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- Reviewing Current Options for the Upregulation of Neurogenesis in the Context of Aging and Alzheimer's Disease
- Elastin Expression May Reduce Cellular Senescence via Interactions with Mitochondria
- It is Never Too Late to Take Up Exercise, Even When Hypertensive
- A Study of OneSkin's Topical Senotherapeutic OS-1 on Skin Function
- A Physical Activity Study in Obese Individuals Suggests the Burden of Senescent Cells is to Some Degree Dynamic
- Planarians Undergo Rejuvenation When Regrowing Lost Tissues
- Results from the PEARL Trial of Rapamycin
- Data Suggests Wealthier People Do More to Maintain their Health
- Cell and Rejuvenation Therapies as a Basis to Treat Neurodegenerative Conditions
- Tim-3 Inhibition in Microglia Encourages Amyloid Clearance in the Brain
- Senescent Endothelial Cells Contribute to Atherosclerosis via CAP1 Signaling
- Exposure to Air Pollution Increases Frailty Risk
- Particular Air Pollution Exposure Correlates with Worse Cognitive Function
- Transfer RNA May Allow Early Detection of Parkinson's Disease via Blood Test
- Platelet Factor 4, an Interesting Target for Modest Rejuvenation of the Aging Brain
Reviewing Current Options for the Upregulation of Neurogenesis in the Context of Aging and Alzheimer's Disease
https://www.fightaging.org/archives/2025/04/reviewing-current-options-for-the-upregulation-of-neurogenesis-in-the-context-of-aging-and-alzheimers-disease/
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.
Elastin Expression May Reduce Cellular Senescence via Interactions with Mitochondria
https://www.fightaging.org/archives/2025/04/elastin-expression-may-reduce-cellular-senescence-via-interactions-with-mitochondria/
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 suggestions 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.
It is Never Too Late to Take Up Exercise, Even When Hypertensive
https://www.fightaging.org/archives/2025/04/it-is-never-too-late-to-take-up-exercise-even-when-hypertensive/
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.
A Study of OneSkin's Topical Senotherapeutic OS-1 on Skin Function
https://www.fightaging.org/archives/2025/04/a-study-of-oneskins-topical-senotherapeutic-os-1-on-skin-function/
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 Physical Activity Study in Obese Individuals Suggests the Burden of Senescent Cells is to Some Degree Dynamic
https://www.fightaging.org/archives/2025/04/a-physical-activity-study-in-obese-individuals-suggests-the-burden-of-senescent-cells-is-to-some-degree-dynamic/
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.
Planarians Undergo Rejuvenation When Regrowing Lost Tissues
https://www.fightaging.org/archives/2025/04/planarians-undergo-rejuvenation-when-regrowing-lost-tissues/
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.
Results from the PEARL Trial of Rapamycin
https://www.fightaging.org/archives/2025/04/results-from-the-pearl-trial-of-rapamycin/
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 suggestions 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.
Data Suggests Wealthier People Do More to Maintain their Health
https://www.fightaging.org/archives/2025/04/data-suggests-wealthier-people-do-more-to-maintain-their-health/
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.
Cell and Rejuvenation Therapies as a Basis to Treat Neurodegenerative Conditions
https://www.fightaging.org/archives/2025/04/cell-and-rejuvenation-therapies-as-a-basis-to-treat-neurodegenerative-conditions/
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.
Tim-3 Inhibition in Microglia Encourages Amyloid Clearance in the Brain
https://www.fightaging.org/archives/2025/04/tim-3-inhibition-in-microglia-encourages-amyloid-clearance-in-the-brain/
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.
Senescent Endothelial Cells Contribute to Atherosclerosis via CAP1 Signaling
https://www.fightaging.org/archives/2025/04/senescent-endothelial-cells-contribute-to-atherosclerosis-via-cap1-signaling/
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.
Exposure to Air Pollution Increases Frailty Risk
https://www.fightaging.org/archives/2025/04/exposure-to-air-pollution-increases-frailty-risk/
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.
Particular Air Pollution Exposure Correlates with Worse Cognitive Function
https://www.fightaging.org/archives/2025/04/particular-air-pollution-exposure-correlates-with-worse-cognitive-function/
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.
Transfer RNA May Allow Early Detection of Parkinson's Disease via Blood Test
https://www.fightaging.org/archives/2025/04/transfer-rna-may-allow-early-detection-of-parkinsons-disease-via-blood-test/
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.
Platelet Factor 4, an Interesting Target for Modest Rejuvenation of the Aging Brain
https://www.fightaging.org/archives/2025/04/platelet-factor-4-an-interesting-target-for-modest-rejuvenation-of-the-aging-brain/
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.
View the full article at FightAging
