue treatment after 6 months. For those that do respond, their vision gains generally plateau after 24 months of treatment and eventually start to decline despite cycling through different anti-VEGF treatment options.

The study results include data from all patients through 24 weeks, and the majority of patients through 36 weeks. UBX1325 treatment led to visual acuity gains of over 5 letters from baseline at weeks 24 and 36, and achieved non-inferiority to aflibercept at 9 out of 10 time points through 36 weeks, except for the average of weeks 20 and 24, where it achieved non-inferiority at an 88% confidence interval (compared to a 90% threshold pre-specified as primary analysis endpoint). UBX1325 continues to demonstrate a favorable safety and tolerability profile across multiple clinical studies to date. There have been no cases of intraocular inflammation, retinal artery occlusion, endophthalmitis or vasculitis across multiple studies.

Excessive lipid droplets in brain cells, particularly microglia, are characteristic of a number of neurodegenerative conditions. Even though cholesterol is vital to cell function, excess cholesterol in cells is toxic, changing behavior for the worse or even killing cells given a large enough excess. A range of other evidence is also supportive of a role for changes in lipid metabolism, including cholesterol metabolism, in the development of conditions such as Alzheimer's disease. Here, researchers report a new finding that implicates the cholesterol intake of neurons in an area of the brain known to be vulnerable to Alzheimer's pathology.

Researchers gathered a large collection of brain tissue samples from deceased patients and compared two different brain regions within the same individual. From each brain, they collected a sample of the dopamine-producing Substantia Nigra (SN), a region resistant to degeneration in AD, and the noradrenaline-producing Locus Coeruleus (LC), a region that is highly vulnerable to Alzheimer's disease. The researchers then analyzed RNA from the different brain regions to measure the expression levels of different genes. They used this gene expression data to provide a full picture of which cellular processes vary between these two neuronal populations.

Their results showed a striking segregation between the LC and SN in how they regulate cholesterol levels. "One key difference between the brain regions had to do with cholesterol metabolism and homeostasis. The LC neurons exhibit signatures suggesting that they are super cholesterol-hungry - these neurons are doing both their best to produce their own cholesterol and take in as much as possible. The SN, on the other hand, doesn't have the same level of demands."

Using immunohistochemistry tissue staining - the gold standard to demonstrate proteins at single cell level in tissue from different cases - the researchers validated these findings. They found that the LC neurons express higher levels of LDLR, a part of a receptor called sigma-2 that helps cells take in cholesterol molecules. A consequence of this, is that toxic amyloid-beta oligomers (small clumps of amyloid-beta protein) may "sneak in" to the neurons via this same receptor. Conversely, the SN expresses a selective degrader of LDLR, making it less susceptible to these oligomers.

Link: https://www.eurekalert.org/news-releases/1078311

When people talk about the klotho gene, they usually mean α-klotho, one of the better documented longevity-associated genes. It encodes a transmembrane protein, is expressed in a number of organs that sheds a portion of its structure to circulate in blood and tissues, interacting with other cells. In animal models artificially increased klotho expression improves late life health and life span while artificially diminished klotho expression worsens late life health and reduces life span. Interestingly, increased levels of klotho can improve cognitive function even in young animals. In humans, data shows the same correlation between circulating levels of klotho and age-related health and longevity.

The mechanisms by which klotho affects health on an organ by organ basis are far from fully understood, particularly when it comes to effects on the brain. It is best understood in the kidney, where it is protective against damage and diminished function with age. One hypothesis is that its body-wide effects are secondary to to kidney function, that loss of kidney function is an important contribution to age-related issues throughout the body. It does seem likely that it has direct effects on other organs as well, however.

The usual challenge in mechanisms relating to aging is that many processes are underway at the same time, interacting with one another. It is somewhere between hard and impossible to determine the relative size of each contribution to the end result of pathology and disease. The fastest path to that goal is to produce a therapy that only affects one contribution and observe the outcomes, but that is not always possible or practical.

Klotho antiaging protein: molecular mechanisms and therapeutic potential in diseases

Aging is not only a compilation of ailments that occur in the later stages of life; it is a dynamic process that unfolds throughout the lifespan. The escalating issue of an aging population is a significant economic, social, and medical concern of modern society. Over time, aging causes a segmental and gradual loss of strength and biological function, which leads to a decline in resistance and increasing physiological weakness. Multiple biochemical pathways actively control aging. It is distinguished by a number of molecular and cellular features, including abnormal nutrient sensing, mitochondrial dysfunction, cellular senescence, epigenetic imbalance, and loss of connectivity between cells. Globally, chronic illnesses tend to be more common in the aging population. Chronic illnesses need lengthy therapy, which alters the character of healthcare facilities and raises demand for them.

On the other hand, Klotho is an anti-aging protein with diverse therapeutic roles in the pathophysiology of different organs, such as the kidneys and skeletal muscle. Numerous pathways implicated in aging processes are regulated by Klotho, including Wnt signaling, insulin signaling, and phosphate homeostasis. It also impacts intracellular signaling pathways, including TGF-β, p53/p21, cAMP, and protein kinase C (PKC). Klotho expression and circulation levels decrease with increasing age. Klotho-deficient mice have excessive phosphate levels because of phosphate excretion imbalance in the urine. However, they also exhibit a complicated phenotype that includes stunted development, atrophy of several organs, hypercalcemia, kidney fibrosis, cardiac hypertrophy, and reduced lifespans. Given that supplementation or Klotho gene expression has been shown to suppress and repair Klotho-deficient phenotypes, it is likely that Klotho might have a protective impact against aging illness.

Recent cross-sectional cohort research with 346 healthy individuals aged 18 to 85 years showed that serum Klotho levels are negatively correlated with age and that older individuals (ages 55 to 85) exhibited the lowest serum α-Klotho levels. Another observational cohort research, which had around 804 adults over 65 years old, was conducted in Italy and found a negative correlation between serum Klotho levels and all-cause mortality. Furthermore, those with decreased serum Klotho levels had a comparable increased risk for all-cause death, according to a meta-analysis of six cohort studies that included adult chronic kidney disease (CKD) patients. Additionally, preclinical research has demonstrated that overexpressing the Klotho gene in transgenic mice can postpone or reverse aging. Therefore, increasing Klotho levels emerges as a promising strategy in diabetic kidney disease, CKD, and aging disorders.

The aging of the gut microbiome involves a shift in the relative numbers of different microbial species. As a result the production of some beneficial metabolites declines while inflammatory microbial activities increase. At present there are few practical ways to permanently adjust the gut microbiome, one of which is the transplantation of fecal matter from a donor. Animal studies have demonstrated that fecal microbiota transplantation from a young animal to an old animal rejuvenates the gut microbiome, improves health, and extends life. Human studies are relatively limited, but this approach to treatment is established for patients with C. difficile infection. It remains to be seen as to whether it will find broader use, versus the more challenging approach of developing the means to culture a full or close to full gut microbiome artificially.

The gut microbiota has become a potential therapeutic target in several diseases, including cardiovascular diseases. Animal models of fecal microbiota transplantation (FMT) were established in elderly and young rats. 16S rRNA sequencing revealed that the gut microbiota of the recipients shifted toward the profile of the donors, with concomitant cardiac structure and diastolic function changes detected via ultrasound and positron emission tomography-computed tomography (PET-CT). The elderly recipient rats that received young fecal bacteria presented an overall reduction in aging characteristics, whereas young rats that received reverse transplantation presented an overall increase in aging characteristics.

After FMT, the structure and function of the hearts of the recipient rats changed correspondingly. The age-related thickening of the left ventricular wall and interventricular septum at the organ level, along with the disordered arrangement of cardiomyocytes and increased interstitial volume at the tissue level, decreased following FMT in young rats. These structural modifications are accompanied by alterations in cardiac function; however, systolic function did not significantly change, whereas diastolic function notably improved. The young rats that received reverse transplantation presented the opposite results as the aged rats did; that is, the structure and function of the heart were lower in the reverse-transplanted rats than in the same-aged control rats.

A group of significantly enriched myocardial metabolites detected by liquid chromatography-mass spectrometry (LC/MS) were involved in the fatty acid β-oxidation process. Together with altered glucose uptake, as revealed by PET-CT, changes in ATP content and mitochondrial structure further verified a metabolic difference related to energy among rats transplanted with the gut microbiota from donors of different ages. This study demonstrated that gut microbes may participate in the physiological aging process of the rat heart by regulating oxidative stress and autophagy. The gut microbiota has been shown to be involved in the natural aging of the heart at multiple levels, from the organ level to the metabolically plastic myocardiocytes and associated molecules.

Link: https://doi.org/10.1016/j.exger.2025.112734

While much of the focus on cellular senescence in aging remains to find ways to selectively destroy these problem cells, there are also efforts to instead change their behavior. The reason why a growing burden of senescent cells in aged tissues is harmful, even when these cells make up only a tiny fraction of the overall cell population, is that they energetically secrete pro-inflammatory factors. This activity is disruptive to tissue structure and function when sustained over time. If senescent cells could be blocked from producing inflammatory secretions, their harms would be much reduced.

Accumulation of DNA damage can accelerate aging through cellular senescence. Previously, we established a Drosophila model to investigate the effects of radiation-induced DNA damage on the intestine. In this model, we examined irradiation-responsive senescence in the fly intestine. Through an unbiased genome-wide association study (GWAS) utilizing 156 strains from the Drosophila Genetic Reference Panel (DGRP), we identified meltrin (the drosophila orthologue of mammalian ADAM19) as a potential modulator of the senescence-associated secretory phenotype (SASP).

Knockdown of meltrin resulted in reduced gut permeability, DNA damage, and expression of the senescence marker β-galactosidase (SA-β-gal) in the fly gut following irradiation. Additionally, inhibition of ADAM19 in mice using batimastat-94 reduced gut permeability and inflammation in the gut. Our findings extend to human primary fibroblasts, where ADAM19 knockdown or pharmacological inhibition decreased expression of specific SASP factors and SA-β-gal. Furthermore, proteomics analysis of the secretory factor of senescent cells revealed a significant decrease in SASP factors associated with the ADAM19 cleavage site. These data suggest that ADAM19 inhibition could represent a novel senomorphic strategy.

Link: https://doi.org/10.18632/aging.206224

Drainage of cerebrospinal fluid from the brain into the body is reduced with age. The known pathways become impaired. Firstly, drainage holes in the cribriform plate behind the nose ossify and close up. Secondly the glymphatic system that carries away fluid from the brain loses lymphatic vessel density and vessel function. The outcome of reduced fluid flow leaving the brain is that metabolic wastes build up, causing inappropriate changes in cell behavior, including an increase in inflammatory signaling produced by the innate immune cells called microglia. Neurodegenerative conditions are characterized by chronic inflammation in the brain, disruptive to tissue structure and function.

As a companion to yesterday's paper on VEGF-C gene therapy to restore glymphatic drainage of cerebrospinal fluid in aged mice, today I'll point out a study that assesses glymphatic fluid flow in aged humans. The researchers correlate reduced flow with both loss of cognitive function and structural changes in the brain characteristic of aging. A relatively recently developed imaging technique known as Diffusion Tensor Image Analysis Along the Perivascular Space (DTI-ALPS) was employed. This uses MRI to obtain an assessment of how much water is flowing out of the brain via lymphatic vessels and perivascular spaces in a region where a number of vessels are conveniently lined up in parallel. The technique doesn't actually measure flow, but rather measures the direction and extent of local diffusion of water molecules in many small volumes. If there is flow, one would expect a very unbalanced "diffusion", with a lot of movement in the direction of the flow. So far the technique appears to be producing good results.

Glymphatic function decline as a mediator of core memory-related brain structures atrophy in aging

This study aimed to elucidate the role of the glymphatic system - a crucial pathway for clearing waste in the brain - in the aging process and its contribution to cognitive decline. We specifically focused on the diffusion tensor imaging analysis along the perivascular space (ALPS) index as a noninvasive biomarker of glymphatic function. Data were drawn from the Alzheimers Disease Neuroimaging Initiative (ADNI) database and a separate validation cohort to analyze the ALPS index in cognitively normal older adults. The relationships among the ALPS index, brain morphometry, and memory performance were examined.

As a biomarker of glymphatic function, the ALPS index appeared to decline with age in both cohorts. According to the brain morphology analysis, the ALPS index was positively correlated with the thickness of the left entorhinal cortex (r = 0.258), and it played a mediating role between aging and left entorhinal cortex thinning. The independent cohort further validated the correlation between the ALPS index and the left entorhinal cortex thickness (r = 0.414). Additionally, in both the primary and validation cohorts, the ALPS index played a significant mediating role in the relationship between age and durable or delayed memory decline.

In conclusion, this study highlights the ALPS index as a promising biomarker for glymphatic function and links it to atrophy of the core memory brain regions during aging. Furthermore, these results suggest that targeting glymphatic dysfunction could represent a novel therapeutic approach to mitigate age-related memory decline.

To my eyes, what one should take away from the study noted here is that adopting any form of healthier diet is beneficial over the long term. Another important item to consider is just how few people make it to age 70 without developing a major chronic medical condition. Thirdly, that the reasonable best case outcome for adjusting diet is to move the odds of avoiding chronic disease at age 70 from less than 10% to something more like 20%. Stepping back to consider the bigger picture, these are not good odds whether or not one's diet is healthy. These numbers are exactly why we need to spend less time focused on ever more detailed diet optimization and more time focused on assisting the development of potential rejuvenation therapies that address the underlying causes of aging.

As the global population ages, it is critical to identify diets that, beyond preventing noncommunicable diseases, optimally promote healthy aging. Here, using longitudinal questionnaire data from the Nurses' Health Study (1986-2016) and the Health Professionals Follow-Up Study (1986-2016), we examined the association of long-term adherence to eight dietary patterns and ultraprocessed food consumption with healthy aging, as assessed according to measures of cognitive, physical and mental health, as well as living to 70 years of age free of chronic diseases.

After up to 30 years of follow-up, 9,771 (9.3%) of 105,015 participants (66% women, mean age = 53 ± 8 years) achieved healthy aging. For each dietary pattern, higher adherence was associated with greater odds of healthy aging and its domains. The odds ratios for the highest quintile versus the lowest ranged from 1.45 (healthful plant-based diet) to 1.86 (Alternative Healthy Eating Index). When the age threshold for healthy aging was shifted to 75 years, the Alternative Healthy Eating Index diet showed the strongest association with healthy aging, with an odds ratio of 2.24.

Higher intakes of fruits, vegetables, whole grains, unsaturated fats, nuts, legumes, and low-fat dairy products were linked to greater odds of healthy aging, whereas higher intakes of trans fats, sodium, sugary beverages, and red or processed meats (or both) were inversely associated. Our findings suggest that dietary patterns rich in plant-based foods, with moderate inclusion of healthy animal-based foods, may enhance overall healthy aging, guiding future dietary guidelines.

Link: https://doi.org/10.1038/s41591-025-03570-5

The epidemiological evidence for exposure to microplastic and nanoplastic particles to be harmful and contribute to age-related disease is sparse at this time, with nowhere near as sizable a weight of compelling evidence as exists for the analogous topic of particulate air pollution. This may be a matter of time, however; give it another two decades and the fields might look quite similar. Or they might not! It is too early to say. There is a lot of hype and excitement around the topic, so it seems likely that the necessary large human studies to establish and quantify any meaningful contribution to age-related disease will be conducted in the years to come. Meanwhile, the first few smaller studies suggesting that such a contribution exists are attracting a fair amount of attention.

Microplastics - defined as fragments of plastic between 1 nanometer and 5 millimeters across - are released as larger pieces of plastic break down. They come from many different sources, such as food and beverage packaging, consumer products and building materials. People can be exposed to microplastics in the water they drink, the food they eat and the air they breathe.

The study examines associations between the concentration of microplastics in bodies of water and the prevalence of various health conditions in communities along the East, West and Gulf Coasts, as well as some lakeshores, in the United States between 2015-2019. While inland areas also contain microplastics pollution, researchers focused on lakes and coastlines because microplastics concentrations are better documented in these areas. They used a dataset covering 555 census tracts from the National Centers for Environmental Information that classified microplastics concentration in seafloor sediments as low (zero to 200 particles per square meter) to very high (over 40,000 particles per square meter).

The researchers assessed rates of high blood pressure, diabetes, stroke, and cancer in the same census tracts in 2019 using data from the U.S. Centers for Disease Control and Prevention. They also used a machine learning model to predict the prevalence of these conditions based on patterns in the data and to compare the associations observed with microplastics concentration to linkages with 154 other social and environmental factors such as median household income, employment rate, and particulate matter air pollution in the same areas.

The results revealed that microplastics concentration was positively correlated with high blood pressure, diabetes, and stroke, while cancer was not consistently linked with microplastics pollution. The results also suggested a dose relationship, in which higher concentrations of microplastic pollution are associated with a higher prevalence of disease. However, researchers said that evidence of an association does not necessarily mean that microplastics are causing these health problems. More studies are required to determine whether there is a causal relationship or if this pollution is occurring alongside another factor that leads to health issues, they said.

Link: https://www.acc.org/About-ACC/Press-Releases/2025/03/25/10/19/New-Evidence-Links-Microplastics-with-Chronic-Disease