Fight Aging!

Genes consist of exon sequences and intron sequences that, once transcribed into RNA, are spliced together to form the final RNA molecule. Exons are usually included and introns usually excluded, but many genes can encode for multiple different RNA molecules via alternative splicing arrangements. The regulation of RNA splicing is complex, and like all complex aspects of our biochemistry it becomes dysfunctional with advancing age. The proportions of normal versus alternative splicing are altered, and outright incorrect RNA molecules can be formed as well.

It remains an open question as to the degree to which RNA splicing dysfunction is an important contribution to degenerative aging. Clearly it can cause harm, but as is the case for much of aging, it is hard to assess whether this harm is meaningful in comparison to other causes of damage, dysfunction, and cell stress. Today's open access paper is one example of a range of evidence that supports a greater rather than lesser role for RNA splicing dysfunction in aging. While focused on one tissue only, if harms can be shown in one location in the body it is reasonable to think they are occurring elsewhere as well.

A related open question is whether it is worth attempting to find ways to directly correct the operation of RNA splicing in aged cells versus attempting to identify and fix the underlying causes of RNA splicing dysfunction. One might expect RNA splicing dysfunction to be downstream of epigenetic changes characteristic of aging, as epigenetic change can cause a reduction in the production of critical molecular machinery or imbalances in the relative numbers of specific molecules needed for RNA splicing. There is the hope that success in developing therapies based on partial reprogramming will address RNA splicing dysfunctions and many other issues by resetting epigenetic marks into a more youthful state. But this remains to be seen, and a number of groups are pursing other approaches that may improve the operation of RNA splicing to some degree.

Dysregulation of alternative splicing patterns in the ovaries of reproductively aged mice

Female reproductive aging is characterized by progressive deterioration of ovarian function, yet the molecular mechanisms driving these changes remain incompletely understood. Here, we used long-read direct RNA-sequencing to map transcript isoform changes in mouse ovaries across reproductive age. Comparing young and aged mice after controlled gonadotropin stimulation, we identified widespread alternative splicing changes, including shifts in exon usage, splice site selection, and transcript boundaries.

Aged ovaries exhibited increased isoform diversity, favoring distal start and end sites, and a significant rise in exon skipping and intron retention events. Many of these age-biased splicing events altered open reading frames, introduced premature stop codons, or disrupted conserved protein domains. Notably, mitochondrial genes were disproportionately affected. We highlight Ndufs4, a mitochondrial Complex I subunit, as a case in which aging promotes the alternative splicing of a truncated isoform lacking the canonical Pfam domain. Structural modeling suggests this splice variant could impair Complex I function, resulting in increased reactive oxygen species (ROS) production.

Our data suggest a mechanistic link between splicing and mitochondrial dysfunction in the aging ovary. These findings support the model of the splicing-energy-aging axis in ovarian physiology, wherein declining mitochondrial function and adaptive or maladaptive splicing changes are intertwined. Our study reveals that alternative splicing is not merely a byproduct of aging but a dynamic, transcriptome-wide regulatory layer that may influence ovarian longevity. These insights open new avenues for investigating post-transcriptional mechanisms in reproductive aging and underscore the need to consider isoform-level regulation in models of ovarian decline.

Researchers here process epidemiological data to arrive at an estimate of the contribution of cytomegalovirus infection to age-related disease. This assumes causation to arrive at these numbers, comparing infection status with presence or absence of specific age-related conditions. Cytomegalovirus is a very prevalent form of persistent herpesvirus infection, with upwards of 90% of older individuals testing positive for its presence. It is thought that cytomegalovirus infection is disruptive to the aged adaptive immune system, either generating excess inflammatory signaling, or driving expansion of memory T cells dedicated to this virus at the expense of T cells capable of responding to novel threats. This in turn contributes to a faster onset and progression of age-related conditions.

Cytomegalovirus (CMV) infection has been indicted in the etiology of multiple aging-related diseases. We aimed to quantify the proportion of diseases that could be prevented with a potential CMV treatment among US older individuals. We analyzed disease prevalence among 8,934 eligible individuals from the US Health and Retirement Study (HRS) in 2016-2020. In our hypothetical intervention, the treatment would improve immune control of CMV and shift the distribution of continuous CMV IgG antibody levels from the highest quartile to the lower 3 quartiles. We estimated top-quartile CMV level attributable fractions for 7 outcomes: heart diseases, stroke, high blood pressure, high cholesterol, cancers, diabetes, and difficulty with Activities of Daily Living using a novel logistic regression-based approach.

In the study sample, a hypothetical intervention that decreased CMV IgG below the highest quartile level in 2016 would result in a 3.57 percentage points reduction of diabetes cases and a 1.81 percentage points reduction of high blood pressure cases among Non-Hispanic White (NHW) women. Among NHW men, the same intervention would lead to a 2.43 percentage points reduction of diabetes, a 2.89 percentage points reduction of heart diseases and a 2.52 percentage points reduction of high blood pressure. Our findings provide initial evidence for the potential population health impact of CMV intervention, specifically on high blood pressure, diabetes, and heart diseases.

Link: https://doi.org/10.1016/j.lana.2025.101122

Researchers here report on the differences in epigenetic aging between mice kept in standard laboratory facilities versus mice allowed to roam a more natural habitat with minimal supervision. The laboratory mice aged more slowly, which one might theorize has to do with greater degrees of care and attention from the laboratory staff. However, the researchers argue that the natural habitat imposes greater stresses upon the mice in various ways, and that in turn accelerates the epigenetic changes characteristic of aging.

We examined differences in age-associated methylation changes between traditionally laboratory-reared mice and "rewilded" C57BL/6J mice, which lived in an outdoor field environment with enhanced ecological realism. Our results lead us to two conclusions. First, the rate of epigenetic changes in the most used biomedical model organism is highly dependent on environmental context, with laboratory-reared animals showing a global bias toward slower rates of epigenetic aging compared to field-reared animals. Second, this more rapid aging of the epigenome is particularly pronounced in sites that gain methylation with age, which are enriched for genes associated with insulin regulation, DNA damage repair, and CTCF and cohesin binding. From the current data, it remains unclear if rewilded mice also show accelerated senescent phenotypes, including early onset disease development and behavioral declines, compared to those in the laboratory.

Our data hold some possible insights into the mechanisms by which animals may display accelerated epigenetic aging in the field compared to the laboratory. From an environmental perspective, animals in the field are exposed to a wide range of different environmental challenges and opportunities, including (1) social competition and potential resource scarcity in males, (2) homeostatic challenges resulting from dynamic weather experiences, (3) social instability when animals die or are born, and (4) reproductive effort in the form of mating and territorial defense in males and pregnancy and reproduction in females. Each of these environmental experiences - which are faced to an extent by all natural populations of vertebrates, including humans - may have contributed to short-term or chronic physiological stress, with downstream impacts on epigenetic aging rates.

Link: https://doi.org/10.1111/acel.70098

Given a body of human epidemiological data, one can typically only draw conclusions on correlations rather than causations: biomarkers A and B correlate with age-related condition X, but may or may not be involved in causing that condition. The research community designs animal studies to produce data on causation, and in many cases it is quite reasonable to lean on the results of those studies as support for the same path of causation in humans, but one can't run those same causation-focused studies in humans.

Thus the research community has developed strategies to tease out support for causation from correlational human data. Mendelian randomization brings in data on genetic variants that are known to affect specific biomarkers or outcomes of age-related disease. When segmenting the human data by these variants changes the outcomes, segment by segment, that suggests a causative relationship between biomarker and age-related disease. Linkage disequilibrium score regression is an analogous approach developed to try to break apart the individual contributions of multiple effects to a given outcome by adding data on genetic variants as a point of comparison.

Today's open access paper is an example of the application of these strategies to the challenge of gaining insight into causation between the aging of the gut microbiome and onset and progression of age-related conditions. The composition of the gut microbiome can be measured accurately via sequencing, and researchers now have a great deal of data to correlate specific changes with specific age-related conditions. Proof of causation has been obtained from animal studies in which restoration of a youthful gut microbiome composition improves health and extends life. Now, researchers would like to see more human data along the same lines.

Causal Analysis Between Gut Microbes, Aging Indicator, and Age-Related Disease, Involving the Discovery and Validation of Biomarkers

The influence of gut microbes on aging has been reported in several studies, but the mediating pathways of gut microbiota, whether there is a causal relationship between the two, and biomarker screening and validation have not been fully discussed. In this study, Mendelian Randomization (MR) and Linkage Disequilibrium Score Regression (LDSC) are used to systematically investigate the associations between gut microbiota, three aging indicators, and 14 age-related diseases. Additionally, this study integrates machine learning algorithms to explore the potential of MR and LDSC methods for biomarker screening.

Gut microbiota is found to be a potential risk factor for 14 age-related diseases. The causal effects of gut microbiota on chronic kidney disease, cirrhosis, and heart failure are partially mediated by aging indicators. Additionally, gut microbiota identified through MR and LDSC methods exhibit biomarker properties for disease prediction (average area under curve, AUC = 0.731). These methods can serve as auxiliary tools for conventional biomarker screening, effectively enhancing the performance of disease models (average AUC increased from 0.808 to 0.832).

This study provides evidence that supports the association between the gut microbiota and aging and highlights the potential of genetic correlation and causal relationship analysis in biomarker discovery. These findings may help to develop new approaches for healthy aging detection and intervention.

Researchers here focus on a signaling mechanism that is diminished with age, the interaction between circulating prostaglandin E2 (PGE2) and its receptor EP4 on muscle stem cells. Levels of both PGE2 and its receptor decline with age, and this appears to broadly impair muscle stem cell function. The proof of that point is that delivering more PGE2 to aged mice improves muscle stem cell function, leading to an improved response following muscle injury.

Researchers examined the effects of circulating prostaglandin E2 (PGE2) and its receptor EP4 on muscle tissue. Their prior research had established that PGE2 signals during muscle injury trigger muscle stem cells to regenerate the muscles of young mice. In aged mice, the team found that EP4 expression on aged muscle stem cells are either lacking or reduced by half of those found in young stem cells. "PGE2 levels in muscle also decline with age, so we see blunted signaling from reductions in both the messenger and receiver. PGE2 is an alarm clock to wake up the stem cells and repair the damage. Aging essentially reduces the volume of the alarm and the stem cells have also put on ear plugs."

It is possible, however, to overcome the effects of aging and reset the intensity of this cellular signal. Researchers gave a stable form of PGE2 to aged mice after muscle injury and in conjunction with exercise. The treated mice gained more muscle mass and were stronger compared to untreated ones. The study revealed that PGE2 treatment restores stem cell function by modulating the activity of key transcription factors which reversed many of the age-related changes that the researchers observed. "The evidence suggests that PGE2 is not just acting on one mechanism. We've previously shown that PGE2 can also benefit the muscle fiber, and neurons that innervate the muscle. PGE2 has been implicated in the regenerative process and signaling for the intestine, liver, and several other tissues, potentially opening up an approach that could restore the renewing capacity of other aged tissues."

Link: https://sbpdiscovery.org/press/turning-back-time-on-muscle-stem-cells-to-prevent-frailty-from-aging/

The core hypothesis of this paper is that epigenetic changes characteristic of aging are all adaptive, beneficial attempts by cells to resist damage and dysfunction. This seems dubious. Looking into the aging body, we can point to any number of maladaptive, harmful changes in function; reactions that would be beneficial in youth, or when operating only temporarily, but become harmful in the aged tissue environment, or when sustained over time. Think of the way the immune system reacts to the age-damaged environment to generate chronic inflammation, for example. Why should epigenetic regulation be exempt from such maladaptive change?

Methylation clocks have found their way into the community of aging research as a way to test anti-aging interventions without having to wait for mortality statistics. But methylation is a primary means of epigenetic control, and presumably has evolved under strong selection. Hence, if methylation patterns change consistently at late ages it must mean one of two things. Either (1) the body is evolved to destroy itself (with inflammation, autoimmunity, etc.), and the observed methylation changes are a means to this end; or (2) the body detects accumulated damage, and is ramping up repair mechanisms in a campaign to rescue itself.

My thesis herein is that both Type 1 and Type 2 changes are occurring, but that only Type 1 changes are useful in constructing methylation clocks to evaluate anti-aging interventions. This is because a therapy that sets back Type 1 changes to an earlier age state has stopped the body from destroying itself; but a therapy that sets back Type 2 changes has stopped the body from repairing itself. Thus, a major challenge before the community of epigenetic clock developers is to distinguish Type 2 from Type 1.

The existence of Type 1 epigenetic changes is in conflict with conventional Darwinian thinking, and this has prompted some researchers to explore the possibility that Type 1 changes might be a form of stochastic epigenetic drift. I argue herein that what seems like directed epigenetic change really is directed epigenetic change. Of five recent articles on "stochastic methylation clocks," only one is based on truly stochastic changes. Using the methodology from this paper and a methylation database, I construct a measure of true methylation drift, and show that its correlation with age is too low to be useful.

Link: https://doi.org/10.18632/aging.206245

Reprogramming of adult cells occurs early in embryonic development, changing the adult germline cell into a pluripotent embryonic stem cell. This also removes epigenetic changes characteristic of age to rejuvenate cell functions, such as mitochondrial activity. A recipe for recreating this reprogramming process in any cell was discovered 20 years ago, and involves increased expression of the four Yamanaka factors. Over time, the interest of the scientific community has expanded from initial efforts to use reprogramming in order to generate patient-matched induced pluripotent stem cells for research and cell therapies. Now, researchers are equally interested in partial reprogramming that can produce epigenetic and functional rejuvenation in tissues without erasing cell type.

Researchers have expected these two aspects of reprogramming, dedifferentiation to pluripotency versus epigenetic rejuvenation, to be regulated separately. That underneath the regulatory layer of the Yamanaka factors, there would be other regulatory layers that distinctly produce dedifferentiation versus epigenetic rejuvenation. So far progress towards concretely identifying these hypothetical lower levels of regulation has been slow. Today's news from the Shift Bioscience team is a claim to an effective way to induce rejuvenation without dedifferentiation, by altering the expression of a single gene. The preprint does not identify the gene, of course, given that this is a corporate rather than an academic research group, but that information will emerge with time. One caution is that the researchers have validated the effects in a few cell types, but it may or may not generalize to all cell types.

A single factor for safer cellular rejuvenation

Ageing is a key driver of the major diseases afflicting the modern world. Slowing or reversing the ageing process would therefore drive significant and broad benefits to human health. Previously, the Yamanaka factors (OCT4, SOX2, KLF4, with or without c-MYC: OSK(M)) have been shown to rejuvenate cells based on accurate predictors of age known as epigenetic clocks. Unfortunately, OSK(M) induces dangerous pluripotency pathways, making it unsuitable for therapeutic use.

To overcome this therapeutic barrier, we screened for novel factors by optimising directly for age reversal rather than for pluripotency. We trained a transcriptomic ageing clock, unhindered by the low throughput of bulk DNA methylation assays, to enable a screen of unprecedented scale and granularity.

Our platform identified what we here designate as SB000, the first single gene intervention to rejuvenate cells from multiple germ layers with efficacy rivalling the Yamanaka factors. Cells rejuvenated by SB000 retain their somatic identity, without evidence of pluripotency or loss of function. These results reveal that decoupling pluripotency from cell rejuvenation does not remove the ability to rejuvenate multiple cell types. This discovery paves the way for cell rejuvenation therapeutics that can be broadly applied across age-driven diseases.

In recent years, researchers have established correlations between the state of the gut microbiome and development of neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease. The balance of microbial populations making up the gut microbiome shifts with age to promote greater inflammation and dysfunction throughout the body, though one can also argue that the aging of the immune system promotes both this gut dysbiosis and neurodegeneration. Assessing the degree to which specific mechanisms are responsible for specific conditions is challenging, given the complexity of aging and its consequences. Nonetheless, there is good reason to think that an aged gut microbiome is actively harmful. Here, researchers note that inappropriate migration of oral bacteria into the gut may also be involved in the aging of the gut microbiome and its impact on the aging of the brain.

The human microbiome is increasingly recognized for its crucial role in the development and progression of neurodegenerative diseases. While the gut-brain axis has been extensively studied, the contribution of the oral microbiome and gut-oral tropism in neurodegeneration has been largely overlooked. Cognitive impairment (CI) is common in neurodegenerative diseases and develops on a spectrum. In Parkinson's Disease (PD) patients, CI is one of the most common non-motor symptoms but its mechanistic development across the spectrum remains unclear, complicating early diagnosis of at-risk individuals.

Here, we generated 228 shotgun metagenomics samples of the gut and oral microbiomes across PD patients with mild cognitive impairment (PD-MCI) or dementia (PDD), and a healthy cohort, to study the role of gut and oral microbiomes on CI in PD. In addition to revealing compositional and functional signatures, the role of pathobionts, and dysregulated metabolic pathways of the oral and gut microbiome in PD-MCI and PDD, we also revealed the importance of oral-gut translocation in increasing abundance of virulence factors in PD and CI. The oral-gut virulence was further integrated with saliva metaproteomics and demonstrated their potential role in dysfunction of host immunity and brain endothelial cells.

Our findings highlight the significance of the oral-gut-brain axis and underscore its potential for discovering novel biomarkers for PD and CI.

Link: https://doi.org/10.1080/19490976.2025.2506843

The research community continues to create aging clocks based on omics data at a fair pace. At this point, there are scores of clocks one might chose from if conducting studies on potential therapies to slow or reverse aspects of aging. Yet the primary challenge remains knowing whether any given clock will accurately reflect future outcomes following a specific form of treatment, meaning reduced risk of age-related disease and lowered mortality. Because there is no detailed map linking the omics data making up a clock to underlying mechanisms of aging or outcomes in aging, researchers do not know in advance how an aging clock will react to changes in the mechanisms targeted by a potential treatment for aging, and whether those reactions are useful. The clock might overestimate the impact, it might underestimate the impact. The only way to find out in certainty is to calibrate the clock against the therapy in long-running, expensive studies, and that somewhat defeats the point of having an aging clock.

The focus of aging research has shifted from increasing lifespan to enhancing healthspan to reduce the time spent living with disability. Despite significant efforts to develop biomarkers of aging, few studies have focused on biomarkers of healthspan. We addressed this by developing a proteomics-based signature of healthspan, termed the Healthspan Proteomic Score (HPS), using proteomic data from the Olink Explore 3072 assay in the UK Biobank Pharma Proteomics Project (53,018 individuals and 2,920 proteins).

A lower HPS was associated with higher mortality risk and several age-related conditions, such as chronic obstructive pulmonary disease, diabetes, heart failure, cancer, myocardial infarction, dementia, and stroke. HPS showed superior predictive accuracy for these outcomes compared to other biological age measures. Proteins associated with HPS were enriched in hallmark pathways such as immune response, inflammation, cellular signaling, and metabolic regulation.

The external validity was evaluated using the Essential Hypertension Epigenetics study with proteomic data also from the Olink Explore 3072 and complementary epigenetic data, making it a valuable tool for assessing healthspan and as a potential surrogate marker to complement existing proteomic and epigenetic biological age measures in geroscience-guided studies.

Link: https://doi.org/10.1073/pnas.2414086122

At a high level, it is fair to say that high blood glucose accelerates aging. The various forms of diabetes involve an excessively dysregulated glucose metabolism, and diabetics do exhibit accelerated aging. In the past, prior to the present greater focus on aging, researchers have even used diabetic mice as stand-ins for naturally aged mice to save time and funding. In comparison to mammals, birds have high blood glucose and relatively long life spans for their size. Is there anything to be learned from the comparative biology of birds and mammals in this context?

In today's open access paper, researchers discuss what the data on bird blood glucose might mean in terms of underlying mechanisms. It seems likely that birds possess mechanisms not present in mammals that allow them to resist the negative consequences of high blood glucose. Obviously this sort of review of the data is a very early starting point on the road to discovery and understanding of those mechanisms, even prior to any assessment regarding whether there is a useful basis for the production of therapies to bring that resistance to humans. One should not expect this research to move rapidly, given the slow pace of progress in other portions of the comparative biology field with much greater interest and funding, such as naked mole rat resistance to cancer.

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 (POLS) hypothesis suggests that organisms' life history and 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) covary 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 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 in the POLS hypothesis, glucose levels increased with maximum lifespan before reaching a plateau. Finally, terrestrial carnivores showed higher albumin glycation compared to omnivores despite not showing higher glucose, which we discuss may be related to additional factors as differential antioxidant levels or dietary composition in terms of fibres or polyunsaturated fatty acids.

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.

Most discussion of protein aggregation is focused on the few proteins that can excessively aggregate to form solid deposits and an associated toxic biochemistry, such as amyloid-β, α-synuclein, tau, and so forth. But many proteins can aggregate to much lesser degrees, particularly when the normal processes of quality assurance and clearance are impaired. Is this broad aggregation of hundreds of specific proteins in cells in aged tissues a sufficiently important contribution to dysfunction to be worth addressing distinctly from the underlying changes in environment and epigenetic regulation of gene expression that cause this issue? That is an interesting question.

Neurodegenerative diseases affect 1 in 12 people globally and remain incurable. Central to their pathogenesis is a loss of neuronal protein maintenance and the accumulation of protein aggregates with aging. We engineered bioorthogonal tools which allowed us to tag the nascent neuronal proteome and study its turnover with aging, its propensity to aggregate, and its interaction with microglia.

We discovered neuronal proteins degraded on average twice as slowly between 4- and 24-month-old mice with individual protein stability differing between brain regions. Further, we describe the aged neuronal 'aggregome' encompassing 574 proteins, nearly 30% of which showed reduced degradation. The aggregome includes well-known proteins linked to disease as well as a trove of proteins previously not associated with neurodegeneration. Unexpectedly, we found 274 neuronal proteins accumulated in microglia with 65% also displaying reduced degradation and/or aggregation with age. Among these proteins, synaptic proteins were highly enriched, suggesting a cascade of events emanating from impaired synaptic protein turnover and aggregation to the disposal of these proteins, possibly by the engulfment of synapses by microglia.

These findings reveal the dramatic loss of neuronal proteome maintenance with aging which could be causal for age-related synapse loss and cognitive decline.

Link: https://doi.org/10.1101/2025.05.20.654652

Near everything that happens in the cosmetics "anti-aging" space is, and has long been, garbage products coated in a layer of marketing, pretty lies that mimic the output of actual science to the degree needed to succeed. At some point this mess will largely go away because topical therapies that actually address mechanisms of aging will emerge, coupled to assessments that demonstrate these therapies to achieve results that the garbage products cannot. Meanwhile, the present state of the market is actively hostile to that progress, as product success has everything to do with marketing and very little to do with whether or not it actually works. What does productive change look like? It might start with calls to action such as the one noted here.

The field of anti-aging research has made remarkable strides with the identification of geroprotectors - compounds capable of extending healthspan and lifespan in animal models - presenting promising implications for human longevity. Building on these advances, we propose a novel product category: longevity cosmeceutical actives and products. Unlike conventional anti-aging products that primarily target superficial signs of aging, longevity cosmeceuticals address the molecular hallmarks of aging, fundamentally enhancing skin health and longevity.

To clearly distinguish these scientifically validated products from marketing-driven claims, we define, for the first time, longevity cosmeceutical actives and products based on stringent criteria: (1) they must directly target and modulate established hallmarks of skin aging; (2) they must demonstrably extend "skinspan" over time, reflected by improved skin viability, structure, and functional integrity; and (3) their efficacy must be validated through clinical trials, preferably with post-trial skin biopsies to evaluate aging hallmark biomarkers, along with comprehensive safety assessments.

This review explores molecular hallmarks of skin aging, highlights geroprotective compounds with potential cosmeceutical applications, and recommends essential biomarkers for assessing prevention of rapid biological aging. Additionally, we propose methodologies for skinspan assessment and emphasize the importance of robust clinical trial designs. By establishing these scientifically rigorous standards, we aim to drive innovation, substantiate longevity claims, and transform the cosmetic industry toward meaningful biological improvements in skin health.

Link: https://doi.org/10.3389/fragi.2025.1586999

Senescent cells grow in number in tissues throughout the body with advancing age. Cells become senescent throughout life, largely as a result of reaching the Hayflick limit on replication, but it can also happen in response to injury, or various forms of cytotoxic stress. These cells are removed by the immune system or programmed cell death and do not accumulate. Only later in life when there are greater levels of damage and cell stress on the one hand, and a failing immune system on the other hand, does creation outpace clearance to allow senescent cells to linger and grow in number.

The research and development communities are pursuing the development of senolytic therapies to selectively destroy senescent cells. To a lesser degree, there are also programs aimed at senostatic approaches to slow the creation of senescent cells or senomorphic approaches to alter the behavior of senescent cells to make them less harmful.

The expansion of these latter two approaches is in part driven by reservations in portions of the research community to the use of senolytics. Today's open access paper touches on most of those concerns, some more hypothetical than others. A few are the usual concerns for new classes of therapy: is the target well enough understood, is there enough knowledge to apply therapies effectively. Some are specific to senescent cells, however, in particular the question of whether senescent cells in any specific circumstance or tissue are actually needed despite the problems they cause, and thus could only be replaced slowly rather than cleared outright.

Is Senolytic Therapy in Cardiovascular Diseases Ready for Translation to Clinics?

Aging is a predominant risk factor for cardiovascular diseases. There is evidence demonstrating that senescent cells not only play a significant role in organism aging but also contribute to the pathogenesis of cardiovascular diseases in younger ages. Encouraged by recent findings that the elimination of senescent cells by pharmacogenetic tools could slow down and even reverse organism aging in animal models, senolytic drugs have been developed, and the translation of results from basic research to clinical settings has been initiated. Because numerous studies in the literature show beneficial therapeutic effects of targeting senescent cells in cardiomyopathies associated with aging and ischemia/reperfusion and in atherosclerotic vascular disease, senolytic drugs are considered the next generation of therapies for cardiovascular disorders.

According to the current research in the literature, we could conclude that senescent cells exhibit two faces in cardiovascular disease and aging, i.e., they have either detrimental effects or beneficial effects. Although the reasons for these contradictory results are not clear, the following considerations may provide hints for explanation and point towards further research directions.

First, it has been demonstrated that not all senescent cells have the same functions. For example, with the development of mouse models for genetic tracing and the manipulation of p16ink4+ cells, specific depletion of senescent cell types, such as endothelial cells and macrophages, and other cell types becomes possible. Moreover, senescent cells derived from the same cell type are not homogenous even in the same disease microenvironment. At least two groups of senescent cells might exist, i.e., pro-inflammatory tissue destructive and anti-inflammatory tissue reparative senescent cells, depending on the profile of the senescence-associated secretory phenotype (SASP).

Second, it therefore seems that the effects of senolytic therapy, whether beneficial or detrimental, are context-dependent in specific diseases. In cardiac diseases, e.g., myocardial infarction, heart failure, or age-related cardiac dysfunction, removal of senescent cardiomyocytes could be detrimental if survived or available cardiomyocytes under the condition are not adequate or not sufficient to support the pumping function of the heart. On the other hand, the elimination of senescent cardiomyocytes will be beneficial if the remaining cardiomyocytes are adequate to compensate for the heart pumping function and the detrimental paracrine effects of cardiomyocytes on other non-myocyte cells, such as fibroblasts, endothelial cells, and immune cells, could be removed.

Moreover, the SASP factor profiles from senescent cells might be different depending on the stimuli that induce cell senescence. Replicative senescent vascular endothelial cells or the endothelium from aged mouse exhibit a pro-inflammatory phenotype, while the SENEX gene induced premature endothelial senescence, revealing an anti-inflammatory phenotype. These observations implicate that senescent cells in different pathological conditions, such as atherosclerosis, insulin resistance, diabetes, hypertension, etc., and natural aging may have different profiles of SASP factors, which may also influence the effects of senolytic and/or senomorphic therapies.

Anti-senescence therapies or senolytic and senomorphic drug therapies are attractive and promising future therapeutic modalities for the treatment of cardiovascular diseases, and they represent a novel research direction for cardiovascular aging and age-associated cardiovascular diseases. However, we shall be cautious not to endorse clinical use of senolytics for the prevention or treatment of cardiovascular diseases or other age-associated chronic diseases until the roles of cell senescence in specific disease development are well-studied and the safety and efficacy of the drugs in well-designed clinical trials are investigated.

Type 2 diabetes is condition produced by excess weight in the vast majority of patients, and losing weight can reverse the progression of the condition even in later stages. Separately, researchers have demonstrated that excess visceral fat tissue promotes a greater burden of cellular senescence in older individuals. Senescent cells contribute to the chronic inflammation of aging, disruptive to tissue structure and function. Here, researchers note that type 2 diabetes patients exhibit a greater burden of cellular senescence, as determined by a range of measures - not all that surprising. Interestingly, other investigations have suggested that senescent cells in the pancreas drive dysfunction in both type 1 diabetes and type 2 diabetes, an important common mechanism in conditions with very different root causes.

Although animal studies have linked cellular senescence to the pathogenesis and complications of type 2 diabetes mellitus (T2DM), there is a paucity of corroborating data in humans. Thus, we measured a previously validated marker for senescent cell burden in humans, T-cell expression of p16 mRNA, along with additional biomarkers, to compare the senescence phenotypes of postmenopausal control (lean, N = 37) and T2DM (N = 27) participants. To control for effects of obesity alone, we included a third group of obese but non-diabetic women (N = 29) who were matched for body mass index to the T2DM participants. In addition, given the increase in fracture risk in T2DM despite preserved or even increased bone mineral density, we related these senescence biomarkers in the T2DM participants to skeletal microarchitectural parameters.

Relative to the lean participants, T-cell p16 and p21Cip1 expression was increased in the T2DM, but not the obese, non-diabetic participants. Expression of p16 and p21Cip1 was positively associated with HbA1c and an index of skin advanced glycation end-products. T2DM was also associated with an increase in a number of SASP factors. Among participants with T2DM, women in the highest tertile for T-cell expression of p16 had significantly reduced tibial cortical area and thickness as compared to those in the lower two tertiles. Overall, our studies link cellular senescence to metabolic and skeletal alterations in T2DM and point to the need for further studies evaluating the role of cellular senescence in mediating skeletal fragility, as well as potentially other complications in T2DM.

Link: https://doi.org/10.1111/acel.70120

Cell reprogramming as a basis for the treatment of aging involves inducing the expression of Yamanaka factors for a short period of time, ideally resulting in a shift in cell epigenetic state to a more youthful configuration without disruption of cell function or the creation of potentially harmful pluripotent stem cells. While early efforts focused on gene therapy technologies, there is a branch of research focused on small molecules that might achieve sufficient Yamanaka factor expression to be interesting. A number of combinations of small molecules have been explored, and the one assessed in mice here has been called the 2c cocktail by other authors. While small molecules have the advantage of effective delivery to the whole body, a goal that remains impossible for adult gene therapies, side-effects remain a sizable concern for the known small molecule reprogramming agents.

Targeting partial cellular reprogramming pathways through specific small molecule combinations holds promise for lifespan extension in model organisms. Chemical cocktails like RepSox and tranylcypromine (TCP) may induce beneficial age-related changes without the risks of full reprogramming. Female C3H mice were divided into two age groups: "old" (16-20 months) and "senior" (10-13 months). They received intraperitoneal injections of RepSox (5 mg/kg) and TCP (3 mg/kg) or DMSO (control) every 72 h for 30 days.

In the "old" group, treated mice showed enhanced neurological status, fur and skeletal health, and increased cortical angiogenesis, though with some adverse histological changes in the liver and brain. In the "senior" group, treated mice displayed a plateau in mortality after month seven, while deaths continued in controls. Although overall survival was not significantly different, maximum lifespan significantly increased in treated mice. Histological findings revealed localized adaptive changes rather than major toxic effects. These results suggest that the combination of RepSox and TCP exerts protective effects on aging phenotypes and may potentially slow systemic aging processes in C3H mice.

Link: https://doi.org/10.1002/brb3.70573