Fight Aging!

Birds are much studied in the comparative biology of aging because they are long-lived for their size in comparison to mammals. The present consensus lumps birds and bats together, in that the evolution of flight and its high metabolic demand is thought to also require the evolution of a greater resistance to stresses placed on cells by oxidative molecules and other sources of molecular damage. One of those other forms of damage is glycation by sugar compounds. High blood sugar in mammals increases the production of a range of glycated molecules, such as the well-studied advanced glycation endproducts (AGEs), that can cause a variety of harms, from inflammation via the receptor for AGEs (RAGE) to cross-linking of the extracellular matrix to stiffen arteries.

Today's open access paper notes that birds exhibit high blood sugar relative to mammals, and that the relationship between blood sugar and species life span is not straightforward. It suggests that some longer lived species have evolved means to protect themselves from harmful glycation. This gives researchers something to look for; one of the long term goals in the study of the comparative biology of aging is to find mechanisms that might give rise to therapies that will slow aging in mammals. As ever, it is far to early to tell how this line of research will turn out in the end.

Birds' high blood sugar defies ageing expectations

The pace-of-life syndrome hypothesis proposes that an organism's metabolic rate, lifespan, reproductive strategies, and behaviour evolve in predictable ways. Under this framework, species with fast metabolisms, short lifespans, and high reproductive rates are expected to have higher blood sugar and glycation levels. Conversely, those with longer lifespans and slower developmental times should have lower blood sugar levels and greater resistance to glycation. However, it is unclear how glycation has coevolved with other traits across species, and so it is undetermined whether glycation fits into the framework of the pace of life hypothesis.

"Birds are particularly relevant in this context, given their relatively high blood sugar levels - on average almost twice as high as similarly sized mammals. This is thought to be an adaptation allowing flight, providing birds with the fuel needed to power intense bursts of aerobic exercise. But it is also paradoxical. Despite their higher blood sugar levels, birds show remarkable longevity compared to their mammalian counterparts, living up to three times longer."

Researchers conducted an analysis of 484 individual birds from 88 different species. They compared blood sugar levels and glycation rates in relation to the birds' life history traits. Their results revealed substantial variation in blood sugar levels across species. Smaller birds had the highest blood sugar levels, while larger species had the lowest. Glycation rates followed a similar trend, with smaller birds showing higher levels and larger birds displaying lower levels. However, the relationship between blood sugar levels and lifespan was more complex. While longer-lived birds generally had higher blood sugar levels, this increase plateaued beyond a certain point. This suggests that some species have evolved mechanisms to prevent glycation-related damage, rather than avoiding high blood sugar levels altogether.

Variation in albumin glycation rates in birds suggests resistance to relative hyperglycaemia rather than conformity to the pace of life syndrome hypothesis

The pace of life syndrome hypothesis (POLS) suggests that organisms' life history, physiological, and behavioural traits should co-evolve. In this framework, how glycaemia (i.e., blood glucose levels) and its reaction with proteins and other compounds (i.e. glycation) co-vary with life history traits remain relatively under-investigated, despite the well documented consequences of glucose and glycation on ageing, and therefore potentially on life history evolution. Birds are particularly relevant in this context given that they have the highest blood glucose levels within vertebrates and still higher mass-adjusted longevity when compared to organisms with similar physiology as mammals.

We thus performed a comparative analysis on glucose and albumin glycation rates of 88 bird species from 22 orders, in relation to life history traits (body mass, clutch mass, maximum lifespan, and developmental time) and diet. Glucose levels correlated positively with albumin glycation rates in a non-linear fashion, suggesting resistance to glycation in species with higher glucose levels. Plasma glucose levels decreased with increasing body mass but, contrary to what is predicted to the POLS hypothesis, glucose levels increased with maximum lifespan before reaching a plateau. These results increase our knowledge about the diversity of glycaemia and glycation patterns across birds, pointing towards the existence of glycation resistance mechanisms within comparatively high glycaemic birds.

This open access review paper outlines what is known of the way in which aging, circadian rhythm, and cancer risk interact with one another. Cancer is a well known as an age-related disease; among other contributing mechanisms, the mutation burden in somatic cells increases with age, while the surveillance conducted by the immune system, intended to destroy cancerous cells long before they form a tumor, declines with age. Separately, circadian rhythm regulation also becomes dysfunctional with advancing age, though the causative mechanisms in this case are little understood in comparison to what is known of the causes of cancer. Lastly, circadian rhythm interacts with cancer risk in potentially complex ways, again an area in which more research is needed before we might be able to say it is well understood.

Cancer, circadian rhythms, and aging are three biological processes closely associated with health and disease. While they may appear to be independent, increasing evidence suggests that there are complex interactions among them. The relationship between aging and cancer is very clear. Aging remains to represent the foremost risk factor across various cancer types, correlating with an elevated incidence of cancer that typically reaches its peak around the age of 85 years. On the mechanism, aging and cancer share many common hallmarks, including genomic instability, epigenetic alterations, chronic inflammation, cellular senescence, and so on, which serve as intermediaries between aging and cancer.

Circadian rhythms are 24-hour cycles that govern a range of physiological processes in living organisms, such as sleep-wake cycles, hormone release, metabolism, and cell proliferation. Disruption of circadian rhythms has also been shown to contribute importantly to the development and progression of cancers, although the exact mechanisms are not yet fully understood. Mechanistically, circadian rhythm proteins exhibit physical interactions with molecules implicated in cancer-related pathways, thus exerting influence over cancer initiation and progression.

Furthermore, there also exist complex and multifaceted relationships between aging and circadian rhythms. On the one hand, the aging process reduces the resilience of circadian rhythms, resulting in disrupted sleep-wake cycles, a diminished ability to synchronize circadian rhythms in peripheral tissues, and changes in the molecular functioning of circadian clock outputs. On the other hand, circadian rhythm dysfunction can accelerate the aging process by compromising essential bodily functions. These disruptions lead to increased oxidative stress, which refers to cellular damage caused by an imbalance between the production of reactive oxygen species (ROS) and the cell's ability to neutralize them. This imbalance of ROS can lead to DNA damage, protein denaturation, and lipid peroxidation, ultimately contributing to inflammation and the development of age-related health issues

Link: https://doi.org/10.34133/research.0612

White matter hyperintensities are small volumes of damage and scarring in the white matter of the brain, named for the way they appear in MRI images of brain tissue. They can be caused by rupture of small blood vessels, but also by any other localized cause of cell death and inflammation. Greater numbers of white matter hyperintensitives are generally indicative of a higher risk of neurodegenerative conditions and cognitive decline. Interestingly, researchers here note that the correlation with cognitive decline only exists for larger white matter hyperintensities.

The association between white matter integrity and adverse brain health outcomes is well-established. Increased white matter lesion burden has consistently been linked to higher risk of stroke, cognitive impairment, dementia, and mortality in cross-sectional and longitudinal studies involving diverse patient populations and healthy older adult cohorts.

This study investigates the relationship between white matter hyperintensities (WMHs) and longitudinal cognitive decline in older adults. Using data from The Irish Longitudinal Study on Ageing (TILDA), we examined WMH characteristics, including volume, location, and microstructural integrity, in a community-dwelling population of 497 individuals over a six-year period. WMHs were categorised into phenotypes based on their size, fractional anisotropy (FA), and mean diffusivity (MD), with subtypes for periventricular and deep white matter lesions. We hypothesised that larger, microstructurally compromised lesions would be associated with accelerated cognitive decline.

We isolated 11,933 WMHs, with an average of 24 WMHs per individual. Of these lesions, 6,056 (51%) were classified as Low Volume - High FA, 3193 (27%) were classified as Low Volume - Low FA and 2684 (22%) were classified as High Volume, Low FA. Our findings demonstrate that high-volume, low FA deep and periventricular lesions were significantly linked to cognitive decline, whereas small periventricular lesions with near normal microstructural properties do not predict cognitive decline. These results suggest that distinct WMH phenotypes may serve as markers for differential risks of cognitive impairment, providing potential targets for early intervention in at-risk populations.

Link: https://doi.org/10.3389/fnagi.2025.1520069

The innate immune cells known as macrophages are found everywhere in the body, outside the brain. Inside the brain an analogous population known as microglia exists. A population of monocytes resides in the spleen and circulates in the bloodstream, capable of differentiating into macrophages and entering tissues when needed. But large numbers of tissue resident macrophages also exist, already in place. Macrophages undertake a wide range of tasks, including the destruction of infectious pathogens and senescent and cancerous cells, coordination of tissue regeneration following injury, and clearance of metabolic waste and debris. Macrophages are diverse in the sense that they can adopt different programs of expression and behavior in response to circumstances and environment. With advancing age, some of these behaviors can become maladaptive in response to the damaged tissue environment.

Today's open access paper is focused on one specific population of macrophages that is implicated as a source of inflammatory signaling in aging. Chronic inflammation is a feature of aging, with many contributing causes. When inflammation continues indefinitely without resolution, it changes cell behavior to cause disruption to tissue structure and function, contributing to the onset and progression of a range of age-related conditions. Since necessary short term inflammation and harmful long-term inflammation are governed by the same regulatory pathways, it is likely that the only truly effective solution to the problem of chronic inflammation in aged tissues involves removing the molecular damage that provokes it and either removing or altering the behavior of the immune cell populations that generate the largest amounts of inflammatory signaling.

SPP1 macrophages across diseases: A call for reclassification?

Recent advances in macrophage biology have revealed a remarkable diversity among these immune cells, highlighting the existence of specialized subpopulations with distinct functional roles in health and disease. Among these, SPP1+ macrophages, characterized by elevated osteopontin (SPP1) expression, have garnered significant attention due to their consistent association with pathological states. Originally identified in cancer as tumor-associated macrophages (TAMs), SPP1+ macrophages have since been implicated in various conditions, including aging, chronic inflammatory disorders, neurodegenerative diseases, and tissue remodeling.

Aging presents a compelling context in which SPP1+ macrophages emerge as key players. Single-cell RNA sequencing studies have revealed their abundance in the skeletal muscle of aged mice, where they exhibit hallmarks of senescence and enhanced angiogenic and lipid metabolic activity. Beyond musculoskeletal systems, SPP1+ macrophages also influence neurodegenerative diseases. In Alzheimer's disease, an upregulation of SPP1-positive microglia correlates with inflammation and synaptic loss. Perivascular macrophages with SPP1 profiles modulate microglial phagocytic activity, offering a potential mechanism underlying synapse degradation. This dual contribution to inflammation and neurodegeneration positions SPP1+ macrophages as central figures in aging-related pathologies.

Their conserved traits, such as promoting fibrosis, remodeling the extracellular matrix, and modulating immune responses, suggest they play a pivotal role in sustaining chronic inflammation and tissue dysfunction. Furthermore, their presence often correlates with poor clinical outcomes, underscoring their relevance as potential therapeutic targets. Despite these shared characteristics, SPP1+ macrophages exhibit functional adaptability across different disease contexts, raising questions about their classification and the underlying mechanisms that drive their diverse roles.

In this perspective, we briefly summarize recent discoveries on the multifaceted roles of SPP1+ macrophages across various pathological conditions, emphasizing their shared traits and the critical differences dictated by the tissue microenvironment and pathological inflammatory context. Based on our comparative literature investigation, we also propose a re-evaluation of their classification, advocating for their recognition as a distinct macrophage subtype linked to prolonged inflammatory states rather than specific to tumors. Such a shift in perspective could not only advance our understanding of macrophage biology but also open new avenues for targeted therapeutic interventions.

Why are there more female than male centenarians? The difference in life expectancy between men and women is well known and well explored. The long list of potential causative mechanisms all come with supportive evidence, but are incompletely understood at the detail level. In particular it remains unclear as to the relative importance of each these contributing factors versus all of the others. Here, researchers focus on differences in immune function and the composition of the gut microbiome in extremely old individuals. These are connected items, as the immune system gardens the gut microbiome by removing potentially problematic microbes, while those problematic microbes can induce chronic inflammation and dysfunction in the immune system.

Extreme longevity, particularly reaching the age of 100 years, is an exceptionally rare trait in the human population, exhibiting significant variations in prevalence between genders. Women generally exhibit greater survival rates than men across all age groups, including centenarians, with the gender gap in life expectancy ranging from 4.2 to 6.2 years. Genetic factors and immune responses play a crucial role in achieving longevity; however, there is limited information regarding the mechanisms that regulate the differences in biological aging between men and women.

A strong immune system is a key factor in determining lifespan, and sex plays an important role in its composition and activity. The sex-based diversity in immunity between males and females is regulated by several mechanisms, including X chromosome inactivation, mosaicism, skewing, and dimorphism in the expression of X chromosome-encoded genes, as well as regulatory genes on the Y chromosome. Generally, women exhibit stronger innate and adaptive immune responses than men.

An additional factor that may contribute to gender differences in the immune system is the gut microbiota. Composition of gut microbiota varies between males and females providing sex-specific differences in immune responses. Notably, it has been demonstrated that the ratio of bacterial cells to human cells differs between males and females, with a ratio of approximately 1.3:1 for males and 2.2:1 for females. However, the mechanisms by which the gut microbiome contributes to conditions conducive to successful aging remain unclear. Consequently, future research should prioritize investigating the causal relationship between sexually dimorphic immunity and the microbiota.

Link: https://doi.org/10.3389/fimmu.2025.1525948

Torpor is characteristic of hibernating mammals, involving reduced body temperature and slowed metabolism. Researchers have discovered a way to induce this state in mice, and demonstrate that implementing a schedule of intermittent repeated periods of torpor produces an extension of healthspan. This ties in to an established literature on the relationships between metabolic rate, body temperature, and lifespan in mammals, in that one would expect reduced body temperature to produce a modest slowing of aging.

Torpor is a state of profoundly decreased metabolic rate, driving a decrease in core body temperature that can last from hours to days, whereas hibernation is a seasonal behavior comprising multiple bouts of torpor interrupted by periodic arousals to euthermia. These extraordinary adaptations raise many unanswered fundamental questions of homeotherm biology, one of the most compelling being the link between torpor and longevity. Natural torpor is characterized by tightly coupled, extreme physiological changes that have been individually implicated in aging and longevity, such as decreased core body temperature and metabolic rate, and caloric restriction. Indeed, hibernating species exhibiting long torpor bouts show extended longevity compared to closely related non-hibernators and longer lifespan than would be expected based on body mass alone.

Here we demonstrate that the activity of a spatially defined neuronal population in the preoptic area, which has previously been identified as a torpor-regulating brain region, is sufficient to induce a torpor-like state (TLS) in mice. Prolonged induction of TLS slows epigenetic aging across multiple tissues and improves healthspan. We isolate the effects of decreased metabolic rate, long-term caloric restriction, and decreased core body temperature on blood epigenetic aging and find that the decelerating effect of the TLS on aging is mediated by decreased body temperature. Taken together, our findings provide novel mechanistic insight into the decelerating effects of torpor and hibernation on aging and support the growing body of evidence that body temperature is an important mediator of the aging processes.

Link: https://doi.org/10.1038/s43587-025-00830-4

Metabolic syndrome is the precursor to type 2 diabetes, and a direct consequence of being sufficiently overweight to experience the necessary disruptions to metabolism. Sarcopenia is the name given to severe loss of muscle mass and strength when it occurs in older people, though it is worth noting that these losses are universal. While a sizable fraction of the muscle atrophy observed in wealthier regions of the world results from a sedentary lifestyle, the other underlying causes resulting from aging occur for everyone. Everyone would reach a state of sarcopenia eventually, if they did not first die due to some other consequence of degenerative aging.

Since sarcopenia is in part driven by chronic inflammation, and chronic inflammation is characteristic of metabolic syndrome, these two conditions can coexist. In today's open access paper, epidemiologists examine data obtained for this patient population in order to quantify the excess mortality risk that these individuals experience as a result of (a) the underlying damage and dysfunction that contributes to these conditions, and (b) the secondary dysfunctions and further damage resulting from these conditions.

Additive impact of metabolic syndrome and sarcopenia on all-cause and cause-specific mortality: an analysis of NHANES

Metabolic syndrome (MetS) and sarcopenia (SP) are increasingly significant public health issues in aging societies, sharing common pathophysiological mechanisms and being associated with severe health consequences. This study analyzed data from the National Health and Nutrition Examination Survey (NHANES) conducted between 1999 and 2018. Mortality data were obtained from the National Death Index up to December 2019. Among the 21,962 participants, 61.5% had neither MetS nor SP (MetS-/SP-), 24.6% had MetS only (MetS+/SP-), 12.2% had SP only (MetS-/SP+), and 1.5% had both MetS and SP(MetS+/SP+).

Compared to the group without MetS and SP, the groups with MetS only, SP only, and both MetS and SP showed increased all-cause mortality, with adjusted hazard ratios (HR) of 1.23, 1.63, and 1.61, respectively. The MetS+/SP+ group had the highest overall mortality risk. For cause-specific mortality, the MetS+/SP+ group exhibited increased cardiovascular mortality (HR: 1.89), cardiac mortality (HR: 1.89), respiratory mortality (HR: 2.63), and diabetes mortality (HR: 8.79) compared to the group without MetS and SP.

Overexpression of the transcription factor XBP1 has been shown to extend life in flies. It is thought to achieve this outcome by increasing the efficiency of the unfolded protein response, a cell maintenance process. Its diverse other effects may also be important, as its regulation of transcription touches on immune function, lipid metabolism, glucose metabolism, and other mechanisms. This extensive portfolio of influences is often the case for transcription factors. Here, researchers apply brain-specific XBP1 overexpression to mouse models of Alzheimer's disease, and observe a reduction in pathology.

The decay of the proteostasis network has been pointed out as a primary hallmark of aging, a phenomenon that may contribute to Alzheimer's disease (AD) pathogenesis. Strategies to improve proteostasis have been tested in multiple models of neurodegenerative diseases, observing outstanding protective effects. One of the central nodes of the proteostasis network altered during aging involves the function of the endoplasmic reticulum (ER), the main site for protein production in the cell. The ER is also highly altered in AD. To cope with ER stress, cells activate an evolutionarily conserved pathway known as the unfolded protein response (UPR), which aims to re-establish proteostasis. The UPR reinforces many processes involved in the function of the secretory pathway to improve protein production and sustain cell function, whereas chronic ER stress results in neurodegeneration and cell death.

The most conserved UPR signaling branch is initiated by the ER stress sensor IRE1, which catalyzes the unconventional splicing of the mRNA encoding XBP1. This event results in the expression of an active transcription factor, termed XBP1s, which enables transcriptional reprogramming. We recently reported that the activity of the IRE1/XBP1 pathway declines in the brain during normal aging in mammals and strategies to enhance the activity of the UPR extend brain healthspan. Importantly, we showed that strategies to express XBP1s in neurons either using transgenic mice or gene therapy delayed synaptic dysfunction and cognitive decline during normal aging, in addition to reducing the content of senescence cells in the brain.

With the idea of testing the effects of artificially enforcing UPR adaptive responses in the AD brain, we overexpressed the active XBP1s form in the nervous system using transgenic mice, in addition to the hippocampus using adeno-associated viral (AAV) vectors. Overexpression of XBP1s dramatically reduced the content of amyloid plaques in the brain and improved cognitive performance and synaptic plasticity in a model of familial AD (5xFAD transgenic animals expressing mutant APP and presenilin-1). Additionally, XBP1s overexpression in the brain improved memory performance on a model of sporadic AD based on the injection of amyloid β oligomers. The beneficial effects of XBP1s expression in the context of experimental AD and normal aging involve a substantial correction of gene expression patterns associated with synaptic function, neuronal morphology, and connectivity. Thus, we speculate that a major protective mechanism of XBP1s in AD relates to its function as a regulator of neuronal physiology that may parallel its effects in reducing amyloid deposition.

Link: https://doi.org/10.4103/NRR.NRR-D-24-00658

Being overweight correlates with an increased risk of age-related disease and mortality in later life. The greater the excess weight, the greater the risk. A sizable fraction of this risk appears to be mediated by the metabolic activity of visceral fat cells, which promote chronic inflammation through a range of mechanisms. These include an increased burden of cellular senescence, visceral fat cells mimicking the signaling associated with infected cells, and an greater amount of debris from dying and dead cells that provokes a maladaptive inflammatory response from immune cells. Chronic inflammation is characteristic of aging, and is disruptive to tissue structure and function.

Body fat distribution in women changes as menopause progresses and estrogen levels decrease, causing the adipose tissue concentrated in the hips and thighs to gradually shift to the midsection as harmful visceral fat. This predisposes women to low-grade inflammation and cardiovascular diseases, which increase significantly after menopause. A study investigated the connection between health behaviours and low-grade inflammation. Health behaviours in this study include sleeping, eating and physical activity, and related disorders.

"In line with previous studies, a higher amount of visceral fat was, as expected, associated with low-grade inflammation. Visceral fat accumulated in the midsection secretes cytokines that increase inflammation, and this can increase the risk of metabolic diseases." The results show that those individuals who exhibit more disordered eating behaviour, as well as those who were physically less active, had more visceral fat, and thus the risk of low-grade inflammation was also higher. When eating and physical activity behaviours were examined together, higher physical activity was associated with lower visceral fat, especially in those women who did not display disordered eating behaviour.

Link: https://www.jyu.fi/en/news/exercise-and-healthy-eating-behaviour-together-provide-the-best-protection-against-cardiovascular

People taken en masse are reflexively conservative, grumbling and resistant to all change, whether or not that change is evidently, clearly positive. So if one takes a tour of what the medical community has to say about the prospects of extending healthy life spans via the development of new forms of therapy that target mechanisms of aging, one will find at least as much grumbling and resistance as optimism. It seems self-evident that more healthy life is a good thing. But it is change, and people don't like change.

A clever editorial is presently doing the rounds, pointing out the parallels between the present development of treatments for aging with the early development of anesthesia for surgical patients across the span of the 1800s. That was a development process that we might today, in hindsight, characterize as much delayed past the point of the initial discovery of the first practical approach to anesthesia. Exactly how much of that delay can be attributed to grumbling and resistance on the part of the medical community is up for debate, but the authors of the editorial have uncovered some choice quotes from influential figures of the time.

Turning Fate into Choice: Patient Self-Determination and Life Extension

The foundations of modern medicine rest upon two revolutionary changes in medical practice. The first is the development of effective treatments that have transformed previously fatal diseases into manageable or curable conditions. A child who developed diabetes in 1900 would have died within months, while today, insulin therapy can provide them with a normal lifespan. The second was a fundamental shift in the doctor-patient relationship, replacing physician paternalism with patient self-determination. Whereas physicians once withheld diagnoses and made unilateral decisions, clinical practice now centers on informed consent and shared decision-making.

This progress in expanding patient choice was neither smooth nor inevitable. Consider anaesthesia, the astonishingly slow development of which reveals how physician attitudes can constrain patient autonomy. After the discovery of nitrous oxide's anaesthetic properties in 1799, patients should have been quickly granted the option of avoiding gratuitous surgical and obstetrical pain. Instead, the potential applications were neglected for 50 years, with one prominent surgeon dismissing it entirely when stating that "The abolishment of pain in surgery is a chimera. It is absurd to go on seeking it." When surgical anaesthesia was finally demonstrated successfully in 1846, one might have expected rapid adoption to promptly provide patients the choice of pain-free surgery. Instead, resistance persisted, with some surgeons in 1847 still insisting that "Pain in surgical operations is in a majority of cases even desirable, and its prevention or annihilation is for the most part hazardous to the patient." While skepticism of new treatment safety is understandable - and indeed, anaesthesia-related complications still occur today - it seems clear that 19th century patients would have welcomed the choice of pain-free surgery, had they been granted the opportunity.

Despite medicine's progress since the 1800s, we believe that the aforementioned neglect and paternalism are repeating themselves again today in attitudes towards aging and death. Take the 2022 Report of the Lancet Commission on the Value of Death, which declared that "it is healthy to die" and "without death every birth would be a tragedy" - statements that echo 19th century claims about the necessity of pain in surgery. This philosophical stance is arguably also manifest institutionally: the U.S. Food and Drug Administration does not even classify aging as a disease process, while the National Institutes of Health dedicates less than 1% of its budget to basic research into ageing and senescence. While we welcome the increasing emphasis on patient choice in end-of-life care, these attitudes reveal a troubling disregard for the wish of many dying patients, no matter their age, to live longer if only they were able. Indeed, one survey found that 70% of terminally ill individuals, including those in their eighties, maintained a strong will-to-live even when death was imminent. Just as patients facing amputation in 1825 would likely have jumped at the chance for pain-free surgery, surely many patients today would choose to extend their lives if offered ways to do so while maintaining their quality of life.

The central nervous system is inconveniently situated for those who wish to examine it in detail in living people, but one tiny portion is at least readily available for visual inspection - the retina at the back of the eye. To the degree that the retina is subject to the same mechanisms of aging as the brain, one might expect to be able to use retinal imagery as a measure of brain aging. A number of studies have done just that, and a number of different aging clocks have been derived from standard forms of retinal imagery. Here, researchers look at just one aspect of retinal structure as a measure of age-related degeneration, the thickness of its different layers.

The retina, an extension of the central nervous system, reflects neurodegenerative changes. Optical coherence tomography (OCT) is a non-invasive tool for assessing retinal health and has shown promise in predicting cognitive decline. However, prior studies produced mixed results. This study investigated a large cohort (n = 490) of Asian individuals attending memory clinics. Participants underwent comprehensive neuropsychological testing annually for five years. Retinal thickness was measured by OCT at baseline. We assessed the association between baseline retinal thickness and subsequent cognitive decline.

Participants with a significantly thinner macular ganglion cell-inner plexiform layer (GCIPL) at baseline (≤ 79 μm) had a 38% greater risk of cognitive decline compared to those who did not (≥ 88 μm). In a multivariable model accounting for age, education, cerebrovascular disease status, hypertension, hyperlipidemia, diabetes and smoking, thinner GCIPL was associated with an increased risk of cognitive decline (hazard ratio = 1.14). Retinal nerve fiber layer (RNFL) thickness was not associated with cognitive decline.

Link: https://doi.org/10.1186/s13195-024-01627-0

Macrophages of the innate immune system exhibit a range of different states known as polarizations. M1 macrophages are inflammatory and focused on attacking pathogens and errant cells. M2 macrophages are anti-inflammatory and focused on tissue maintenance, playing an important role in regeneration from injury. Not a vital role, strictly speaking, as wounds still heal in the absence of macrophages, but the presence of macrophages in the M2 polarization accelerates the process. As researchers demonstrate here, ways to guide macrophages into the desired pro-regenerative M2 state can further speed wound healing.

Macrophages play a key role in wound healing. Dysfunction of their transition from the M0 unpolarized state to the M2 polarization leads to disorders of the wound immune microenvironment and chronic inflammation, which affects wound healing. Regulating the polarization of M0 macrophages to M2 macrophages is an effective strategy for treating wound healing. Mesenchymal stem cells (MSCs) deliver endogenous regulatory factors via paracrine extracellular vesicles, which may play a key role in wound healing, and previous studies have shown that apoptotic bodies (ABs) are closely associated with inflammation regression and macrophage polarization. However, the specific regulatory mechanisms involved in ABs remain unknown.

In the present study, we designed an MSC-AB (MSC-derived AB)-loaded polycaprolactone (PCL) scaffold, evaluated the macrophage phenotype and skin wound inflammation in vivo and in vitro, and explored the ability of MSC-AB-loaded PCL scaffolds to promote wound healing. Our data suggest that the PCL scaffold regulates the expression of the CCL-1 gene by targeting the delivery of mmu-miR-21a-5p by local sustained-release MSC-ABs, and drives M0 macrophages to program M2 macrophages to regulate inflammation and angiogenesis, thereby synergistically promoting wound healing. This study provides a promising therapeutic strategy and experimental basis for treating various diseases associated with imbalances in proinflammatory and anti-inflammatory immune responses.

Link: https://doi.org/10.1016/j.gendis.2024.101388

Nearly 15 years have passed since the first compelling demonstration of rejuvenation produced by clearance of senescent cells in the tissues of aged mice. At that time the study of senescent cells was fairly slow and sedate, not a major area of research. How things change! At present a very energetic community of academic groups and biotech companies is mining the biochemistry of cellular senescence in search of better ways to selectively destroy these cells, ways to change their behavior to reduce their contribution to systemic inflammation and tissue dysfunction, and even ways to turn back the normally irreversible transition into the senescent state. There are incentives: any new discovery could be the starting point for development of a therapy that significantly slows or reverses aspects of aging.

The damage done by the growing burden of senescent cells found in aged tissues is thought to be near entirely caused by the senescence-associated secretory phenotype (SASP), the mix of pro-growth, pro-inflammatory signaling that is energetically produced by these cells. As the thinking goes, a way to eliminate the SASP could be as beneficial as clearing senescent cells from tissues. There are drawbacks to this approach, which is that the SASP is actually beneficial in the short term, helpful in wound healing and suppression of potentially cancerous cells. Periodic destruction of senescent cells would not interfere in their beneficial short-term behaviors, while chronic dosing to suppress the SASP would do so. Nonetheless, as today's open access paper illustrates, there is a growing interest in finding ways to reduce or even eliminate SASP signaling.

ACSS2 drives senescence-associated secretory phenotype by limiting purine biosynthesis through PAICS acetylation

The senescence-associated secretory phenotype (SASP) mediates the biological effects of senescent cells on the tissue microenvironment and contributes to ageing-associated disease progression. Acetate-dependent acetyl-CoA synthetase 2 (ACSS2) produces acetyl-CoA from acetate and epigenetically controls gene expression through histone acetylation under various circumstances. However, whether and how ACSS2 regulates cellular senescence remains unclear.

Here, we show that pharmacological inhibition and deletion of Acss2 in mice blunts SASP and abrogates the pro-tumorigenic and immune surveillance functions of senescent cells. Mechanistically, ACSS2 directly interacts with and promotes the acetylation of PAICS, a key enzyme for purine biosynthesis. The acetylation of PAICS promotes autophagy-mediated degradation of PAICS to limit purine metabolism and reduces deoxyribonucleotide triphosphate (dNTP) pools for DNA repair, exacerbating cytoplasmic chromatin fragment accumulation and SASP.

Altogether, our work links ACSS2-mediated local acetyl-CoA generation to purine metabolism through PAICS acetylation that dictates the functionality of SASP, and identifies ACSS2 as a potential senomorphic target to prevent senescence-associated diseases.

This review paper looks at what is known of hypoxia-inducible factor (HIF) signaling in the aging of lung tissue, with a particular focus on the burden of cellular senescence as a measure of age-related dysfunction. In the view of these researchers, chronic expression of HIF with age promotes cellular senescence. Why HIF expression becomes dysregulated with age is one of many questions that are hard to answer; it takes a great deal of effort to trace the chain of cause and consequence that leads to any given alteration in gene expression, and in near all cases the long and winding connection to some fundamental causative mechanism of aging has not been definitively established.

Hypoxia-inducible factor (HIF) is a key transcriptional mediator of cellular responses to low oxygen, which regulates lung physiology and pathogenesis. It is a central regulator of hypoxic adaptation in lung tissues and plays a dual role in maintaining homeostasis and driving pathological processes. At low levels, hypoxia induced activation of HIF is hormetic, triggering adaptive cellular responses that enhance stress resistance and longevity. However, excessive or prolonged HIF activation skews this adaptive response, fostering fibrosis, inflammation, and disease progression.

During normal aging, HIF maintains oxygen homeostasis, regulates mitochondrial activity, and supports adaptive stress responses in lung tissues. With advancing age, HIF signaling efficiency declines, leading to reduced stress tolerance and impaired repair mechanisms in lung cells. Chronic HIF dysregulation in aging lungs has been linked to increased oxidative stress, senescence induction, and pro-inflammatory signalling. In the lungs, HIF is also essential for oxygen homeostasis and adaptation to hypoxic environments. Beyond its role in oxygen sensing, HIF modulates cellular metabolism, inflammation, and senescence pathways, directly influencing lung aging.

Recent studies indicate that HIF and cellular senescence interact at multiple levels, where HIF can both induce and suppress senescence, depending on cellular conditions. While transient HIF activation supports tissue repair and stress resistance, chronic dysregulation exacerbates pulmonary pathologies. Emerging evidence suggests that targeting HIF and senescence pathways could offer new therapeutic strategies to mitigate age-related lung diseases. This review explores the intricate crosstalk between these mechanisms, shedding light on how their interplay influences pulmonary aging and disease progression.

Link: https://doi.org/10.1007/s10522-025-10208-z

Age-related cataract formation in the lens of the eye causes blindness. This growing opacity of the lens appears to be driven in large part by a growing burden of cellular senescence in lens cells. Could senolytic therapies to clear senescent cells reduce the need for surgery and the development of cell therapies and tissue engineered replacement lenses? This seems plausible, but cataract are a long way removed from the top of the priority list of conditions that might be beneficially affected by senolytic treatments. It is unclear as to whether any group is working towards clinical trials of senolytics in patients at risk of cataract formation.

Cellular senescence plays a dual role in health and disease, acting as both a guardian against uncontrolled proliferation and a driver of age-related pathologies, including cataract formation. The intricate interplay between oxidative stress, mitochondrial dysfunction, and chronic inflammation underscores the complexity of senescence in lens epithelial cells (LECs), essential for maintaining lens transparency and particularly vulnerable to oxidative stress-induced senescence.

The progressive senescence of LECs represents a critical factor in age-related cataractogenesis. Advances in senotherapeutics may offer promising strategies to mitigate LEC senescence, either by eliminating senescent cells through senolytics or modulating the harmful effects of the senescence-associated secretory phenotype (SASP) with senomorphics. Natural compounds like fisetin, luteolin, and metformin, along with innovative therapies such as FOXO4-DRI and gene editing, highlight the growing potential for targeted interventions to delay cataract progression.

Future research on cellular senescence in cataract formation holds significant potential to uncover novel therapeutic strategies aimed at delaying or preventing lens opacity. A deeper understanding of the molecular drivers of LEC senescence, particularly the role of oxidative stress, mitochondrial dysfunction, and protein aggregation, will be essential for developing targeted interventions. Investigating the interplay between SASP factors and changes in the lens microenvironment could provide insights into how chronic inflammation accelerates cataract progression. Senescence research could pave the way for innovative treatments that preserve lens transparency and prevent age-related cataracts.

Link: https://doi.org/10.3390/ph18020244