Fight Aging! Newsletter, February 3rd 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/
Longevity Industry Consulting Services
Reason, the founder of Fight Aging! and Repair Biotechnologies, offers strategic consulting services to investors, entrepreneurs, and others interested in the longevity industry and its complexities. To find out more: https://www.fightaging.org/services/
- Reviewing the Mechanisms of Muscle Aging
- Evidence for Mutational Damage as a Cause of Age-Related Epigenetic Change
- The Biology of Cancer Progression Changes with Age
- Promoting Autophagy via KIF9 in an Alzheimer's Mouse Model
- Senescent Cells Implicated in Loss of Salivary Secretion in Aging
- Nicotinamide Riboside Fails to Improve Measures of Cognitive Function in Mild Cognitive Impairment Patients
- A Snapshot of Population Aging Effects on Mortality and Disability
- GATA4 in Mesenchymal Stem Cell Senescence
- Further Investigating the Biochemistry of Natural Killer Cell Surveillance of Senescent Cells
- Mincle Provokes Inflammation in Response to Microbes Leaking from the Aged Intestine
- Arginase II Deficiency Slows Muscle Aging in Mice
- Reviewing What is Known of Exerkines
- A Novel Way to Interfere in NF-κB Signaling to Reduce Inflammation in the Brain
- Targeting the Behavior of Astrocytes in the Treatment of Neurodegenerative Conditions
- An Epigenetic View of the Benefits of Calorie Restriction in Aged Rats
Reviewing the Mechanisms of Muscle Aging
https://www.fightaging.org/archives/2025/01/reviewing-the-mechanisms-of-muscle-aging/
With advancing age, muscle mass and muscle strength are both steadily reduced, leading to sarcopenia and dynapenia. Interestingly, a sizable fraction of the observed outcomes of aging on muscle function in wealthier populations are avoidable, a consequence of our modern age of comfort and machineries of transport. We exercise a good deal less than our ancestors did. Humans evolved in a hunter-gatherer environment of daily exertion. Present day hunter-gatherers exhibit a good deal less heart disease and greater maintenance of muscle mass and function than is the case for those of us who drive to work and the grocery store. Use it or lose it, as they say.
Nonetheless, even the athletic succumb to aging eventually. A great deal is known of the various contributions to muscle aging, such as loss of stem cell function, mitochondrial dysfunction, inflammation, detrimental changes in neuromuscular junctions, and so forth. This is a microcosm of aging as a whole, in that: (a) there is little understanding of which of the many contributions are most important, (b) there is little understanding of how these contributions interact with one another, which are primary, which are secondary, and (c) for every mechanism there is essentially an unlimited amount of exploratory research into relevant cellular biochemistry that could be conducted. Mining sometimes finds gold, fundamental research sometimes finds something that can be turned into a therapy.
From molecular to physical function: The aging trajectory
Aging is accompanied by a decline in muscle mass, strength, and physical function, a condition known as sarcopenia. Muscle disuse attributed to decreased physical activity, hospitalization, or illness (e.g. sarcopenia) results in a rapid decline in muscle mass in aging individuals and effectively accelerates sarcopenia. Consuming protein at levels above (at least 50-100% higher) the current recommended intakes of ∼0.8 g protein/kg bodyweight/day, along with participating in both resistance and aerobic exercise, will aid in the preservation of muscle mass.
Physiological muscle adaptations often accompany the observable changes in physical independence an older adult undergoes. Muscle fibre adaptations include a reduction in type 2 fibre size and number, a loss of motor units, reduced sensitivity to calcium, reduced elasticity, and weak cross-bridges. Mitochondrial function and structure are impaired in relation to aging and are worsened with inactivity and disease states but could be overcome by engaging in exercise.
Intramuscular connective tissue adaptations with age are evident in animal models; however, the adaptations in collagenous tissue within human aging are less clear. We know that the satellite muscle cell pool decreases with age, and there is a reduced capacity for muscle repair/regeneration. Finally, a pro-inflammatory state associated with age has detrimental impacts on the muscle. The purpose of this review is to highlight the physiological adaptations driving muscle aging and their potential mitigation with exercise/physical activity and nutrition.
Evidence for Mutational Damage as a Cause of Age-Related Epigenetic Change
https://www.fightaging.org/archives/2025/01/evidence-for-mutational-damage-as-a-cause-of-age-related-epigenetic-change/
How does stochastic nuclear DNA damage contribute to degenerative aging? Most mutation occurs in regions of the genome that are not used, in somatic cells with few divisions remaining before the Hayflick limit and self-destruction. Thus the impact is minimal. One point of view on this topic is that only mutations in stem cells are important. These mutations spread slowly in waves throughout a tissue, replicated in the somatic cell lineages descended from mutated stem cells, a process known as somatic mosaicism. There is some evidence for somatic mosaicism to contribute to a few age-related dysfunctions, but not very much of it.
Another point of view with limited evidence, but very interesting evidence, is that the process of repairing repeated double strand breaks, wherever they occur in the genome, changes the molecular mechanisms responsible for controlling the structure of nuclear DNA in deterministic ways, such as by depleting specific factors. This leads to the characteristic epigenetic changes of aging in every cell, as every cell undergoes this form of stochastic DNA damage.
In today's open access paper, researchers propose another, quite different way in which DNA damage can be linked to epigenetic changes. The authors argue for mutational damage to the genome to directly alter epigenetic regulation of the structure of DNA. The researchers looked at mutations occurring at CpG sites where the genome is methylated to adjust its structure, and found that mutation at a CpG site doesn't just affect the methylation status of that CpG site, but also nearby sites as well, altering the expression of numerous genes in predictable way.
Why Our Biological Clock Ticks: Research Reconciles Major Theories of Aging
There are two prevailing theories about the relationship between aging and DNA. The somatic mutation theory suggests that aging is caused by the accumulation of mutations, permanent changes in our DNA sequence that occur randomly. The epigenetic clock theory suggests that aging occurs due to the accumulation of epigenetic modifications, minor changes to the chemical structure of DNA that do not alter the underlying sequence, but instead change which genes are on or off. Unlike mutations, epigenetic modifications can also be reversed in some cases.
Researchers analyzed data from 9,331 patients catalogued in the Cancer Genome Atlas and the Pan-Cancer Analysis of Whole Genomes. By comparing genetic mutations to epigenetic modifications, they found that mutations were predictably correlated with changes in DNA methylation, one type of epigenetic modification. They found that a single mutation could cause a cascade of epigenetic changes across the genome, not just where the mutation occurred. Using this relationship, the researchers were able to make similar predictions of age using either mutations or epigenetic changes.
Somatic mutation as an explanation for epigenetic aging
DNA methylation marks have recently been used to build models known as epigenetic clocks, which predict calendar age. As methylation of cytosine promotes C-to-T mutations, we hypothesized that the methylation changes observed with age should reflect the accrual of somatic mutations, and the two should yield analogous aging estimates. In an analysis of multimodal data from 9,331 human individuals, we found that CpG mutations indeed coincide with changes in methylation, not only at the mutated site but with pervasive remodeling of the methylome out to ±10 kilobases. This one-to-many mapping allows mutation-based predictions of age that agree with epigenetic clocks, including which individuals are aging more rapidly or slowly than expected. Moreover, genomic loci where mutations accumulate with age also tend to have methylation patterns that are especially predictive of age. These results suggest a close coupling between the accumulation of sporadic somatic mutations and the widespread changes in methylation observed over the course of life.
The Biology of Cancer Progression Changes with Age
https://www.fightaging.org/archives/2025/01/the-biology-of-cancer-progression-changes-with-age/
Cancer is, evidently, an age-related disease. The immune system becomes less able to prevent precancerous cells from progressing to form a cancer. The burden of mutational damage is higher, increasing the odds of a cancerous combination of mutations arising. Lingering senescent cells pump out pro-growth, pro-inflammatory factors that make tissues more hospitable to growth of cancerous cells. Aging doesn't just affect the odds of cancer, however. The damage and dysfunction of aging induces changes in the behavior of cancer cells and progression of cancer that one might reasonably expect to be just as large and significant as the changes inflicted by aging upon normal cells and tissue function.
In today's open access editorial, researchers consider the intersection between mechanisms of aging and the progression of cancer. Extremely old people differ from younger old cohorts in important ways, including a more advanced decline of immune function, important to the way in which immunotherapies interact with cancerous tissues, and a greater burden of senescent cells, altering the tissue microenvironment with their secretions. Immunotherapies are on their way to eventually becoming the dominant form of cancer therapy, and in their best implementations represent a major advance over chemotherapeutics. As ever more of the standard treatments for forms of cancer become immunotherapies, there will be an ever greater interest in the fine details of interaction between cancer and the aging of the immune system and tissue microenvironment.
Aging and Cancer-Inextricably Linked Across the Lifespan
As patients age, several factors evolve that can profoundly influence cancer progression and responses to therapies. These factors include immune system changes, environmental exposures over a lifetime (exposome), frailty, the cumulative impact of stress (i.e., allostatic burden), comorbidities, and the varying degrees of physical and psychosocial resilience that come with aging and lived experiences. Additionally, a patient's treatment history and the secondary effects of those treatments on organ function play a crucial role in determining the efficacy of future therapies and could be pivotal in tailoring treatment options.
Hematological indications such as leukemias and lymphomas are more readily accessible for such analyses relative to solid tumor indications and represent powerful opportunities to understand the evolutionary process of therapeutic resistance. Notably, the age-dependent expansions of clones (often bearing cancer-associated mutations) in our tissues, which are associated with both malignant and nonmalignant disease risk as shown for the hematopoietic system, still represent a relatively unexplored frontier, particularly regarding the impact of these clonal expansions on patient responses to therapies and overall well-being.
Because the immune system undergoes change throughout the life course (e.g., age-related decline in naïve CD8+ T cells and expansion/exhaustion of memory phenotypes; increasing presence of GMZK+ CD8+ T cells; and biased expansion of myeloid-to-lymphoid cells) the function of immunotherapies such as checkpoint inhibitors and CAR-T cells, as well as immune-related adverse events, may vary accordingly. In infants and children, while CAR T cells have demonstrated success for B-cell acute lymphocytic leukemias, immune checkpoint inhibitor therapies have been less effective, likely due to the low mutation burden of pediatric cancers. Older and geriatric adults who are experiencing immune systemic and cellular senescence changes associated with aging still exhibit responses to checkpoint inhibitors, and CAR-T cell therapy can still be effective against B-cell lymphomas, albeit with reduced responses in those over 75. For older persons, factors such as prior antigen exposure and overall health status should clearly play roles but currently are understudied.
Additional immunotherapeutic opportunities include identifying approaches to limit the accumulation of senescent cells and exhausted cells; limiting genotoxic stress and radiation treatment induced DNA damage and senescence; as mentioned earlier, overcoming tissue contextual changes in the extracellular matrix within the tumor microenvironment that often limit access to tumors; adapting immunotherapies given the age-related increases in PD1 expression on T cells and age-related changes in metabolites (e.g., methylmalonic acid); and anticipating treatment-related complications and comorbidities, such as frailty.
Further to this point, aging is often accompanied by the accumulation of both subclinical and clinical comorbid conditions, which can alter treatment responses and influence disease progression. Different comorbidities (e.g., metabolic disease, cardiovascular disease, inflammatory syndromes) can modulate the pathophysiology of cancer through shared risk factors and biological pathways such as inflammation and immune function. Therefore, acknowledging and addressing these comorbidities is essential in crafting effective, patient-specific treatment plans.
Promoting Autophagy via KIF9 in an Alzheimer's Mouse Model
https://www.fightaging.org/archives/2025/01/promoting-autophagy-via-kif9-in-an-alzheimers-mouse-model/
Autophagy is the name given to a collection of processes for recycling damaged structures in the cell. It is complex, involving means of determining that a structure is in some way damaged or excess to requirements, wrapping that structure in a membrane called an autophagosome, transporting the autophagosome into contact with a lysosome, and then merging autophagosome and lysosome to allow the enzymes of the lysosome to break down and recycle the autophagosome contents. Increased efficiency in autophagy is a feature of many of the interventions demonstrated to slow aging in animal studies, including lifestyle interventions such as exercise and calorie restriction. Evidence suggests that the age-slowing effects of calorie restriction depend upon this upregulation of autophagy, that it is the most important aspect of the changed biochemistry that results from a reduced availability of nutrients.
Given all of this, there is considerable interest in the development of therapies capable of selectively improving the operation of autophagy. Despite a broad range of research and development programs, little beyond the known repurposed calorie restriction mimetic drugs (such as rapamycin) has yet made it as far as the clinic. Still, new programs continually arise in the research community. Today's open access paper offers an example of one such program at an early stage, an attempt to apply upregulation of autophagy to the thorny problem of Alzheimer's disease. The hope is that improved autophagy will reduce amyloid deposition and consequent pathology, perhaps directly by clearing amyloid more rapidly, perhaps indirectly via reduced inflammation or similar mechanisms.
KIF9 Ameliorates Neuropathology and Cognitive Dysfunction by Promoting Macroautophagy in a Mouse Model of Alzheimer's Disease
Alzheimer's disease (AD) is a prevalent neurodegenerative disorder affecting the elderly. The imbalance of protein production and degradation processes leads to the accumulation of misfolded and abnormally aggregated amyloid-beta (Aβ) in the extracellular space and forms senile plaques, which constitute one of the most critical pathological hallmarks of AD. KIF9, a member of the kinesin protein superfamily, mediates the anterograde transport of intracellular cargo - such as autophagosomes and lysosomes - along microtubules. However, the exact role of KIF9 in AD pathogenesis remains largely elusive.
In this study, we reported that the expression of KIF9 in the hippocampus of APP23/PS45 double-transgenic AD model mice declined in an age-dependent manner, concurrent with macroautophagy dysfunction. Furthermore, we found that KIF9 mediated the transport of lysosomes through kinesin light chain 1 (KLC1), thereby participating in the degradation of amyloidogenic pathway-related proteins of Aβ precursor protein (APP) in AD model cells through promoting the macroautophagy pathway.
Importantly, genetic upregulation of KIF9 via adeno-associated virus (AAV) diminished Aβ deposition and alleviated cognitive impairments in AD model mice by enhancing macroautophagy function. Collectively, our findings underscore the ability of KIF9 to promote macroautophagy through KLC1-mediated anterograde transport of lysosomes, effectively ameliorating cognitive dysfunction in AD model mice. These discoveries suggest that KIF9 may represent a novel therapeutic target for the treatment of AD.
Senescent Cells Implicated in Loss of Salivary Secretion in Aging
https://www.fightaging.org/archives/2025/01/senescent-cells-implicated-in-loss-of-salivary-secretion-in-aging/
Among the many dysfunctions of aging, significant loss of salivary gland activity is one of those that likely never crosses the mind of anyone other than those suffering from or treating its consequences. Nonetheless, the salivary gland is a complex structure, and like all tissues, is negatively impacted by the mechanisms of aging. Inadequate production of saliva and contribute to the difficulties of eating experienced by very old people, as well as alter the oral microbiome in detrimental ways.
As for many aspects of aging, the relative importance of the various mechanisms of aging in salivary gland dysfunction is not known. Today's open access paper focuses on the age-related accumulation of senescent cells, which at this point has been comprehensively demonstrated to contribute to many specific dysfunctions of aging in animal models. Senescent cells secrete inflammatory, disruptive signals. The more senescent cells there are in a tissue, the greater the negative impact on tissue structure and function.
Cellular Senescence Contributes to the Dysfunction of Tight Junctions in Submandibular Glands of Aging Mice
Saliva is essential for maintaining oral health, playing a role in lubrication, taste, chewing, swallowing and initial immune defense. Studies have shown that older people experience decreased salivary secretion, leading to symptoms such as dysphagia, increased risk of dental caries, and dysbiosis of the oral microbiota. Increasing research suggests a strong link between the excessive accumulation of senescent cells and age-related diseases. The accumulation of senescent cells, particularly those positive for p16Ink4a, is associated with inflammatory responses and reduced lifespan. Conversely, the elimination of these cells can attenuate tissue dysfunction and improve health.
Tight junctions, cell-to-cell adhesion complexes located at the apical regions of adjacent epithelial/endothelial cells, dynamically regulate material transport through the paracellular pathway, playing a crucial role in saliva secretion. Recent researches have shown that dysfunction of tight junctions contributes to abnormalities in salivary secretion in diseases such as diabetes mellitus. Numerous studies have demonstrated significant alterations in tight junctions in various tissues and organs during aging, such as the skin, gastrointestinal tract, and blood-brain barrier (BBB).
This study investigates the mechanism of aging-related submandibular dysfunction and evaluates the therapeutic potential of dental pulp stem cell-derived exosomes (DPSC-exos). We found that the stimulated salivary flow rate was significantly reduced in naturally aging and D-galactose-induced aging mice (D-gal mice) compared to control mice. Acinar atrophy and periductal fibrosis in submandibular and parotid glands were observed in naturally aging and D-gal mice, whereas sublingual glands had no notable alterations. We observed the accumulation of senescent cells in the submandibular glands.
Injecting DPSC-exos into the submandibular glands of D-gal mice improved stimulated salivary flow rate, reduced acinar atrophy, and decreased SA-β-gal activity. Our study identified that increased senescence of submandibular glands in aging mice can cause a decrease in salivary secretion by disrupting the expression and distribution of tight junction molecules, and injection of DPSC-exos ameliorates submandibular secretory dysfunction. These findings may provide new clues to novel therapeutic targets for aging-related dysfunction of submandibular glands.
Nicotinamide Riboside Fails to Improve Measures of Cognitive Function in Mild Cognitive Impairment Patients
https://www.fightaging.org/archives/2025/01/nicotinamide-riboside-fails-to-improve-measures-of-cognitive-function-in-mild-cognitive-impairment-patients/
Using vitamin B3 derivatives as a means to modestly improve metabolism to treat various conditions has a several decade history. The results have been poor; largely this is a history of failed clinical trials. This mostly predates the recent focus on declining NAD+ levels in mitochondria in aging, and the use of vitamin B3 derivatives, such as nicotinamide riboside, to increase NAD+ levels. Exercise produces larger gains than these supplement approaches in NAD+ levels. The clinical trial noted here is fairly characteristic of the type; one sees modest gains in some of the parameters that one might expect to be linked to improved mitochondrial function, but no significant effect on the disease state.
Age-associated depletion in nicotinamide adenine dinucleotide (NAD+) concentrations has been implicated in metabolic, cardiovascular, and neurodegenerative disorders. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), offers a potential therapeutic avenue against neurodegenerative pathologies in aging, Alzheimer's disease, and related dementias. A crossover, double-blind, randomized placebo (PBO) controlled trial was conducted to test the safety and efficacy of 8 weeks' active treatment with NR (1 gram/day) on cognition and plasma Alzheimer's disease biomarkers in older adults with subjective cognitive decline and mild cognitive impairment.
The primary efficacy outcome was the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Secondary outcomes included plasma phosphorylated tau 217 (pTau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Exploratory outcomes included Lumosity gameplay (z-scores) for cognition and step counts from wearables.
Forty-six participants aged over 55 were randomized to NR-PBO or PBO-NR groups; 41 completed baseline visits, and 37 completed the trial. NR supplementation was safe and well tolerated with no differences in adverse events reported between NR and PBO treatment phases. For the between-group comparison, there was a 7% reduction in pTau217 concentrations after taking NR, while an 18% increase with PBO. No significant between-group differences were observed for RBANS, other plasma biomarkers(GFAP and NfL), Lumosity gameplay scores, or step counts. For the within-individual comparison, pTau217 concentrations significantly decreased during the NR phase compared to the PBO, while step counts significantly increased during the NR phase than PBO.
A Snapshot of Population Aging Effects on Mortality and Disability
https://www.fightaging.org/archives/2025/01/a-snapshot-of-population-aging-effects-on-mortality-and-disability/
Population aging is a shift in the distribution of ages across the population from younger to older. This is a part of the great demographic transition taking place across most of the world today, accompanying the rise in wealth and overall quality of life. As we do not yet have the means to control aging through medicine, it is the case that as the older fraction of the population grows, so too does the overall incidence of age-related disease and disability. The paper noted here is one of any number of views into the sizable amount of data on this phenomenon. As the authors' scenario 3 illustrates, just to keep up with the aging of the population, just to maintain the present rates of death and disability, would require sizable improvements in the ability of medical services to extend healthy life span.
We used health-adjusted life expectancy (HALE) to measure quality of life and disability-adjusted life years (DALY) to quantify the burden of disease for the population of Guangzhou. Changes in HALE and DALY between 2010-2020 and 2020-2030 were decomposed to isolate the effects of population aging. Three scenarios were analyzed to examine the relative relationship between disease burden and population aging. In Scenarios 1 and 2, the disease burden rates in 2030 were assumed to either remain at 2020 levels or follow historical trends. In Scenario 3, it was assumed that the absolute numbers of years of life lost (YLL) and years lived with disability (YLD) in 2030 would remain unchanged from the 2020 levels.
Between 2010 and 2020, 56.24% [69.73%] of the increase in male [female, values in brackets] HALE was attributable to the mortality effects in the population aged 60 and over, while -3.74% [-9.29%] was attributable to the disability effects. The increase in DALY caused by changes in age structure accounted for 72.01% [46.68%] of the total increase in DALY. From 2020 to 2030, 61.43% [69.05%] of the increase in HALE is projected to result from the mortality effects in the population aged 60 and over, while -3.88% [4.73%] will be attributable to the disability effects.
The increase in DALY due to changes in age structure is expected to account for 102.93% [100.99%] of the total increase in DALY. In Scenario 1, YLL are projected to increase by 45.0% [54.7%], and YLD by 31.8% [33.8%], compared to 2020. In Scenario 2, YLL in 2030 is expected to decrease by -2.9% [-1.3%], while YLD will increase by 12.7% [14.7%] compared to 2020. In Scenario 3, the expected YLL rates and YLD rates in 2030 would need to be reduced by 15.3% [15.4%] and 15.4% [15.6%], respectively, compared to 2020.
GATA4 in Mesenchymal Stem Cell Senescence
https://www.fightaging.org/archives/2025/01/gata4-in-mesenchymal-stem-cell-senescence/
In recent years, the level of GATA4 expression has been connected to a variety of age-related issues, such as scarring in heart tissue. More generally GATA4 is associated with cellular senescence, a major issue in aging. Senescent cells accumulate with age to disrupt tissue structure and function via pro-inflammatory signaling. Additionally, senescence in specific cell populations, such as stem cells, impairs the ability of these cells to support and maintain tissues. In this context, researchers here review what is known of the role of GATA4 in the senescence of mesenchymal stem cells specifically.
The Mesenchymal Stem Cell (MSC) is a multipotent progenitor cell with known differentiation potential towards various cell lineages, making it an appealing candidate for regenerative medicine. One major contributing factor to age-related MSC dysfunction is cellular senescence, which is the hallmark of relatively irreversible growth arrest and changes in functional properties. GATA4, a zinc-finger transcription factor, emerges as a critical regulator in MSC biology. Originally identified as a key regulator of heart development and specification, GATA4 has since been connected to several aspects of cellular processes, including stem cell proliferation and differentiation.
Accumulating evidence suggests that the involvement of GATA4-nuclear signalizing in the process of MSC senescence-related traits may contribute to age-induced alterations in MSC behavior. GATA4 emerged as the central player in MSC senescence, interacting with several signaling pathways. Studies have shown that GATA4 expression is reduced with age in MSCs, which is associated with increased expression levels of senescence markers and impaired regenerative potential. At the mechanistic level, GATA4 regulates the expression of genes involved in cell cycle regulation, DNA repair, and oxidative stress response, thereby influencing the senescence phenotype in MSCs.
The findings underscore the critical function of GATA4 in MSC homeostasis and suggest a promising new target to restore stem cell function during aging and disease. A better understanding of the molecular mechanisms that underlie GATA4 mediated modulation of MSC senescence would provide an opportunity to develop new therapies to revitalize old MSCs to increase their regenerative function for therapeutic purposes in regenerative medicine.
Further Investigating the Biochemistry of Natural Killer Cell Surveillance of Senescent Cells
https://www.fightaging.org/archives/2025/01/further-investigating-the-biochemistry-of-natural-killer-cell-surveillance-of-senescent-cells/
Senescent cells accumulate with age in part because the immune system becomes less able to clear senescent cells in a timely manner. Researchers have much yet to discover regarding the details of this decline, but some of the existing discoveries seem analogous to the ways in which cancer cells can shield themselves from the immune system via altered surface features. Such discoveries pave the way for the development of ways to restore at least some of the lost competence of the aged immune system, encouraging it to better destroy senescent cells. Here, the focus is on natural killer cells, now well known to be involved in clearance of senescent cells and the target of a number of research programs in this context.
Induction of senescence by chemotherapeutic agents arrests cancer cells and activates immune surveillance responses to contribute to therapy outcomes. In this investigation, we searched for ways to enhance the natural killer (NK)-mediated elimination of senescent cells. We used a staggered screen approach, first identifying siRNAs potentiating the secretion of immunomodulatory cytokines to later test for their ability to enhance NK-mediated killing of senescent cells.
We identified that genetic or pharmacological inhibition of SMARCA4 enhanced senescent cell elimination by NK cells. SMARCA4 expression is elevated during senescence and its inhibition derepresses repetitive elements, inducing the senescence-associated secretory phenotype (SASP) via activation of cGAS/STING and MAVS/MDA5 pathways. Moreover, a PROTAC targeting SMARCA4 synergized with cisplatin to increase the infiltration of CD8 T cells and mature, activated NK cells in an immunocompetent model of ovarian cancer. Our results indicate that SMARCA4 inhibitors enhance NK-mediated surveillance of senescent cells and may represent senotherapeutic interventions for ovarian cancer.
Mincle Provokes Inflammation in Response to Microbes Leaking from the Aged Intestine
https://www.fightaging.org/archives/2025/01/mincle-provokes-inflammation-in-response-to-microbes-leaking-from-the-aged-intestine/
The aged intestinal wall exhibits an impaired mucosal barrier, leading to leakage of microbes from the intestines into tissues and circulatory system. This is known to provoke chronic inflammation, which in turn is disruptive to tissue function and contributes to the onset and progression of age-related conditions. Here, researchers identify one specific mechanism by which intestinal microbes can provoke the immune system into a maladaptive inflammatory response. Suppressing that response sounds like a worse option than preventing intestinal barrier dysfunction, as it would likely have negative consequences for immune function considered more broadly. Nonetheless, suppression of specific signaling remains the dominant approach to inflammatory conditions, even given side effects of this nature.
A new study shows how an increase in intestinal permeability allows the natural gut bacteria to cross the intestinal barrier and reach the bone marrow, where they induce epigenetic changes in the stem cells that give rise to immune cells. The epigenetic changes induced by the translocated gut bacteria generate "trained" immune cells primed to respond more efficiently to future infections. However, this same ability to amplify the immune response can also aggravate the inflammatory conditions such as cardiovascular and neurodegenerative diseases.
Until very recently, scientists believed that adaptive immunity was the only type with memory, able to generate cells that 'remember' previous encounters with pathogens and unleash a specific immune response. In contrast, the innate immune response, which is not specific to a particular pathogen, was believed to lack memory. "We now know that innate immunity can be 'trained' to produce a stronger response to later, unrelated infections. What is more, the effects of this training are long-lasting. The main intestinal bacteria we find in the bone marrow is Enterococcus faecalis. These bacteria interact with and activate the pattern recognition receptor Mincle in hematopoietic precursors, inducing epigenetic changes that generate immune cells with an augmented inflammatory capacity."
In animal models, increased intestinal permeability causes colonic inflammation (colitis). This inflammatory reaction does not occur in mice engineered to lack Mincle, suggesting that the detection of translocated bacteria by Mincle plays an important role in the inflammation associated with trained immunity. Strategies aimed at blocking Mincle could thus be protective in the context of these systemic inflammatory diseases.
Arginase II Deficiency Slows Muscle Aging in Mice
https://www.fightaging.org/archives/2025/01/arginase-ii-deficiency-slows-muscle-aging-in-mice/
Researchers here demonstrate that the increased level of arginase II observed with advancing age is causing some degree of issues, using mice from a lineage in which arginase II was removed by genetic engineering. Mice lacking arginase II exhibit slowed loss of muscle mass with age, and a lower burden of cellular senescence. Given what is known of arginase II, reduced cellular senescence and inflammatory signaling seem likely to be the important mediating mechanisms, but there are other possibilities to consider. Perhaps the more interesting point is that removing arginase II isn't evidently problematic, only beneficial.
Age-associated sarcopenia decreases mobility and is promoted by cell senescence, inflammation, and fibrosis. The mitochondrial enzyme arginase-II (Arg-II) plays a causal role in aging and age-associated diseases. Therefore, we aim to explore the role of Arg-II in age-associated decline of physical activity and skeletal muscle aging in a mouse model. Young (4-6 months) and old (20-24 months) wild-type (wt) mice and mice deficient in arg-ii (arg-ii-/-) of both sexes are investigated. We demonstrate a decreased physical performance of old wt mice, which is partially prevented in arg-ii-/- animals, particularly in males.
The improved phenotype of arg-ii-/- mice in aging is associated with reduced sarcopenia, cellular senescence, inflammation, and fibrosis, whereas age-associated decline of microvascular endothelial cell density, satellite cell numbers, and muscle fiber types in skeletal muscle is prevented in arg-ii-/- mice. Finally, we demonstrate an increased arg-ii gene expression level in aging skeletal muscle and found Arg-II protein expression in endothelial cells and fibroblasts, but not in skeletal muscle fibers, macrophages, and satellite cells. Our results suggest that increased Arg-II in non-skeletal muscle cells promotes age-associated sarcopenia, particularly in male mice.
Reviewing What is Known of Exerkines
https://www.fightaging.org/archives/2025/01/reviewing-what-is-known-of-exerkines/
An exerkine is a signaling molecule secreted in response to exercise. Classifying signaling in this way is a fairly recent development, and so mapping the space of exerkines is an ongoing exercise. Myokines, signal molecules released by muscle, are another recently established category, and there is some overlap between exerkines and myokines. Exerkines are a broader category, and might in principle be produced in any tissue in response to exercise. Evidently regular exercise is beneficial, and the goal of exerkine research is to better understand how those benefits are produced, potentially with the goal of producing exercise mimetic drugs.
Exerkines are bioactive molecules released by various tissues in response to exercise and are essential mediators in the anti-aging effects of physical activity. Initially, it was believed that exerkines were primarily produced by skeletal muscle, but recent studies have shown that multiple organs, including the liver, adipose tissue, bone, and the nervous system, also secrete these molecules. These exerkines not only act locally but also exert systemic effects across the body, regulating metabolic processes, reducing inflammation, supporting tissue repair, and maintaining cognitive function.
The release of exerkines is a highly coordinated process that involves multiple tissues and organs. These exerkines function in a synergistic manner to combat the cellular and molecular changes associated with aging, such as oxidative stress, inflammation, mitochondrial dysfunction, and tissue degeneration. By enhancing the production of these molecules, regular exercise creates an environment that promotes tissue maintenance, metabolic balance, cardiovascular health, and cognitive resilience. This highlights the central role of exerkines in the anti-aging benefits of exercise, as they help to preserve functional capacity and overall health as we age.
Exercise promotes the release of exerkines such as IGF-1, GPLD1, BDNF, clusterin, and PF4, leading to enhanced synaptic plasticity, improved neuroprotection, and reduced neuroinflammation. The upregulation of PGC-1α in response to exercise contributes to cardiomyocyte hypertrophy, increased proliferation, and anti-apoptotic effects, which support overall cardiac health and longevity. Exercise decreases hepatic steatosis and modulates the inflammatory response via the increased secretion of IL-10 and irisin, reducing liver inflammation and improving metabolic homeostasis. Exerkines like FGF-21 and apelin stimulate lipid oxidation, decrease fat mass, and promote the browning of adipose tissue, contributing to improved metabolic function and fat utilization. NOX4 and HSP90 are upregulated during exercise, improving muscular contractility, and enhancing the antioxidant capacity of mitochondria, thereby reducing oxidative stress.
A Novel Way to Interfere in NF-κB Signaling to Reduce Inflammation in the Brain
https://www.fightaging.org/archives/2025/01/a-novel-way-to-interfere-in-nf-%ce%bab-signaling-to-reduce-inflammation-in-the-brain/
NF-κB is important in inflammatory signaling, and one of many possible targets for suppression of inflammation. The usual caveats apply, in that unwanted, harmful, chronic inflammation uses the same signaling pathways as normal, necessary, short-term inflammatory responses to pathogens and injury. Researchers have yet to find a suppression approach that only affects chronic inflammation, and does not also suppress beneficial functions of the immune system. In principle the only reliable way to achieve that goal is to remove the damage of aging that causes inflammation, which is not presently the primary focus of researchers concerned with inflammation.
Neuroinflammation, a significant contributor to various neurodegenerative diseases, is strongly associated with the aging process; however, to date, no efficacious treatments for neuroinflammation have been developed. In aged mouse brains, the number of infiltrating immune cells increases, and the key transcription factor associated with increased chemokine levels is nuclear factor kappa B (NF-κB). Exosomes are potent therapeutics or drug delivery vehicles for various materials, including proteins and regulatory genes, to target cells.
In the present study, we evaluated the therapeutic efficacy of exosomes loaded with a nondegradable form of IκB (Exo-srIκB), which inhibits the nuclear translocation of NF-κB to suppress age-related neuroinflammation. Single-cell RNA sequencing revealed that these anti-inflammatory exosomes targeted macrophages and microglia, reducing the expression of inflammation-related genes. Treatment with Exo-srIκB also suppressed the interactions between macrophages/microglia and T cells and B cells in the aged brain. We demonstrated that Exo-srIκB successfully alleviates neuroinflammation by primarily targeting activated macrophages and partially modulating the functions of age-related interferon-responsive microglia in the brain.
Thus, our findings highlight Exo-srIκB as a potential therapeutic agent for treating age-related neuroinflammation.
Targeting the Behavior of Astrocytes in the Treatment of Neurodegenerative Conditions
https://www.fightaging.org/archives/2025/01/targeting-the-behavior-of-astrocytes-in-the-treatment-of-neurodegenerative-conditions/
There is a growing appreciation for the contribution of supporting cells in the brain to the progression of neurodegenerative conditions. Astrocytes perform a diverse range of functions in the brain, but can undergo maladaptive changes in behavior in response to the damage of aging and disease, making things worse. These reactive astrocytes are in some ways analogous to senescent cells, in that they provoke inflammation but are also involved in repair of injury and remodeling of tissue. As is the case for senescent cells, too much of this tips over from being helpful to being harmful to surrounding tissues.
For over a century after their discovery astrocytes were regarded merely as cells located among other brain cells to hold and give support to neurons. Astrocytes activation, "astrocytosis", was considered a detrimental mechanism against neuronal survival. Recently, the scientific view on astrocytes has changed. Accumulating evidence indicate that astrocytes are not homogeneous, but rather encompass heterogeneous subpopulations of cells that differ from each other in terms of transcriptomics, molecular signature, function, and response in physiological and pathological conditions. In this review, we report and discuss the recent literature on the phenomic differences of astrocytes in health and their modifications in disease conditions, focusing mainly on the hippocampus, a region involved in learning and memory encoding, in the age-related memory impairments, and in Alzheimer's disease (AD) dementia.
The morphological and functional heterogeneity of astrocytes in different brain regions may be related to their different housekeeping functions. Astrocytes that express diverse transcriptomics and phenomics are present in strictly correlated brain regions and they are likely responsible for interactions essential for the formation of the specialized neural circuits that drive complex behaviors. In the contiguous and interconnected hippocampal areas CA1 and CA3, astrocytes show different, finely regulated, and region-specific heterogeneity. Heterogeneous astrocytes have specific activities in the healthy brain, and respond differently to physiological or pathological stimuli, such as inflammaging present in normal brain aging or beta-amyloid-dependent neuroinflammation typical of AD.
To become reactive, astrocytes undergo transcriptional, functional, and morphological changes that transform them into cells with different properties and functions. Alterations of astrocytes affect the neurovascular unit, the blood-brain barrier, and reverberate to other brain cell populations, favoring or dysregulating their activities. It will be of great interest to understand whether the differential phenomics of astrocytes in health and disease can explain the diverse vulnerability of the hippocampal areas to aging or to different damaging insults, in order to find new astrocyte-targeted therapies that might prevent or treat neurodegenerative disorders.
An Epigenetic View of the Benefits of Calorie Restriction in Aged Rats
https://www.fightaging.org/archives/2025/01/an-epigenetic-view-of-the-benefits-of-calorie-restriction-in-aged-rats/
One way to look at the impact of aging versus the impact of an intervention to slow aging is to examine transcriptional changes in cells. Pick a tissue and cell type, assess the whole transcriptome of RNA molecules produced by that cell type, then compare old versus young animals and treated versus untreated old animals. Here, researchers compare the effects of aging in rat muscle versus the effects of calorie restriction, an intervention known to slow aging in mammals. As one might expect, calorie restriction reduces the magnitude of many of the changes in transcription that take place with age.
Age-related muscle wasting, sarcopenia is an extensive loss of muscle mass and strength with age and a major cause of disability and accidents in the elderly. Mechanisms purported to be involved in muscle ageing and sarcopenia are numerous but poorly understood, necessitating deeper study. Hence, we employed high-throughput RNA sequencing to survey the global changes in protein-coding gene expression occurring in skeletal muscle with age. Caloric restriction (CR) is a known prophylactic intervention against sarcopenia. Therefore, total RNA was isolated from the muscle tissue of both rats fed ad libitum and CR rats. RNA-seq data were subjected to Gene Ontology, pathway, co-expression, and interaction network analyses. This revealed the functional pathways most activated by both ageing and CR, as well as the key "hub" proteins involved in their activation.
RNA-seq revealed 442 protein-coding genes to be upregulated and 377 to be downregulated in aged muscle, compared to young muscle. Upregulated genes were commonly involved in protein folding and immune responses; meanwhile, downregulated genes were often related to developmental biology. CR was found to suppress 69.7% and rescue 57.8% of the genes found to be upregulated and downregulated in aged muscle, respectively. In addition, CR uniquely upregulated 291 and downregulated 304 protein-coding genes. This data may provide the initial evidence for several targets for potential future therapeutic interventions against sarcopenia.