Fight Aging! Newsletter, February 24th 2025
Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter, please visit: https://www.fightaging.org/newsletter/
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- Reviewing the Biochemistry of the Longevity-Associated BPIFB4 Gene Variant
- Bimagrumab Treatment Increases Bone Density and Muscle Mass in Mice
- Incrementally Mapping the Effects of Cytomegalovirus on the Aged Immune System
- Long-Lived Individuals Exhibit a More Youthful Red Blood Cell Biochemistry
- Rejuvenation Science Institute Seeks Charitable Donations to Support a Reproduction of the Yuvan Research Young Plasma Study
- Assessing Effects of Vitamin D, Omega-3 and Exercise on Aging Clocks in Older People
- An Aging Clock Based on Abdominal CT Imagery
- Physical Activity Correlates with Reduced Mortality Even in Patients with Multimorbidity
- Extracellular Vesicles Derived from Stem Cell Aggregates Improve Bone Density in Aged Mice
- Brain Injury Accelerates Later Amyloid Aggregation to Increase Risk of Alzheimer's Disease
- CD150 Expression Distinguishes Dysfunctional Hematopoietic Cells in Aged Bone Marrow
- A More Favorable Way of Looking at the Modest Effects of Amyloid-Clearing Immunotherapies in Alzheimer's Patients
- Lowered Expression of TOP2B Slows Epigenetic Aging in Multiple Species
- Another Example of Senescent Cell Clearance as a Treatment for Periodontitis
- Psoriasis Accelerates Some Measures of Biological Age
Reviewing the Biochemistry of the Longevity-Associated BPIFB4 Gene Variant
https://www.fightaging.org/archives/2025/02/reviewing-the-biochemistry-of-the-longevity-associated-bpifb4-gene-variant/
Many drugs have their origin in a human gene variant or mutation that was discovered to be protective in some way. Typically such drugs are less effective than possessing the mutation, for all the usual reasons. A drug is only used for some years rather than the whole lifespan, doesn't give the 100% coverage of cells in a tissue that the mutation does, and usually only recreates a fraction of the effects of the mutation in any given cell. Thus mutations that lower circulating LDL-cholesterol in the bloodstream can produce as much as a 50% reduction in lifetime risk of cardiovascular mortality, but drugs that reduce LDL-cholesterol levels produce only a 10-20% reduction, depending on which studies one chooses to take as representative.
Nonetheless, the discovery of protective mutations and gene variants is a sizable concern continues to lead to drug development programs. Today's open access paper reviews the mechanisms by which a longevity-associated variant of BPIFB4 is thought to lower risk of mortality. It appears to act in two ways, firstly by improving vascular function in older people, and secondly by reducing inflammation. The effects on vascular function are complex, involving reduced stiffening of vessels due to smooth muscle dysfunction, increased formation of new vessels, and increased antioxidant activity to reduce oxidative stress. As is usually the case, it is unclear as to which of these mechanisms is most important in determining the observed outcome of reduced late life mortality; one could make a good case for most of them.
Protective role of the longevity-associated BPIFB4 gene on cardiac microvascular cells and cardiac aging
The longevity-associated variant (LAV) of BPIFB4 was discovered using a stringent threshold of statistical significance for genome-wide association studies (GWAS) in three independent cohorts of centenarians in Italy, Europe, and the US. The LAV-BPIFB4 haplotype was inversely correlated with frailty in elderly subjects, strengthening its relevance in influencing the health status and longevity of the elderly.
Further analyses showed that the LAV homozygous genotype was positively associated with high endothelial nitric oxide (eNOS) phosphorylation in mononuclear cells, which translates to augmented nitric oxide (NO) production and beneficial functions in the cardiovascular system. In keeping with the benefits to the vascular compartment, recombinant LAV-BPIFB4 protein supplementation enhanced the proangiogenic activity of young and senescent endothelial cells. Importantly, these advantages can be transferred through LAV-BPIFB4 gene therapy in older mice, whereas eNOS phosphorylation and vessel activity are restored to levels observed in young mice.
Alongside the eNOS downstream substrate, the SDF-1/CXCR4 axis is a crucial effector of the cardiovascular protective and immunomodulatory activity of LAV-BPIFB4. In this regard, LAV-BPIFB4 activates SDF-1/CXCR4 signaling to remodel the immune system and resolve inflammation through various mechanisms, such as protective macrophage polarization toward the pro-resolving M2 phenotype, favorable redistribution of circulating monocyte cell subsets, and reduction in T-cell activation.
Bimagrumab Treatment Increases Bone Density and Muscle Mass in Mice
https://www.fightaging.org/archives/2025/02/bimagrumab-treatment-increases-bone-density-and-muscle-mass-in-mice/
Bimagrumab is a monoclonal antibody targeting αActRIIA and αActRIIB. These receptors are involved in the inhibition of muscle growth via the activity of myostatin; circulating myostatin binds to αActRIIB. Various means of preventing this from happening produce sizable muscle growth in a variety of animal species. Most of the examples involve mutation of the myostatin gene, but a few of the other approaches have made it into clinical trials, including antibodies to reduce circulating myostatin levels and gene therapies to increase circulating levels of follistatin, a protein that blocks the activity of myostatin. The point of all of this is to find a viable approach to produce muscle growth without the need for exercise, and turn back the loss of muscle mass and strength that occurs with age.
Bimagrumab is currently in clinical trials aimed at obesity, as the present generation of GLP-1 receptor agonist drugs used for weight loss produce significant loss of muscle mass alongside loss of fat mass. Drugs that might counteract that undesirable loss of muscle mass are much sought after. In today's open access paper, researchers demonstrate that bimagrumab treatment is quite effective at increasing muscle mass and bone mineral density in mice. This increase in bone mineral density is also a feature of other approaches centered around myostatin, though not so often reported or the focus of research aimed at muscle tissue.
The Effect of Anti-Activin Receptor Type IIA and Type IIB Antibody on Muscle, Bone and Blood in Healthy and Osteosarcopenic Mice
Anti-Activin Receptor Type IIA and Type IIB antibody (αActRIIA/IIB ab) is a recently developed drug class that targets the activin receptor signalling pathway. Inhibition of receptor ligands (activins, myostatin, growth differentiation factor 11, etc.) can lead to skeletal muscle hypertrophy and bone formation. Despite the αActRIIA/IIB ab, bimagrumab, having progressed to clinical trials, two crucial questions about αActRIIA/IIB ab therapy remain: Does αActRIIA/IIB ab influence bone metabolism and bone strength similarly to its generic classmates (activin receptor-based ligand traps)? Therefore, the aim of the present study was to investigate the therapeutic potential of αActRIIA/IIB ab in a mouse model of concurrent sarcopenia and osteopenia and to investigate the effect on bonein more detail.
In C57BL/6JRj mice, combined sarcopenia and osteopenia were induced locally by injecting botulinum toxin A into the right hindlimb, resulting in acute muscle paresis. Immediately after immobilization, mice received twice-weekly intraperitoneal injections with αActRIIA/IIB ab (10 mg/kg) for 21 days, after which they were sacrificed. Muscle mass, skeletal muscle fibre size and Smad2 expression were analysed in the rectus femoris and gastrocnemius muscles. Bone mass and bone microstructure were analysed in the trabecular bone and cortical bone.
αActRIIA/IIB ab caused a large increase in muscle mass in both healthy (+21%) and immobilized (sarcopenic and osteopenic) (+12%) mice. Furthermore, αActRIIA/IIB ab increased trabecular bone (bone volume fraction) for both healthy (+65%) and immobilized (+44%) mice. For cortical bone, αActRIIA/IIB ab caused a small, but significant, increase in bone area (+6%) for immobilized mice, but not for healthy mice. These results suggest a potential in the treatment of concurrent osteopenia and sarcopenia.
Incrementally Mapping the Effects of Cytomegalovirus on the Aged Immune System
https://www.fightaging.org/archives/2025/02/incrementally-mapping-the-effects-of-cytomegalovirus-on-the-aged-immune-system/
Cytomegalovirus, CMV, is a prevalent form of herpesvirus, a persistent infection that cannot be effectively cleared by the immune system and continues to resurface over time following the initial exposure. Upwards of 90% of older people in the developed world have been exposed to CMV at some point in their lives. The immediate symptoms of CMV infection for most people are mild to non-existent, but there is reason to suspect that CMV acts over time to corrode the effectiveness of the adaptive immune system.
The adaptive immune system is a complex collection of many subpopulations of cells. One high-level view of the harm done by CMV is that its presence forces an expansion of the population of memory T cells dedicated to this one infectious agent at the expense of the myriad other duties that the T cell population should be undertaking. Any given category of T cells is not a monolith, however, is made up of many different T cell subtypes and behaviors, and the real picture is no doubt more complex than a simple expansion of one subtype.
Further, CMV most likely affects other portions of the immune system to a similar degree, and some of those influences may also be harmful over the long term, contributing to degenerative aging. In today's open access paper, researchers report on their investigation of the effects of CMV infection on immune cell populations that include innate immune cells known as monocytes. Monocytes and their descendant macrophages are involved in defense against pathogens, modulation of inflammatory signaling, tissue maintenance, and other duties. Note that the study is only comparing young versus old individuals with exposure to CMV, not uninfected individuals, however.
Markers of immunosenescence in CMV seropositive healthy elderly adults
A significant increase in life expectancy has accompanied the growth of the world's population. Approximately 10% of the global population are adults over 60, and it is estimated that 2050 this figure will double. This increase in the proportion of older adults leads to a more significant burden of age-related diseases. Immunosenescence predisposes elderly individuals to a higher incidence of infectious and chronic non-communicable diseases with higher mortality rates. Despite advances in research, it is necessary to evaluate the cellular characteristics of the aging immune system in populations with a high incidence of latent viruses such as cytomegalovirus (CMV). To that end, this study employed a group of 10 young people (18-28 years old with an average age of 24.5 ± 2.98 years, five men and five women) and a group of ten older adults (60-85 years old with a mean age of 67.9 ± 9.07 years, five men and five women).
Monocytes play a fundamental role in the immune response due to their phagocytic capacity, which is necessary for the processing and presentation of antigens and the production of cytokines. In aging, monocytes are critical cells in age-related immune dysfunction. Our study observed a decrease in classical CD14++CD16- monocytes and an increase in CD14+CD16+ intermediate monocytes in older adults. The intermediate monocytes are characterized as proinflammatory cells that produce cytokines such as TNFα and IL-6. These cytokines have been associated with chronic low-grade inflammation or inflammaging. Furthermore, previous studies have shown an association between variation in circulating monocyte subpopulations and the development of diseases such as coronary heart disease and various types of cancer.
When we analyzed natural killer (NK) cells in our sample, we observed a significant increase in CD56neg cells, increased expression of CD57, and a notable decrease in CD56bright cells in older adults. These findings align with previous immunosenescence research reporting a decrease in immature NK and an increase in CD56dim cells with CD57 expression. Studies have shown that CD56neg cells are less functional regarding cytotoxicity and responsiveness, especially in CMV+ individuals.
In this study, using the differential expression of CD62L and CD45RO, the distribution of memory subpopulations in the T cells was determined. A significant decrease in the naïve cell subpopulation was observed in CD4+ and CD8+ T cells in the older adult group. Although the total number of T cells remains relatively constant with aging, reducing the naïve T cells is a hallmark of immunosenescence. Furthermore, we observed a significant increase in terminally differentiated effector CD8+ T cells in older adults. This increase in T cell effectors has been observed in both aging and chronic infections, such as those caused by CMV, which is the case for our individuals.
Long-Lived Individuals Exhibit a More Youthful Red Blood Cell Biochemistry
https://www.fightaging.org/archives/2025/02/long-lived-individuals-exhibit-a-more-youthful-red-blood-cell-biochemistry/
Erythrocytes, the red blood cells that carry oxygen around the body, are not often the topic of the day in aging research. Red blood cells are made by the hematopoietic cells that reside in the bone marrow, and a great deal of effort is spent on studying the aging of the hematopoietic system. This research is largely focused on changes in the production and behavior of white blood cells and consequent harms to the function of the immune system, however.
In today's open access paper, researchers report on an analysis of the biochemistry of erythrocytes in a study population that included a group of long-lived individuals over the age of 90. The long-lived individuals exhibited a more youthful erythrocyte metabolism. The researchers propose mechanisms linking this to improved function throughout the body, but as is always the case in aging and cell biochemistry, the challenge lies in determine which of the many options on the table is actually the most important. The only way to find out in certainty is to fix that one mechanism in isolation and observe the outcomes.
Longevity Humans Have Youthful Erythrocyte Function and Metabolic Signatures
Individuals who live past the age of 90 are defined as longevity individuals and are examples of highly successful aging, often referred to as increased healthspan. These individuals are equipped with a better capability to counteract chronic tissue hypoxia, inflammation, and oxidative stress and thus a lower susceptibility to age-related diseases including cardiovascular disease and Alzheimer's disease. Such an advantage makes longevity individuals an ideal population for the investigation of cellular and molecular mechanisms underlying better aging with the ultimate goal of promoting lifespan and healthspan and decreasing the burden of degenerative diseases with important social and economic benefits.
We unexpectedly discovered that longevity individuals exhibit erythrocyte oxygen release function similar to young individuals, whereas most elderly show reduced oxygen release capacity. Untargeted erythrocyte metabolomics profiling revealed that longevity individuals are characterized by youth-like metabolic reprogramming and these metabolites effectively differentiate the longevity individual from the elderly individual. Quantification analyses led us to identify multiple novel longevity-related metabolites within erythrocytes including adenosine, sphingosine-1-phosphate (S1P), and glutathione (GSH) related amino acids.
Mechanistically, we revealed that increased bisphosphoglycerate mutase (BPGM) and reduced MFSD2B protein levels in the erythrocytes of longevity individuals collaboratively work together to induce elevation of intracellular S1P, promote the release of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from membrane to the cytosol, and thereby orchestrate glucose metabolic reprogramming toward the Rapoport-Luebering Shunt pathway to induce the 2,3-BPG production and trigger oxygen delivery. Furthermore, increased glutamine and glutamate transporter expression coupled with the enhanced intracellular metabolism underlie the elevated GSH production and the higher anti-oxidative stress capacity in the erythrocytes of longevity individuals.
As such, longevity individuals displayed less systemic hypoxia-related metabolites and more antioxidative and anti-inflammatory metabolites in the plasma, thereby healthier clinical outcomes including lower inflammation parameters as well as better glucose-lipid metabolism, and liver and kidney function.
Rejuvenation Science Institute Seeks Charitable Donations to Support a Reproduction of the Yuvan Research Young Plasma Study
https://www.fightaging.org/archives/2025/02/rejuvenation-science-institute-seeks-charitable-donations-to-support-a-reproduction-of-the-yuvan-research-young-plasma-study/
The Rejuvenation Science Institute (ICR) is a Brazilian group engaged in advocacy and research initiatives, in many ways analogous to Lifespan.io in the US. At present, the ICR staff are seeking to reproduce and improve on the study sponsored by Yuvan Research in which a plasma fraction derived from young pigs was used to produce benefits in aged rats. Yuvan Research is somewhere in the process of trying to bring this to the clinic as a therapy.
Independent reproduction of results is important in the scientific community, and more generally in the development of new technologies. The ICR principals recently sent me their pitch for charitable donations to help crowdfund this reproduction study. As they note, they have already set things in motion, conducted a preliminary proof of concept study for the treatment, and are now just waiting on their laboratory rats to age into the right age range for treatment. If you want to support this work, visit the ICR website and donate.
The Rejuvenation Science Institute (ICR) is preparing the reproduction of the seminal Yuvan Research experiment in which rats were rejuvenated with extracellular particles from young pig's blood. The experiment will be carried out in June 2026 and it is partially funded, but we need donations for its complete funding. Back in 2020, when the Yuvan Research principals published the first article about the experiment, it was not reveal what was given to the rats, but in October 2023, the full article was published in Geroscience journal, detailing the whole procedure. So, now, after a lot of hard work to organize the reproduction in Brazil of this experiment, we finally scheduled the beginning of the injections in the rats to June 2026, as we need 25-months-old animals, and we need to wait for them to age.
By the way, our institute has already carried out a small experiment together with the State University of Campinas, commonly known as Unicamp - one of the leading research universities in Latin America, that will also collaborate with ICR in the full experiment of rats rejuvenation - in which we injected the extracellular particles in young rats to assess acute immunogenicity and toxicity, described in our recent scientific publication.
Regarding the funding for the full reproduction of the Yuvan Research experiment, the ICR received the promise of a donation from an institution that will partially cover the costs of the experiment. This donation will cover the costs from Unicamp, the university we are collaborating with. However, the work the ICR will perform still needs to be funded. So we are asking the people interested in the experiment results to become financial collaborators to our institute, which can be done via the donations page of our website.
The ICR is committed to publishing all the results obtained, be them positive or negative. Also, all methods and materials will be published immediately after the experiment, together with those results. Yuvan Research used 6 rats per group, but we will use 10 rats per group, in order for the study to be more robust. Also, by suggestion of professor Marcelo Mori from Unicamp, we will also include a group of young treated rats, to see if we are able to keep young rats young, and not just rejuvenate old rats. And if the rats are rejuvenated (or kept young, regarding the young treated rats), we intend to let them live indefinitely, applying the treatment periodically, as there will be no better evidence of success than extension of life span.
Even though the experiment is still 1 year and 4 months away, we are already working to make all the necessary preparations, both technical and bureaucratic. To follow the preparations for the experiment, you can subscribe to our newsletter.
Assessing Effects of Vitamin D, Omega-3 and Exercise on Aging Clocks in Older People
https://www.fightaging.org/archives/2025/02/assessing-effects-of-vitamin-d-omega-3-and-exercise-on-aging-clocks-in-older-people/
The various aging clocks only become truly useful to the degree that there is enough existing data on their performance to understand whether or not one can trust their outputs for a given novel intervention targeting aging. A way to rapidly assess effects on biological age will steer the development of therapies towards the most effective approaches much more rapidly than is presently the case. Even through the clocks have issues, the largest of which being that the research community cannot link clock components to specific mechanisms of aging via a clear chain of cause and effect, using them broadly in as many human trials as possible is a good idea, including lifestyle interventions and supplements thought to have only modest effects. In this study, for example, researchers found that a few of these interventions slowed the increase of biological age over time in older people by something like 10%, on average.
While observational studies and small pilot trials suggest that vitamin D, omega-3, and exercise may slow biological aging, larger clinical trials testing these treatments individually or in combination are lacking. Here, we report the results of a post hoc analysis among 777 participants aged 70 years and older of the DO-HEALTH trial on the effect of vitamin D (2,000 IU per day) and/or omega-3 (1 g per day) and/or a home exercise program on four next-generation DNA methylation (DNAm) measures of biological aging (PhenoAge, GrimAge, GrimAge2 and DunedinPACE) over 3 years.
Omega-3 alone slowed the DNAm clocks PhenoAge, GrimAge2 and DunedinPACE, and all three treatments had additive benefits on PhenoAge. Overall, from baseline to year 3, standardized effects ranged from 0.16 to 0.32 units (2.9-3.8 months). In summary, our trial indicates a small protective effect of omega-3 treatment on slowing biological aging over 3 years across several clocks, with an additive protective effect of omega-3, vitamin D and exercise based on PhenoAge.
An Aging Clock Based on Abdominal CT Imagery
https://www.fightaging.org/archives/2025/02/an-aging-clock-based-on-abdominal-ct-imagery/
The body changes with age, and many of those changes are fairly similar from person to person in their relationship with disease and mortality. Thus any sufficiently large set of data on body structure or biochemistry can be used to produce a clock algorithm that reflects mortality risk and the burden of age-related damage and dysfunction. Typically the result is framed as a measure of age, and called biological age, though there are some who think that researchers should be more careful in how they talk about what exactly is being measured by a clock.
Biological age (BA) is a potentially useful construct that attempts to reflect the cumulative physiologic effect of lifestyle habits, genetic predisposition, and superimposed disease processes beyond simply the number of years lived. Attempts at deriving an effective BA date back at least half a century, but with only limited success. Much of the current geroscience focus to date for attempting to derive an effective BA has centered on various "frailomics" at the cellular and subcellular levels, including genomics and epigenomics (e.g., telomere length and epigenetic clock), proteomics, and metabolomics, as well as various other laboratory and clinical measures.
Imaging biomarkers have generally received less attention for estimating BA, but arguably may better reflect the cumulative macroscopic effects of aging at the tissue and organ levels. In particular, abdominal computed tomography (CT) represents an appealing candidate for a more personalized investigation. Thus we derived and tested a CT-based biological age model for predicting longevity that quantifies skeletal muscle, abdominal fat, aortic calcification, bone density, and solid abdominal organs.
We applies this tool to abdominal CT scans from 123,281 adults (mean age, 53.6 years; 47% women). The final weighted CT biomarker selection was based on the index of prediction accuracy. The CT model significantly outperforms standard demographic data for predicting longevity (index of prediction accuracy, IPA = 29.2 vs. 21.7). Age- and sex-corrected survival hazard ratio for the highest-vs-lowest risk quartile was 8.73 for the CT biological age model, and increased to 24.79 after excluding cancer diagnoses within 5 years of CT. Muscle density, aortic plaque burden, visceral fat density, and bone density contributed the most.
Physical Activity Correlates with Reduced Mortality Even in Patients with Multimorbidity
https://www.fightaging.org/archives/2025/02/physical-activity-correlates-with-reduced-mortality-even-in-patients-with-multimorbidity/
Older patients exhibiting multimorbidity, meaning the presence of two or more diagnosed age-related conditions, are typically in relatively poor shape. Researchers here note that, in this population specifically, greater levels of exercise still correlate with reduced mortality over time. While human data can only show correlation and not causation, extensive animal studies of physical activity give us good reason to think that exercise does in fact act to improve health and that this isn't just a case of less healthy individuals being less able to exercise.
Our study represents one of the pioneering multinational efforts to investigate the longitudinal relationship between physical activity (PA) levels and mortality in individuals with multimorbidity. We found that higher levels of physical activity could significantly reduce mortality risk over an average 12-year follow-up period, even among those dealing with multiple chronic conditions. Our results show that, after adjusting for several potential confounding factors, individuals with multimorbidity who reported moderately low, moderately high and high levels of PA had a 36%, 47%, and 51% reduced mortality risk, respectively, compared to those with low levels of PA.
PA may reduce mortality through several mechanisms. First, engaging in regular PA boosts mitochondrial function, enhancing energy production and decreasing oxidative stress, thereby protecting cells from damage. PA also increases the expression of antioxidant enzymes, which help neutralize harmful free radicals. Second, PA regulates inflammation by lowering pro-inflammatory cytokine levels and raising anti-inflammatory interleukins. It also stimulates autophagy, the process by which cells remove damaged proteins and organelles, ensuring cellular health. Thirdly, PA enhances insulin sensitivity, aiding in blood glucose regulation and potentially slowing the accumulation of molecular damage. Together, these hormonal and molecular changes reduce the risk of chronic diseases and decrease overall mortality.
Extracellular Vesicles Derived from Stem Cell Aggregates Improve Bone Density in Aged Mice
https://www.fightaging.org/archives/2025/02/extracellular-vesicles-derived-from-stem-cell-aggregates-improve-bone-density-in-aged-mice/
The Golgi apparatus receives relatively little attention in the context of aging, but it suffers dysfunction like all structures in the cell. It is involved in directing newly manufactured proteins to their destination, whether inside the cell or to be secreted in extracellular vesicles. Researchers here show that extracellular vesicles harvested from a particular form of stem cell culture can act to improve Golgi apparatus function in aged tissues, and in doing so aid in improving bone density and bone regeneration in aged mice.
The production of stem cell aggregates (CA) is a regenerative technique that promotes normal stem cell function by encouraging high-density stem cells to secrete large amounts of extracellular matrix (ECM), which serves as an excellent cellular scaffold. Our previous studies have further revealed that CA-derived extracellular vesicles (CA-EVs) are featured with proteins that effectively promote tissue/organ regeneration.
In this study, we investigated the mechanisms underlying bone marrow mesenchymal stem cell (BMSCs) senescence in bone aging and explored whether CA-EVs can improve bone mass and regeneration with the advanced age. Surprisingly, we discovered that alterations of Golgi apparatus contributed to senescence of resident BMSCs and led to a reduction in the release of endogenous EVs, which has not been previously reported. We further found that locally transplanted CA lost its ability to promote bone regeneration in the aging microenvironment, which was also attributed to impaired structure and function of Golgi.
Intriguingly, in-depth analysis suggested that CA-EVs exposed functional surface proteins to assemble the Golgi apparatus, such as Syntaxin 5 (STX5), which helped restore function of senescent BMSCs. Importantly, CA-EV replenishment promoted regeneration of bone defects and counteracted osteoporosis in aging mice. These findings provide the first evidence that Golgi-based vesicular disorders contribute to cell senescence and that CA-EVs effectively mitigate BMSC aging to retard age-related osteoporosis and safeguard aging bone regeneration.
Brain Injury Accelerates Later Amyloid Aggregation to Increase Risk of Alzheimer's Disease
https://www.fightaging.org/archives/2025/02/brain-injury-accelerates-later-amyloid-aggregation-to-increase-risk-of-alzheimers-disease/
Why do traumatic brain injury survivors exhibit an increased risk of Alzheimer's disease? Researchers here observe a specific set of changes in the vasculature of the injured brain that appear to accelerate deposition of amyloid-β, an outcome supportive of the amyloid cascade hypothesis for the development of Alzheimer's disease. Despite the inability of amyloid-β clearance to much affect patient outcomes in the later stages of Alzheimer's disease, it remains the case that many lines of evidence support amyloid-β aggregation as the foundational pathology that initially causes Alzheimer's disease.
Traumatic brain injury (TBI) often leads to impaired regulation of cerebral blood flow, which may be caused by pathological changes of the vascular smooth muscle cells (VSMCs) in the arterial wall. Moreover, these cerebrovascular changes may contribute to the development of various neurodegenerative disorders such as Alzheimer's-like pathologies that include amyloid beta aggregation. Despite its importance, the pathophysiological mechanisms responsible for VSMC dysfunction after TBI have rarely been evaluated.
Here, we show that acute human TBI resulted in early pathological changes in leptomeningeal arteries, closely associated with a decrease in VSMC markers such as NOTCH3 and alpha smooth muscle actin (α-SMA). These changes coincided with increased aggregation of variable-length amyloid peptides including Aβ1-40/42, Aβ1-16, and β-secretase-derived fragment (βCTF) (C99) caused by altered processing of amyloid precursor protein (APP) in VSMCs. The aggregation of Aβ1-40/42 peptides were also observed in the leptomeningeal arteries of young TBI patients.
These pathological changes also included higher β-secretase (BACE1) in the leptomeningeal arteries, plausibly caused by hypoxia and oxidative stress as shown using human VSMCs in vitro. Importantly, BACE1 inhibition not only restored NOTCH3 signalling but also normalized ADAM10 levels in vitro. Furthermore, we found reduced ADAM10 activity and decreased NOTCH3, along with increased βCTF (C99) levels in mice subjected to an experimental model of TBI. This study provides evidence of early post-injury changes in VSMCs of leptomeningeal arteries that can contribute to vascular dysfunction and exacerbate secondary injury mechanisms following TBI.
CD150 Expression Distinguishes Dysfunctional Hematopoietic Cells in Aged Bone Marrow
https://www.fightaging.org/archives/2025/02/cd150-expression-distinguishes-dysfunctional-hematopoietic-cells-in-aged-bone-marrow/
Researchers here note the discovery of a marker of dysfunctional hematopoietic cells in bone marrow. Hematopoietic stem cells and their immediate descendants are responsible for producing red blood cells and immune cells. The activities of hematopoietic cells are detrimentally affected by aging, as for every other cell population in the body, and some fraction of immune system aging derives from changes in the behavior and numbers of hematopoietic cells. If only some of these cells are very dysfunctional, however, then selectively clearing out the most problematic cells, or at least reducing their relative numbers as a fraction of all hematopoietic cells, should help to restore lost immune function.
Aging is a process accompanied by functional decline in tissues and organs with great social and medical consequences. Developing effective anti-aging strategies is of great significance. In this study, we demonstrated that transplantation of young hematopoietic stem cells (HSCs) into old mice can mitigate aging phenotypes, underscoring the crucial role of HSCs in the aging process.
Through comprehensive molecular and functional analyses, we identified a subset of HSCs in aged mice that exhibit "younger" molecular profiles and functions, marked by low levels of CD150 expression. Mechanistically, CD150low HSCs from old mice but not their CD150high counterparts can effectively differentiate into downstream lineage cells. Notably, transplantation of old CD150low HSCs attenuates aging phenotypes and prolongs lifespan of elderly mice compared to those transplanted with unselected or CD150high HSCs. Importantly, reducing the dysfunctional CD150high HSCs can alleviate aging phenotypes in old recipient mice.
Thus, our study demonstrates the presence of "younger" HSCs in old mice, and that aging-associated functional decline can be mitigated by reducing dysfunctional HSCs.
A More Favorable Way of Looking at the Modest Effects of Amyloid-Clearing Immunotherapies in Alzheimer's Patients
https://www.fightaging.org/archives/2025/02/a-more-favorable-way-of-looking-at-the-modest-effects-of-amyloid-clearing-immunotherapies-in-alzheimers-patients/
There is now enough human data for immunotherapies that clear amyloid-β from the brain for researchers to say something useful and coherent about the effects of these drugs on Alzheimer's disease. It is clear that the effect size is nowhere close to the hoped for reversal of disease, and is small enough to be hard to detect without sizable patient populations or long-term follow up. This indicates that amyloid-β aggregation is not the most important pathological mechanism in later stages of the condition. It may well be the initially important mechanism that sets the stage for other forms of dysfunction, such as tau aggregation and neuroinflammation, but it will require years more to produce sufficient data in patients with early, mild cognitive symptoms to know whether or not these anti-amyloid immunotherapies can prevent Alzheimer's disease to any meaningful degree.
Alzheimer's patients and their families are faced with the tough question of whether to undergo a treatment that will not make them better. It won't even stop them from getting worse. At best, treatment with lecanemab or donanemab could slow the inevitable cognitive decline that characterizes Alzheimer's. Add to this the facts that treatment is expensive, requires biweekly or monthly infusions, and carries risks such as brain bleeds and brain swelling that are usually mild and go away on their own but can, in rare cases, be life-threatening. But just because the benefits are limited doesn't mean they are not valuable to patients and their families.
There are two critical inflection points on the continuum between independence and dependency. The first is the point where a person can no longer live independently because of an impaired ability to manage everyday tasks such as preparing meals, driving, paying bills and remembering appointments. The second point comes when a person can no longer care for his or her own body, and requires assistance with bathing, dressing, and toileting. To calculate the effects of treatment, researchers first estimated when people could expect to lose each of the two kinds of independence if left untreated. They analyzed the experiences of 282 people who participated in research studies. All participants met the criteria for treatment with the two new drugs, but hadn't received them previously. The researchers also calculated how quickly symptoms progressed without treatment.
Using these data on independence and progression, combined with the reported effects of the two drugs, the researchers calculated the amount of time a person at each stage of the disease could be expected to live or care for themselves independently without treatment, and how this progression would compare to those who received treatment. A typical person with very mild symptoms could expect to live independently for another 29 months without treatment, 39 months with lecanemab, and 37 months with donanemab. Most people with mild symptoms - as opposed to very mild symptoms - were already unable to live independently at baseline, so for them the more relevant measure was how much longer they would be able to care for themselves. The researchers calculated that a typical person at this stage of the disease could expect to manage self-care independently for an additional 26 months if treated with lecanemab, 19 months with donanemab.
Lowered Expression of TOP2B Slows Epigenetic Aging in Multiple Species
https://www.fightaging.org/archives/2025/02/lowered-expression-of-top2b-slows-epigenetic-aging-in-multiple-species/
Epigenetic mechanisms determine the structure of nuclear DNA, largely via specific chemical decorations attached to specific locations on the genome or to the histone molecules that act as spindles for nuclear DNA to wrap around. The structure of DNA, which regions are spooled and hidden versus unspooled and exposed, determines which proteins are manufactured from their genetic blueprints, and thus the behavior of the cell. Here, researchers report on a search for genetic interventions that might reduce the magnitude or slow the progression of harmful age-associated epigenetic changes. The researchers found that knockout of TOP2B produces this outcome in yeast, nematode worms, and mice. In mice, reducing TOPB2 expression adds about 10% to life expectancy. While a fair amount is known of the specific functions of TOP2B within the complex processes of managing the structure of DNA, it remains unknown as to how it is that reduced TOP2B expression can produce modestly slowed aging.
In the simple model organism yeast, the lifespans of the nonessential gene knockout mutants have been measured systematically through a multi-year effort and ~200 mutants with extended lifespans were identified. As a significant fraction of the nonessential gene knockout mutants have been profiled transcriptionally, we analyzed the correlation between the gene expression profile and the lifespan of the mutants and identified a number of essential genes whose downregulation strongly correlates with extended lifespan across multiple mutants. Among the top hits is the DNA topoisomerase Top2, with an essential function in managing DNA topology and regulating replication and transcription.
Yeast Top2 has two mammalian homologs, TOP2A and TOP2B. While TOP2A is primarily expressed in proliferating cells and is crucial for DNA replication, TOP2B is expressed in all cell types and plays a more prominent role in DNA replication, chromatin remodeling, and transcriptional regulation that is closely tied to aging. TOP2B is an essential double-stranded DNA topoisomerase, pivotal in identifying DNA topological configurations and relieving DNA torsional strain via cutting, rotating, and reconnecting DNA strands. TOP2B has been much less studied in the context of aging.
In this study, we investigate whether reduction of Top2 or TOP2B confers a longevity phenotype across species and explore the potential mechanisms. We found that knocking down Top2 or TOP2B extends the lifespan of yeast, C. elegans, and mice. TOP2B reduction also extends the health span of mice, and alleviates the characteristics and pathologies of aging in multiple tissues. At the cellular/molecular level, Top2 or TOP2B reduction attenuates the major hallmarks of aging, such as cellular senescence, deregulated nutrient-sensing, epigenetic alterations, and lysosomal dysfunction. We observed that TOP2B reduction alters the epigenetic landscape of various tissues in old mice toward those of the young animals, and differentially downregulates genes with active promoter and high expression. Our observations suggest that Top2 or TOP2B reduction confers longevity effect via remodeling of epigenetic and transcriptional landscapes and suppression of aberrantly expressed genes in old cells.
Another Example of Senescent Cell Clearance as a Treatment for Periodontitis
https://www.fightaging.org/archives/2025/02/another-example-of-senescent-cell-clearance-as-a-treatment-for-periodontitis/
You might recall a recent paper in which researchers showed that senolytic drugs could reduce the impact of gum disease, an inflammatory condition characterized by the presence of senescent cells in the inflamed gum tissue. Removing those senescent cells helps. To accompany that paper, here is another in which researchers examine periodontitis in the P16-3MR mouse model, which is genetically engineered to allow senescent cells to be efficiently and selectively cleared by treatment with ganciclovir. Here too, clearance of senescent cells is beneficial, reducing both inflammation and bone loss.
The occurrence and severity of periodontitis (PD) tend to increase with age, and yet the underlying mechanisms remain unclear. Immune senescence is known to be triggered in mice and humans as they age. Experimental PD in mice has been shown to induce senescence biomarkers p16INK4a and p21, dysfunction of antigen-presenting cells (APCs), and activation of the senescence-associated secretory phenotype (SASP). However, the causal links of senescence to experimental PD are not yet established. This study aims to elucidate the role of senescence in experimental PD at a causal level.
The P16-3MR mouse model harbors the p16INK4a (Cdkn2a) promoter, driving in vivo expression of synthetic Renilla luciferase, monomeric red fluorescent protein (mRFP), and herpes simplex virus-1 thymidine kinase (HSV-TK). This facilitates in vivo assessment of p16INK4a activation at the cellular level and the consequences of selective elimination of p16INK4a-positive cells by ganciclovir (GCV) treatment. Mice were treated with/without GCV for two weeks during ligature-induced PD. In vivo bioluminescence imaging quantified p16INK4a activation, while Western blot and immunofluorescence analyses assessed key senescence and inflammatory markers (p16, p21, p53, Cyclin D1, p-H2A.X, IL17, and IL1β). Alveolar bone volume was analyzed by micro-CT and histomorphometry.
Our findings demonstrate that clearance of senescent cells in mice subjected to experimental PD alleviates inflammation and mitigates bone loss. These results suggest a causal role for senescence in PD pathology, raising the future prospect of senolytic agents for therapeutic intervention in PD.
Psoriasis Accelerates Some Measures of Biological Age
https://www.fightaging.org/archives/2025/02/psoriasis-accelerates-some-measures-of-biological-age/
One should probably expect inflammatory and autoimmune conditions that are known to increase mortality risk, such as psoriasis, to also accelerate biological age, as measured by various aging clocks. Or at least a clock that doesn't exhibit this behavior is not a good clock in this context. Conducting assessments of biological age in many contexts and conditions is a necessary part of establishing confidence in aging clocks, so expect to see many studies similar in nature to the one noted here in the years ahead. Here, researchers obtained aging clock measurements for patients with psoriasis and assessed the degree to which these measures of biological age are predictive of actual mortality. Given fifty such studies for a range of conditions, one might gain a sense of how a given clock performs, enough to provide guidance and comfort regarding its use in a new context, or to assess a potential rejuvenation therapy.
Psoriasis is an immune-mediated genetic disorder characterized by scaly skin lesions, affects approximately 0.14%-1.99% of the global population. Compared to the general population, patients with psoriasis are at increased risk for immune and metabolic comorbidities including cardiovascular disease, diabetes mellitus, metabolic dysfunction-associated steatotic liver disease and inflammatory bowel disease. A survey based on the United States population noted that psoriasis was associated with a two-fold increased risk of all-cause mortality.
Patients with psoriasis and non-psoriasis were recruited from National Health and Nutrition Examination Survey (NHANES) (12,973 cases), Medical Information Mart for Intensive Care (MIMIC-IV) (558 cases) and The First Clinical Medical College of Zhejiang Chinese Medical University (206 cases). Biological age was calculated using Klemera-Doubal method age (KDM-age) and phenotypic age (PhenoAge). Linear regression and logistic regression were used to explore the association between psoriasis and biological age advance. Cox regression was used to investigate the association between biological age advance and mortality. Finally, biological age advance was used to predict the death of psoriasis patients.
In NHANES, linear regression showed that psoriasis led to an increase in PhenoAge (Beta: 0.54). The KDM-age increase due to psoriasis was not statistically significant. Using data from China, we came to the new conclusion that for every unit rise in Psoriasis Area and Severity Index, PhenoAge rose by 0.12 (Beta: 0.12). Using NHANES data, cox regression shows for every unit rise in PhenoAge advance patients had an 8% rise in mortality. Using MIMIC-IV, logistic regression showed a 13% increase in mortality within 28 days of admission for every 1 unit rise in PhenoAge advance. Finally, we used PhenoAge advance to predict death, with an area under curve (AUC) of 0.71 in the NHANES, an ACU of 0.79 for predicting death within 1 years in the general ward of MIMIC-IV. In the ICU of MIMIC-IV, the AUC for predicting death within 28 days was 0.71.