Fight Aging! Newsletter, January 27th 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/
- Targeting the Mitochondrial Integrated Stress Response to Slow Aging
- Cyclarity Therapeutics to Start a First Human Trial for Clearance of 7-ketocholesterol
- An Age-Associated T-Cell Population Linked to Benign Prostate Hyperplasia
- Delivery of RANKL as a Basis for Regrowth of the Aged Thymus
- miR-302b Rejuvenates Mice by Allowing Senescent Cells to Replicate Once More
- Physical Activity Slows Age-Related Transcriptomic Changes in Brain Cells
- RNA Dysregulation in Neurodegenerative Conditions
- Mitochondrial Dysfunction and Ovarian Aging
- An Assessment of Inflammatory Regulators in Monocytes Demonstrates the Complexity of Immune Aging
- Hearing Impairment Correlates with Risk of Parkinson's Disease
- Senolytic Treatment Reduces Periodontal Bone Loss in Aged Mice
- Intermittent Fasting as a Treatment for Neurodegenerative Conditions
- The Hippo Signaling Pathway is Connected to Cellular Senescence
- A Snapshot of One Portion of the Ongoing Debate over Causes and Processes of Aging
- Immune Aging as a Driver of Brain Aging
Targeting the Mitochondrial Integrated Stress Response to Slow Aging
https://www.fightaging.org/archives/2025/01/targeting-the-mitochondrial-integrated-stress-response-to-slow-aging/
It is probably fair to say that the majority of work conducted to date on the treatment of aging as a medical condition has focused on mimicking and enhancing beneficial cellular responses to stresses such as lack of nutrients, heat, cold, toxins, and so forth. The bounds of the possible are illustrated by the results of regular exercise and the practice of calorie restriction. These interventions trigger all of the stress response mechanisms, so it seems unlikely that researchers will greatly improve on their performance with a therapy that targets only one of those mechanisms, or only one of the many regulators governing a given response mechanism. Both exercise and calorie restriction only slow the progression of aging, and are far removed from anything we might regard as a rejuvenation therapy capable of significant reversal of aging.
Autophagy is the most well studied of the cellular stress responses, the processes by which a cell recycles damaged structures. A number of drug development programs have aimed at increased autophagy as a means to improve aspects of health. An equally interesting set of mechanisms is covered in today's open access review paper, the integrated stress response that operates in mitochondria to produce outcomes that affect the behavior of the whole cell and its signaling to other cells. There are ways to manipulate this stress response to produce beneficial outcomes, some of which have produced life extension in mice approaching that of calorie restriction.
The mitochondrial integrated stress response: A novel approach to anti-aging and pro-longevity
Mitochondria play a pivotal role in cellular energy metabolism, primarily responsible for the production of most cellular adenosine triphosphate (ATP) through a process known as oxidative phosphorylation (OXPHOS). However, this significant burden also causes mitochondria to be under constant stress. Especially under the condition of aging, mitochondrial function deteriorates due to the accumulation of mtDNA mutations, the destabilization of respiratory chain complexes, and alterations in mitochondrial dynamics. Consequently, the mitochondrial quality control system, which is primarily comprised of proteases, can be initiated. Furthermore, mitochondrial stress can also trigger cellular nonautonomous factors that facilitate communication between organelles, thereby regulating gene expression, metabolic reprogramming, and organismal longevity. Collectively, these processes form the mitochondrial integrated stress response (ISRmt).
Current studies indicate that the activation of the ISRmt relies primarily on mitochondrial stressors. The mild or early stage of ISRmt may elicit an adaptive stress response that is conducive to well-being and longevity while postponing the onset of multiple mitochondrial disorders. Evidence from model organisms reveals that mutations that reduce the activity of the mitochondrial respiratory chain yield a mean adult lifespan increase ranging from 20% to 300% in C. elegans. A similar increase in longevity has been achieved by reducing the expression of electron transport chain (ETC) components through the use of RNA interference (RNAi). In mice, a reduction in ETC proteins, particularly complex I subunits, increases lifespan by approximately 30%. The improvements in mitochondrial function and oxidative metabolism are contingent upon the adaptive ISRmt. Therefore, this beneficial adaptive stress response, which is induced by the inhibition of OXPHOS complexes, the depletion of mtDNA, or the uncoupling of mitochondria, has the potential to antagonize age-related diseases and promote longevity in clinical settings.
However, it is of paramount importance to address the off-target effects and toxicity associated with chronic ISRmt activation, especially in clinical trials. In this paper, we put forward three suggestions. Firstly, the induction of ISRmt should be reversible, such as the use of ETC component inhibitors rather than gene mutations. Secondly, the therapeutic strategy targeting the ISRmt should focus on boosting endogenous adaptive factors including FGF21, GDF15, and MTHFD2. Finally, pharmacological modulation of the core elements of ISRmt (eIF2α phosphorylation) warrants greater consideration due to the highly variable metabolic phenotypes. In comparison to pharmacological methods, FGF21, and its analogs have been proven to be generally well tolerated in clinical trials. Metformin, the most widely applied ISRmt inducer, has been approved by the FDA for treating type 2 diabetes, indicating its potential for human application.
Cyclarity Therapeutics to Start a First Human Trial for Clearance of 7-ketocholesterol
https://www.fightaging.org/archives/2025/01/cyclarity-therapeutics-to-start-a-first-human-trial-for-clearance-of-7-ketocholesterol/
A quarter of humanity dies from heart attack and stroke, caused when an atherosclerotic plaque ruptures to create fragments that block an important blood vessel. Everyone develops atherosclerotic plaque to some degree with advancing age. Cholesterol is manufactured in the liver and transported in the bloodstream attached to forms of low density lipoprotein (LDL) particles. Excess cholesterol is ingested by macrophages and then attached to high density lipoprotein (HDL) particles for transport back to the liver and reuse. This is a complex system of many moving parts and regulators and sensors, and like all complex systems, it runs awry with the damage of aging or obesity. In particular, excess deposition of cholesterol into blood vessel walls starts to overwhelm the ability of macrophages to clean it up, and a fatty plaque begins to form to narrow and weaken that blood vessel.
That is a very high level description, but dive deeper and there is increasing complexity in the details. Other factors are involved, such as the state of chronic inflammation, making macrophages less able to undertake repair activities. Or the presence of oxidized cholesterols or oxidized LDL particles that are more disruptive than cholesterol and LDL, molecule for molecule. Or other mechanisms that can hamper macrophages, increase inflammatory reactions in blood vessels, or otherwise alter cholesterol transport for the worse, from the effects of hypertension on cells in blood vessel walls to the pro-inflammatory signaling of senescent cells to raised levels of lipoprotein (a).
To date, most approaches to the treatment of atherosclerosis have focused on lowering LDL cholesterol levels in the bloodstream. Unfortunately this only (a) slows plaque growth, (b) very slowly, over years, makes plaques a little less likely to rupture by reducing their lipid content. Lowering LDL cholesterol in the bloodstream cannot reliably or rapidly regress atherosclerotic plaque, and so a quarter of humanity continues to die from the consequences of having atherosclerotic plaque. There are a great many other targets that research and development programs might choose as a basis for therapy, however. The challenge, as ever in the matter of everything to do with aging, is that the only good way to find out whether a given approach works well is to try it. Determining just how important one mechanism is versus all the others can only really be determined by fixing that one problem in isolation and observing the results.
So far, all of the well-funded alternative approaches to lowering LDL cholesterol in the bloodstream have failed to demonstrate the ability to reliably and rapidly regress atherosclerotic plaque. Bitterroot Bio's CD47-based approach only slows plaque growth. The same goes for the Silence Therapeutics approach to lowering circulating lipoprotein (a). And so forth. Of the less well funded approaches that have made it out of the laboratory and into preclinical development in biotech companies, so far as I am aware only Repair Biotechnologies and VasoRx have mouse data showing significant plaque regression.
(To be clear, every boutique cardiovascular physician can roll out a few patients with amazing plaque reduction from whatever their special combination of lifestyle interventions, LDL-lowering therapies, and other treatments happens to be. The problem is that any degree of regression of atherosclerotic plaque isn't the reliable outcome for any of these approaches. The average for plaque regression is close to zero. New technologies, new approaches are needed).
Cyclarity Therapeutics is an interesting case. Like Repair Biotechnologies, this company emerged from the SENS community, though unlike Repair Biotechnologies the scientific program giving rise to the company was developed at the SENS Research Foundation. The company uses carefully designed cyclodextrins to sequester and clear 7-ketocholesterol, a toxic altered form of cholesterol that is suggested to be important in driving atherosclerosis by incapacitating the macrophages attempting to repair atherosclerotic plaque. There is no animal model that exhibits a human-like level of 7-ketocholesterol, however. It would be very costly in time and funding to produce and validate such a model, so the Cyclarity leadership chose to move directly into humans without the usual preclinical animal data to show effects on plaque - and fortunately found investors willing to fund that program. We can hope that clearing 7-ketocholesterol will be a way to reliably regress atherosclerotic plaque! Yet it may prove to be another way to only slow the growth of plaque. The only way to find out is to try it and see.
Cyclarity Therapeutics Secures Approval for First-in-Human Clinical Trial
Cyclarity Therapeutics is pleased to announce regulatory approval to begin its first-in-human clinical trial. The trial will be conducted at CMAX, one of Australia's leading clinical research centers, in partnership with Monash University. This effort will be led by Dr. Stephen Nicholls of the Victorian Heart Institute (VHI), a distinguished leader in cardiovascular medicine. In addition to a traditional single (SAD) and multiple ascending dose (MAD) phase 1 trial, the authorization includes an allowance to enroll 12 patients with Acute Coronary Syndrome (ACS) to assess the safety of UDP-003 in individuals with plaque buildup, as well as to explore anecdotal evidence of efficacy. This represents a critical first step in evaluating the potential impact of our therapy in a population with high unmet need.
Cyclarity Therapeutics: Our Science
Cyclarity aims to deliver simple and affordable therapies for cardiovascular disease and other chronic diseases of aging. Cyclarity's research has combined computational and synthetic chemistry programs to create custom-engineered cyclodextrins (polysaccharides with known industrial and pharmaceutical excipient uses) to capture, and remove from cells, oxidized cholesterol derivatives such as 7-ketocholesterol, which are broadly toxic molecules with no known biological function. Our Lead Product: UDP-003 is a first-in-class drug; a specially engineered cyclodextrin which will target and remove toxic oxidized cholesterol, a key driver of atherosclerosis, neurodegenerative diseases, and other chronic diseases. UDP-003 is designed to restore the cardiovascular self-repair function and reduce arterial plaque.
An Age-Associated T-Cell Population Linked to Benign Prostate Hyperplasia
https://www.fightaging.org/archives/2025/01/an-age-associated-t-cell-population-linked-to-benign-prostate-hyperplasia/
Benign prostate hyperplasia is a common aspect of aging in men, an enlargement of the prostate over time that occurs for underlying reasons that remain incompletely understood. Given too much enlargement the condition becomes far from benign, as it can interrupt the ability to urinate. It also appears to increase the risk of later prostate cancer. Empirically, various medications and lifestyle changes seem to help in some patients, but reliable prevention and reversal of the condition remains out of reach.
In today's preprint paper, researchers provide evidence linking a subpopulation of T cells that arises with age to the development of benign prostate hyperplasia, implying a link to immune aging. This is particularly interesting in the context that prior infection and inflammation of the prostate (known as prostatitis) has been shown to increase the risk of later benign prostate hyperplasia. This may also be tied in to the presence and activity of senescent cells present in the aged prostate, with the T cells encouraging greater bad behavior on the part of senescent cells.
Immune cell single-cell RNA sequencing analyses link an age-associated T cell subset to symptomatic benign prostatic hyperplasia
Benign prostatic hyperplasia (BPH) is among the most common age-associated diseases in men; however, the contribution of age-related changes in immune cells to BPH is not clear. The current study determined that an age-associated CD8+ T cell subset (Taa) with high Granzyme K (GZMKhi) and low Granzyme B (GZMBlow) gene expression infiltrate aged human prostates and positively correlate with International Prostate Symptom Score (IPSS).
A velocity analysis indicated that CD8+ T cell differentiation is altered in large BPH prostates compared to small age-matched prostates, favoring Taa accumulation. In vitro granzyme K treatment of human BPH patient-derived large prostate fibroblasts increased secretion of pro-inflammatory senescence-associated secretory phenotype (SASP)-associated cytokines. This data suggests that granzyme K-mediated stimulation of prostate stromal fibroblast SASP cytokine and chemokine production promotes prostate immune cell recruitment and activation. Overall, these results connect symptomatic BPH with immune aging.
Delivery of RANKL as a Basis for Regrowth of the Aged Thymus
https://www.fightaging.org/archives/2025/01/delivery-of-rankl-as-a-basis-for-regrowth-of-the-aged-thymus/
The thymus is a small organ, and the location in which thymocytes created in the bone marrow mature into T cells of the adaptive immune system. Unfortunately, the thymus atrophies steadily with advancing age. Active tissue is replaced with fat, reducing the supply of new T cells to a tiny fraction of what it was in early adult life. This process is a major factor in the aging of the immune system, leading over time to an adaptive immune system packed full of exhausted, senescent, malfunctioning T cells, the consequence of a lack of replacements.
A range of approaches are under development aimed at producing regrowth of the aged thymus, and consequent restoration of the adaptive immune system. In today's open access paper, researchers here comment on a novel approach to the regrowth of the aged, atrophied thymus. It involves delivery of RANKL, a transmembrane protein that also has a circulating form. RANKL appears necessary for sustained thymic function, and levels are reduced with age. It is likely that selective delivery of RANKL to only cells relevant to thymic function would be necessary in order to produce a viable therapy, however, as the protein is known to be involved in other processes throughout the body.
Rejuvenating the immune system
A recent study elucidates the role of the RANK-RANKL axis in the thymus during aging. The study demonstrates that decreased RANKL levels occur in thymocytes, leading to impaired cellularity and function of thymic epithelial cells (TECs) and endothelial cells (ECs), and subsequently to thymic involution. Their findings were recapitulated in young mice by neutralizing RANKL levels, while exogenous RANKL administration in aged mice restored thymic architecture, TEC and EC abundance, and their functional properties. Similarly, RANKL stimulated cellularity and maturation of epithelial and endothelial cells in human thymic organocultures. Moreover, RANKL treatment in aged mice improved T-cell progenitor homing to the thymus and boosted T-cell production. As an outcome, peripheral T-cell renewal and effective antitumor and vaccine responses were achieved.
In the aging thymus, apart from reduced key thymocyte subsets, diminished RANKL expression in these cells was also evident. The aging process is characterized by accumulation of DNA lesions, due to impaired efficiency of DNA repair networks with age as well as by epigenetic changes. Overall, these changes result in profound chromatin modifications reflected by global heterochromatin loss and redistribution. These events subsequently drive transcriptional changes that are anticipated to affect potent RANKL regulators such as hormones, cytokines, and signaling cascade components. As an example, histone demethylases influence lifespan by modulating components of cardinal longevity routes, such as the IGF-1 axis. IGF-1 induces RANKL and its levels are known to decrease with age, thus providing a possible explanation of low RANKL expression during thymic involution.
miR-302b Rejuvenates Mice by Allowing Senescent Cells to Replicate Once More
https://www.fightaging.org/archives/2025/01/mir-302b-rejuvenates-mice-by-allowing-senescent-cells-to-replicate-once-more/
Senescent cells accumulate with age, and contribute to the dysfunction of aging via their inflammatory secretions. A cell becomes senescent in response to reaching the Hayflick limit on replication, or in response to damage or stress. In the normal course of events, a senescent cell ceases replication, and this is an irreversible change. A few approaches have been demonstrated to reverse this aspect of the senescent state. The question is whether it is a good idea to do so. For example, senescent cells accumulate DNA damage on entry to the senescent state. Some senescent cells are senescent for good reason, such as potentially cancerous DNA damage. It has been thought that allowing these cells to replicate again is just asking for trouble.
Still, some researchers have explored reversal of senescence. In today's open access paper, quite compelling evidence is provided for reversal of senescence to be a good thing: the mice involved in the study live longer, show improved function, and suffer no increase in cancer incidence. This is quite fascinating, and certainly not what one might expect. One way to look at this is to theorize that most senescent cells present in an aged animal are not in fact senescent for any good reason, and that much of their DNA damage is innocuous or can be repaired on exiting the senescent state. Possibly, as seems to be the case for telomerase gene therapy, increased cancer risk due to enabling the activity of problem cells is outweighed by improvements in immune function and surveillance of those problem cells.
Exosomal miR-302b rejuvenates aging mice by reversing the proliferative arrest of senescent cells
Senescent cells (SnCs) accumulate during aging and secrete the senescence-associated secretory phenotype (SASP), promoting secondary senescence and disrupting normal tissue functions. Consequently, targeting SnCs has emerged as a promising strategy to prolong healthspan and delay the onset of age-related diseases. Therapies targeting SnCs are broadly divided into two major categories: elimination of SnCs (senolytic) and suppression of pathological SASP signaling (senomorphic). These strategies have shown therapeutic benefits in aging and related diseases, including extending lifespan, alleviating inflammation, and improving cognition. However, they also have certain limitations. While the senolytic strategy may effectively eliminate SnCs when scarce, the prevalence of SnCs in tissues increases as individuals age. Eliminating them may result in considerable tissue damage and compromise normal organ function. Moreover, although SASP suppression has rejuvenating effects, it can impede immune surveillance of pathogens and cancer cells. Developing new rejuvenation strategies that target SnCs is crucial to address these challenges.
In this study, we demonstrated that human embryonic stem cell-derived exosomes (hESC-Exos) reversed senescence by restoring the proliferative capacity of SnCs in vitro. In aging mice, hESC-Exos treatment remodeled the proliferative landscape of SnCs, leading to rejuvenation, as evidenced by extended lifespan, improved physical performance, and reduced aging markers. Analysis identified miR-302b enriched in hESC-Exos that specifically targeted the cell cycle inhibitors Cdkn1a and Ccng2. Furthermore, miR-302b treatment reversed the proliferative arrest of SnCs in vivo, resulting in rejuvenation without safety concerns over a 24-month observation period. These findings demonstrate that exosomal miR-302b has the potential to reverse cellular senescence, offering a promising approach to mitigate senescence-related pathologies and aging.
Physical Activity Slows Age-Related Transcriptomic Changes in Brain Cells
https://www.fightaging.org/archives/2025/01/physical-activity-slows-age-related-transcriptomic-changes-in-brain-cells/
One of the benefits of physical fitness and the physical activity required to sustain that fitness is a slower aging of the brain. Human data provides only correlational data, but animal studies have demonstrated causation in the improved health and slowed aspects of aging resulting from exercise. Researchers here delve into the biochemistry of aging in brain and body cells, finding a great deal more downregulation of gene expression in the brain than elsewhere in the body with aging, and that physical exercise can reduce the extent of those changes.
It is been noted that the expression levels of numerous genes undergo changes as individuals age, and aging stands as a primary factor contributing to age-related diseases. In this study, we screened for aging genes using RNAseq data of 32 human tissues from the Genotype-Tissue Expression (GTEx) project. RNAseq datasets from the Gene Expression Omnibus (GEO) were used to study whether aging genes drives age-related diseases, or whether anti-aging solutions could reverse aging gene expression.
Aging transcriptome alterations showed that brain aging differ significantly from the rest of the body, furthermore, brain tissues were divided into four group according to their aging transcriptome alterations. Numerous genes were downregulated during brain aging versus body tissue aging, with functions enriched in synaptic function, ubiquitination, mitochondrial translation, and autophagy.
Transcriptome analysis of age-related diseases and retarding aging solutions showed that downregulated aging genes in the hippocampus underwent further downregulation in Alzheimer's disease but this downregylation was effectively reversed by high physical activity. Furthermore, the neuron loss observed during aging was reversed by high physical activity.
RNA Dysregulation in Neurodegenerative Conditions
https://www.fightaging.org/archives/2025/01/rna-dysregulation-in-neurodegenerative-conditions/
The assembly, processing, and activities of RNA molecules in the cell is a vast topic, even if narrowed to just one part of the body. A short paper can really only briefly summarize the primary areas of interest for researchers involved in the study of neurodegenerative conditions, as is the case here. Transcription of genes to produce RNA molecules is the first step in gene expression, and sweeping changes in gene expression take place with age. A cell is a state machine, its state largely determined by which RNAs and proteins are produced, and in what amount, at any given time. The state of cells determines the function of tissues. Even just the RNA portion of this picture is an enormously complex, incompletely understood soup of molecular interactions.
Neurodegenerative diseases are prevalent age-related diseases. As of 2024, approximately 6.9 million Americans are affected by Alzheimer's disease (AD), making it the most common neurodegenerative disease, followed by Parkinson's disease (PD). There are also many less prevalent or rare neurodegenerative diseases such as Huntington's disease (HD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). Though the clinical symptoms of these diseases vary, multiple neurodegenerative diseases share similar underlying pathological mechanisms. The presence of pathological inclusions and causative mutations of RNA-binding proteins (RBPs) is increasingly observed among neurodegenerative diseases. In addition, pathological repeat expansion in multiple diseases, such as ALS, FTD, HD and various types of spinocerebellar ataxia, yields repeat-containing RNAs that could cause neurotoxicity via various mechanisms.
In the post-genomic era, a variety of RNA processing pathways and emerging types of coding and noncoding RNAs have been commonly identified in the disease context, with potential contributions to neurodegeneration. Therapeutic strategies targeting RNA to modulate disease-linked genes have achieved significant success. Here, we focus on RNA-related pathogenic mechanisms in neurodegenerative diseases and updates on RNA-targeting therapeutic approaches that hold great promise. We start with the various RNA processing pathways and provide representative examples of how these pathways are dysregulated in neurodegenerative diseases. Next, we discuss the mechanisms that lead to RBP dysfunction, resulting in dysregulation of RNA processing. Finally, we review the current progress in RNA-targeting therapeutics. The different RNA processing pathways are often interconnected, and most RBPs have multifunctional roles across several RNA processing steps, creating significant interplay among them.
Mitochondrial Dysfunction and Ovarian Aging
https://www.fightaging.org/archives/2025/01/mitochondrial-dysfunction-and-ovarian-aging/
The ovaries exhibit significant age-related loss of function somewhat ahead of the rest of the body. Why is this the case? There is no good answer at present as to why the underlying mechanisms of aging produce a faster decline in the ovaries. The ability to compare the biochemistry of aging in the ovaries with the biochemistry of aging in the rest of the body may be an opportunity to learn something about aging more generally, however. So one sees papers such as this one, in which researchers review what is known of the mitochondrial dysfunction associated with aging specifically in the ovaries versus its role in aging elsewhere in the body.
Ovarian aging is a major health concern for women. Ovarian aging is associated with reduced health span and longevity. Mitochondrial dysfunction is one of the hallmarks of ovarian aging. In addition to providing oocytes with optimal energy, the mitochondria provide a co-substrate that drives epigenetic processes. Studies show epigenetic alterations, both nuclear and mitochondrial contribute to ovarian aging. Both, nuclear and mitochondrial genomes cross-talk with each other, resulting in two ways orchestrated anterograde and retrograde response that involves epigenetic changes in nuclear and mitochondrial compartments.
Epigenetic alterations causing changes in metabolism impact ovarian function. Key mitochondrial co-substrate includes acetyl CoA, NAD+, ATP, and α-ketoglutarate. Thus, enhancing mitochondrial function in aging ovaries may preserve ovarian function and can lead to ovarian longevity and reproductive and better health outcomes in women. This article describes the role of mitochondria-led epigenetics involved in ovarian aging and discusses strategies to restore epigenetic reprogramming in oocytes by preserving, protecting, or promoting mitochondrial function.
An Assessment of Inflammatory Regulators in Monocytes Demonstrates the Complexity of Immune Aging
https://www.fightaging.org/archives/2025/01/an-assessment-of-inflammatory-regulators-in-monocytes-demonstrates-the-complexity-of-immune-aging/
At the high level, we can say that the immune system becomes less capable and more inflammatory with age. The immune system is very complex, however, and so the details of its age-related decline are also very complex. There are countless different populations of cells with distinct behaviors and gene expression profiles, even within a clearly demarcated cell type, such as T cells or circulating monocytes. These various populations interact with one another and tissues and molecules outside cells to generate the overall character of the immune response. As is the case for all of the aging of biological systems, establishing the specifics of cause and effect is challenging.
Aging profoundly affects the immune system leading to an increased propensity for inflammation. Age-related dysregulation of immune cells is implicated in the development and progression of numerous age-related diseases such as: cardiovascular diseases, neurodegenerative disorders, and metabolic syndromes. Monocytes and monocyte-derived macrophages, being important players in the inflammatory response, significantly influence the aging process and the associated increase in inflammatory disease risk. Ischemic stroke is among age-related diseases where inflammation, particularly monocyte-derived macrophages, plays an important deteriorating role but could also strongly promote post-stroke recovery. Also, biological sex influences the incidence, presentation, and outcomes of ischemic stroke, reflecting both biological differences between men and women.
Here, we studied whether human peripheral blood monocyte subtype (classical, intermediate, and non-classical) expression of genes implicated in stroke-related inflammation and post-stroke tissue regeneration depends on age and sex. A flow cytometry analysis of blood samples from 44 healthy volunteers (male and female, aged 28 to 98) showed that in contrast to other immune cells, the proportion of natural killer cells increased in females. The proportion of B-cells decreased in both sexes with age.
Gene expression analysis by qPCR identified several genes differentially correlating with age and sex within different monocyte subtypes. Interestingly, ANXA1 and CD36 showed a consistent increase with aging in all monocytes, specifically in intermediate (CD36) and intermediate and non-classical (ANXA1) subtypes. Other genes (IL-1β, S100A8, TNFα, CD64, CD33, TGFβ1, TLR8, CD91) were differentially changed in monocyte subtypes with increasing age. Most age-dependent gene changes were differentially expressed in female monocytes. Our data shed light on the nuanced interplay of age and sex in shaping the expression of inflammation- and regeneration-related genes within distinct monocyte subtypes.
Hearing Impairment Correlates with Risk of Parkinson's Disease
https://www.fightaging.org/archives/2025/01/hearing-impairment-correlates-with-risk-of-parkinsons-disease/
Hearing loss has been correlated with the risk of numerous forms of neurodegenerative condition. There are many studies similar to the one noted here, correlating degree of hearing loss with risk of Parkinson's disease. While it seems to be the case that hearing loss can accelerate degeneration in the brain, a consequence of reduced input and brain activity in some areas, it is also the case that both hearing loss and neurodegenerative conditions arise from the same underlying forms of cell and tissue damage that drive aging more generally.
Hearing impairment is implicated as a risk factor for Parkinson's disease (Parkinson's) incidence, with evidence suggesting that clinically diagnosed hearing loss increases Parkinson's risk 1.5-1.6 fold over 2-5 years follow up. However, the evidence is not unanimous with additional studies observing that self-reported hearing capabilities do not significantly influence Parkinson's incidence. Thus, additional cohort analyses that draw on alternative auditory measures are required to further corroborate the link between Parkinson's and hearing impairment.
This was a pre-registered prospective cohort study using data from the UK Biobank. Data pertaining to 159,395 individuals, who underwent speech-in-noise testing via the Digit Triplet Test, DTT, and were free from Parkinson's at the point of assessment, were analysed. A Cox Proportional Hazard model, controlling for age, sex and educational attainment was conducted. During a median follow up of 14.24 years, 810 cases of probable Parkinson's were observed. The risk of incident Parkinson's increased with baseline hearing impairment [hazard ratio: 1.57], indicating 57% increase in risk for every 10dB increase in speech-reception threshold (SRT). However, when hearing impairment was categorised in accordance with UK Biobank SRT norms neither 'Insufficient' nor 'Poor' hearing significantly influenced Parkinson's risk compared to 'Normal' hearing.
In conclusion, the congruence of these findings with prior research further supports the existence of a relationship between hearing impairment and Parkinson's incidence.
Senolytic Treatment Reduces Periodontal Bone Loss in Aged Mice
https://www.fightaging.org/archives/2025/01/senolytic-treatment-reduces-periodontal-bone-loss-in-aged-mice/
Senescent cells accumulate with age in tissues throughout the body, and their pro-inflammatory signaling becomes increasingly disruptive to tissue structure and function. Studies suggest that senescent cells contribute meaningfully to near all age-related conditions. Selective clearance of senescent cells has produced sometimes quite impressive regression of age-related disease in animal models. One more example of this sort of research is presented here, in which researchers show that senolytic treatment to reduce the burden of cellular senescence in aged mice reduces the negative impact of periodontal disease, such as bone loss.
Cellular senescence has emerged as one of the central hallmarks of aging and drivers of chronic comorbidities, including periodontal diseases. Senescence can also occur in younger tissues and instigate metabolic alterations and dysfunction, culminating in accelerated aging and pathological consequences. Senotherapeutics, such as the combination of dasatinib and quercetin (DQ), are being increasingly used to improve the clinical outcomes of chronic disorders and promote a healthy life span through the reduction of senescent cell burden and senescence-associated secretory phenotype (SASP). Recent evidence suggests that senescent cells and SASP can contribute to the pathogenesis of periodontal diseases as well.
In this study, we investigated the effect of DQ interventions on periodontal tissue health using preclinical models of aging. In vitro, DQ ameliorated biological signatures of senescence in human gingival keratinocytes upon persistent exposure to periodontal bacteria, Fusobacterium nucleatum, by modulating the levels of key senescence markers such as p16, SA-β-galactosidase, and lamin-B1, and inflammatory mediators associated with SASP including interleukin-8, matrix metalloproteinase (MMP)-1, and MMP-3. In vivo, the oral administration of DQ mitigated senescent cell burden and SASP in gingival tissues and reduced naturally progressing periodontal bone loss in aged mice. Collectively, our findings provide proof-of-concept evidence for translational studies and reveal that targeting gingival senescence and the senescence-associated secretome can be an effective strategy to improve periodontal health, particularly in vulnerable populations.
Intermittent Fasting as a Treatment for Neurodegenerative Conditions
https://www.fightaging.org/archives/2025/01/intermittent-fasting-as-a-treatment-for-neurodegenerative-conditions/
Forms of calorie restriction and fasting tend to reduce the chronic inflammation characteristic of aging, and also produce numerous other beneficial alterations to the operation of metabolism. In the case of inflammatory age-related diseases, such as neurodegenerative conditions, a body of work exists to suggest that some benefit can be obtained via these lifestyle interventions. As pointed out here, the human data on the effects of calorie restriction and fasting on the progression of neurodegenerative conditions is far from rigorous and extensive enough to keep scientists happy, however.
Interest has grown in intermittent fasting (IF) as a potential lifestyle intervention for promoting brain health and slowing cognitive decline. IF has been shown to increase levels of circulating ketones to higher levels than caloric restriction (CR), supporting its potential for neuroprotection. As more research emerges, the question is whether IF can be integrated into existing lifestyle recommendations to further support cognitive function in the face of decline. The objective of this review is to discuss IF as it relates to neuroplasticity, inflammation, and neurocognitive disorders. Rather than examining IF as a preventive strategy, this paper evaluates its potential as a therapeutic approach to mitigate existing symptoms and improve brain function in the context of early to advanced neurocognitive disorders.
Preclinical evidence demonstrates that IF enhances hippocampal neurogenesis and synaptic plasticity through pathways involving BDNF and CREB. IF also reduces neuroinflammation, as shown in animal models of Alzheimer's disease, vascular cognitive impairment, and high-fat diet-induced cognitive impairment. Human studies, though limited, suggest that regular IF may improve cognitive function and reduce markers of oxidative stress and inflammation in individuals with mild cognitive impairment. Further clinical research is necessary to confirm long-term safety and efficacy and to refine IF protocols for broader clinical application.
The Hippo Signaling Pathway is Connected to Cellular Senescence
https://www.fightaging.org/archives/2025/01/the-hippo-signaling-pathway-is-connected-to-cellular-senescence/
Researchers have investigated inhibition of the Hippo pathway as a potential basis for regenerative therapies. Meanwhile some of the factors connected to Hippo, such as YAP and TAZ, have been connected to regulation of cellular senescence. This review outlines more of bigger picture of the relationship between Hippo signaling and cellular senescence, an important contribution to degenerative aging.
The Hippo pathway, a kinase cascade, coordinates with many intracellular signals and mediates the regulation of the activities of various downstream transcription factors and their coactivators to maintain homeostasis. Therefore, the aberrant activation of the Hippo pathway and its associated molecules imposes significant stress on tissues and cells, leading to cancer, immune disorders, and a number of diseases.
Cellular senescence, the mechanism by which cells counteract stress, prevents cells from unnecessary damage and leads to sustained cell cycle arrest. It acts as a powerful defense mechanism against normal organ development and aging-related diseases. On the other hand, the accumulation of senescent cells without their proper removal contributes to the development or worsening of cancer and age-related diseases.
A correlation was recently reported between the Hippo pathway and cellular senescence, which preserves tissue homeostasis. This review is the first to describe the close relationship between aging and the Hippo pathway, and provides insights into the mechanisms of aging and the development of age-related diseases. In addition, it describes advanced findings that may lead to the development of tissue regeneration therapies and drugs targeting rejuvenation.
A Snapshot of One Portion of the Ongoing Debate over Causes and Processes of Aging
https://www.fightaging.org/archives/2025/01/a-snapshot-of-one-portion-of-the-ongoing-debate-over-causes-and-processes-of-aging/
A person dies, and there is the irresistible urge to draw a line under their life and summarize. So to Mikhail Blagosklonny and his contributions to the modern debate over the causes of aging. Hyperfunction theory doesn't end with the originator, any more than any thread of scientific thought on the matter of aging - Robert Bradbury would no doubt be most interested to see where thought on the role of double stranded breaks in DNA as a mechanism of aging has ended up these days, were he still alive. Still, here we are, a chance to look back at one portion of the ongoing debate over programmed aging versus antagonistic pleiotropy, and the primacy versus secondary nature of molecular damage.
Blagosklonny directly engaged with Aubrey de Grey, a proponent of damage-based theories, in a 2021 exchange. Blagosklonny emphasized that hyperfunction, not damage accumulation, underpins aging, arguing that Hyperfunction Theory explains why damage accumulates - not from aging but as a downstream byproduct of hyperactive signaling: "Hyperfunction of signaling pathways can occur without progressive changes of their activity. For example, when the same activity of growth-promoting pathways remains unchanged in postdevelopment, it is a hyperfunction. By analogy, a car driving 65 mph on highway is not speeding (hyperfunction) but driving 65 mph on the driveway is. In the latter case, the car certainly will be damaged, but not by rusting (molecular damage), but by damage of its macroparts. Similarly, hyperfunction does not cause molecular damage, but causes organ damage. Thus, the brain is damaged by stroke, which can be a result of hypertension, which, in turn, is developed by hyperfunctional cells of multiple tissues. There is no place for molecular damage in this sequence of events..."
In his rebuttal, de Grey argued that while the Hyperfunction Theory offers valuable insights, damage repair remains essential for addressing aging: "While hyperfunction undoubtedly contributes to aging, it cannot fully explain the accumulation of oxidative and genetic damage that impairs cellular function." Blagosklonny further posited that while molecular damage accumulates, it does not necessarily constrain lifespan under typical conditions; however, if interventions extend lifespan significantly, such damage may become more limiting. This dialogue highlights the contrasting paradigms while reinforcing Blagosklonny's central assertion that aging interventions should prioritize targeting hyperfunction at its source.
Building on the Hyperfunction Theory, Blagosklonny proposed that targeting overactive growth pathways could mitigate aging and its associated diseases. This theoretical framework directly informs the exploration of rapamycin, an mTOR inhibitor, as a potential therapeutic agent. The Hyperfunction Theory, together with João Pedro de Magalhães' related developmental model has inspired the emergence of an expanding suite of programmatic theories, encompassing hypofunction, costly programs, constraint theory, and adaptive death.
Immune Aging as a Driver of Brain Aging
https://www.fightaging.org/archives/2025/01/immune-aging-as-a-driver-of-brain-aging/
The immune system isn't just a means to defend against pathogens and potentially cancerous cells. It is also intimately involved in tissue function and maintenance, in regeneration from damage, in clearing debris, and communicates at a distance throughout the body via a panoply of signaling molecules. Beyond these functions, which are affected by the age-related decline of the immune system, there is also the point that chronic inflammation changes cell behavior for the worse. A sizable part of the problem of immune aging is the rise of unresolved inflammatory signaling and its effects on tissues.
For decades, the general assumption was that the immune system had no impact on the healthy central nervous system (CNS) and was often regarded as exclusively harmful in the context of brain disorders. This understanding was largely based on the concept of "CNS immune privilege," supported by the presence of the blood-brain barrier (BBB) and the presumed absence of a lymphatic system in the CNS. More recently, a transformed understanding of brain-immune relationships has been established, which opened new avenues in the field of neuroscience, highlighting the fact that neurons require the assistance and tuning provided by the adaptive immune system in the form of novel communication routes between the two systems. According to this view, brain fitness depends on immune fitness, which in turn is modified by our lifestyle.
This intricate dance between the immune and the nervous systems takes part primarily at the brain's borders, where immune cells are concentrated. In aging, the function of these borders and the immune cell composition change, thereby altering the signals transmitted to the brain, negatively impacting brain function. This implies that the cognitive decline observed in aging is not caused solely by the decline in neural function but also by the age-dependent alterations in both the immune niches surrounding the brain and the peripheral immune system. Understanding this lifelong communication route and identifying those immune processes that become defective in aging could aid in developing potential strategies for immune system rejuvenation as a means to slow down or even arrest brain aging.