Fight Aging! Newsletter, January 13th 2025
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- Fasting Reduces Age-Related Hypertension in Rats
- Clearance of Microglia Produces Only a Transient Reduction in Amyloid in a Mouse Model of Alzheimer's Disease
- Relationships Between Atherosclerosis and Other Age-Related Conditions
- Number of Respiratory Cycles in a Lifetime is Fairly Consistent Across Species
- Senescent Cells Express GD3 to Evade Immune Clearance by Natural Killer Cells
- Age-Related Loss of Bone Density is Independent of the Gut Microbiome
- Harmfully Altered Mitochondrial Communication as a Consequence of Age-Related Mitochondrial Dysfunction
- Senolytics Targeting Lipofuscin as a Signature of Cellular Senescence
- Retinal Microvascular Abnormalities Correlate with Raised Risk of Mortality
- Forgetting Changes Little in Healthy Older People
- A Transcriptomic Map of Brain Aging in Mice
- Continued Discussion of Herpesvirus Infection as a Contributing Cause of Alzheimer's Disease
- The Nucleolus as a Factor in Age-Related Loss of Proteostasis
- HMGA1 Expression Promotes Heart Regeneration in Mammals
- Better Muscle Mitochondrial Function Correlates with Slower Brain Aging
Fasting Reduces Age-Related Hypertension in Rats
https://www.fightaging.org/archives/2025/01/fasting-reduces-age-related-hypertension-in-rats/
The raised blood pressure of age-related hypertension is an interesting problem because (a) it causes a great deal of downstream harm in the form of pressure damage to tissues and associated dysfunctions, (b) the mechanisms controlling blood pressure are actually quite well understood, and so (c) there are many different ways to reduce blood pressure without actually addressing the underlying cell and tissue damage that causes aging. Studies suggest that control of hypertension via present pharmaceutical approaches can sizeably reduce the risk of age-related disease.
Broadly speaking, blood pressure is determined by the combination of heart rate, constriction of blood vessels throughout the body, and regulation of water content of blood by the kidneys. Complex feedback loops of pressure sensing, blood sodium sensing, and downstream signaling juggle these processes to maintain blood pressure at a given level. Pharmaceuticals are used to block or upregulate portions of that signaling in order to induce reduced blood volume via greater uptake of water by the kidneys or lesser degrees of vessel constriction in order to expand the volume of the vascular system. Heart rate is not typically targeted in this context, for all of the obvious reasons.
In today's open access paper, researchers note that the use of calorie restriction as an intervention acts to reduce the increase of blood pressure in aged rats. It functions via the renin-angiotensin system of the kidney, a part of the regulatory systems that control the water content of blood and thus blood volume. Calorie restriction prevents some of the age-related disruption of this regulatory system, and thus removes some fraction of age-related hypertension.
Fasting recovers age-related hypertension in the rats: reset of renal renin-angiotensin system components and klotho
Aging is associated with imbalances in hormonal and metabolic processes that contribute to homeostasis and enable the organism to adapt to changes in its environment. One of the key control systems that changes during the aging process is the renin-angiotensin system (RAS), which is a critical control system that affects the regulation of blood pressure and sodium balance. During aging, RAS through over activation of AngII/Ang II type 1 receptor and overproduction of reactive oxygen species (ROS) and inflammatory responses acts as an accelerator in cell and organ senescence, and causes to hypertension, chronic kidney disease, atherosclerosis, and sarcopenia. On the other hand, the other parts of RAS, AngII/Ang II type 2 receptor and ACE2 (angiotensin converting enzyme 2)/ Ang (1-7)/Mas receptor, modulate the harmful effect of ACE/Ang II/AT1 receptor and play a positive impact in RAS balance and delay senescence. It seems that both local (tissue) and circulating RAS are involved in aging-related disease.
Several studies suggest the anti-aging effects of ACE-inhibitors and angiotensin receptor blockers (ARBs) in rodent models. Beneficial effects of RAS blockers on aging through increased klotho and sirtuin expression and activation of vitamin D signaling parallel the effects of calorie restriction (CR) in delaying aging. Evidence shows that fasting has a beneficial role on human health by improving various metabolic markers. Our recent findings revealed that the restoration of RAS equilibrium in both the aorta and heart may be a part of involving mechanisms of fasting benefits on its cardiovascular rejuvenation.
In this study, age-related changes in kidney RAS components were evaluated. Then, the effect of a 3-month period of two fasting regimes, fasting one day per week (FW) or fasting every other day (EOD) on the components of renal RAS and arterial blood pressure in three age groups of rats was investigated. The results showed that changes in the blood pressure and kidney-RAS system were not significant until middle age. However, senescence was correlated with a significant increase in blood pressure, decrease in the amount of AT2R protein of kidney, a significant rise in the AT1R / AT2R proteins ratio of kidney and plasma Ang II level, and a significant decrease in klotho plasma level in older rats contrast to young rats. On the other hand, EOD fasting reversed the aging effect on blood pressure and RAS, so that under EOD the mentioned parameters in old rats reduced to levels of young animals and also the ACE2 protein was significantly higher than young animals.
Clearance of Microglia Produces Only a Transient Reduction in Amyloid in a Mouse Model of Alzheimer's Disease
https://www.fightaging.org/archives/2025/01/clearance-of-microglia-produces-only-a-transient-reduction-in-amyloid-in-a-mouse-model-of-alzheimers-disease/
Microglia are innate immune cells of the central nervous system, analogous to macrophages elsewhere in the body, involved in tissue maintenance as well as defense against pathogens. Like macrophages, microglia adopt packages of behaviors called polarizations. The two of greatest interest are M1, inflammatory and hunting down pathogens and errant cells, versus M2, anti-inflammatory and engaging in tissue maintenance. An increase in inflammatory microglia, a maladaptive response of the innate immune system to molecular damage characteristic of aging, is thought to contribute to the aging of the brain.
There are a few ways to selectively destroy microglia, one of which is use of pexidartinib, PLX3397. This drug inhibits CSF1R activity, which causes microglia to die. The population of microglia then recovers within a few weeks after use of the drug ceases. The newly created microglia tend to exhibit fewer of the maladaptive traits of the old, cleared population, such as overly inflammatory behavior. This has allowed researchers to test microglial clearance as a basis for therapy in animal models of various neurodegenerative conditions. So far the results seem generally positive, but in today's open access paper, results in a mouse model of Alzheimer's disease are not as hoped for.
Partial microglial depletion and repopulation exert subtle but differential effects on amyloid pathology at different disease stages
Microglia are the resident innate immune cells of the central nervous system (CNS). They play a key role in neurodevelopment and plasticity, as well as in the pathogenesis of a wide array of neurodevelopmental and neurodegenerative disorders. In Alzheimer's disease (AD), genetic risk factors are disproportionately linked to immune receptors expressed by microglia, positioning these cells as important targets for disease-modifying therapies. However, in the chronic neuroinflammatory environment in AD, the role of microglia is complex. In fact, removal of microglia in AD mouse models via inhibition of colony-stimulating factor 1 receptor (CSF1R), which is critical for microglial survival and proliferation, reduced plaque formation when administered early but not during advanced amyloid pathology, which is more translationally relevant. Additionally, while some studies have shown that late loss of microglia improved learning and memory, and lessened neuronal loss, others demonstrated that it also increased plaque-associated neuritic damage.
Rather than removing microglia, renewing them through depletion followed by repopulation presents another exciting strategy. Adult microglia are capable of rapidly replenishing their niche within 1 week after removal of CSF1R inhibitor, restoring their morphology and physiological functions. In several injury models and in aging, repopulated microglia have been shown to be beneficial in promoting brain recovery and reversing age-related neuronal deficits. However, in the context of AD, we previously found no beneficial effects of microglial repopulation on either amyloid pathology nor cognitive function in aged transgenic mice harboring both amyloid and tau pathology. On the other hand, early microglia renewal was suggested to partially rescue cognitive deficits by restoring the microglial homeostatic phenotype.
Here, we sought to delineate the dynamic effects of microglial depletion followed by repopulation on microglia function and amyloid-β plaque burden during different stages of amyloid pathology. We administered the CSF1R inhibitor PLX3397 (hereafter referred to as PLX) in 5xFAD mice and tracked microglia-plaque dynamics with in vivo imaging. We revealed a transient improvement in plaque burden that occurred during either the depletion or repopulation period depending on the animal's age. Interestingly, while the improvement in plaque load did not persist long-term, repopulated microglia during mid-to-late pathology stages appeared to retain or increase their sensitivity to noradrenergic signaling, which is largely thought to be anti-inflammatory.
Relationships Between Atherosclerosis and Other Age-Related Conditions
https://www.fightaging.org/archives/2025/01/relationships-between-atherosclerosis-and-other-age-related-conditions/
Atherosclerosis is the growth of fatty plaques in blood vessel walls, eventually growing to the point of narrowing vessels to reduce blood flow. Rupture of a plaque can cause a downstream blockage, and this is the cause of heart attack and stroke. As a result, atherosclerosis is the largest cause of human mortality. This remains the case even today because present approaches to the treatment of atherosclerosis do not reliably produce any sizable reduction in plaque size, and are very slow to remove enough plaque lipids to reduce risk of rupture by stabilizing the plaque structure. Available approaches have near entirely focused on reducing inflammation and lowering the transport of cholesterol via LDL particles, but this only modestly slows plaque growth and modestly reduces risk of rupture. New approaches capable of reversing the disease are very much needed.
Like every other dysfunction in the body, atherosclerosis interacts with other aspects of aging and age-related disease processes. In today's open access paper, researchers conduct a tour of some of the better explored relationships between atherosclerosis and other common age-related conditions. In some cases there are shared mechanisms driving both conditions, in other cases there is good reason to think that one condition helps to accelerate the development of the other. Certainly, even without the ability of atherosclerosis-induced reduction of blood flow to make other conditions worse, there is reason enough for greater funding to be devoted to new approaches to treatment.
Association between atherosclerosis and the development of multi-organ pathologies
Atherosclerosis and atherosclerotic cardiovascular disease (ASCVD) has long been known to be associated with the development of various multiorgan pathologies characterised by chronic inflammation, oxidative stress, and dyslipidaemia. However, the significant advances made over the past decade have greatly expanded our understanding of how atherosclerosis-associated pathological changes affect the metabolism of vascular cells in different tissues and organs. It is challenging to distinguish the specific pathways affected by atherosclerosis, as many of the adverse effects associated with atherosclerosis are also attributed to the manifestation of other closely related conditions (such as metabolic syndrome, diabetes mellitus, obesity and others) that share common risk factors with atherosclerosis (primarily hypertension, dyslipidaemia, smoking, advanced age, stress, genetic factors and many others).
A strong association has been established between atherosclerosis and ischemic stroke, with napkin-ring sign plaques, a 'spotty' pattern of plaque calcification, and elevated serum levels of aldosterone, C-reactive protein, and ELAVL1 protein being potent stroke biomarkers. Interestingly, atherosclerosis and Alzheimer's disease have been shown to promote each other through several pathways. Notably, the well-studied C/EBPβ/AEP signalling pathway has been demonstrated to connect atherosclerosis and AD through ApoE-mediated vascular dysfunction. Additionally, the ε4 allele of the ApoE gene has been associated with more severe forms of atherosclerosis and a higher rate of cognitive decline in Alzheimer's disease.
Furthermore, chronic kidney disease (CKD) and atherosclerosis have been shown to exacerbate one another. Kidney dysfunction increases the accumulation of certain uraemic toxins, which impair the antioxidant system, increase reactive oxygen species (ROS) generation and promote oxidative damage, thereby exacerbating vascular dysfunction and the development of atherosclerosis. On the other hand, the rupture of atherosclerotic plaques can release cholesterol crystals into the bloodstream, which can become lodged in arterioles, leading to ischaemia and infarction in various tissues and organs, including the kidneys. Similarly, atherosclerosis and kidney stones have been linked through dyslipidaemia and oxLDL accumulation. Atherosclerosis-like responses to inflammation and perivascular calcification have been shown to promote kidney stone formation. Kidney stones, in turn, up-regulate a wide range of atherosclerosis-promoting genes (such as adhesion molecules, extracellular matrix molecules and pro-inflammatory cytokines), which increase the risk of ASCVD.
The role of atherosclerosis in pancreas dysfunction has been mechanistically explained by atherosclerosis-mediated reductions in blood flow to the pancreas, which causes islet hypoxia and β-cell dysfunction. Finally, dyslipidaemia, hypertension, endothelial dysfunction and a hypercoagulable state have been proposed as the major risk factors linking thyroid dysfunction and ASCVD. In vivo and in vitro experiments have demonstrated that thyroid hormones directly activate the expression and production of pro-inflammatory cytokines and adhesion molecules. In particular, TSH has been shown to aggravate vascular inflammation and promote atherosclerosis development.
The results discussed suggest that regular monitoring and timely treatment of atherosclerosis-related vascular risk factors may be a valuable strategy for treating and preventing Alzheimer's disease, pancreas and thyroid dysfunctions, kidney stones, and CKD. On the other hand, the pathologies of many organs may manifest through ASCVD, complicating diagnosis and treatment and potentially leading to life-threatening conditions. Overall, further studies deciphering the diverse mechanisms by which atherosclerosis is associated with multiple organ pathologies would help generate new therapeutic strategies to mitigate the adverse effects of atherogenesis on other organs.
Number of Respiratory Cycles in a Lifetime is Fairly Consistent Across Species
https://www.fightaging.org/archives/2025/01/number-of-respiratory-cycles-in-a-lifetime-is-fairly-consistent-across-species/
Rate of living theories of aging emerged from the observation that metabolism is generally slower in larger, longer-lived species. There are enough exceptions to disprove any specific hypothesis regarding what exactly might limit life span in species with a fast metabolism, however, and for this and other reasons rate of living theories fell to the wayside, somewhere along the way towards the development of a modern understanding of cellular biochemistry. Nonetheless, we are left with the observed that, yes, larger species tend to live longer, and yes, species with slower metabolisms also tend to live longer. Exceptions aside, that does suggest that something is there to be learned.
Here, researchers propose that the count of respiratory cycles over the course of a lifetime is the underlying roughly constant number that links all of the observed correlations of mass and metabolism across the majority of species. One can hypothesize, as was the case for the free radical theory of aging, that the apparent evidence for rate of living theories must say something about evolutionary limits placed on the amount of oxidation and cell damage an organism can sustain. This is, in turn, because oxidative molecules produce DNA damage at some pace, and there may be an evolutionary limit on the amount of mutational damage that can be sustained. At the same time, mutational damage is necessary for evolution to occur, and organisms that sustain more mutational damage will evolve more rapidly, potentially outcompeting those that evolve more slowly. We may be observing the result of optimization into a narrow window of possibilities.
On the causal connection in lifespan correlations and the possible existence of a 'number of life' at molecular level
Understanding the relevant processes that drive ageing and determine the longevity of organisms has been a subject of research for several decades, with many proposed theories of ageing that can be divided by the level of the primary factor: molecular, cellular, system, and evolutionary level. One of the theories at molecular level, is the somatic mutation theory of ageing, in which accumulation of mutations in the somatic DNA over time eventually cause a functional decline. This theory has been recently supported by, that reported a strong inverse relationship of the somatic mutation rate per year with species lifespan, with no other life-history trait showing a comparable association. Reference also found that the lifespan mutation burden varied only by a factor of around 3, despite widely different life histories among the species examined (i.e variation of around 30-fold in lifespan and around 40,000-fold in body mass). This result, established among the species, can be interpreted as support for a approximately constant total number of mutations over the lifetime of mammals and thus, being some kind of 'Number of Life' which effectively predetermines the extension of life.
Another 'Number of Life', to be approximately constant for different classes of living organisms (not only mammals), has been also proposed recently: the total number of 'respiration cycles' in a lifespan, Nr, which generalize the well-known empirical relation between the heart frequency and the lifespan, namely Nh the total number of heartbeats in a lifetime. In this paper, we study the causal connection in lifespan correlations, showing that six phenotypic traits (metabolic rate, mass, female and male sexual maturity, litter size, and heart frequency) acting at the system level, are all related to lifespan thru the existence of an approximately constant number of respiration cycles in a lifespan.
Consistent with a direct proportionality between the somatic mutation rate and the respiration frequency, which might suggest a possible origin of the constant number of cycles per lifetime at molecular level, thru being a manifestation at system level the fixed number of end-of-lifespan mutation burden at molecular level (or vice versa). One possible link between the respiration process and the rate of somatic mutations, might be through the byproducts of the respiration process, such as free radicals and oxidants that are candidates traditionally hypothesized to be responsible of the ageing process, as far as production rates of those byproducts of respiration determines the rate of somatic mutations.
Senescent Cells Express GD3 to Evade Immune Clearance by Natural Killer Cells
https://www.fightaging.org/archives/2025/01/senescent-cells-express-gd3-to-evade-immune-clearance-by-natural-killer-cells/
Senescent cells are created constantly throughout life, but are rapidly removed by the immune system. Only in later life does the efficiency of immune clearance falter to allow senescent cells to accumulate. Lingering senescent cells cause harm in proportion to their numbers, secreting inflammatory signals that disrupt tissue structure and function. Numerous approaches to the selective clearance of senescent cells exist, and numerous companies are developing senolytic therapies that should improve health in later life, turning back aspects of aging by removing the senescent cells that are actively maintaining a degraded state of tissue function.
Instead of clearing senescent cells via present methods that attack features of senescent cell biochemistry to force apoptosis, is it possible to address the age-related changes that cause slowed immune clearance? On the one hand there are many avenues of research and development that might restore some lost function in the aged immune system, and it remains to be seen as to how they will affect surveillance of senescent cells. On the other hand, it appears that senescent cells in older individuals are different from those in younger individuals in ways that hamper the immune system. In today's open access paper, researchers find that senescent cells expressing GD3 at their cell surface can evade the attention of natural killer cells of the innate immune system. Sabotaging this mechanism would aid in immune clearance of senescent cells in aged individuals.
A ganglioside-based immune checkpoint enables senescent cells to evade immunosurveillance during aging
Advancing age goes hand in hand with the increased susceptibility to develop diseases that lead to functional decline, loss of autonomy, and healthcare system saturation. Mechanistically, the accumulation of senescent cells (SnCs) in tissues emerges as a key driver of aging and age-associated diseases. Thus, according to the geroscience hypothesis, considerable efforts are being made to find senotherapeutic strategies that allow the elimination or modification of SnCs to prevent and simultaneously treat many age-related diseases. Different senolytic compounds target the SnC intrinsic property to resist apoptosis due to Bcl-2 family protein overexpression.
Despite the existence of immune pathways to eliminate them, some SnCs can be tolerated in tissues for decades, and how they can be tolerated by the immune system remains an open question. The mechanisms by which these SnCs evade T cell surveillance can depend on immune checkpoints such as PD-L1. However, how SnC cells can evade from innate immunity, such as natural killer (NK) cell killing, is still elusive. In the present study, we discovered that SnCs can gain an immune privilege when they express at their cell surface a high level of the ganglioside GD3, leading to the escape from natural killer (NK) cell killing. This is the case for a large panel of SnC types, which upregulate the ST8SIA1 gene encoding the enzyme synthesizing GD3. In contrast, oncogene-induced SnCs do not trigger ST8SIA1 expression, enabling their elimination by NK cells.
Moreover, we demonstrate that anti-GD3 immunotherapy in mice prevents the development of bleomycin-induced lung fibrosis and attenuates different types of age-related disorders: lung and liver fibrosis and osteoporosis. These findings reveal GD3 as a senescence immune checkpoint and as a promising target for anti-senescence therapy.
Age-Related Loss of Bone Density is Independent of the Gut Microbiome
https://www.fightaging.org/archives/2025/01/age-related-loss-of-bone-density-is-independent-of-the-gut-microbiome/
The trajectory of bone density over time is affected by the balance of activities between osteoblast cells that build bone and osteoclast cells that break down bone. With age, osteoclast activity begins to outweigh osteoblast activity, leading eventually to osteoporosis. There is some evidence for this age-related loss of bone density to be influenced by the composition of the gut microbiome. To the degree in which everything in aging is connected by mechanisms of chronic inflammation, this makes some sense: a more inflammatory gut microbiome could make everything worse, including osteoporosis. Here, however, researchers use germ-free mice to show that dramatic differences in the presence of a gut microbiome make little difference to age-related loss of bone density. This argues for a minimal role for the gut microbiome, inflammation or otherwise.
Emerging evidence suggests a significant role of gut microbiome in bone health. Aging is well recognized as a crucial factor influencing the gut microbiome. In this study, we investigated whether age-dependent microbial change contributes to age-related bone loss in CB6F1 mice. The bone phenotype of 24-month-old germ-free (GF) mice was indistinguishable compared to their littermates colonized by fecal transplant at 1-month-old. Moreover, bone loss from 3 to 24-month-old was comparable between GF and specific pathogen-free (SPF) mice. Thus, GF mice were not protected from age-related bone loss.
16S rRNA gene sequencing of fecal samples from 3-month and 24-month-old SPF males indicated an age-dependent microbial shift with an alteration in energy and nutrient metabolism potential. An integrative analysis of 16S predicted metagenome function and LC-MS fecal metabolome revealed an enrichment of protein and amino acid biosynthesis pathways in aged mice. Microbial S-adenosyl methionine metabolism was increased in the aged mice, which has previously been associated with the host aging process. Collectively, aging caused microbial taxonomic and functional alteration in mice.
To demonstrate the functional importance of young and old microbiome to bone, we colonized GF mice with fecal microbiome from 3-month or 24-month-old SPF donor mice for 1 and 8 months. The effect of microbial colonization on bone phenotypes was independent of the microbiome donors' age. In conclusion, our study indicates age-related bone loss occurs independent of gut microbiome.
Harmfully Altered Mitochondrial Communication as a Consequence of Age-Related Mitochondrial Dysfunction
https://www.fightaging.org/archives/2025/01/harmfully-altered-mitochondrial-communication-as-a-consequence-of-age-related-mitochondrial-dysfunction/
As noted here, mitochondria accomplish much more than only manufacturing adenosine triphosphate (ATP) to power the cell. Yes, they are power plants, but also communication hubs, generating molecular signals of many sorts that influence other mitochondria, the surrounding cell, and other cells. When mitochondria become dysfunctional in the ways characteristic of aged tissue, these communications are altered in potentially harmful ways. How this all plays out in detail is by no means fully mapped and understood, and this is typical of much of the overlap between degenerative aging and cell biochemistry.
Mitochondria have roles beyond energy generation. They are essential for pathways within cells and organisms that control immunity, stress reactions, metabolism, and cellular fate. To carry out these duties, mitochondria have formed intricate intercellular and intracellular communication systems. Within cells, communication pathways consist of direct connections between mitochondria and other subcellular structures and indirect transportation of ions, metabolites, and other intracellular messengers through vesicles. Mitochondria can trigger stress reactions or other cellular alterations that release mitochondrial cytokine factors outside of cells. These factors can move between different tissues and react to immunological challenges originating from outside of cells.
Mitochondrial communication refers to the processes by which mitochondria share information and energy capacity with neighboring mitochondria. Additionally, it encompasses the physical interactions and exchange of chemicals and metabolites between mitochondria and other organelles. Nevertheless, the process of mitochondrial communication relies on the synchronized effort of numerous elements, and as a result, it is not infallible. The deregulation of communication between mitochondria and host cells has significant implications and serves as a fundamental element in various pathological diseases, including the aging process.
In this review, we comprehensively discuss the signal transduction mechanisms of intercellular and intracellular mitochondrial communication, as well as the interactions between mitochondrial communication and the hallmarks of aging. This review emphasizes the indispensable position of intercellular and intracellular mitochondrial communication in the aging process of organisms, which is crucial as the cellular signaling hubs. In addition, we also specifically focus on the status of mitochondria-targeted interventions to provide potential therapeutic targets for age-related diseases.
Senolytics Targeting Lipofuscin as a Signature of Cellular Senescence
https://www.fightaging.org/archives/2025/01/senolytics-targeting-lipofuscin-as-a-signature-of-cellular-senescence/
Researchers here propose a way to make existing senolytic small molecules more efficient by attaching them to a compound that binds to lipofusin, a form of molecular waste originating in lysosomes that is hard to break down. The resulting compound senolytic molecule is encapsulated in some form of delivery system for cell uptake, here a micelle, but other forms of nanoparticle would probably also do the job. Lipofuscin accumulation is a feature of senescent cells. It is also found in very long-lived non-dividing cells in old tissues, such as neurons, so some thought should probably be given to limiting their exposure to such a drug.
The emerging field of senolytics is centered on eliminating senescent cells to block their contribution to the progression of age-related diseases, including cancer, and to facilitate healthy aging. Enhancing the selectivity of senolytic treatments toward senescent cells stands to reduce the adverse effects associated with existing senolytic interventions. Taking advantage of lipofuscin accumulation in senescent cells, we describe here the development of a highly efficient senolytic platform consisting of a lipofuscin-binding domain scaffold, which can be conjugated with a senolytic drug via an ester bond.
As a proof of concept, we present the generation of GL392, a senolytic compound that carries a dasatinib senolytic moiety. Encapsulation of the GL392 compound in a micelle nanocarrier (termed mGL392) allows for both in vitro and in vivo (in mice) selective elimination of senescent cells via targeted release of the senolytic agent with minimal systemic toxicity. Our findings suggest that this platform could be used to enhance targeting of senotherapeutics toward senescent cells.
Retinal Microvascular Abnormalities Correlate with Raised Risk of Mortality
https://www.fightaging.org/archives/2025/01/retinal-microvascular-abnormalities-correlate-with-raised-risk-of-mortality/
Given that there are several aging clocks built on machine learning based analyses of retinal images, it shouldn't be too surprising to find that specific aspects of aging in the retinal microvasculature can be correlated the old-fashioned way with an increased risk of mortality. As researchers note here, the small vessels of the body and brain are prone to clearly identifiable forms of structural damage that result from processes associated with aging. This damage is only easily viewed in the retina, however.
The retinal arteriole has similar anatomical and physiological features to cerebral and coronary circulations. Given that retinal vessels can be easily and noninvasively observed, they can be used to monitor microvascular health status in vivo. Retinal microvascular abnormalities (RMA), including retinopathy, generalized or focal arteriolar narrowing (FAN), arteriovenous nicking (AVN), and Hollenhorst plaque (HP), are common in older persons, even in those without diabetes. These findings reflect cumulative vascular damage from hypertension, aging, and other biological processes and are hypothesized to serve as potential markers for cardiovascular diseases (CVD).
This study aimed to examine the relationships between RMA and the risk of all-cause and specific-cause mortality among U.S. adults. 5,775 individuals aged ≥ 40 years were included from the U.S. National Health and Nutrition Examination Survey, 2005-2008. RMA and its subtypes were manually graded from retinal photographs. Associations between RMA and the risk of all-cause and cause-specific mortality were examined with Cox regression analysis.
RMA were present in 1,251 participants (weighted, 17.9%), of whom 710 (weighted, 9.8%) had retinopathy, 635 (weighted, 9.3%) had AVN, 64 (weighted, 1.0%) had FAN, and 21 (weighted, 0.3%) had HP. During a median of 12.2 years of follow-up, 1,488 deaths occurred, including 452 associated with cardiovascular disease (CVD), 341 associated with cancer, and 695 associated with other causes. After adjusting confounding factors, the presence of any RMA and retinopathy at baseline was associated with higher risk of all-cause mortality (hazard ratios 1.26 and 1.36 respectively), CVD mortality (hazard ratios 1.36 and 1.53 respectively) and other-cause mortality (hazard ratios 1.33 and 1.55 respectively). Additionally, FAN was significantly associated with an increased risk of other-cause mortality (hazard ratio 2.06). Although AVN was not associated with mortality in the whole population, it was significantly related to higher risks of all-cause and CVD death in those with obesity (hazard ratios 1.68 and 1.96 respectively).
Forgetting Changes Little in Healthy Older People
https://www.fightaging.org/archives/2025/01/forgetting-changes-little-in-healthy-older-people/
It is commonplace in the research and medical communities to attempt to distinguish normal aging from pathological aging. This seems problematic, as it is all aging under the hood. A healthy older person is still impacted by the mechanisms of aging, a burden of molecular damage and its consequences, just less impacted than a similarly aged peer suffering evident age-related diseases. The pace of aging, and which forms of damage build upon one another to the point of runaway dysfunction and pathology, varies considerably from individual to individual. Nonetheless, there is still the drive to attempt to distinguish normal aging from pathological aging, particularly when it comes to cognitive function.
Aging is typically associated with declines in episodic memory, executive functions, and sleep quality. Therefore, the sleep-dependent stabilization of episodic memory is suspected to decline during aging. This might reflect in accelerated long-term forgetting, which refers to normal learning and retention over hours, yet an abnormal retention over nights and days. Accelerated long-term forgetting has been observed in dementia, mild cognitive impairment, and in people with memory complaints.
Here, we explored whether accelerated long-term forgetting also manifests in healthy aging. We investigated verbal episodic memory in 236 healthy men and women between 18 and 77 years of age. All participants were mentally intact in terms of executive functions, working memory, episodic memory, verbal intelligence, and mood. We related their forgetting rates over one week following learning to their subjective sleep quality and executive functions. Fifteen words were freely recalled and then recognized among 30 distractor words at 30 minutes and again at one week following learning. Although the healthy older adults compared to the healthy younger adults reported a diminished sleep efficiency and learned fewer words, they exhibited no disproportionate forgetting over days.
Hence, accelerated long-term forgetting is not present in healthy aging but might be a first sign of memory dysfunction due to neuropathology.
A Transcriptomic Map of Brain Aging in Mice
https://www.fightaging.org/archives/2025/01/a-transcriptomic-map-of-brain-aging-in-mice/
The amount of data on aging in animal models is only going to grow. Many large initiatives are focused on generating as much of a map of the biochemistry of aging as presently possible, and their output already far outpaces the ability of the broader scientific community to synthesize and understand this data. The new transcriptomic map noted here is an example of the type, and enormous research that will keep researchers busy in the decades ahead. A comprehensive understanding of the detailed progression of aging is perhaps less important to the near future of therapies to treat aging, however, as these will emerge from what is presently known of the contributing causes of aging, not from an understanding of the damage done by those causative mechanisms.
Biological ageing can be defined as a gradual loss of homeostasis across various aspects of molecular and cellular function. Mammalian brains consist of thousands of cell types, which may be differentially susceptible or resilient to ageing. Here we present a comprehensive single-cell RNA sequencing dataset containing roughly 1.2 million high-quality single-cell transcriptomes of brain cells from young adult and aged mice of both sexes, from regions spanning the forebrain, midbrain, and hindbrain. High-resolution clustering of all cells results in 847 cell clusters and reveals at least 14 age-biased clusters that are mostly glial types. At the broader cell subclass and supertype levels, we find age-associated gene expression signatures and provide a list of 2,449 unique differentially expressed genes (age-DE genes) for many neuronal and non-neuronal cell types.
Whereas most age-DE genes are unique to specific cell types, we observe common signatures with ageing across cell types, including a decrease in expression of genes related to neuronal structure and function in many neuron types, major astrocyte types and mature oligodendrocytes, and an increase in expression of genes related to immune function, antigen presentation, inflammation, and cell motility in immune cell types and some vascular cell types. Finally, we observe that some of the cell types that demonstrate the greatest sensitivity to ageing are concentrated around the third ventricle in the hypothalamus, including tanycytes, ependymal cells, and certain neuron types in the arcuate nucleus, dorsomedial nucleus, and paraventricular nucleus that express genes canonically related to energy homeostasis. Many of these types demonstrate both a decrease in neuronal function and an increase in immune response. These findings suggest that the third ventricle in the hypothalamus may be a hub for ageing in the mouse brain.
Overall, this study systematically delineates a dynamic landscape of cell-type-specific transcriptomic changes in the brain associated with normal ageing that will serve as a foundation for the investigation of functional changes in ageing and the interaction of ageing and disease.
Continued Discussion of Herpesvirus Infection as a Contributing Cause of Alzheimer's Disease
https://www.fightaging.org/archives/2025/01/continued-discussion-of-herpesvirus-infection-as-a-contributing-cause-of-alzheimers-disease/
A variety of epidemiological data argues for a role for persistent viral infection in the development of Alzheimer's disease. This is disputed, however. Some conflicting data shows no signs of a relationship, which suggests that the situation is complicated. Mechanistically, persistent viral infections such as herpesviruses might accelerate the onset of neurodegenerative conditions by provoking greater inflammation, greater numbers of dysfunctional microglia in the brain, and greater amounts of the antimicrobial peptide amyloid-β. Here, however, researchers find evidence for a herpesvirus to promote tau protein aggregation, characteristic of later, more damaging stages of Alzheimer's disease. This adds another interesting wrinkle to the present state of data on mechanisms and epidemiology.
Researchers identified forms of HSV-1-related proteins in Alzheimer's brain samples, with greater amounts of viral proteins co-localized with tangles of phosphorylated tau - one of the hallmarks of Alzheimer's disease pathology - in brain regions especially vulnerable to Alzheimer's across disease stages. Further studies on miniature models of human brains in a Petri dish suggested that HSV-1 infection could modulate levels of brain tau protein and regulate its function, a protective mechanism that seemed to decrease post-infection death of human neurons.
While the precise mechanisms by which HSV-1 influences tau protein and contributes to Alzheimer's disease are still unknown, researchers plan to explore those questions in future research. They aim to test potential therapeutic strategies that target viral proteins or fine-tune the brain's immune response and investigate whether similar mechanisms are involved in other neurodegenerative diseases, such as Parkinson's disease and ALS.
The Nucleolus as a Factor in Age-Related Loss of Proteostasis
https://www.fightaging.org/archives/2025/01/the-nucleolus-as-a-factor-in-age-related-loss-of-proteostasis/
The nucleolus structure of the cell is where ribosomes are built, but it appears to be influential in a range of mechanisms relating to stress response, quality control, and damage repair in cells. All of these are in turn linked to pace of aging. The relationships are by no means fully understood in detail, however. This is an area of ongoing exploration in which researchers are finding ways to adjust nucleolar function to slow aging in model organisms such as yeast and nematode worms.
To cope with hazardous protein toxicity (proteotoxicity), protein quality control mechanisms act in concert to supervise the integrity of nascent and mature proteins and direct terminally damaged proteins for degradation. In the early stages of life, this protein homeostasis (proteostasis) network successfully maintains the integrity of the proteome; however, with ageing, misfolded proteins aggregate and accumulate within and outside cells. These aggregates challenge the proteostasis network and often underlie the development of disorders known as 'proteinopathies', including neurodegenerative conditions.
Accordingly, the maintenance of proteostasis through late stages of life bears the promise to delay the emergence of these devastating diseases. Yet the identification of proteostasis regulators is needed to assess the feasibility of this approach. Here we report that knocking down the activity of the nucleolar FIB-1-NOL-56 complex protects model nematodes from proteotoxicity of the Alzheimer's disease-causing amyloid-β peptide and of abnormally long poly-glutamine stretches. This mechanism promotes proteostasis across tissues by modulating the activity of TGFβ signalling and by enhancing proteasome activity. Our findings point at research avenues towards the development of proteostasis-promoting therapies for neurodegenerative maladies.
HMGA1 Expression Promotes Heart Regeneration in Mammals
https://www.fightaging.org/archives/2025/01/hmga1-expression-promotes-heart-regeneration-in-mammals/
Numerous research groups are investigating the cellular biochemistry of highly regenerative species such as salamanders and zebrafish. The goal is to find the differences that ensure regrowth of lost tissue rather than the scarring that occurs in mammals. So far, many of these differences appear to involve the continued operation of processes of regulated growth that take place during embryonic development. It is hoped that some of these differences can form a practical basis for regenerative therapies that will allow the safe regrowth of loss limbs and organ tissues. The approach noted here appears promising, as it is just a difference in expression of a gene regulating chromatin structure, rather than a difference in protein structure and function between species. Engineering higher or lower expression of specific native genes is practical, but introducing novel proteins with different sequences into an adult organism is more challenging to achieve safely, as the immune system can react poorly.
In contrast to adult mammalian hearts, the adult zebrafish heart efficiently replaces cardiomyocytes lost after injury. Here we reveal shared and species-specific injury response pathways and a correlation between Hmga1, an architectural non-histone protein, and regenerative capacity, as Hmga1 is required and sufficient to induce cardiomyocyte proliferation and required for heart regeneration. In addition, Hmga1 was shown to reactivate developmentally silenced genes, likely through modulation of H3K27me3 levels, poising them for a pro-regenerative gene program.
Furthermore, AAV-mediated Hmga1 expression in injured adult mouse hearts led to controlled cardiomyocyte proliferation in the border zone and enhanced heart function, without cardiomegaly and adverse remodeling. Histone modification mapping in mouse border zone cardiomyocytes revealed a similar modulation of H3K27me3 marks, consistent with findings in zebrafish. Our study demonstrates that Hmga1 mediates chromatin remodeling and drives a regenerative program, positioning it as a promising therapeutic target to enhance cardiac regeneration after injury.
Better Muscle Mitochondrial Function Correlates with Slower Brain Aging
https://www.fightaging.org/archives/2025/01/better-muscle-mitochondrial-function-correlates-with-slower-brain-aging/
Mitochondria are the power plants of the cell, producing chemical energy store molecules used to power cell activities. Energy hungry tissues such as muscle and brain are particularly sensitive to differences in mitochondrial function. Here, researchers show in a human study population that better mitochondrial function in muscle tissue correlates with slower aging in many areas of the brain. Interestingly, this relationship occurs regardless of physical fitness, though it is true that any given individual can be expected to achieve better mitochondrial function through attaining a greater degree of physical fitness. Physical fitness is beneficial in many ways, but it is the improvement in mitochondrial function resulting from greater physical fitness that drives the relationship with brain aging noted here, not the fitness per se.
This longitudinal study demonstrates a significant relationship between skeletal muscle mitochondrial oxidative capacity and brain structural changes up to over a decade, emphasizing the strong connection between mitochondrial health and brain aging and neurodegeneration. By investigating two different neuroimaging modalities across multiple brain regions, we identified specific brain regions and connecting tracts that were related to mitochondrial oxidative capacity assessed in the skeletal muscle. These longitudinal findings provide mechanistic insights into the connection between muscle bioenergetics and brain aging and lay a foundation for future research on mitochondrial bioenergetics in the brain.
One potential mechanism is that muscle mitochondrial function indicates general mitochondrial health and that muscle mitochondria can be considered a proxy measure of mitochondrial health across multiple tissues, including the brain. Another possibility is that the measure of oxidative capacity captures general muscle health and that positive signaling through soluble molecules and/or microvesicles may act in neurotrophic signaling that promotes brain health. While skeletal muscle oxidative capacity is related to fitness, the longitudinal associations between skeletal muscle oxidative capacity and brain atrophy were independent of concurrent fitness levels. Longitudinal associations with microstructural change persisted after accounting for the fitness measure of 400-meter walk time but were attenuated after adjusting for VO2 max. This attenuation is not surprising as fitness and vascular factors are strongly associated with white matter microstructure.
Because of the observational nature of this study, the detected longitudinal associations may shed light on but do not prove a causal relationship. In addition, we cannot exclude that higher skeletal muscle oxidative capacity reflects in part the lifetime history of exercise and physical activity which may affect several aspects of brain health but may not be fully captured by the assessment of current fitness levels.